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					     In the name of GOD




        Updtaes On:




    Breast Cancer

www.vancls.info
  (July and August 2008)


                By:



      Nasrinossadat Alavi , M.D

      www.banooyesalem.com




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                     Contents:



Surgry…………………………………………………………………………………….٣



Radiotherapy oncology………………………………………………………….13



Medical oncology…………………………………………………………………….23



Pathology………………………………………………………………………………..36



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Radiology…………………………………………………………………………………..44



Gene cs……………………………………………………………………………………54



Screening…………………………………………………………………………………..6٦



Supportive care………………………………………………………………………….7٢



Nucleare medicine……………………………………………………………………..7٧



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                                              surgery


1-Internal mammary lymph drainage and sentinel node biopsy in breast cancer - A
study on 1008 pa ents.

Heuts EM, van der Ent FW, von Meyenfeldt MF, Voogd AC.

Department of Surgery, University Hospital Maastricht, Postbus 5800, 6202 AZ, Maastricht, The
Netherlands.

INTRODUCTION: Nowadays, axillary sentinel node (SN) biopsy is a standard procedure in the staging of
breast cancer. Although the internal mammary (IM) lymph node status is a major independent
prognostic factor in breast cancer patients, sampling of IM sentinel nodes (IMSNs) is not performed
routinely. The aim of this study was to determine the likelihood of finding IM lymph node metastases in
case of IM hotspots on lymphoscintigraphy and evaluate the relevance of IMSN biopsy as a method to
improve staging.

PATIENTS AND METHODS: Between April 1997 and May 2006, a total of 1008 consecu ve pa ents with



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clinically node-negative operable primary breast cancer were enrolled in a prospective study on SN
biopsy. Both axillary and IMSNs were sampled, based on lymphoscintigraphy, intraoperative gamma
probe detec on and blue dye mapping, using 10mCi (370MBq) (99m)Tc-nanocolloid injected
peritumorally, and 0.5-1.0ml Patent Blue V injected intradermally.

 RESULTS: Lymphoscin graphy showed axillary sen nel nodes in 98% (989/1008) and IMSNs in 20% of
the pa ents (196/1008). Sampling the IM basin, as based on the results of lymphoscin graphy, was
successful in 71% of the pa ents (139/196) and revealed metastases in 22% (31/139). In 29% of the
pa ents with posi ve IMSNs (9/31) no axillary metastases were found.

 CONCLUSION: Evaluation of IMSNs improves nodal staging in breast cancer. Patients with IM hotspots
on lymphoscin graphy have a substan al risk (22%) of metastatic involvement of the IM chain. In
addition, true IM node-negative patients can be spared the morbidity associated with adjuvant
radiotherapy.
Eur J Surg Oncol. 2008 Aug 4.
PMID: 18684584


2- Touch imprint cytology of the sentinel lymph nodes might not be indicated in
early breast cancer patients with ultrasonically uninvolved axillary lymph nodes.

Perhavec A, Besić N, Hocevar M, Zgajnar J.

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Department of Surgical Oncology, Ins tute of Oncology Ljubljana, Zaloska Cesta 2, 1000 Ljubljana,
Slovenia.

BACKGROUND: Touch imprint cytology (TIC) is a fast, cheap and specific intraoperative examination of
the sentinel lymph nodes (SLNs) in early breast cancer patients. The results of TIC in patients with
ultrasonically (US) uninvolved axillary lymph nodes are not known. The objective of our study was to
compare the results of TIC in the patients with US uninvolved axillary lymph nodes (US group) and those
with only clinically uninvolved axillary lymph nodes (non-US group).

METHODS: A total of 470 pa ents were included in the study, 257 in the US group and 213 in the non-
US group. TIC results were compared to the definite histology, and the sensitivity of TIC was calculated
for both groups of patients. A subgroup analysis of TIC findings with regard to the primary tumor size
was performed.

RESULTS: Overall sensitivity and sensitivity for detecting macrometastases was significantly lower in the
US group compared with the non-US group. In the US group, TIC results changed the course of
treatment in 9% of pa ents, while in the non-US group, the course of treatment was changed in 22% of
patients. In the non-US group, the proportion of positive TIC results increased with increasing tumor
size, whereas in the US group it did not.




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CONCLUSION: The sensitivity of TIC is lower in the patients with US uninvolved axillary lymph nodes
compared to those with only clinically uninvolved axillary lymph nodes. TIC might not be indicated in
patients with US uninvolved axillary lymph nodes as it changes the course of treatment in only 9% of
patients.
Ann Surg Oncol. 2008 Aug;15(8):2257-62.
PMID: 18484140



3- Optimizing pedicled transverse rectus abdominis muscle flap breast
reconstruction.

Kanchwala SK, Bucky LP.

From the Division of Plastic and Reconstructive Surgery, Hospital of the University of Pennsylvania,
Philadelphia, PA.

With improved detection and genetic screening for breast cancer, increasing numbers of patients are
choosing mastectomy and immediate breast reconstruction. Advances in breast reconstruction and
mastectomy techniques over the last 25 years have increased expecta ons for breast reconstruction.
The purpose of this review is to describe the role of the pedicled transverse rectus abdominis muscle
(TRAM) flap in modern breast reconstruction.The pedicled TRAM flap is the most common method of

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autologous breast reconstruction. TRAM flap reconstruction involves the transfer of lower abdominal
skin and subcutaneous fat based on the superior epigastric vessels. Common risk factors for
complications from pedicled TRAM flap reconstruction include smoking, obesity, and postoperative
radiotherapy. Patients with these risk factors are often candidates for a vascular delay procedure whose
purpose is to enhance the blood flow within the TRAM flap.Despite advances in free flap breast
reconstruction, pedicled TRAM flap breast reconstruction remains an excellent option for unilateral
breast reconstructions. Unlike microsurgical breast reconstruction, the pedicled TRAM flap does not
require sophisticated postoperative monitoring and can be performed efficiently in any hospital setting.
Furthermore, with the addition of a vascular delay procedure, pedicled TRAM reconstructions can be
safely performed even in traditionally "high risk" patients.

PMID: 18677131




4- Radiofrequency Thermal Ablation of Breast Cancer Local Recurrence: A Phase II
Clinical Trial.

Garbay JR, Mathieu MC, Lamuraglia M, Lassau N, Balleyguier C, Rouzier R.




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Department of Surgery, Pathology and Radiology, and the Breast Unit, Institut Gustave Roussy, Villejuif,
France.

BACKGROUND: The role of radiofrequency (RF) ablation to treat local recurrence of breast cancer is
unknown.

METHODS: We conducted a two-stage phase II clinical trial. Eligible patients had a histologically
confirmed noninflammatory and </=3 cm ipsilateral breast tumor recurrence. The tumor site was
identified by intraoperative sonography. A LeVeen needle electrode (RadioTherapeutics Corp, Mountain
View, Calif) was inserted into a single site within the tumor and radiofrequency ablation was performed
using a RF-2000 generator (RadioTherapeu cs Corp). A er comple on of radiofrequency, a mastectomy
was performed. Conventional staining and nicotinamide adenine dinucleotide-diaphorase (NADH-
diaphorase) cell viability staining were performed.

RESULTS: During the first stage, procedures were uneventful. Conventional, cytokeratin, and NADH-
diaphorase staining identified persistent viable tumor cells in the RF-ablated region in three patients.
This phase II trial was stopped after completion of the first stage because of insufficient efficacy.

CONCLUSION: We demonstrate in this study that RF ablation is a potential technique to destroy local
recurrence of breast tumors but the technique we tested in this phase II clinical trial had insufficient
efficacy to recommend its use in routine.
Ann Surg Oncol. 2008 Aug 15
PMID: 1870941

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5- Staging of breast cancer in the neoadjuvant setting.

Jeruss JS, Mittendorf EA, Tucker SL, Gonzalez-Angulo AM, Buchholz TA, Sahin AA, Cormier JN, Buzdar
AU, Hortobagyi GN, Hunt KK.

Department of Surgery, Northwestern University Feinberg School of Medicine and Robert H. Lurie
Comprehensive Cancer Center, Chicago, Illinois 60611, USA. jjeruss@nmh.org

The use of neoadjuvant chemotherapy has become more prevalent in the treatment of breast cancer
patients. The finding of a pathologic complete response to neoadjuvant chemotherapy (no evidence of
residual invasive cancer in the breast and lymph nodes at the time of surgical resection) has been shown
to correlate with improved survival. The current version of the American Joint Committee on Cancer
(AJCC) staging for breast cancer has a pretreatment clinical stage designation that is determined by
clinical and radiographic examination of the patient and a postoperative pathologic stage classification
based on the findings in the breast and regional lymph nodes removed at surgery. Pathologic staging has
not been validated for patients receiving neoadjuvant chemotherapy; thus, prognosis is determined for
these patients based on the pretreatment clinical stage. We hypothesized that clinical and pathologic
staging variables could be combined with biological tumor markers to provide a novel means of
determining prognosis for patients treated with neoadjuvant chemotherapy. Two scoring systems,
based on summing binary indicators for clinical and pathologic substages, negative estrogen receptor



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status, and grade 3 tumor pathology, were devised to predict 5-year patient outcomes. These scoring
systems facilitated separation of the study population into more refined subgroups by outcome than the
current AJCC staging system for breast cancer, and provide a novel means for evaluating prognosis after
neoadjuvant therapy.
Cancer Res. 2008 Aug 15;68(16):6477-81

PMID: 18701468

6- Rou ne use of serial plasma c CA 15-3 determina ons during the follow-up of
patients treated for breast cancer. Evaluation as factor of early diagnosis of
recurrence.

Chourin S, Veyret C, Chevrier A, Loeb A, Gray C, Basuyau J.

Laboratoire de biologie clinique.

Purpose: at our ins tu on, CA 15-3 assays are rou nely used for the early diagnosis of recurrence during
the follow-up of patients treated for breast cancer, although published guidelines do not recommend
this procedure. So, we decided to totally re-assess the usefulness of this policy. Patients and methods:
all records of pa ents presen ng a first recurrence, local (50 cases) or metasta c (88 cases), of breast
cancer during 2003 were re-examined. An increase in CA 15-3 concentra on of more than 25% was


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considered significant. Results: an increase was observed in 18% of non metasta c recurrences. These
increases had a prognos c value. CA 15-3 levels remained stable in 23% of metastasis cases and
increased in 77%. In 14% of cases, the increase in CA 15-3 levels confirmed a clinically or radiologically
suspected metastasis. Moreover, increased CA 15-3 levels in the absence of sugges ve clinical or
radiological signs led to the diagnosis in 18% of metastasis, 50% of which involved the bone. Conclusion:
our study demonstrates that CA 15-3 is useful for the early diagnosis of recurrence. Eighteen per cent of
metastases were diagnosed by a marker increase alone. CA 15-3 assays could be useful in the early
management of these metastases in patients treated for breast cancer.

Ann Biol Clin (Paris). 2008 Jul-Aug;66(4):385-9 PMID: 18725339




7- Patient choice significantly affects mastectomy rates in the treatment of breast
cancer.

Kirby RM, Basit A, Manimaran N.

ABSTRACT: : Mastectomy rates may be affected by pa ent choice. 203 pa ents who had a Total
Mastectomy for breast cancer were invited to complete questionnaires at routine follow up clinics to



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ascertain if they had been offered a choice of Breast Conserving Surgery (BCS), and to establish the
reasons for their preference. Questionnaires were checked against medical and nursing records to
confirm the reasons for the pa ents' choice of mastectomy. 130 pa ents (64%) chose to have a
mastectomy, repor ng that they felt safer (n=119); wanted to decrease the risk of further surgery
(n=87) and/or wished to avoid radiotherapy (n=34). Some were advised not to have BCS if they had a
large tumour size, central or multifocal tumours and/or associated extensive microcalcification on
mammography (n=29). 24 pa ents had BCS as first opera on but had repeat surgery for involved or
narrow excision margins. Despite being advised that there is no difference between survival rates of this
and breast conserving surgery, many patients still feel safer with mastectomy.
Int Semin Surg Oncol. 2008 Aug 11;5(1):20.
PMID: 18694514



8- Residual Risk of Breast Cancer Recurrence 5 Years A er Adjuvant Therapy.

Brewster AM, Hortobagyi GN, Broglio KR, Kau SW, Santa-Maria CA, Arun B, Buzdar AU, Booser DJ,
Valero V, Bondy M, Esteva FJ.

Affiliations of authors: Departments of Clinical Cancer Prevention (AMB), Breast Medical Oncology
(GNH, S-WK, CAS-M, BA, AUB, DJB, VV, FJE), Division of Quantitative Sciences (KRB), Department of
Epidemiology (MB), The University of Texas M.D. Anderson Cancer Center, Houston, TX.


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There is limited prognostic information to identify breast cancer patients who are at risk for late
recurrences after adjuvant or neoadjuvant systemic therapy (AST). We evaluated the residual risk of
recurrence and prognos c factors of 2838 pa ents with stage I-III breast cancer who were treated with
AST between January 1, 1985, and November 1, 2001, and remained disease free for 5 years. Residual
recurrence-free survival was es mated from the landmark of 5 years a er AST to date of first recurrence
or last follow-up using the Kaplan-Meier method. The log-rank test (two-sided) was used to compare
groups. Residual recurrence-free survival rates at 5 and 10 years were 89% and 80%, respec vely, and
216 pa ents developed a recurrence event. The 5-year residual risks of recurrence for patients with
stage I, II, and III cancers were 7% (95% confidence interval [CI] = 3% to 15%), 11% (95% CI = 9% to 13%),
and 13% (95% CI = 10% to 17%), respec vely (P = .02). In mul variable analysis, stage, grade, hormone
receptor status, and endocrine therapy were associated with late recurrences. Breast cancer patients
have a substantial residual risk of recurrence, and selected tumor characteristics are associated with late
recurrences.
J Natl Cancer Inst. 2008 Aug 11.
PMID: 18695137



9- Arm and shoulder morbidity in breast cancer patients after breast-conserving
therapy versus mastectomy.


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Nesvold IL, Dahl AA, Løkkevik E, Marit Mengshoel A, Fosså SD.
Department of Cancer Rehabilitation-Physiotherapy, Rikshospitalet, University of Oslo: Division The
Norwegian Radium Hospital, Montebello, Oslo, Norway. inger.lise.nesvold@radiumhospitalet.no

INTRODUCTION: The objective of this study was to compare the prevalence of late effects in the arm
and shoulder in patients with breast cancer stage II who had radical modified mastectomy (RM) or
breast-conserving therapy (BCT) followed by loco-regional adjuvant radiotherapy with or without
chemotherapy/anti-oestrogen.

MATERIAL AND METHODS: All patients had axillary lymph node dissection. At a median of 47 months
(range 32-87) post-surgery, 263 women (RM: n=186, BCT: n=77) were seen during an outpa ent visit
and had their arm and shoulder function and the presence of lymphedema assessed by a clinical
examination, interview and self-rating. Volume calculation was used to measure lymphedema. RESULTS:
In the RM group 20% had developed arm lymphedema versus 8% in the BCT group (p=0.02). In
multivariate analysis lymphedema was associated with a higher number of metastatic axillary lymph
nodes [OR1.14, p=0.02], RM [OR 2.75, p=0.04] and increasing body mass index (BMI) [OR 1.11, p<0.01].
In the RM group 24% had a restricted range of mo on in shoulder flexion compared to 7% in the BCT
group (p<0.01). Shoulder pain was reported by 32% in the RM group and by 12% in the BCT group
(p=0.001). Increasing observa on me, RM, and increasing BMI were significantly associated with
impaired arm/shoulder function.


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DISCUSSION: Arm/shoulder problems including lymphedema were significantly more common after RM
compared to BCT in irradiated breast cancer patients who have undergone axillary lymph node
dissection. The performance of BCT should be encouraged when appropriate, to ensure a low
prevalence of arm/shoulder morbidity including lymphedema.
Acta Oncol. 2008;47(5):835-42.
PMID: 18568481



10- Radioguided occult lesion localization (ROLL) for treatment and diagnosis of
malignant and premalignant breast lesions combined with sentinel node biopsy: A
prospec ve clinical trial with 100 pa ents.

Sarlos D, Frey LD, Haueisen H, Landmann G, Kots LA, Schaer G.

Department of Obstetrics and Gynaecology, Kantonsspital Aarau, Switzerland.

Advanced breast cancer screening techniques and their availability increased the number of non-
palpable breast lesions requiring surgery. Consequently reliable and efficient therapeutic management
permitting accurate localization and removal of these occult lesions is essential. AIMS: In our study we



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evaluated radioguided occult lesion localization (ROLL) for effectiveness of localization, oncological
safety and feasibility of concomitant sentinel node biopsy.

METHODS: Hundred pa ents (120 lesions) underwent ROLL and tumour excision with or without
sentinel node biopsy after confirmed histopathological findings via intra-tumoral injec on of Tc99m-
labelled macro-aggregate albumin for ROLL and Tc99m-labelled nanocolloids with periareolar-
subdermal injection for simultaneous sentinel node biopsy.

RESULTS: Our detec on rate for ROLL was 98.3%, respec vely, 98.6% for sen nel nodes in cases of
concomitant sen nel node biopsy. We had a radical excision rate of 55 out of 69 cases of invasive ductal
cancer and 17 out of 26 cases of DCIS to achieve 1mm, respec vely, 10mm tumour-free margins.

 CONCLUSIONS: Intra-tumoral tracer injection of for ROLL and periareolar-subdermal tracer injection for
simultaneous sentinel node biopsy seem to be a sensitive technique. According to our results ROLL is a
safe, precise and simple technique permitting definitive therapeutic removal of malignant or
premalignant breast lesions. The high detection rate of the sentinel node in cases with concomitant
sentinel node biopsy shows that the combination of both procedures is possible and safe. In our opinion
ROLL is an excellent therapeutic option after histological confirmation of malignancy or premalignant
disease.
Eur J Surg Oncol. 2008 Aug 7.
PMID: 18692358




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11- Breast cancer-related lymphoedema risk reduction advice: A challenge for
health professionals.

Nielsen I, Gordon S, Selby A.

Discipline of Physiotherapy, James Cook University, Townsville, QLD 4811, Australia.

Breast cancer-related lymphoedema (BCRL) is a debilitating, distressing condition affecting
approximately one in five breast cancer survivors (Clark B, Sitzia J, Harlow W. Incidence and risk of arm
oedema following treatment for breast cancer: a three-year follow-up study. QJM 2005;98:343-8). The
evidence-base for breast cancer-related lymphoedema risk reduction advice is scant and contradictory,
with most studies in the area limited by small numbers, retrospective design and other methodological
inadequacies. Current advice has the capacity to profoundly alter quality of life following treatment for
breast cancer. Health professionals should review the risk reduction advice they provide to reflect the
current understanding of aetiology and risk factors. Further research is required to provide more
evidence for the content, to identify optimal methods of precautionary education delivery and to
determine the effect of the advice on the patient's quality of life and perception of recovery.
Cancer Treat Rev. 2008 Aug 6
PMID: 18691823




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12- Hereditary breast cancer: From molecular pathology to tailored therapies.

Tan DS, Marchio C, Reis Filho JS.

Institute of Cancer Research, United Kingdom.

Hereditary breast cancer accounts for up to 5-10% of all breast carcinomas. Recent studies have
demonstrated that mutations in two high penetrance genes, namely BRCA1 and BRCA2, are responsible
for about 16% of the familial risk of breast cancer. Even though subsequent studies have failed to find
another high-penetrance breast cancer susceptibility gene, several genes that confer moderate to low
risk of breast cancer development have been identified; moreover, hereditary breast cancer can be part
of multiple cancer syndromes. In this review we will focus on the hereditary breast carcinomas caused
by muta ons in BRCA1, BRCA2, Fanconi Anaemia (FANC) genes, CHK2 and ATM tumour suppressor
genes. We describe the hallmark histological features of these carcinomas compared with non-
hereditary breast cancers and show how an accurate histopathological diagnosis may help improve the
identification of patients to be screened for mutations. Finally, novel therapeutic approaches to treat
pa ents with BRCA1 and BRCA2 germline muta ons, including cross-linking agents and PARP inhibitors,
are discussed.
J Clin Pathol. 2008 Aug 4
PMID: 18682420

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13- Breast reconstruction combined with radiation therapy: long-term risks and
factors related to decision making.

McCormick B, Wright J, Cordiero P.

From the Departments of *Radiation Oncology and daggerSurgery, Reconstructive Surgery Service,
Memorial Sloan Kettering Cancer Center, New York.

Mastectomy with immediate breast reconstruction is a surgical procedure that addresses both the need
to perform a cancer operation, and the desire of the patient to emerge from anesthesia with a
replacement breast. An increasing number of these women with invasive breast cancer will benefit from
chest wall and regional nodal radiation, in terms of both a decreased risk in local-regional recurrence
and an increased chance of overall survival at 10 years and beyond, based on the most recent 2005
Oxford Overview.Indications for recommending radiation are based primarily on the pathologic
assessment of the primary tumor and the axillary lymph nodes. More than a decade ago, only women
with 10 or more involved nodes were thought to benefit from this treatment; that recommenda on
shi ed to women with 4 or more involved nodes with the publica on of the American Society for
Clinical Oncology (ASCO) guidelines in 2001 and more recently to considering postmastectomy radia on
(PMRT) in women with 1 to 3 posi ve nodes.In some scenarios, the need for PMRT is recognized before
the patient goes to surgery, and reconstruction can be planned with this in mind, as discussed elsewhere


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in this issue. In other scenarios, the need for radiation is not realized until the final pathology report is
back in the surgeon's hands. If that patient has elected an immediate reconstruction, is the radiation
feasible and is it effective? Our published experience at Memorial Sloan Kettering (MSK) Cancer Center
suggests the answer to both questions is "yes." However, our results differ dramatically from that of
other major centers. Both our experience and that of others is discussed in this article.
Cancer J. 2008 Jul-Aug;14(4):264-8.
PMID: 18677136

14- Bilateral ductal carcinoma in situ of the breast after radiation therapy for
Ewing's sarcoma of the vertebra in a young woman: Report of a case.

Keskek M, Kilic M, Ertan T, Erdem A, Yoldas O.

Fifth Department of Surgery, Ankara Numune Training and Research Hospital, Resat Nuri Sokak, No:
102/B-16, Yukari Ayranci, Ankara, Turkey.

Thoracic radia on in the early years of life is a known risk factor for breast cancer later in life. A 21-year-
old woman who had received thoracic radia on therapy for Ewing's sarcoma of the vertebra 9 years
earlier was referred to our hospital for investigation of a palpable mass in her left breast.
Ultrasonography and excisional biopsy showed ductal carcinoma in situ (DCIS) of the left breast, with no
detectable pathology in the right breast except that it was more hypoplastic than the left breast.

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Considering the known risk factors for invasive breast cancer in both breasts, we performed bilateral
skin-sparing mastectomy with immediate breast reconstruction using subpectoral implants. The final
histopathological diagnosis was bilateral DCIS.
Surg Today. 2008;38(8):739-42
PMID: 18668319




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                                      Radiotherapy oncology


15- Coverage of Axillary Lymph Nodes in Supine vs. Prone Breast Radiotherapy.

Alonso-Basanta M, Ko J, Babcock M, Dewyngaert JK, Formenti SC.

Department of Radiation Oncology, New York University School of Medicine, New York, NY.

PURPOSE: To compare the dosimetry of target and normal tissue when tangents with the breast tissue
were applied in a subset of breast cancer patients who had undergone computed tomography (CT)
planning both supine and prone.

 METHODS AND MATERIALS: The CT images of 20 pa ents who had undergone simula on in supine and
prone positions were used for planning. The axillary lymph node regions (level I-III), breast tissue, tumor
bed, heart, and bilateral lungs were manually contoured. Standard tangent fields were designed for the
whole breast to deliver a prescribed dose of 50 Gy. Dose-volume histograms were compared between
the two sets.

RESULTS: In each patient, coverage of breast tissue and tumor bed was readily achieved by either
technique. In either position, treatment of the nodal regions was inadequate. On average, the mean


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dose to the nodal regions for levels I-III was approximately 50% less in the prone as compared with the
supine posi on. The mean ipsilateral lung volume receiving 95% of the prescribed dose was 6.3% in the
supine posi on compared to 0.43% in the prone posi on. When planned supine, the mean heart volume
receiving 30 Gy was 0.56% compared with 0.30% in the prone posi on.

CONCLUSIONS: Planning in either position was found to achieve adequate coverage of the breast tissue
and tumor bed for all patients. Lung was better spared prone. Coverage of axillary nodes was
inadequate in either position, but further reduced in the prone vs. supine position. The choice of optimal
setup should take into considerations stage and risk of nodal recurrence.
Int J Radiat Oncol Biol Phys. 2008 Aug 5.
PMID: 18687534



16- Accelerated Whole Breast Irradiation with Intensity-Modulated Radiotherapy
to the Prone Breast.

Croog VJ, Wu AJ, McCormick B, Beal KP.

PURPOSE: Whole breast irradiation (WBI) is the standard of care for patients with early-stage breast
cancer who opt for breast conservation. After a randomized trial demonstrated equivalent cosmesis and
disease control with accelerated WBI (AWBI), our institution began to offer AWBI to appropriate

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patients. The aim of this study was to examine our unique experience with AWBI using prone positioning
and simplified intensity-modulated radiotherapy (IMRT) planning with a sequential boost to the tumor
bed.

 METHODS AND MATERIALS: We iden fied 356 pa ents who had been treated with prone WBI using
IMRT in our department between January 2004 and December 2006. Of these, 128 (36%) pa ents had
received AWBI (represen ng 131 treated breasts), consis ng of 16 daily frac ons of 265 cGy to a total
dose of 4,240 cGy followed by a conventionally fractionated boost.

RESULTS: Patients who opted for AWBI were similar demographically to the patients undergoing
conven onal WBI. In the AWBI cohort, 83% of the pa ents had Stage T1 disease and 22% had nodal
involvement (N1). The tumors were estrogen receptor-positive, progesterone receptor-positive and Her-
2/Neu-amplified in 82%, 69%, and 11%, respec vely. The median dura on of AWBI plus a boost was 29
days, and no patient required a toxicity-related treatment break. No Grade 3 or greater acute toxicity
developed. At a median follow-up of 18 months, one ipsilateral breast recurrence developed that was
salvaged with mastectomy and immediate reconstruction.

CONCLUSION: AWBI to the prone breast using simplified IMRT with a sequential boost offers women
requiring breast-only adjuvant radiotherapy an abbreviated treatment with early tumor control and
cosmesis comparable to that with standard fractionation.

Int J Radiat Oncol Biol Phys. 2008 Aug 1.


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PMID: 18676095



17- High Mammographic Breast Density Is Independent Predictor of Local But Not
Distant Recurrence After Lumpectomy and Radiotherapy for Invasive Breast
Cancer.

Park CC, Rembert J, Chew K, Moore D, Kerlikowske K.

Department of Radiation Oncology, San Francisco, School of Medicine, San Francisco, CA.

PURPOSE: Biologically meaningful predictors for locoregional recurrence (LRR) in patients undergoing
breast-conserving surgery (BCS) and radiotherapy (RT) are lacking. Tissue components, including
extracellular matrix, could confer resistance to ionizing radiation. Fibroglandular and extracellular matrix
components of breast tissue relative to adipose tissue can be quantified by the mammographic breast
density (MBD), the proportion of dense area relative to the total breast area on mammography. We
hypothesized that the MBD might be a predictor of LRR after BCS and RT for invasive breast cancer.

METHODS AND MATERIALS: We conducted a nested case-control study of 136 women with invasive
breast cancer who had undergone BCS and RT and had had the MBD ascertained before, or at,


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diagnosis. Women with known recurrence were matched to women without recurrence by year of
diagnosis. The median follow-up was 7.7 years. The percentage of MBD was measured using a
computer-based threshold method.
RESULTS: Pa ents with a high MBD (>/=75% density) vs. low (</=25%) were at increased risk of LRR
(hazard ra o, 4.30; 95% confidence interval, 0.88-021.0; p = 0.071) but not distant recurrence. In
addition, we found a complete inverse correlation between high MBD and obesity (body mass index,
>/=30 kg/m(2)). In a mul variate Cox propor onal hazards model, pa ents with MBD in the greatest
quar le were at significantly greater risk of LRR (hazard ra o, 6.6; 95% confidence interval, 1.6-27.7; p =
0.01). Obesity without a high MBD also independently predicted for LRR (hazard ra o, 19.3; 95%
confidence interval, 4.5-81.7; p < 0.001).

CONCLUSION: The results of our study have shown that a high MBD and obesity are significant
independent predictors of LRR after BCS and RT for invasive breast cancer. Additional studies are
warranted to validate these findings.

PMID: 18692323 Int J Radiat Oncol Biol Phys. 2008 Aug 7.




18- Comprehensive Locoregional Treatment and Systemic Therapy for
Postmastectomy Isolated Locoregional Recurrence.


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Kuo SH, Huang CS, Kuo WH, Cheng AL, Chang KJ, Chia-Hsien Cheng J.

Department of Oncology, National Taiwan University Hospital and National Taiwan University College of
Medicine, Taipei, Taiwan; Cancer Research Center, National Taiwan University College of Medicine,
Taipei, Taiwan; Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine,
Taipei, Taiwan; Department of Oncology, National Taiwan University Hospital Yun-Lin Branch, Yunlin,
Taiwan.

PURPOSE: To assess the impact of comprehensive locoregional therapy and systemic therapy on disease
control and survival for postmastectomy patients with isolated locoregional recurrence (ILRR).

METHODS AND MATERIALS: A total of 115 postmastectomy breast cancer pa ents treated for ILRR were
included. Of the pa ents, 98 underwent comprehensive locoregional treatment (local tumor excision
plus postopera ve radiotherapy), and 17 received defini ve radiotherapy alone. Involved-field
radiotherapy was given to 69 pa ents, whereas en re-field radiotherapy (both involved-field and
elective-field, involving the chest wall and regional lympha cs) was given to 46 pa ents. Systemic
therapy consis ng of hormone therapy, chemotherapy, or both was given to 69% of pa ents.

RESULTS: Patients treated with comprehensive locoregional treatment had a significantly be er 5-year
invasive disease-free survival (IDFS) and overall survival (OS) after ILRR than patients treated with
defini ve radiotherapy alone (IDFS rate, 51% vs. 16%, p = 0.006; OS rate, 62% vs. 37%, p = 0.017).

                                                                                                       15
Patients with the most comprehensive locoregional treatment (recurrent tumor excision and entire-field
radiotherapy) and systemic therapy had a significantly be er 5-year IDFS and OS than patients given
either treatment or neither treatment (IDFS rate, 52% vs. 39%, p = 0.011; OS rate, 63% vs. 50%, p =
0.026). Mul variate analysis revealed that posi ve axillary lymph nodes, Grade III tumor, nega ve
estrogen and progesterone receptor status at primary diagnosis, disease-free interval of less than 2
years, and less comprehensive locoregional treatment were significantly associated with worse IDFS and
OS.

 CONCLUSIONS: Use of comprehensive locoregional therapy and systemic therapy can achieve good
survival outcome in a substantial proportion of postmastectomy patients with ILRR.
Int J Radiat Oncol Biol Phys. 2008 Aug 7.
PMID: 18692329

19- Timing of Chemotherapy After MammoSite Radiation Therapy System Breast
Brachytherapy: Analysis of the American Society of Breast Surgeons MammoSite
Breast Brachytherapy Registry Trial.

Haffty BG, Vicini FA, Beitsch P, Quiet C, Keleher A, Garcia D, Snider H, Gittleman M, Zannis V, Kuerer H,
Whitacre E, Whitworth P, Fine R, Keisch M.




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Department of Radiation Oncology, The Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson
Medical School, New Brunswick, NJ.

PURPOSE: To evaluate cosmetic outcome and radiation recall in the American Society of Breast Surgeons
registry trial, as a function of the interval between accelerated partial breast irradiation (APBI) and
initiation of chemotherapy (CTX).

 METHODS AND MATERIALS: A total of 1440 pa ents at 97 ins tu ons par cipated in this trial. A er
lumpectomy for early-stage breast cancer, patients received APBI (34 Gy in 10 frac ons) with
MammoSite RTS brachytherapy. A total of 148 pa ents received CTX within 90 days of APBI. Cosme c
outcome was evaluated at each follow-up visit and dichotomized as excellent/good or fair/poor.

RESULTS: Chemotherapy was ini ated at a mean of 3.9 weeks a er the final MammoSite procedure and
was administered </=3 weeks a er APBI in 54 pa ents (36%) and >3 weeks a er APBI in 94 pa ents
(64%). The early and delayed groups were well balanced with respect to multiple factors that may
impact on cosmetic outcome. There was a superior cosmetic outcome in those receiving chemotherapy
>3 weeks a er APBI (excellent/good in 72.2% at </=3 weeks vs. excellent/good in 93.8% at >3 weeks; p =
0.01). Radia on recall in those receiving CTX at </=3 weeks was 9 of 50 (18%), compared with 6 of
81(7.4%) in those receiving chemotherapy at >3 weeks (p = 0.09).

CONCLUSION: The majority of patients receiving CTX after APBI have excellent/good cosmetic outcomes,
with a low rate of radia on recall. Chemotherapy ini ated >3 weeks a er the final MammoSite
procedure seems to be associated with a better cosmetic outcome and lower rate of radiation recall. An

                                                                                                      16
excellent/good cosme c outcome in pa ents receiving CTX a er 3 weeks was similar to the cosmetic
outcome of the overall patient population who did not receive CTX.
Int J Radiat Oncol Biol Phys. 2008 Aug 7
PMID: 18692330


20- Patients With T1 to T2 Breast Cancer With One to Three Posi ve Nodes Have
Higher Local and Regional Recurrence Risks Compared With Node-Negative
Patients After Breast-Conserving Surgery and Whole-Breast Radiotherapy.

Truong PT, Jones SO, Kader HA, Wai ES, Speers CH, Alexander AS, Olivotto IA.

Radiation Therapy Program, British Columbia Cancer Agency, Vancouver Island Centre, University of
British Columbia, Victoria, BC, Canada; Breast Cancer Outcomes Unit, British Columbia Cancer Agency,
Vancouver Island Centre, University of British Columbia, Victoria, BC, Canada.

PURPOSE: To evaluate locoregional recurrence according to nodal status in women with T1 to T2 breast
cancer and zero to three posi ve nodes (0-3N+) treated with breast-conserving surgery (BCS).

 METHODS AND MATERIALS: The study subjects comprised 5,688 women referred to the Bri sh



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Columbia Cancer Agency between 1989 and 1999 with pT1 to T2, 0-3N+, M0 breast cancer, who
underwent breast-conserving surgery with clear margins and radiotherapy (RT) of the whole breast. The
10-year Kaplan-Meier local, regional, and locoregional recurrence (LR, RR, and LRR, respectively) were
compared between the N0 (n = 4,433) and 1-3N+ (n = 1,255) cohorts. The LRR was also examined in
patients with one to three positive nodes (1-3N+) treated with and without nodal RT. Mul variate
analysis was performed using Cox regression modeling.

 RESULTS: Median follow-up was 8.6 years. Systemic therapy was used in 97% of 1-3N+ and 41% of N0
pa ents. Nodal RT was used in 35% of 1-3N+ pa ents. The 10-year recurrence rates in N0 and 1-3N+
cohorts were as follows: LR 5.1% vs. 5.8% (p = 0.04); RR 2.3% vs. 6.1% (p < 0.001), and LRR 6.7% vs.
10.1% (p < 0.001). Among 817 1-3N+ pa ents treated without nodal RT, 10-year LRR were 13.8% with
age <50 years, 20.3% with Grade III, and 23.4% with estrogen receptor (ER)-negative disease. On
mul variate analysis, 1-3N+ status was associated with significantly higher LRR (hazard ra o [HR], 1.85;
95% confidence interval, 1.34-2.55, p < 0.001), whereas nodal RT significantly reduced LRR (HR, 0.59;
95% confidence interval, 0.38-0.92, p = 0.02).

CONCLUSION: Pa ents with 1-3N+ and young age, Grade III, or ER-negative disease have high LRR risks
approxima ng 15% to 20% despite BCS, whole-breast RT and systemic therapy. These patients may
benefit with more comprehensive RT volume encompassing the regional nodes.
Int J Radiat Oncol Biol Phys. 2008 Aug 1
PMID: 18676091



                                                                                                       17
21- 3D Ultrasound Can Contribute to Planning Ct to Define the Target for Par al
Breast Radiotherapy.

Berrang TS, Truong PT, Popescu C, Drever L, Kader HA, Hilts ML, Mitchell T, Soh SY, Sands L, Silver S,
Olivotto IA.

Radiation Therapy Program, British Columbia Cancer Agency, Vancouver Island Centre, Victoria, BC,
Canada; University of British Columbia, Vancouver Island Health Authority, Victoria, BC, Canada.

PURPOSE: The role of three-dimensional breast ultrasound (3D US) in planning par al breast
radiotherapy (PBRT) is unknown. This study evaluated the accuracy of coregistra on of 3D US to
planning computerized tomography (CT) images, the seroma contouring consistency of radiation
oncologists using the two imaging modalities and the clinical situations in which US was associated with
improved contouring consistency compared to CT.

 MATERIALS AND METHODS: Twenty consecutive women with early-stage breast cancer were enrolled
prospectively after breast-conserving surgery. Subjects underwent 3D US at CT simula on for adjuvant
RT. Three radia on oncologists independently contoured the seroma on separate CT and 3D US image
sets. Seroma clarity, seroma volumes, and interobserver contouring consistency were compared
between the imaging modalities. Associations between clinical characteristics and seroma clarity were



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examined using Pearson correlation statistics.

 RESULTS: 3D US and CT coregistra on was accurate to within 2 mm or less in 19/20 (95%) cases. CT
seroma clarity was reduced with dense breast parenchyma (p = 0.035), small seroma volume (p < 0.001),
and small volume of excised breast ssue (p = 0.01). US seroma clarity was not affected by these factors
(p = NS). US was associated with improved interobserver consistency compared with CT in 8/20 (40%)
cases. Of these 8 cases, 7 had low CT seroma clarity scores and 4 had heterogeneously to extremely
dense breast parenchyma.

CONCLUSION: 3D US can be a useful adjunct to CT in planning PBRT. Radia on oncologists were able to
use US images to contour the seroma target, with improved interobserver consistency compared with
CT in cases with dense breast parenchyma and poor CT seroma clarity.
Int J Radiat Oncol Biol Phys. 2008 Aug 7.
PMID: 18692322


22- Estimating the lifetime utilization rate of radiotherapy in cancer patients: The
Multicohort Current Utilization Table (MCUT) method.

Zhang-Salomons J, Mackillop WJ.
Department of Community Health and Epidemiology, Queen's University, Kingston, Ont. K7L 3N6,
Canada.

                                                                                                         18
Extensive research has been carried out to establish the appropriate proportion of cancer patients
requiring radiotherapy at some point during their illness. However, it is difficult to compare the actual
rates against the appropriate rate, because calculating the actual rates requires life-long follow up of
cancer patients. We have developed a method, referred to as the Multicohort Current Utilization Table
(MCUT) method, to estimate the predicted lifetime utilization rates based on current medical practice.
We implemented the method in SAS as a macro, and validated it by comparing the predicted and the
actual utilization rates of radiotherapy in lung, breast, and prostate cancer cases diagnosed in Ontario,
Canada. The MCUT method could be used to predict lifetime utilization rate of any medical services.
Comput Methods Programs Biomed. 2008 Aug 1.
PMID: 18676052



23- Impact of radiotherapy on the quality of life of elderly patients with localized
breast cancer. A prospective study.

Arraras JI, Manterola A, Domínguez MA, Arias F, Villafranca E, Romero P, Martínez E, Illarramendi JJ,
Salgado E.




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Radiotherapeutic Oncology Department, Hospital of Navarre, Pamplona, Spain.

Introduction: There are few studies on the effect on quality of life (QL) of cancer-related illness and
treatment in elderly patients. The aim of this work was to evaluate prospectively QL in a sample of
elderly patients with stages I.III breast cancer who started radiotherapy treatment and compare their QL
with that of a sample of younger patients. Materials and methods Forty-eight pa ents, >/= 65 years of
age completed the European Organization for Research and Treatment of Cancer (EORTC) QL
questionnaires QLQ-C30 and QLQ-BR23, and the Interview for Deteriora on in Daily Living Ac vi es in
Dementia (IDDD) daily activities scale three times throughout treatment and follow-up periods. Clinical
and demographic data were also recorded. Fi y pa ents ages 40-64 years with the same disease stage
and treatment modality had previously completed the QL questionnaires. QL scores, changes in them
among the three assessments, differences between groups based on clinical factors, and differences
between the two samples were calculated. Results QL scoring was good and stable (>70/100 points) in
most areas, in line with clinical data. Light and moderate limitations occurred in global QL and some
emotional, sexual, and treatment-related areas. Moderate decreases (10-20) appeared in some toxicity-
related areas, which recovered during the follow-up period. Breast-conservation and sentinel-node
patients presented higher scores in emotional areas. There were few QL differences among agebased
samples. Conclusions QL and clinical data indicate radiotherapy was well tolerated. Age should not be
the only factor evaluated when deciding upon treatment for breast cancer patients.
Clin Transl Oncol. 2008 Aug;10(8):498-504.
PMID: 18667381


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24- Oligometastatic breast cancer treated with curative-intent stereotactic body
radiation therapy.

Milano MT, Zhang H, Metcalfe SK, Muhs AG, Okunieff P.

Department of Radia on Oncology, University of Rochester Medical Center, 601 Elmwood Ave, P.O. Box
647, Rochester, NY, 14642, USA, MTMilano@yahoo.com.

Purpose Prospective pilot study to assess patient outcome after stereotactic body radiation therapy
(SBRT) for limited metastases from breast cancer. Methods Forty pa ents with </=5 metasta c lesions
received curative-intent SBRT, while 11 pa ents with >5 lesions, undergoing SBRT to </=5 metasta c
lesions, were treated with palliative-intent.

Results :Among those treated with curative-intent, 4-year actuarial outcomes were: overall survival of
59%, progression-free survival of 38% and lesion local control of 89%. On univariate analyses, 1
metasta c lesion (versus 2-5), smaller tumor volume, bone-only disease, and stable or regressing lesions
prior to SBRT were associated with more favorable outcome. Patients treated with palliative-intent SBRT
were spared morbidity and mortality from progression of treated lesions, though all developed further
metasta c progression shortly (median 4 months) a er enrollment.




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Conclusions :SBRT may yield prolonged survival and perhaps cure in select patients with limited
metastases. Palliative-intent SBRT may be warranted for symptomatic or potentially symptomatic
metastases.
Breast Cancer Res Treat. 2008 Aug 22.
PMID: 18719992



25- Partial breast irradiation as sole therapy for low risk breast carcinoma: Early
toxicity, cosmesis and quality of life results of a MammoSite brachytherapy phase
II study.

Belkacémi Y, Chauvet MP, Giard S, Villette S, Lacornerie T, Bonodeau F, Baranzelli MC, Bonneterre J,
Lartigau E.

Department of Radiation Oncology, Oscar Lambret Anti-Cancer Center, Cedex, France; Breast Cancer
Unit, Oscar Lambret Center, Cedex, France; Lille II University, Lille, France.

PURPOSE: The MammoSite is a device that was developed with the goal of making breast-conserving
surgery (BCT) more widely available. Our objective was to evaluate the MammoSite device
performances after an open cavity placement procedure and quality of life in highly selected patients
with early-stage breast cancer.

                                                                                                        20
METHODS AND MATERIALS: From March 2003 to March 2005, 43 pa ents with T1 breast cancer were
enrolled in a phase II study. The median age was 72 years. Twenty-five (58%) pa ents were treated with
high-dose rate brachytherapy using the MammoSite applicator to deliver 34Gy in 10 frac ons. The main
disqualifying factor was pathologic sen nel node involvement (10/43; 23%). There were no device
malfunctions, migration or rupture of the balloon.

RESULTS: After a median follow-up of 13 months, there were no local recurrences and one contralateral
lobular carcinoma. Seventeen (68%), 13 (52%), 8 (32%), 5 (20%) and 2 (8%) pa ents had erythema,
seroma, inflamma on, hematoma and sever infec on, respec vely. Only 2 pa ents developed
telangiectasia. At 1 year the rate of "good to excellent" cosme c results was 84%. Significant changes in
QoL were observed for emotional and social well-being between 3 and 12 months. At 24 months, only
emotional well-being subscore changes were sta s cally significant (p=0.015).

 CONCLUSIONS: Our data in pa ents older than 60 years support the previously published data.
Histologic features were the main disqualifying criteria. With higher skin spacing levels we observed very
low incidence of telangiectasia. QoL evaluation indicates that baseline scores were satisfactory. Changes
concerned emotional and social well-being.
Radiother Oncol. 2008 Aug 8.
PMID: 18692927

26- Study of quadrant high-dose intraoperative radiation therapy for early-stage


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breast cancer.

Sacchini V, Beal K, Goldberg J, Montgomery L, Port E, McCormick B.

Breast Service, Memorial Sloan-Kettering Cancer Center, New York, USA.

BACKGROUND: Partial breast irradiation has been tested in limited pilot studies and shown to provide
acceptable cosmesis, minimal toxicity and adequate local control. The aim of this study was to
determine the feasibility of using quadrant high-dose intraoperative radiation therapy (IORT) for the
treatment of early-stage breast cancer.

METHODS: Fifty-two women with early-stage breast cancer were treated with breast-conserving
therapy and IORT between October 2002 and January 2006. The first 18 women received a radia on
dose of 20 Gy. The protocol was then amended and the remaining 34 women were treated with 18 Gy.
Each pa ent was evaluated a er surgery, and at 3, 6 and 12 months; complica ons, toxicity and
cosmetic outcomes were recorded by the breast surgeon.

RESULTS: Women treated with 18 Gy appeared to have a more favourable cosmetic outcome compared
with the earlier treatment group. At last follow-up, none of the women treated on the protocol had a
breast recurrence.




                                                                                                        21
CONCLUSION:Experience suggests that this IORT technique is feasible, although further follow-up is
necessary to assess its therapeu c value. Copyright (c) 2008 Bri sh Journal of Surgery Society Ltd.
Published by John Wiley & Sons, Ltd.
Br J Surg. 2008 Aug 8;95(9):1105-1110.
PMID: 18690634




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                                                                                                      22
                                         Medical oncology



27- Phase II trial of vinorelbine and trastuzumab in pa ents with HER2-positive
metastatic breast cancer. A prospective, open label, non-controlled, multicenter
phase II trial (to investigate efficacy and safety of this combination chemotherapy).

Schilling G, Bruweleit M, Harbeck N, Thomssen C, Becker K, Hoffmann R, Villena C, Schütte M, Hossfeld
DK, Bokemeyer C, de Wit M.

Onkologisches Zentrum, II. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf,
Mar nistr. 52, 20246, Hamburg, Germany, g.schilling@uke.uni-hamburg.de.

The purpose of this study was to evaluate the efficacy (progression free survival (PFS) and response rate)
and safety of vinorelbine and trastuzumab combination chemotherapy in pa ents with HER2-
overexpressing, metastatic breast cancer as a first line chemotherapy regimen. Patients with
histologically confirmed, HER2-posi ve (immunohistochemistry (ICH) 3+, or 2+ and FISH+) metasta c
breast cancer who had nor received prior vinorelbine or anti-HER2 therapy in the adjuvant se ng,
received at least eight weeks of vinorelbine i.v. (25 mg/g weekly) and trastuzumab (4 mg/kg on day 1


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followed by 2 mg/kg weekly). Forty-one women from six participating centers were enrolled into the
trial. The overall response rate, was 43.9% (18 of 41 pa ents), (CI 28-60.3%), 30% of pa ents were
progression free a er 1 year. Four pa ents reached complete remission, 14 par al remission and five
had stable disease for at least 18 weeks. Six pa ents developed primary progression. 35 pa ents (85%)
experienced progression a er a median me of 235 days. Therapy was in general well-tolerated. There
were two CTC grade 4 infusion syndromes and two pa ents experienced cardiotoxicity at least grade 2.
This phase II trial of vinorelbine and trastuzumab demonstrated an effective and well-tolerated regimen
with a favourable safety profile.
Invest New Drugs. 2008 Aug 12.
PMID: 18696011




28- A Prospec ve Trial on Ini a on Factor 4E (eIF4E) Overexpression and Cancer
Recurrence in Node-Negative Breast Cancer.

Holm N, Byrnes K, Johnson L, Abreo F, Sehon K, Alley J, Meschonat C, Md QC, Li BD.

Louisiana State University Health Sciences Center and the Feist-Weiller Cancer Center, 1501 Kings
Highway, Shreveport, LA, 71130, USA.



                                                                                                       23
BACKGROUND: Eukaryo c Ini a on Factor 4E (eIF4E) plays a crucial role in transla on control. High
eIF4E increase in tumor specimens independently predicted recurrence by mul variate analysis. This
prospective trial of node-negative only breast cancer patients was initiated to test the hypothesis that
high eIF4E increase predicts cancer recurrence and death, independent of nodal status. METHODS: The
trial was powered to detect a 2.4-fold increase in rela ve risk for cancer recurrence in 240 node-
negative patients on the basis of high versus low eIF4E increase in tumor specimens (type I error = .05,
sta s cal power = .08). eIF4E level was quan fied by using Western blot test. Treatment and
surveillance regimens were standardized. Primary endpoints were cancer recurrence and cancer-related
death.

RESULTS: Of the 242 pa ents accrued, 112 were in the low eIF4E group (<7.5-fold), 82 were in the
intermediate eIF4E group (7.5- to 15-fold), and 48 were in the high eIF4E group (>15-fold). Patients in
the high eIF4E group had a sta s cally significant higher rate of cancer recurrence and cancer-related
death (P = .0001 and P </= .0001, log rank test). The rela ve risk for cancer recurrence was 2.2-fold
higher in the high eIF4E group (P = .001, Cox model), and 3.7-fold higher for cancer-related death (P =
.0009).

CONCLUSIONS: In node-nega ve breast cancer, high eIF4E increase predicted a higher rate of cancer
recurrence and death. High eIF4E pa ents had a >2-fold increase in relative risk for cancer recurrence
and nearly a 4-fold increase in relative risk for death. This supports our hypothesis that high eIF4E is an
independent predictor for breast cancer outcome independent of nodal status.



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Ann Surg Oncol. 2008 Aug 22.
PMID: 18719964




29- Effect of lapatinib on the outgrowth of metastatic breast cancer cells to the
brain.

Gril B, Palmieri D, Bronder JL, Herring JM, Vega-Valle E, Feigenbaum L, Liewehr DJ, Steinberg SM,
Merino MJ, Rubin SD, Steeg PS.

Women's Cancers Section, Laboratory of Molecular Pharmacology, National Cancer Institute, National
Ins tutes of Health, 9000 Rockville Pike, Building 37, Room 1122, MSC 4254, Bethesda, MD 20892, USA.

BACKGROUND: The brain is increasingly being recognized as a sanctuary site for metastatic tumor cells
in women with HER2-overexpressing breast cancer who receive trastuzumab therapy. There are no
approved or widely accepted treatments for brain metastases other than steroids, cranial radiotherapy,
and surgical resection. We examined the efficacy of lapatinib, an inhibitor of the epidermal growth
factor receptor (EGFR) and HER2 kinases, for preven ng the outgrowth of breast cancer cells in the brain
in a mouse xenograft model of brain metastasis.



                                                                                                          24
 METHODS: EGFR-overexpressing MDA-MB-231-BR (231-BR) brain-seeking breast cancer cells were
transfected with an expression vector that contained or lacked the HER2 cDNA and used to examine the
effect of lapatinib on the activation (ie, phosphorylation) of cell signaling proteins by immunoblotting,
on cell growth by the tetrazolium salt 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide
assay, and on cell migra on using a Boyden chamber assay. The outgrowth of large (ie, >50 microm(2))
and micrometastases was counted in brain sections from nude mice that had been injected into the left
cardiac ventricle with 231-BR cells and, beginning 5 days later, treated by oral gavage with lapa nib or
vehicle (n = 22-26 mice per treatment group). All sta s cal tests were two-sided.

 RESULTS: In vitro, lapatinib inhibited the phosphoryla on of EGFR, HER2, and downstream signaling
proteins; cell prolifera on; and migra on in 231-BR cells (both with and without HER2). Among mice
injected with 231-BR-vector cells, those treated with 100 mg lapa nib/kg body weight had 54% fewer
large metastases 24 days a er star ng treatment than those treated with vehicle (mean number of
large metastases per brain sec on: 1.56 vs 3.36, difference = 1.80, 95% confidence interval [CI] = 0.92 to
2.68, P < .001), whereas treatment with 30 mg lapa nib/kg body weight had no effect. Among mice
injected with 231-BR-HER2 cells, those treated with either dose of lapa nib had 50%-53% fewer large
metastases than those treated with vehicle (mean number of large metastases per brain section, 30
mg/kg vs vehicle: 3.21 vs 6.83, difference = 3.62, 95% CI = 2.30 to 4.94, P < .001; 100 mg/kg vs vehicle:
3.44 vs 6.83, difference = 3.39, 95% CI = 2.08 to 4.70, P < .001). Immunohistochemical analysis revealed
reduced phosphoryla on of HER2 in 231-BR-HER2 cell-derived brain metastases from mice treated with
the higher dose of lapa nib compared with 231-BR-HER2 cell-derived brain metastases from vehicle-


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treated mice (P < .001).

CONCLUSIONS: Lapa nib is the first HER2-directed drug to be validated in a preclinical model for
activity against brain metastases of breast cancer.

J Natl Cancer Inst. 2008 Aug 6;100(15):1092-103
PMID: 18664652


30- Zoledronic acid and skeletal complications in patients with solid tumors and
bone metastases: analysis of a National Medical claims database.

Hatoum HT, Lin SJ, Smith MR, Barghout V, Lipton A.

Department of Pharmacy Administration, University of Illinois, Chicago, Illinois.

BACKGROUND.: Bone is among the most common sites of metastasis in patients with advanced cancer,
and the development of bone metastases places patients at increased risk for skeletal complications.
METHODS.: This retrospective claims analysis included only patients with a diagnosis of bone metastasis
who had a single type of solid tumor of the breast (women), prostate, or lung and experienced >/=1
skeletal complica on between January 2002 and October 2005.


                                                                                                       25
RESULTS: The mean follow-up (+/-standard deviation) for zoledronic acid (ZA)-treated patients versus
untreated pa ents was 12.2 +/- 9.05 months versus 8.7 +/- 9.28 months, respec vely (P < .001). The
monthly rate of skeletal complications in ZA-treated pa ents versus untreated pa ents was 0.29 +/- 0.3
per month versus 0.43 +/- 0.4 per month, respec vely (P < .001). Persistent ZA use was associated with
longer follow-up dura on (P < .05) and a greater probability of con nuing follow-up. Greater persistency
was associated with lower monthly rates of skeletal complica ons (P < .05). The length of follow-up for
ZA use according to the recommended dosing schedule was 17.11 months compared with 9.93 months
for nonrecommended schedules and 8.68 months for no treatment (analysis of variance; P < .001). The
rate of skeletal complica ons with ZA use on the recommended schedule was 0.16 events per month
versus 0.31 events per month for nonrecommended schedules and 0.43 events per month for no
treatment. In the subgroup analysis, the mean me to first complica on was 185 +/- 210 days in the ZA-
treated group versus 98 +/- 161 days in the untreated group (P < .0001). The mean time from the first
complica on to the second complica on was 111 +/- 124 days in the ZA-treated group versus 86 +/- 114
days in the untreated group (P < .05).
CONCLUSIONS.: Real-world evidence indicated that ZA reduced the skeletal morbidity rate and delayed
the me to skeletal complica ons. Cancer 2008. (c) 2008 American Cancer Society.
Cancer. 2008 Aug 21
PMID: 18720527

31- Screening and management of osteoporosis in breast cancer patients on


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aromatase inhibitors.

Gibson K, O'Bryant CL.

Department of Pharmacy, Rose Medical Center, Denver, CO.

OBJECTIVE: Breast cancer patients are at an increased risk of osteoporosis due to age, cancer,
chemotherapy, and aromatase inhibitor therapy. This retrospective review determined if patients
treated with aromatase inhibitors received appropriate screening and management for osteoporosis.

DESIGN: University of Colorado Cancer Center breast cancer patients treated with aromatase inhibitor
therapy during July 2005 through July 2006 were studied. Data was collected for each pa ent from the
time of breast cancer diagnosis up to April 2007. The study endpoints included (1) appropriate screening
for osteoporosis, (2) incidence of osteoporosis diagnosis, and (3) ini a on of appropriate drug therapy
for bone loss. Appropriate management was defined as adherence to the 2003 American Society of
Clinical Oncology guidelines for bone health issues in women with breast cancer.

 RESULTS: Of the 54 pa ents included in this study, 12 (22.2%) had no DEXA scans documented, 22
(40.7%) pa ents received a baseline DEXA scan and 8 (14.8%) pa ents received baseline and yearly
DEXA scans. During the study meline, 26 (48%) pa ents were diagnosed with osteopenia and 4 (7%)
patients were diagnosed with osteoporosis. Forty-one (75.9%) pa ents received calcium and vitamin D


                                                                                                     26
therapy. Bisphosphonate therapy was received by less than one-third of the osteopenic patients and
three-fourths of the osteoporotic patients.

 CONCLUSIONS: The majority of patients were not adequately screened which may have falsely lowered
the diagnosis of osteoporosis resulting in omission of drug therapy. All high-risk patients should receive
calcium and vitamin D therapy and be evaluated for bisphosphonate therapy. Screening and medical
management for osteoporosis in breast cancer patients on aromatase inhibitors is an important area for
clinical intervention.
J Oncol Pharm Pract. 2008 Sep;14(3):139-45.
PMID: 18719068

32- Adjuvant endocrine therapy plus zoledronic acid in premenopausal women
with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral
density substudy.

Gnant M, Mlineritsch B, Luschin-Ebengreuth G, Kainberger F, Kässmann H, Piswanger-Sölkner JC, Seifert
M, Ploner F, Menzel C, Dubsky P, Fitzal F, Bjelic-Radisic V, Steger G, Greil R, Marth C, Kubista E, Samonigg
H, Wohlmuth P, Mittlböck M, Jakesz R; on behalf of the Austrian Breast and Colorectal Cancer Study
Group (ABCSG), Vienna, Austria.




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Department of Surgery, Medical University of Vienna, General Hospital Vienna, Vienna, Austria.

BACKGROUND: The Austrian Breast and Colorectal Cancer Study Group trial-12 (ABCSG-12) bone
substudy assesses zoledronic acid for preventing bone loss associated with adjuvant endocrine therapy
and reports on long-term findings of bone-mineral density (BMD) during 3 years of treatment and 2
years after completing adjuvant treatment with or without zoledronic acid. The aim of this substudy is to
gain insight into bone health in this setting.

METHODS: ABCSG-12 is a randomised, open-label, phase III, 4-arm trial comparing tamoxifen (20
mg/day orally) and goserelin (3.6 mg subcutaneously every 28 days) versus anastrozole (1 mg/day orally)
and goserelin (3.6 mg subcutaneously every 28 days), both with or without zoledronic acid (4 mg
intravenously every 6 months) for 3 years in premenopausal women with endocrine-responsive breast
cancer. This prospec ve bone subprotocol measured BMD at 0, 6, 12, 36, and 60 months. The primary
endpoint of the bone substudy (secondary endpoint in the main trial) was change in BMD at 12 months,
assessed by dual-energy X-ray absorptiometry in assessable patients. Analyses were intention to treat.
Statistical significance was assessed by t tests. The ABCSG-12 trial is registered on the ClinicalTrials.gov
website, number NCT00295646.
 FINDINGS: 404 pa ents were prospec vely included in the bone substudy and randomly assigned to
endocrine therapy alone (goserelin and anastrozole or goserelin and tamoxifen; n=199) or endocrine
therapy concurrent with zoledronic acid (goserelin, anastrozole, and zoledronic acid or goserelin,
tamoxifen, and zoledronic acid; n=205). A er 3 years of treatment, endocrine therapy alone caused

                                                                                                         27
significant loss of BMD at the lumbar spine (-11.3%, mean difference -0.119 g/cm(2) [95% CI -0.146 to -
0.091], p<0.0001) and trochanter (-7.3%, mean difference -0.053 g/cm(2) [-0.076 to -0.030], p<0.0001).
In patients who did not receive zoledronic acid, anastrozole caused greater BMD loss than tamoxifen at
36 months at the lumbar spine (-13.6%, mean difference -0.141 g/cm(2) [-0.179 to -0.102] vs -9.0%,
mean difference -0.095 g/cm(2) [-0.134 to -0.057], p<0.0001 for both). 2 years a er the comple on of
treatment (median follow-up 60 months [range 15.5-96.6]), pa ents not receiving zoledronic acid s ll
had decreased BMD at both sites compared with baseline (lumbar spine -6.3%, mean difference -0.067
g/cm(2) [-0.106 to -0.027], p=0.001; trochanter -4.1%, mean difference -0.03 g/cm(2) [-0.062 to 0.001],
p=0.058). Pa ents who received zoledronic acid had stable BMD at 36 months (lumbar spine +0.4%,
mean difference 0.004 g/cm(2) [-0.024 to 0.032]; trochanter +0.8%, mean difference 0.006 g/cm(2) [-
0.018 to 0.028]) and increased BMD at 60 months at both sites (lumbar spine +4.0%, mean difference
0.039 g/cm(2) [0.005-0.075], p=0.02; trochanter +3.9%, mean difference 0.028 g/cm(2) [0.003-0.058],
p=0.07) compared with baseline.
 INTERPRETATION: Goserelin plus tamoxifen or anastrozole for 3 years without concomitant zoledronic
acid caused significant bone loss. Although there was par al recovery 2 years a er comple ng
treatment, patients receiving endocrine therapy alone did not recover their baseline BMD levels.
Concomitant zoledronic acid prevented bone loss during therapy and improved BMD at 5 years.
FUNDING: AstraZeneca (London, UK) and Novartis (Basel, Switzerland).
Lancet Oncol. 2008 Aug 19.
PMID: 18718815



www.vancls.info
33- Is there a qualitative interaction between adjuvant trastuzumab and size of the
primary tumor in breast cancer?

P V, B M.

Benefit of adjuvant trastuzumab in breast cancer has been reported in four randomized trials of phase
III, and these results are consistent in showing improvement in disease-free survival (DFS). Current
evidence for homogeneity of this DFS benefit in subgroups of patients with the different size of the
primary HER2-positive tumor treated according to the HERA trial is reviewed. It is evident that current
published evidence is insufficient to rule out that there is a cohort of pa ents with HER2-positive disease
who do not achieve a reduction in the risk of recurrence by adjuvant treatment with trastuzumab after
completion of previous adjuvant chemo- and radiotherapy. An alternative interpretation of results of
the HERA trial currently available in two primary reports (1-year, and 2-year median follow- up,
respectively) is discussed. The risk factors of central nervous system (CNS) metastases in breast cancer
and problem of CNS metastases in HER2-positive tumors are briefly reviewed. A hypothesis on the
relations between brain metastases, their risk factors, the size of the primary tumor, and their impact on
the DFS in pa ents with HER2-positive tumors treated with adjuvant trastuzumab is proposed based on
the results of the HERA trial. Altogether, some direct evidence is presented here based on the published
results of the HERA trial, and still more indirect evidence based on the information on related topics in


                                                                                                        28
literature, to show that current clinical practice of adjuvant trastuzumab in mono-therapy, which is
based on assumption that there is a homogeneous benefit as for disease-free survival for all sizes of
primary HER2-posi ve tumors above 1 cm, may not be based on such firm evidence as is commonly
presented. Key words: breast cancer; trastuzumab; adjuvant; brain metastases.
Neoplasma. 2008;55(5):375-80.
PMID: 18665746


34- Monitoring of early response to neoadjuvant chemotherapy in breast cancer
with (1)H MR spectroscopy: Comparison to sequen al 2-[18F]-fluorodeoxyglucose
positron emission tomography.

Tozaki M, Sakamoto M, Oyama Y, O'uchi T, Kawano N, Suzuki T, Yamashiro N, Ozaki S, Sakamoto N,
Higa K, Abe S, Ogawa T, Fukuma E.

Breast Center, Kameda Medical Center, Chiba, Japan.

PURPOSE: To assess the efficacy of (1)H MR spectroscopy (MRS) to evaluate early responses to
neoadjuvant chemotherapy in breast cancer patients, as compared to that of the standardized uptake
value (SUV) in (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET).



www.vancls.info
MATERIALS AND METHODS: This retrospective study included seven patients with breast cancer who
had both single-voxel (1)H MRS and PET/computed tomography (CT) acquired before, during, and after
neoadjuvant chemotherapy.
RESULTS: The averages of the Choline (Cho) integral value and peak SUV before chemotherapy were 2.5
(range, 1.2-5.3) and 7.5 (range, 1.9-19), respec vely. Three cases became negative for both Cho and
peak SUV after two cycles of chemotherapy, and one patient became negative before surgery. In the
remaining three patients, the curves of both values paralleled the time course of chemotherapy
treatment. The difference between Cho and peak SUV before, during, and after chemotherapy was r =
0.65 (P = 0.12), r = 0.80 (P = 0.03), and r = 0.99 (P < 0.001), respec vely. The reduc on rate (RR) of both
values a er chemotherapy was also correlated (r = 0.84, P = 0.02).

CONCLUSION: A change in the Cho integral value is well correlated with that of peak SUV in the time
course of neoadjuvant chemotherapy; thus, breast (1)H MRS is thought to be an alterna ve to
sequen al (18)F-FDG PET. J. Magn. Reson. Imaging 2008;28:420-427. (c) 2008 Wiley-Liss, Inc.
J Magn Reson Imaging. 2008 Aug;28(2):420-7
PMID: 18666159



35- Non-metastatic breast cancer specific-survival of patients after treatment with
adjuvant chemotherapy.]

                                                                                                         29
[Article in Portuguese]

Cintra JR, Guerra MR, Bustamante-Teixeira MT.

Programa de Pós-graduação em Saúde Brasileira, NATES/Faculdade de Medicina, UFJF, Juiz de Fora, MG.

OBJECTIVE: Analyze the 5-year breast cancer specific-survival rate of women diagnosed with invasive
non-metastatic disease, who as part of their primary treatment underwent surgery followed by adjuvant
chemotherapy.

METHODS: Four hundred twenty eight patients diagnosed between 1998 and 2000 were recruited from
all oncology services of the municipality of Juiz de Fora, MG, Brasil. Survival time was counted from the
date of the histopathological diagnosis and the date of death due to breast cancer was considered the
adverse event. Women alive un l December 2005, the final date of the follow-up, were censored. For
those who interrupt treatment, censor date was the last follow-up in the medical records. Kaplan-Meier
survival curves were estimated, with the differences assessed by the log-rank test.

RESULTS: Mean age was 51.2 years, and most (72.6%) were Caucasian. Clinical Stages II (47.4%) and III
(38.6%) predominated. Breast cancer specific five-year survival rate was 82.0%. A worst survival was
observed among women with disease diagnos c before menopause (p=0.02), with tumor size greater



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than 2.0cm (p=0.05), with lymph node involvement (p=0,000), in a more advanced disease stage
(p=0.000), on a full adjuvant chemotherapy regimen (p=0.03), and who used hormone therapy (p=0.05).

CONCLUSION: This research allowed identification of the profile and disease survival of breast cancer
patients who used adjuvant chemotherapy. These results stimulated the adoption of intensive strategies
by the local health authorities for disease control and prevention in this population, emphasizing the
increasing need of breast cancer screening, mainly for women considered as of high risk and the
availability of timely treatment for all cases diagnosed.
Rev Assoc Med Bras. 2008 Jul-Aug;54(4):339-4

PMID: 18719793

36- Management of hand-foot syndrome in patient treated with capecitabine.

[Article in Japanese]

Fujii C, Anami S, Fujino M, Yasui Y, Fujita M, Inoue M, Nakayama T, Kamigaki S, Tatsuta M, Furukawa
H.
Dept. of Pharmacy, Sakai Municipal Hospital.

Capecitabine is one of the most effective oral regimens of chemotherapy against advanced or recurrent
breast cancer. In addition, capecitabine could widely be used for treatment of colon cancer. It appears

                                                                                                       30
that more patients will be administered capecitabine because of its QOL benefits. However, Hand-Foot
Syndrome(HFS)may appear to be about 50% of the pa ents who take this regimen. As a result, the
patient's QOL is hindered and led to a reduction of the dosage or discontinuation of the treatment
depending on the grade of adverse event. This time, we evaluated the efficacy of topical emollients,
creams and vitamin B6 for prevention and reduction of HFS symptoms for patients who received
capecitabine. We found the efficacy of preventa ve measures that the occurrence of HFS grade 1 or
above could be decreased and delayed. We also noticed that these preventative measures appear to be
decreased the occurrence of HFS grade 2 or above, which led to a reduc on of dosage or
discontinuation of the treatment. For continuation and completion of the treatment and securing of
patient's QOL, the supportive measures are needed to control a variety of side effects, such as HFS and
others, and a team care support is indispensable.
Gan To Kagaku Ryoho. 2008 Aug;35(8):1357-60.
PMID: 18701848



37- Epothilones in breast cancer: current status and future directions.

Atzori F, Fornier M.

Department of Medical Oncology, Vall d'Hebron University Hospital, Passeig de la Vall d'Hebron, 08001


www.vancls.info
Barcelona, Spain. fatzori@vhebron.net

Taxanes have become fundamental in the treatment of early and advanced breast cancer. However,
tumors vary in their sensitivity to these agents; resistance can be acquired or de novo resistance can
occur. Epothilones and associated analogs are novel microtubule-stabilizing agents that induce
apoptosis and promote cell death. There is now a growing body of clinical data describing the efficacy of
epothilones in breast cancer patients who have progressed on taxanes and anthracyclines. This
culminated with US FDA approval in October 2007 of ixabepilone (Ixempra, Brystol Myers Squibb, NJ,
USA) either as single agent or in combination with capecitabine for the treatment of breast cancer,
which has progressed after prior therapies. The results of ongoing and future randomized clinical trials
will further define how epothilones, in particular ixabepilone, will be integrated into the management of
early and metastatic breast cancer. In parallel, the search for biomarkers predictive of sensitivity to
epothilones continues in an attempt to tailor these therapies to patients with greater accuracy.
Expert Rev Anticancer Ther. 2008 Aug;8(8):1299-311.
PMID: 18699766

38- tAnGo: a randomised phase III trial of gemcitabine in paclitaxel-containing,
epirubicin/cyclophosphamide-based, adjuvant chemotherapy for early breast
cancer: a prospective pulmonary, cardiac and hepatic function evaluation.



                                                                                                      31
Wardley AM, Hiller L, Howard HC, Dunn JA, Bowman A, Coleman RE, Fernando IN, Ritchie DM, Earl HM,
Poole CJ; tAnGo Trial Collaborators.Collaborators (11)

Howard H, Loi S, Atwal M, Foster L, McDermaid M, Pollard S, Watson C, Walker A, Parr D,
Hiller L, Dunn J.

CR UK Department of Medical Oncology, Chris e Hospital, Manchester M20 4BX, UK.
Andrew.Wardley@christie.nhs.uk

tAnGo is a large randomised trial assessing the addition of gemcitabine(G) to paclitaxel(T), following
epirubicin(E) and cyclophosphamide(C) in women with invasive higher risk early breast cancer. To assess
the safety and tolerability of adding G, a detailed safety substudy was undertaken. A total of 135
patients had cardiac, pulmonary and hepatic function assessed at (i) randomisation, (ii) mid-
chemotherapy, (iii) immediately post-chemotherapy and (iv) 6 months post-chemotherapy. Skin toxicity
was assessed during radiotherapy. No differences were detected in FEV(1) or FVC levels between
treatment arms or me points. Diffusion capacity (TL(CO)) reduced during treatment (P<0.0001), with a
significantly lower drop in EC-GT pa ents (P=0.02). Most of the reduc on occurred during EC and
recovered by 6-months post treatment. There was no difference in cardiac function between treatment
arms. Only 11 pa ents had echocardiography/MUGA results change from normal to abnormal during
treatment, with only five having LVEF<50%. Transient transaminitis occurred in both treatment arms
with significantly more in EC-GT patients post-chemotherapy (AST P=0.03, ALT P=0.003), although the


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majority was low grade. There was no correlation between transaminitis and other toxicities. Both
treatment regimens reported temporary reductions in pulmonary functions and transient transaminitis
levels. Despite these being greater with EC-GT, both regimens appear well tolerated.
Br J Cancer. 2008 Aug 19;99(4):597-603
PMID: 18665163

39- Risks and benefits of therapy with menopausal hormones versus selective
estrogen-receptor modulators in peri- and postmenopausal women at increased
breast cancer risk.

Col NF, Chlebowski RT.

Center for Outcomes Research and Evalua on, Maine Medical Center, Portland, ME 04101, USA.
coln@mmc.org

Decision making about menopausal therapies is complex because of the number of clinical factors that
must be considered. Menopausal hormone therapy can relieve the vasomotor symptoms of menopause,
but the most common preparation, combination estrogen and progesterone, increases the risk of breast
cancer. Both tamoxifen and raloxifene can reduce the risk of developing invasive breast cancer, but the
adverse effects of these drugs differ substantially. Risk models have been built to identify women at high
risk for developing breast cancer, but their application in clinical practice has been develop

                                                                                                       32
disappointingly low. We propose an approach for identifying and managing menopausal women at high
risk for breast cancer that can be readily implemented in clinical practice. The first step is to identify
women at sufficiently high risk for breast cancer to merit treatment. For women aged 45 or older, the
presence of one or more first-degree relatives with breast cancer and one or more previous breast
biopsies will iden fy those whose 5-year risk is 2% or higher. For women 55 years or older, the presence
of either one of these risk factors is sufficient. Any woman with a family history of breast cancer should
be assessed as to whether she is likely to carry a BRCA mutation and referred for genetic counseling and
possible genetic testing. Decisions about treatment options should be based on the presence or absence
of bothersome vasomotor symptoms, an intact uterus, and risk factors for cardiovascular disease. A
simple algorithm is presented to streamline identification and management of menopausal women at
high risk for breast cancer.
Menopause. 2008 Jul-Aug;15(4 Suppl):804-9.
PMID: 18596602

40- Risks, benefits, and effects on quality of life of selective estrogen-receptor
modulator therapy in postmenopausal women at increased risk of breast cancer.

Ganz PA, Land SR.

School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los



www.vancls.info
Angeles, CA, USA. pganz@mednet.ucla.edu

The evidence regarding the risks, benefits, and quality of life impact of tamoxifen and raloxifene for
prevention of breast cancer in postmenopausal women was reviewed. Five placebo-controlled trials
were identified, four with tamoxifen and one with raloxifene. The individual placebo-controlled trials of
tamoxifen for breast cancer prevention vary in size and risk status of the women who participated. An
overview of the four trials found a 30% to 40% reduc on in the risk of breast cancer. Serious adverse
events include an increased risk of uterine cancer, venous thromboembolic events, and cataracts.
Fracture risk was reduced. Quality of life was not significantly impaired, but women treated with
tamoxifen had more vasomotor symptoms and vaginal discharge. In the single trial of raloxifene in
postmenopausal women, there was a substantial reduction in the risks of breast cancer and fracture and
no increased risk of uterine cancer. However, there was an increased risk of venous thromboembolic
events. In the trial directly comparing tamoxifen with raloxifene in postmenopausal high-risk women,
there was no significant difference in the risk of invasive breast cancer, but tamoxifen significantly
reduced noninvasive breast cancer. The toxicity profiles for the two drugs were similar, with the
exception of fewer hysterectomies, pulmonary emboli, and deep vein thrombosis in the raloxifene-
treated group. There are now two effective Selective estrogen-receptor modulators available for use in
postmenopausal women to reduce the risk of breast cancer. Women at high risk of breast cancer should
be offered this therapy, and if one drug is not well tolerated, the other should be considered.
Menopause. 2008 Jul-Aug;15(4 Suppl):797-803.
PMID: 18596601


                                                                                                       33
41- An Antimetastatic Role for Decorin in Breast Cancer.

Goldoni S, Seidler DG, Heath J, Fassan M, Baffa R, Thakur ML, Owens RT, McQuillan DJ, Iozzo RV.
From the Department of Pathology, Anatomy and Cell Biology,* and Urology, Thomas Jefferson
University, Philadelphia, Pennsylvania, the Cancer Cell Biology and Signaling Program, Kimmel Cancer
Center, Thomas Jefferson University, Philadelphia, Pennsylvania, Department of Radiology, the
Radiopharmaceutical Research Center, Thomas Jefferson University, Philadelphia, Pennsylvania and the
LifeCell Corporation, Branchburg, New Jersey.

Decorin, a member of the small leucine-rich proteoglycan gene family, down-regulates members of the
ErbB receptor tyrosine kinase family and attenuates their signaling, leading to growth inhibition. We
inves gated the effects of decorin on the growth of ErbB2-overexpressing mammary carcinoma cells in
comparison with AG879, an established ErbB2 kinase inhibitor. Cell prolifera on and anchorage-
independent growth assays showed that decorin was a potent inhibitor of breast cancer cell growth and
a pro-apopto c agent. When decorin and AG879 were used in combina on, the inhibitory effect was
synergistic in proliferation assays but only additive in both colony formation and apoptosis assays. Active
recombinant human decorin protein core, AG879, or a combina on of both was administered
systemically to mice bearing orthotopic mammary carcinoma xenografts. Primary tumor growth and
metabolism were reduced by approximately 50% by both decorin and AG879. However, no synergism
was observed in vivo. Decorin specifically targeted the tumor cells and caused a significant reduction of



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ErbB2 levels in the tumor xenogra s. Most importantly, systemic delivery of decorin prevented
metastatic spreading to the lungs, as detected by novel species-specific DNA detection and quantitative
assays. In contrast, AG879 failed to have any effect. Our data support a role for decorin as a powerful
and effective therapeutic agent against breast cancer due to its inhibition of both primary tumor growth
and metastatic spreading.
Am J Pathol. 2008 Aug 7.
PMID: 18688028

42- Evaluation of endometrial thickness in hormone receptor positive early stage
breast cancer postmenopausal women switching from adjuvant tamoxifen
treatment to anastrozole.

Valenzano Menada M, Costantini S, Moioli M, Bogliolo S, Papadia A, Ferrero S, Dugnani MC.

Department of Obstetrics and Gynecology, University of Genova, San Martino Hospital, L.go R Benzi Pad
1, 16100 Genova, Italy.

Evaluation of endometrial thickness by transvaginal ultrasonography (TVUS) in postmenopausal
estrogen receptor positive breast cancer patients treated with anastrozole after tamoxifen therapy. This
study included 70 postmenopausal estrogen receptor posi ve breast cancer pa ents who switched to
anastrozole a er tamoxifen; pa ents had endometrial thickness >4mm and no endometrial malignancy.

                                                                                                        34
Endometrial thickness was measured after anastrozole treatment. Endometrial thickness during
anastrozole therapy was lower than a er tamoxifen therapy (p<0.001); the mean reduc on in
endometrial thickness was 4.5mm (+/-3.0). Cys c endometrial appearance was more frequent in
patients under tamoxifen than in those under anastrozole (p<0.001). Dura on of tamoxifen therapy was
not correlated to the endometrial thickness at the time of its suspension. Duration of tamoxifen therapy
and endometrial thickness at the time of tamoxifen suspension was correlated to the relative reduction
of endometrial thickness during anastrozole therapy. Anastrozole reverses tamoxifen-induced increased
endometrial thickness and sonographic endometrial cystic appearance.
Breast. 2008 Jul 5.
PMID: 18606545

43- Cost-Effectiveness of Primary versus Secondary Prophylaxis with Pegfilgrastim
in Women with Early-Stage Breast Cancer Receiving Chemotherapy.

Ramsey SD, Liu Z, Boer R, Sullivan SD, Malin J, Doan QV, Dubois RW, Lyman GH.

Fred Hutchinson Cancer Research Center and University of Washington Department of Medicine,
Seattle, WA, USA.

Objective: Prophylaxis with granulocyte colony-stimulating factor (G-CSF) reduces the risk of febrile



www.vancls.info
neutropenia (FN) in patients receiving myelosuppressive chemotherapy. We estimated the incremental
cost-effectiveness of G-CSF pegfilgras m primary (star ng in cycle 1 and con nuing in subsequent cycles
of chemotherapy) versus secondary (only after an FN event) prophylaxis in women with early-stage
breast cancer receiving myelosuppressive chemotherapy with a >/=20% FN risk.

Methods: A decision-analytic model was constructed from a health insurer's perspective with a lifetime
study horizon. The model considers direct medical costs and outcomes related to reduced FN and
potential survival benefits because of reduced FN-related mortality. Inputs for the model were obtained
from the medical literature. Sensitivity analyses were conducted across plausible ranges in parameter
values.

Results: The incremental cost-effectiveness ratio (ICER) of pegfilgrastim as primary versus secondary
prophylaxis was $48,000/FN episode avoided. Adding survival benefit from avoiding FN mortality yielded
an ICER of $110,000/life-year gained (LYG) or $116,000/quality-adjusted life-year (QALY) gained. The
most influential factors included FN case-fatality, FN relative risk reduction from primary prophylaxis,
and age at diagnosis.

Conclusions: Compared with secondary prophylaxis, the cost-effectiveness of pegfilgrastim as primary
prophylaxis may be equivalent or superior to other commonly used supportive care interventions for
women with breast cancer. Further assessment of the direct impact of G-CSF on short- and long-term
survival is needed to substantiate these findings.
Value Health. 2008 Jul 31.
PMID: 18673353

                                                                                                       35
                                             Pathology

44- Interlobular and intralobular mammary stroma: genotype may not reflect
phenotype.

Fleming JM, Long EL, Ginsburg E, Gerscovich D, Meltzer PS, Vonderhaar BK.

Mammary Biology and Tumorigenesis Laboratory, Center for Cancer Research, National Cancer Institute,
Na onal Ins tutes of Health, Bethesda, MD 20892, USA. flemingjo@mail.nih.gov

BACKGROUND: The normal growth and function of mammary epithelial cells depend on interactions
with the supportive stroma. Alterations in this communication can lead to the progression or expansion
of malignant growth. The human mammary gland contains two distinctive types of fibroblasts within the
stroma. The epithelial cells are surrounded by loosely connected intralobular fibroblasts, which are
subsequently surrounded by the more compacted interlobular fibroblasts. The different proximity of
these fibroblasts to the epithelial cells suggests distinctive functions for these two subtypes. In this
report, we compared the gene expression profiles between the two stromal subtypes.

METHODS: Fresh normal breast tissue was collected from reduction mammoplasty patients and



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immediately placed into embedding medium and frozen on dry ice. Tissue sections were subjected to
laser capture microscopy to isolate the interlobular from the intralobular fibroblasts. RNA was prepared
and subjected to microarray analysis using the Affymetrix Human Genome U133 GeneChip. Data was
analyzed using the Affy and Limma packages available from Bioconductor. Findings from the microarray
analysis were validated by RT-PCR and immunohistochemistry.

 RESULTS: No statistically significant difference was detected between the gene expression profiles of
the interlobular and intralobular fibroblasts by microarray analysis and RT-PCR. However, for some of
the genes tested, the protein expression patterns between the two subtypes of fibroblasts were
significantly different.

CONCLUSION: This study is the first to report the gene expression profiles of the two distinct fibroblast
populations within the human mammary gland. While there was no significant difference in the gene
expression profiles between the groups, there was an obvious difference in the expression pattern of
several proteins tested. This report also highlights the importance of studying gene regulation at both
the transcriptional and post-translational level.
BMC Cell Biol. 2008 Aug 18;9:46.

PMID: 18710550




                                                                                                         36
45- Intraoperative frozen section analysis for breast-conserving therapy in 1016
patients with breast cancer.

Riedl O, Fitzal F, Mader N, Dubsky P, Rudas M, Mittlboeck M, Gnant M, Jakesz R.

LKH Krems, Department of Surgery, Austria.

OBJECTIVE: We evaluate the number of surgical two-stage procedures after FSA during breast-
conserving therapy (clinical false negative result of FSA) and investigate the influence of
microcalcifications, small tumour diameter, neoadjuvant therapy and preoperative biopsy on the clinical
false nega ve rate of FSA. SUBJECTS: We retrospec vely examined 1016 pa ents a er intraopera ve
FSA during breast-conserving therapy for breast cancer operated between 1995 and 2001 at the Medical
University Vienna.

RESULTS: Only 9% of all pa ents had to undergo a two-stage operation due to a false negative
intraopera ve FSA result. The annual local recurrence rate was 1.2% in all pa ents with no difference
between one- and two-stage operated patients. In situ and pT1 lesions were similarly distributed
between one-stage and two-stage operated patients. The use of neoadjuvant therapy and stereotactic
biopsy (reflecting non-palpable lesions and microcalcifications) were significantly predictive for a false
negative FSA result. The use of a preoperative core biopsy, however, reduced the necessity of



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performing a two-stage operation.

 CONCLUSION: Our study demonstrates that FSA leads to a low rate of two-stage operations. Small
lesions and microcalcifications as well as the occurrence of intraductal cancer cells and neoadjuvant
therapy increased while preoperative core biopsy reduced the false negative rate of FSA. Overall local
recurrence rates after FSA were acceptable.
Eur J Surg Oncol. 2008 Aug 15.
PMID: 18706785



46- Optimization of the method of RNA isolation from paraffin blocks to assess
gene expression in breast cancer.

Jarzab M, Rózanowski P, Kowalska M, Zebracka J, Rudnicka L, Stobiecka E, Jarzab B, Stachura J,
Pawlega J.

Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice.

Molecular oncology increasingly needs the assessment of tumor gene expression profile
(transcriptome), most commonly by determination of RNA-based molecular markers employing the
technique of quantitative real-time polymerase chain reaction (Q-PCR). However, as all are methods

                                                                                                         37
based on RNA, to date, the experience in Q-PCR is mostly limited to freshly collected material frozen at -
80 degrees C, i.e. showing no signs of RNA degradation. The aim of the present study was to implement
into practice a method of RNA isolation from formalin-fixed and paraffin-embedded (FFPE) breast
carcinoma samples collected during routine surgical and histopathological procedure, to further employ
it in expression analysis by Q-PCR. The RNA isolation kit RNeasy FFPE (QIAGEN) was used. It was
demonstrated that in samples subjected to DNAse digestion, the mean concentration of the obtained
RNA was low (46 ng/microl), while during the isolation performed using solely gDNA Eliminator columns,
the authors obtained RNA with an almost fourfold higher concentration value. A comparison was made
between isolation effectiveness using varying amounts of input material. It was noted that isolation
efficacy was lower when three sec ons were employed (the concentra on value of 178 ng/microl) as
compared to 5-8 sec ons (279 and 302 ng/microl, respec vely). RNA quality assessment was also
performed employing the method of capillary electrophoresis by the "lab-on-a-chip" technology of
Agilent Bioanalyzer 2100. Freshly prepared material yielded in single cases samples containing RNA18S
and RNA28S popula ons, while in samples isolated from archival paraffin blocks, the obtained RNA
showed more considerable degrada on, thus, was of lesser quality. In the analysis of 20 samples from
the second collected series, the majority of samples were characterized by the RNA Integrity Number
(RIN) values in the range of 2-2.5, s ll indica ve of a substan al degree of RNA degradation. The mean
isola on effec veness in the second series was 885 ng/microl. In 10 of 20 blocks isolated, we succeeded
in obtaining sufficient RNA concentra on, above 500 ng/microl. It was also noted that the storage me
did not affect the amount of RNA obtained from a block: while isolating RNA from freshly prepared



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blocks, we achieved similar concentrations as when analyzing the archival material. Conclusions: the key
in preserving RNA quality in paraffin blocks is the timing of material collection and fixing. Routine
paraffin blocks allow for obtaining RNA for molecular studies, yet with features of considerable
degradation.
Pol J Pathol. 2008;59(2):85-91.
PMID: 18669173



47- Clinical validation of a molecular assay for intra-operative detection of
metastases in breast sentinel lymph nodes.

Martin Martinez MD, Veys I, Majjaj S, Lespagnard L, Schobbens JC, Rouas G, Filippov V, Noterman D,
Hertens D, Feoli F, Bourgeois P, Durbecq V, Larsimont D, Nogaret JM.

Department of Pathology, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium.

BACKGROUND: In breast cancer patients, the status of the sentinel lymph nodes (SLNs) has been shown
to accurately reflect the presence of metastases in the axillary lymph nodes (ALNs). Intra-operative SLN
evaluation by frozen section histology may miss positive cases, leading to a second surgery for complete
ALN dissection. Permanent section histology itself has tissue sampling limitations and is partially
dependent on pathologist expertise.

                                                                                                       38
METHODS: A prospec ve study (N=78) was conducted in our ins tu on to validate a new intra-
operative molecular assay, the GeneSearchtrade mark breast lymph node (BLN) assay. This assay
quantifies the expression of mammaglobin and cytokeratin-19 genes using quan ta ve RT-PCR
technology to determine SLN status. Fresh SLN sec ons (2mm thick) were analyzed alterna vely by BLN
assay or post-operative histology (haematoxylin-eosin and immunohistochemistry). The subject was
considered posi ve when histology revealed a focus >0.2mm.

RESULTS: BLN assay results corroborated with histologic results in 75 out of 78 pa ents for an overall
agreement of 96%, a sensi vity of 92%, and a specificity of 97%. The posi ve and nega ve predic ve
values of the BLN assay were of 86% (12/14) and 98% (63/64), respec vely. Interes ngly, a sta s cally
significant correlation was observed between the metastases' histologic size and both assay markers'
expression levels as represented by cycle me to posi vity (rho>/=0.71, all p<0.0001).

CONCLUSIONS: The performance of the BLN assay in iden fying nodal metastases >0.2mm was similar
to that of permanent section histology, with the added advantages of an objective and rapid output that
could be used for intra-operative decision to remove additional ALN.
Eur J Surg Oncol. 2008 Jul 16.
PMID: 18639429



48- Immunohistochemistry on Frozen Section of Sentinel Lymph Nodes in Breast

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Cancer With Improved Morphology and Blocking of Endogenous Peroxidase.

Jylling AM, Lindebjerg J, Nielsen L, Jensen J.

Department of Pathology, Vejle Hospital, Region of Southern Denmark, Denmark.

Sentinel lymph node biopsy in the management of patients with breast cancer is the clinical practice.
Peropera ve examina on means that more pa ents can be treated in a 1-step procedure. The addition
of immunohistochemistry to frozen section slides improves the detection rate of especially
micrometastasis. We present a novel method for immunohistochemical staining on a frozen section
material that gives better morphology and blocks endogenous peroxidase sufficiently.
Appl Immunohistochem Mol Morphol. 2008 Jul 15.
PMID: 18633322




49- Novel intraoperative molecular test for sentinel lymph node metastases in
patients with early-stage breast cancer.

Julian TB, Blumencranz P, Deck K, Whitworth P, Berry DA, Berry SM, Rosenberg A, Chagpar AB,

                                                                                                     39
Reintgen D, Beitsch P, Simmons R, Saha S, Mamounas EP, Giuliano A.

Allegheny Breast Care Center, Allegheny General Hospital, 320 E North Ave, Pi sburgh, PA 15212, USA.
tjulian@wpahs.org

PURPOSE: An accurate, intraoperative sentinel lymph node (SLN) test could decrease delayed axillary
dissections. Molecular tests may be more sensitive than current intraoperative tests but historically
have not been rapid enough and have not been properly validated. We present the results from a large,
prospective evaluation of the first rapid molecular SLN test, the Breast Lymph Node (BLN) Assay.

METHODS: A beta trial (n = 304) to determine the threshold levels of mammaglobin and cytokera n 19
correla ng with metastasis greater than 0.2 mm and a valida on trial (n = 416) to validate the threshold
cutoffs were conducted. Alternating portions from each SLN were processed for histology and the BLN
Assay.

RESULTS: BLN Assay performance against extensive permanent-section histology verified by central
pathology review was similar to that expected of standard permanent-section histology: sensitivity,
87.6%; specificity, 94.2%; posi ve predic ve value, 86.2%; and nega ve predic ve value (NPV), 94.9%. In
319 pa ents with both frozen-section hematoxylin and eosin results and BLN Assay results, the BLN
Assay had higher sensi vity (95.6%) and NPV (98.2%) than frozen sec on (sensi vity, 85.6%; NPV,
94.5%). The assay can be performed in approximately 36 to 46 minutes for one to three nodes.



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CONCLUSION: The BLN Assay allows a rapid evalua on of 50% of each SLN. Comparison with
permanent-section histology on adjacent node pieces evaluated by expert pathologists indicated that
the BLN Assay was more sensitive than current intraoperative techniques while maintaining high
specificity. These data indicate that the assay may be clinically useful for intraoperative or postoperative
axillary lymph node dissection decisions.
J Clin Oncol. 2008 Jul 10;26(20):3338-45.
PMID: 18612150



50- Intraoperative immunohistochemistry staining of sentinel nodes in breast
cancer: Clinical and economical implications.
Holm M, Paaschburg B, Balslev E, Axelsson CK, Willemoe GL, Flyger HL.

Department of Breast Surgery, Herlev Hospital, University of Copenhagen, Herlev Ringvej 75, DK-2730
Herlev, Denmark.

The study aimed to evaluate intraoperative immunohistochemistry (IHC) staining of sentinel nodes in
primary breast cancer surgery. We analysed retrospec vely 1209 consecu ve sen nel node procedures
and compared the rate of late positive metastases in sentinel node biopsy (SNB) and the duration of the
surgical procedures before (n=706) and a er (n=503) introducing intraopera ve IHC on frozen sec on.

                                                                                                         40
We also did a cost analysis. Intraoperative IHC staining led to a lowering of the late positive SNB rate.
Introducing IHC gave a decrease in the late posi ve rate from 93 to 52% (p<0.0001) for isolated tumour
cell metastasis, from 56 to 36.4% (p<0.02) for micrometastasis, and from 16 to 5% (p<0.01) for
macrometastasis. The surgical procedures were slightly prolonged for lumpectomies but not for
mastectomies after introducing intraoperative IHC staining. The cost analysis showed an overall cost
saving of approximately 40%. In conclusion, intraopera ve IHC staining of the SNB lowered the late
positive rate and gave an overall cost saving.
Breast. 2008 Aug;17(4):372-5.
PMID: 18490162

51- Refinement of breast cancer classification by molecular characterization of
histological special types.

Weigelt B, Horlings H, Kreike B, Hayes M, Hauptmann M, Wessels L, de Jong D, Van de Vijver M, Veer
LV, Peterse J.
Division of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Most invasive breast cancers are classified as invasive ductal carcinoma not otherwise specified (IDC
NOS), whereas about 25% are defined as histological 'special types'. These special-type breast cancers
are categorized into at least 17 discrete pathological en es; however, whether these also cons tute



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discrete molecular entities remains to be determined. Current therapy decision-making is increasingly
governed by the molecular classification of breast cancer (luminal, basal-like, HER2+). The molecular
classification is derived from mainly IDC NOS and it is unknown whether this classification applies to all
histological subtypes. We aimed to refine the breast cancer classification systems by analysing a series
of 11 histological special types [invasive lobular carcinoma (ILC), tubular, mucinous A, mucinous B,
neuroendocrine, apocrine, IDC with osteoclastic giant cells, micropapillary, adenoid cystic, metaplastic,
and medullary carcinoma] using immunohistochemistry and genome-wide gene expression profiling.
Hierarchical clustering analysis confirmed that some histological special types constitute discrete
entities, such as micropapillary carcinoma, but also revealed that others, including tubular and lobular
carcinoma, are very similar at the transcriptome level. When classified by expression profiling, IDC NOS
and ILC contain all molecular breast cancer types (ie luminal, basal-like, HER2+), whereas histological
special-type cancers, apart from apocrine carcinoma, are homogeneous and only belong to one
molecular subtype. Our analysis also revealed that some special types associated with a good prognosis,
such as medullary and adenoid cystic carcinomas, display a poor prognosis basal-like transcriptome,
providing strong circumstantial evidence that basal-like cancers constitute a heterogeneous group.
Taken together, our results imply that the correct classification of breast cancers of special histological
type will allow a more accurate prognostication of breast cancer patients and facilitate the identification
of op mal therapeu c strategies. Copyright (c) 2008 Pathological Society of Great Britain and Ireland.
Published by John Wiley & Sons, Ltd.
J Pathol. 2008 Jul 14.
PMID: 18720457


                                                                                                        41
52- Expression of EGFR in rela on to BRCA1 status, basal-like markers and
prognosis in breast cancer.

Arnes JB, Bégin LR, Stefansson IM, Brunet JS, Nielsen TO, Foulkes WD, Akslen LA.

Department of Pathology, The Gade Institute, Haukeland University Hospital, Bergen, Norway, Norway.

AIMS: BRCA1-related breast cancer is associated with a basal-like phenotype, and is frequently estrogen
receptor and HER2-negative. The expression of EGFR has been considered to be one component of the
basal-like phenotype, but no standard criteria exist. We have studied the relationship between EGFR
expression, BRCA1 status and basal markers with respect to clinico-pathological associations and
prognosis, in addition to an evaluation of different criteria for EGFR assessment by
immunohistochemistry.

METHODS: A ssue microarray comprising 230 available cases from our series of primary invasive breast
cancer diagnosed in Ashkenazi Jewish women during 1980-1995, was stained for EGFR using the Dako
PharmDX kit, and evaluated by Webslide virtual microscopy.

RESULTS: EGFR was posi ve in 9-19% according to different criteria. Expression was associated with
BRCA1 carrier status and basal-like markers as nega ve ER, posi ve CK 5/6 and posi ve P-cadherin



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staining. EGFR was prognostically significant by univariate and multivariate analysis within the group
carrying germ-line BRCA1 muta ons. Histological grade, axillary lymph node status and P-cadherin
status had significant independent value in the final multivariate model including all cases, whereas
EGFR was not significant in this model. All five scoring systems gave comparable results concerning
clinico-pathological associations and patient outcome, although the most restrictive criteria (EGFR-HI)
tended to be most sensi ve in predic ng BRCA1-status, a basal phenotype, and patient prognosis.

CONCLUSIONS: EGFR expression, being present in 9-19% of the cases, was prognos cally significant
among BRCA1 mutated cases only. In mul variate survival analysis of all cases, no independent effect
was seen. Still, EGFR immunostaining might be relevant to predict the response to targeted therapy, and
this should be studied further.
J Clin Pathol. 2008 Aug 4.
PMID: 18682421



53- Adenosis tumor of the breast: cytological and radiological features of a case
confirmed by histology.

El Aouni N, Balleyguier C, Mansouri D, Mathieu MC, Suciu V, Delaloge S, Vielh P.
Department of Medical Biology and Pathology, Institut Gustave Roussy, Villejuif, France.

We report the case of a 63-year-old woman who presented with a right breast lump detected by

                                                                                                          42
screening mammography. The lesion was nonpalpable, and the ultrasonography revealed suspicious
features. In contrast with imaging features, fine-needle aspiration cytology showed benign ductal cells
arranged in groups, with fragments of hyalinized eosinophilic stroma, and round or bipolar bare nuclei in
the background, findings consistent with a benign tumor. A core needle biopsy performed to rule out a
breast cancer revealed an adenosis tumor of the breast. (c) 2008 Wiley-Liss, Inc.
Diagn Cytopathol. 2008 Jul;36(7):496-8
PMID: 18528894




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                                      Radiology& Imaging



54- Detection of incidental breast tumors by noncontrast spiral computed
tomography of the chest.

Shojaku H, Seto H, Iwai H, Kitazawa S, Fukushima W, Saito K.

Department of Radiology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan,
hshojaku@pd.ctt.ne.jp.

PURPOSE: The aim of this study was to investigate the frequency of breast tumors and breast cancers
with noncontrast spiral chest computed tomography (CT).

MATERIAL AND METHODS: A clinical study was conducted to evaluate findings in the mammary region
of 1008 consecu ve pa ents with no mammary symptoms or signs who underwent noncontrast spiral
CT of the chest from April 2003 to March 2006.

 RESULTS: Six cases of breast abnormality were detected among the 1008 women. Three were primary
breast cancers, one was metastatic breast cancer, and two were benign tumors. All four breast cancer


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patients were over 70 years old. The characteris cs of the tumor margins on CT scans corresponded to
the mammography and ultrasonography findings. The mammographic background density ranged from
inhomogeneous high-density breast to fatty breast. The detection rate of primary breast cancer by
noncontrast spiral CT was 0.30%.

CONCLUSION: Noncontrast spiral chest CT occasionally detects nonsymptomatic breast cancers,
especially in elderly patients.

Radiat Med. 2008 Jul;26(6):362-7

55- US-guided 14-gauge core-needle breast biopsy: results of a validation study in
1352 cases.

Schueller G, Jaromi S, Ponhold L, Fuchsjaeger M, Memarsadeghi M, Rudas M, Weber M, Liberman L,
Helbich TH.

Department of Radiology and Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-
1090 Vienna, Austria. gerd.schueller@meduniwien.ac.at

PURPOSE: To retrospectively determine the false-negative rate and the underestimation rate of
ultrasonography (US)-guided 14-gauge core-needle breast biopsy (CNB) in nonpalpable lesions, with


                                                                                                      44
validation at surgical excision histologic examination and with stability during clinical and imaging
follow-up.

 MATERIALS AND METHODS: Informed consent was waived by the institutional review board for this
retrospec ve review of 1352 cases. In 1061 cases, pa ents underwent surgical excision of lesions visible
at US subsequent to US-guided 14-gauge CNB. Follow-up of another 291 benign lesions at US-guided 14-
gauge CNB histologic examination showed stability during clinical and imaging follow-up for at least 2
years. US and histologic findings were reviewed and compared for agreement. A false-negative finding
was defined as pathologically proved cancer for which biopsy results were benign. The false-negative
rate was defined as the proportion of all breast cancers with a diagnosis of benign disease at US-guided
14-gauge CNB. The underestimation rate was defined as an upgrade of a high-risk lesion at US-guided
14-gauge CNB to malignancy at surgery.

RESULTS: US 14-gauge CNB yielded 671 (63.2%) malignant, 86 (8.1%) high-risk, and 304 (28.7%) benign
lesions. Each of the 291 benign lesions without surgery remained stable during follow-up. The
agreement of US-guided 14-gauge CNB results, surgical excision findings, and follow-up results was
95.8% (kappa = 0.93). False-nega ve findings were encountered in 11 (0.8%) of 1352 cases, and the
false-nega ve rate was 1.6% (11 of 671 malignancies). All false-negative findings were prospectively
identified owing to discordance between imaging results and US-guided 14-gauge CNB histologic
findings. The underes ma on rate was 31.4%.




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CONCLUSION: US-guided 14-gauge CNB is an alternative to surgical excision for assessing nonpalpable
breast lesions.
Radiology. 2008 Aug;248(2):406-13.
PMID: 18641246



56- Finding early invasive breast cancers: a practical approach.

Harvey JA, Nicholson BT, Cohen MA.

Department of Radiology, University of Virginia Health Sciences Center, PO Box 800170, Charlo esville,
VA 22908, USA. jah7w@virginia.edu

Detec on of early invasive breast cancer is important, as pa ent survival is high when the cancer is 2 cm
or smaller. Invasive breast cancers typically manifest mammographically as focal asymmetries or
masses. Strategies for detecting focal asymmetries and masses on screening mammograms include side-
by-side comparison, looking for parenchymal contour deformity, close inspection of the retromammary
fat, identifying the presence of associated findings, and comparison with prior mammograms. Focal
asymmetries are often normal but are concerning when there is distortion of the normal breast
architecture. Masses and focal asymmetries are best evaluated in the diagnostic setting by using spot
compression and true lateral views and, frequently, ultrasonography. Management of a lesion depends

                                                                                                        45
on the worst imaging feature. Indications for an assessment of probably benign findings are very specific
but are often misapplied. This review for residents provides a practical approach to the detection and
management of breast masses and focal asymmetries. (c) RSNA, 2008.

Radiology. 2008 Jul;248(1):61-76.


PMID: 18566169

57- New diagnostic techniques for breast cancer detection.

Singh V, Saunders C, Wylie L, Bourke A.

University of Western Australia, School of Surgery, QEII Medical Centre, Perth 6009, Australia.
drvineeta123@yahoo.com

Breast imaging has made huge advances in the last decade, and along with newer techniques to
diagnose primary breast cancer, many novel methods are being used and look promising in detecting
distant metastasis, recurrent disease and assessing response to treatment. Full-field digital
mammography optimizes the lesion-background contrast and gives better sensitivity, and it is possible
to see through the dense tissues by altering computer windows; this may be particularly useful in



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younger women with dense breasts. The need for repeat imaging is reduced, with the added advantage
of reduced radiation dose to patients. Computer-aided detection systems may help the radiologist in
interpretation of both conventional and digital mammograms. MRI has a role in screening women at
high risk for breast cancer. It also aids in cancer management by assessing response to treatment and
can help in deciding appropriate surgery by providing accurate information on the extent of the tumor.
Newer diagnostic techniques such as sestamibi scans, optical imaging and molecular diagnostic
techniques look promising, but need more investigation into their use. Their roles will appear clearer in
coming years, and they may prove to be of help in further investigating lesions that are indeterminate
on standard imaging. Other upcoming techniques are contrast-enhanced mammography and
tomosynthesis. These may give additional information in indeterminate lesions, and when used in
screening they aid in reducing recall rates, as shown in recent studies. PET/computed tomography has a
role in detecting local disease recurrence and distant metastasis in breast cancer patients.
Future Oncol. 2008 Aug;4(4):501-13
PMID: 18684061



58- Dynamic contrast-enhanced MRI in the diagnosis and management of breast
cancer.

Turnbull LW.


                                                                                                       46
Centre for MR Investigations, Hull Royal Infirmary, Hull, UK.

Dynamic contrast-enhanced MRI (DCE-MRI) is an evolving tool for determining breast disease, which
benefits from the move to imaging at 3 T. It has major capabili es for the diagnosis, detec on and
monitoring of malignancy. It benefits from being non-invasive and three-dimensional, allowing
visualisation of the extent of disease and its angiogenic properties, visualisation of lesion heterogeneity,
detection of changes in angiogenic properties before morphological alterations, and the potential to
predict the overall response either before the start of therapy or early during treatment. In addition,
DCE-MRI is emerging as a powerful tool for screening high-risk patients and for detecting high-grade
ductal carcinoma in situ. However, there are also a number of limitations, including the overlap in
enhancement patterns between malignant and benign disease, the failure to resolve microscopic
disease particularly in the neoadjuvant setting, and the inconsistent predictive value of the
enhancement pattern for clinical outcome. Careful consideration should be given to the technical
requirements of individual examinations and the need for automation of post-processing techniques to
appropriately handle the growing volume of data acquired. Research continues, focusing on the use of
higher field strengths with improved spatial and temporal resolution data, improving understanding of
the mechanism of contrast enhancement at the cellular level, and developing macromolecular and
targeted contrast agents. Copyright (c) 2008 John Wiley & Sons, Ltd.
NMR Biomed. 2008 Jul 23
PMID: 18654999



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59- Recent advances in breast MRI and MRS.

Sinha S, Sinha U.

Department of Radiology, University of California-San Diego, CA, USA.

Breast MRI is an area of intense research and is fast becoming an important tool for the diagnosis of
breast cancer. This review covers recent advances in breast MRI, MRS, and image post-processing and
analysis. Several studies have explored a multi-parametric approach to breast imaging that combines
analysis of traditional contrast enhancement patterns and lesion architecture with novel methods such
as diffusion, perfusion, and spectroscopy to increase the specificity of breast MRI studies. Diffusion-
weighted MRI shows some potential for increasing the specificity of breast lesion diagnosis and is even
more promise for monitoring early response to therapy. MRS also has great potential for increasing
specificity and for therapeutic monitoring. A limited number of studies have evaluated perfusion
imaging based on first-pass contrast bolus tracking, and these clearly identify that vascular indices have
great potential to increase specificity. The review also covers the relatively new acquisition technique of
MR elastography for breast lesion characterization. A brief survey of image processing algorithms
tailored for breast MR, including registration of serial dynamic images, segmentation and extraction of
morphological features of breast lesions, and contrast uptake modeling, is also included. Recent

                                                                                                          47
advances in MRI, MRS, and automated image analysis have increased the utility of breast MR in
diagnosis, screening, management, and therapy monitoring of breast cancer. Copyright (c) 2008 John
Wiley & Sons, Ltd.
NMR Biomed. 2008 Jul 23
PMID: 18654998



60- MR imaging-guided 10-gauge vacuum-assisted breast biopsy: Histological
characterisation.

Perretta T, Pistolese CA, Bolacchi F, Cossu E, Fiaschetti V, Simonetti G.

Dipartimento di Diagnostica per Immagini, Imaging Molecolare, Radiologia Interventistica e Terapia
Radiante, Policlinico Universitario "Tor Vergata" (PTV), Viale Oxford 81, 00133, Roma, Italy,
tommasoperretta@libero.it.

PURPOSE. THE AIM OF THIS STUDY WAS TO EVALUATE A HANDHELD VACUUM-ASSISTED DEVICE FOR
MAGNETIC RESONANCE IMAGING (MRI)-GUIDED BREAST BIOPSY: MATERIALS AND METHODS. IN 47
PATIENTS, A TOTAL OF 47 SUSPICIOUS BREAST LESIONS (MEAN MAXIMUM DIAMETER 9 MM) SEEN
WITH MRI (NO SUSPICIOUS CHANGES ON BREAST ULTRASOUND OR MAMMOGRAPHY) WERE SAMPLED


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USING A 10-GAUGE VACUUM-ASSISTED BREAST BIOPSY (VAB) DEVICE UNDER MRI GUIDANCE.
HISTOLOGY OF BIOPSY SPECIMENS WAS COMPARED WITH FINAL HISTOLOGY AFTER SURGERY OR WITH
FOLLOW-UP IN BENIGN LESIONS: RESULTS. TECHNICAL SUCCESS WAS ACHIEVED IN ALL BIOPSIES.
HISTOLOGICAL RESULTS FROM VAB REVEALED MALIGNANCY IN 15 LESIONS (32%), ATYPICAL DUCTAL
HYPERPLASIA IN FOUR LESIONS (8%) AND BENIGN FINDINGS IN 28 LESIONS (60%). ONE OF FOUR
LESIONS WITH ATYPICAL DUCTAL HYPERPLASIA WAS UPGRADED TO DUCTAL CARCINOMA IN SITU AFTER
SURGERY. ONE OF SEVEN LESIONS SHOWING DUCTAL CARCINOMA WAS UPGRADED TO INVASIVE
CARCINOMA AFTER SURGERY. TWO LESIONS DIAGNOSED AS INFILTRATING CARCINOMA BY VAB WERE
NOT VALIDATED AT EXCISIONAL BIOPSY DUE TO COMPLETE REMOVAL OF THE LESION DURING THE
PROCEDURE. DURING THE FOLLOW-UP (MEAN 18 MONTHS) OF HISTOLOGICALLY BENIGN LESIONS, WE
OBSERVED NO CASES OF BREAST CANCER DEVELOPMENT. BECAUSE OF MORPHOLOGICAL CHANGES ON
FOLLOW-UP MRI SCANS, TWO LESIONS UNDERWENT SURGICAL EXCISION, WHICH CONFIRMED THEIR
BENIGN NATURE. BESIDES MINOR COMPLICATIONS (MASSIVE BLEEDING, N=1) REQUIRING NO FURTHER
THERAPEUTIC INTERVENTION, NO COMPLICATIONS OCCURRED: CONCLUSIONS. MRI-GUIDED BIOPSY OF
BREAST LESIONS USING A HANDHELD VACUUM-ASSISTED DEVICE IS A SAFE AND EFFECTIVE METHOD
FOR THE WORKUP OF SUSPICIOUS LESIONS SEEN ON BREAST MRI ALONE:
Radiol Med (Torino). 2008 Jul 5.
PMID: 18633687

61- Breast Cancer Staging in a Single Session: Whole-Body PET/CT Mammography.


                                                                                                     48
Heusner TA, Kuemmel S, Umutlu L, Koeninger A, Freudenberg LS, Hauth EA, Kimmig KR, Forsting M,
Bockisch A, Antoch G.

Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen,
University at Duisburg-Essen, Essen, Germany; 2Department of Gynecology and Obstetrics, University
Hospital Essen, University at Duisburg-Essen, Essen, Germany; and 3Department of Nuclear Medicine,
University Hospital Essen, University at Duisburg-Essen, Essen, Germany.

Our objective was to compare the diagnostic accuracy of an all-in-one protocol of whole-body (18)F-FDG
PET/CT and integrated (18)F-FDG PET/CT mammography with the diagnostic accuracy of a multimodality
algorithm for initial breast cancer staging.

METHODS: Forty women (mean age, 58.3 y; range, 30.8-78.4 y; SD, 12 y) with suspected breast cancer
were included. For the primary tumor, we compared (18)F-FDG PET/CT mammography versus MRI
mammography; for axillary lymph node status, (18)F-FDG PET/CT versus clinical investigation and
ultrasound; and for distant metastases, (18)F-FDG PET/CT versus a multimodality staging algorithm.
Histopathology and clinical follow-up served as the standard of reference. The Fisher exact test
evaluated the significance of differences (P < 0.05). Altera ons in pa ent management caused by (18)F-
FDG PET/CT were documented.

RESULTS: No significant differences were found in the detec on rate of breast cancer lesions ((18)F-FDG



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PET/CT, 95%; MRI, 100%; P = 1). (18)F-FDG PET/CT correctly classified lesion focality significantly more
o en than did MRI ((18)F-FDG PET/CT, 79%; MRI, 73%; P < 0.001). MRI correctly defined the T stage
significantly more o en than did (18)F-FDG PET/CT (MRI, 77%; (18)F-FDG PET/CT, 54%; P = 0.001). (18)F-
FDG PET/CT detected axillary lymph node metastases in 80% of cases; clinical inves ga on/ultrasound,
in 70%. This difference was not sta s cally significant (P = 0.067). Distant metastases were detected
with (18)F-FDG PET/CT in 100% of cases, and the mul modality algorithm identified distant metastases
in 70%. This difference was not sta s cally significant (P = 1). Three pa ents had extraaxillary lymph
node metastases that were detected only by PET/CT (cervical, retroperitoneal, mediastinal/internal
mammary group). (18)F-FDG PET/CT changed pa ent management in 12.5% of cases.

 CONCLUSION: Our data suggest that a whole-body (18)F-FDG PET/CT mammography protocol may be
used for staging breast cancer in a single session. This ini al assessment of the (18)F-FDG PET/CT
protocol indicates similar accuracy to MRI for the detection of breast cancer lesions. Although MRI
seems to be more accurate when assessing the T stage of the tumor, (18)F-FDG PET/CT seems able to
more accurately define lesion focality. Although (18)F-FDG PET/CT mammography was able to detect
axillary lymph node metastases with a high sensitivity, this method cannot soon be expected to replace
the combination of clinical examination, ultrasound, and sentinel lymph node biopsy for axillary
assessment.
J Nucl Med. 2008 Aug;49(8):1215-1222.
PMID: 18632831




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62- Breast US computer-aided diagnosis workstation: performance with a large
clinical diagnostic population.

Drukker K, Gruszauskas NP, Sennett CA, Giger ML.

Department of Radiology, University of Chicago, MC 2026, 5841 S Maryland Ave, Chicago, IL 6063, USA.
kdrukker@uchicago.edu

PURPOSE: To evaluate the performance of a computer-aided diagnosis (CAD) workstation in classifying
cancer in a realistic data set representative of a clinical diagnostic breast ultrasonography (US) practice.

MATERIALS AND METHODS: The database consisted of consecutive diagnostic breast US scans collected
with informed consent with a protocol approved by the institutional review board and compliant with
the HIPAA. Images from 508 pa ents with a total of 1046 dis nct abnormali es were used. One hundred
one patients had breast cancer. Results both for patients in whom the lesion abnormality was proved
with either biopsy or aspiration (n = 183) and for all pa ents irrespec ve of biopsy status (n = 508) are
presented. The ability of the CAD workstation to help differentiate malignancies from benign lesions was
evaluated with a leave-one-out-by-case analysis. The clinical specificity of the radiologists for this
dataset was determined according to the biopsy rate and outcome.




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RESULTS: In the task of differentiating cancer from all other lesions sent to biopsy, the CAD workstation
obtained an area under the receiver operating characteristic curve (AUC) value of 0.88, with 100%
sensi vity at 26% specificity (157 cancers and 362 lesions total). The radiologists' specificity at 100%
sensitivity for this set was zero. When analyzing all lesions irrespective of biopsy status, which is more
representa ve of actual clinical prac ce, the CAD scheme obtained an AUC of 0.90 and 100% sensi vity
at 30% specificity (157 cancers and 1046 lesions total). The radiologists' specificity at 100% sensi vity for
this set was 77%.

CONCLUSION: Current levels of computer performance warrant a clinical evaluation of the potential of
US CAD to aid radiologists in lesion work-up recommendations.
Radiology. 2008 Aug;248(2):392-7.
PMID: 18574139



63- Finding early invasive breast cancers: a practical approach.

Harvey JA, Nicholson BT, Cohen MA.

Department of Radiology, University of Virginia Health Sciences Center, PO Box 800170, Charlo esville,
VA 22908, USA. jah7w@virginia.edu

Detec on of early invasive breast cancer is important, as pa ent survival is high when the cancer is 2 cm

                                                                                                          50
or smaller. Invasive breast cancers typically manifest mammographically as focal asymmetries or
masses. Strategies for detecting focal asymmetries and masses on screening mammograms include side-
by-side comparison, looking for parenchymal contour deformity, close inspection of the retromammary
fat, identifying the presence of associated findings, and comparison with prior mammograms. Focal
asymmetries are often normal but are concerning when there is distortion of the normal breast
architecture. Masses and focal asymmetries are best evaluated in the diagnostic setting by using spot
compression and true lateral views and, frequently, ultrasonography. Management of a lesion depends
on the worst imaging feature. Indications for an assessment of probably benign findings are very specific
but are often misapplied. This review for residents provides a practical approach to the detection and
management of breast masses and focal asymmetries. (c) RSNA, 2008.
Radiology. 2008 Jul;248(1):61-76.
PMID: 18566169



64- Classification of benign and malignant breast tumors using neural networks
and three-dimensional power Doppler ultrasound.

Kuo SJ, Hsiao YH, Huang YL, Chen DR.

Comprehensive Breast Cancer Center, Surgical Research Laboratory, Changhua Christian Hospital,


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Changhua, Taiwan.

OBJECTIVES: To evaluate the use of three-dimensional (3D) power Doppler ultrasound in the differential
diagnosis of solid breast tumors using a neural network model as a classifier.

METHODS: Data from 102 benign and 93 malignant breast tumor images that had pathological
confirma on were collected consecu vely from January 2003 to February 2004. We used 3D power
Doppler ultrasound to calculate three indices (vascularization index (VI), flow index (FI) and
vasculariza on flow index (VFI)) for the tumor itself and for the tumor plus a 3-mm shell surrounding it.
These data were applied to a multilayer perception (MLP) neural network model and we evaluated the
model as a classifier to assess the capability of 3D power Doppler sonography to differen ate between
benign and malignant solid breast tumors.

RESULTS: The accuracy of the MLP model for classifying malignancy was 84.6%, the sensi vity was
90.3%, the specificity was 79.4%, the posi ve predic ve value was 80.0% and the nega ve predic ve
value was 90.0%. When the neural network was used to combine the three 3D power Doppler indices,
the area under the receiver-opera ng characteris cs curve was 0.89.

CONCLUSIONS: 3D power Doppler ultrasound may serve as a useful tool in dis nguishing between
benign and malignant breast tumors, and its capability may be increased by using a MLP neural network
model as a classifier.



                                                                                                       51
Ultrasound Obstet Gynecol. 2008 Jul;32(1):97-102.
PMID: 18521971



65- Breast MRI in the evaluation of eligibility for accelerated partial breast
irradiation.

Godinez J, Gombos EC, Chikarmane SA, Griffin GK, Birdwell RL.

Department of Radiation Oncology, Brigham and Women's Hospital and the Dana-Farber Cancer
Ins tute, 75 Francis St., Boston, MA 02115, USA.

OBJECTIVE: Eligibility for accelerated partial breast irradiation is generally determined by physical
examination in conjunction with conventional imaging techniques such as mammography and breast
sonography. MRI is recognized as a significant imaging tool in diagnosing breast cancer and has shown
the ability to identify mammographically occult carcinoma. Our purpose was to retrospectively assess
preoperative breast MRI examinations in women with early-stage breast cancer who were theoretically
eligible for accelerated partial breast irradiation and to explore the use of MRI in selecting patients for
this treatment.
MATERIALS AND METHODS: Seventy-nine patients with core needle biopsy-proven breast cancer, who


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were eligible candidates for breast-conserving surgery and accelerated partial breast irradiation,
underwent bilateral breast MRI examinations. At review, the presence and location of occult tumor sites
(detected on MRI only) were documented and subsequently correlated with pathology findings.
RESULTS: From 79 pa ents, a total of 126 suspicious areas, including the index tumors, were detected by
MRI. Additional sites of cancer other than the index tumor were observed in 30 pa ents (38%). Of these,
eight (10%) had an addi onal cancer in a different quadrant from the index tumor.

 CONCLUSION: The treatment effect of whole-breast irradiation on microscopic tumor cells and on
additional occult foci in other quadrants of the breast is lost with partial breast irradiation. Our results
suggest that MRI before accelerated partial breast irradiation may be of benefit to patients to ensure
they do not have multifocal or multicentric disease, remote from the lumpectomy bed.
AJR Am J Roentgenol. 2008 Jul;191(1):272-7.
PMID: 18562758

66- Comparison of diagnostic accuracy of breast masses using digitized images
versus screen-film mammography.

Liang Z, Du X, Liu J, Yao X, Yang Y, Li K.

Department of Radiology, Xuanwu Hospital, Capital Medical University, Beijing, China.



                                                                                                               52
BACKGROUND: Medical film digitizers play an important transitory role as digital-analogue bridges in
radiology. Digitized mammograms require evaluation of performance to assure medical image quality.
PURPOSE: To compare the diagnostic accuracy in the interpretation of breast masses using original
screen-film mammograms versus digitized images.

 MATERIAL AND METHODS: A total of 72 female pa ents between 55 and 81 years of age suspected of
having breast cancer were selected by two non-observing radiologists. Of these, 31 cases were benign
lesions and 41 cases were cancer. The mammography films were digi zed using a laser film digi zer.
Three radiologists, each with more than 10 years of experience in mammography, interpreted the
screen-film mammograms and digitized images respectively. The me interval was 4 weeks. A four-point
malignancy scale was used, with 1 defined as definitely not malignant, 2 as probably not malignant, 3 as
probably malignant, and 4 as definitely malignant. Receiver opera ng characteris c (ROC) curves,
sensitivity, and specificity were compared.

RESULTS: The average area-under-the-curve (Az) value of the original screen-film mammograms was
0.921, and the average Az value of the digi zed images was 0.859. This difference was not sta s cally
significant (P=0.131). The detec on specificity of extremely dense breasts was lower than that for other
breast compositions for both digitized images and screen-film mammograms. No statistical significance
in sensitivity and specificity was observed between digitized images and mammograms for each breast
composition. Original screen-film mammograms were observed to perform better than digitized images.




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CONCLUSION: Digi zed images with a spa al resolu on of 175 microm can be used instead of screen-
film mammograms in the diagnosis of breast cancer.

Acta Radiologica ,2008, July, 49(6).618-22
PMID: 18568552




                                                                                                       53
                                               Genetics


67- Secondary BRCA1 and BRCA2 altera ons and acquired chemoresistance.

Wang W, Figg WD.

Medical Oncology Branch, Na onal Cancer Ins tute; Bethesda, Maryland 20892, USA.

Tumor suppressor BRCA1 and BRCA2 are frequently mutated in familial breast and ovarian cancer. More
than ten percent of women with breast or ovarian cancer carry BRCA1 or BRCA2 (BRCA1/2) muta ons.
Cancers that arise in mutation carriers have often lost the wild-type allele through somatic alterations
during tumor progression. BRCA1/2 play important roles in homologous recombination repair of DNA
double-strand breaks. Because of this, BRCA1/2-deficient cancers often have a better response to DNA
cross-linking agents such as platinum analogues and to poly(ADP-ribose) polymerase (PARP) inhibitors.
However, over time, the majority of these BRCA1/2-deficient cancers become resistant and patients die
from refractory diseases. Three recent studies demonstrated that acquired resistance to platinum
analogues or PARP inhibitors in tumors carrying frame-shi BRCA1/2 muta ons came from restored
BRCA1/2 expression and HR func on due to secondary intragenic muta ons that corrected the open



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reading frames of mutated BRCA1/2.
Cancer Biol Ther. 2008 Jul;7(7):1004-5.

PMID: 18720553

68- Down-regula on of tumor suppressor gene FEZ1/LZTS1 in breast carcinoma
involves promoter methylation and associates with metastasis.

Chen L, Zhu Z, Sun X, Dong XY, Wei J, Gu F, Sun YL, Zhou J, Dong JT, Fu L.

Key Laboratory of Breast Cancer Research, Department of Breast Cancer Pathology and Research
Laboratory, Cancer Hospital of Tianjin Medical University, Huan Hu Xi Road, Tianjin, 300060, China.

FEZ1/LZTS1 is a tumor suppressor gene located in chromosomal band 8p22, and methylation has been
iden fied as a mechanism for its loss of func on in tumors. Chromosomal dele on at 8p22 is also
frequent in breast cancer. We therefore examined whether LZTS1 plays a role in breast cancer. We
analyzed expression of LZTS1 at both the RNA and protein levels, and promoter methylation in a number
of primary tumors and cell lines from breast cancer. We also examined the associa on between LZTS1
expression and different clinicopathological parameters of breast cancer. We found that the expression
of LZTS1 mRNA was reduced in 25 of 50 (50%) primary tumors and 29 of 30 (97%) breast cancer cell
lines. Immunohistochemical staining showed that LZTS1 protein was absent or down-regulated in 72
(72%) of 100 primary breast carcinomas. Reduced expression of LZTS1 at either the RNA or protein level

                                                                                                      54
was significantly correlated with lymph node metastases (P < 0.05). DNA methyla on analysis revealed
that the LZTS1 gene was frequently methylated in both cell lines and primary tumors from breast
cancer, and the extent of DNA methylation was correlated with reduced expression of the gene. These
findings suggest that LZTS1 plays a role in the development and progression of breast cancer at least
through promoter methylation-mediated transcriptional downregulation.
Breast Cancer Res Treat. 2008 Aug 7.
PMID: 18686028

69- Telomere-mediated genomic instability and the clinico-pathological
parameters in breast cancer.

Poonepalli A, Banerjee B, Ramnarayanan K, Palanisamy N, Putti TC, Hande MP.

Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

A study was undertaken to correlate telomere dysfunction and genomic instability with the
histopathological grades and the estrogen and progesterone receptor status in breast cancer. Sixty-one
archived breast ssues (38 cancer ssues and 23 paired normal tissues) were used in the study. The
breast tumor ssues showed significantly shorter telomeres (7.7 kb) compared with the paired adjacent
  ssues (9.0 kb) by Southern blot analysis. Moreover, telomere shortening was more significant in Grade



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III tumors than in the Grade II tumors (P = 0.05). Quan ta ve fluorescence in situ hybridiza on on
paraffin tissue sections revealed a similar trend in telomere shortening. Telomere attrition was
associated with telomere dysfunction as revealed by the presence of significantly higher anaphase
bridges in tumor cells which was tumor grade dependent. Furthermore, estrogen receptive negative
tumors displayed higher anaphase and internuclear bridges. Selected samples from each grade showed
greater genomic imbalances in the higher grades than the lower grade tumors as detected by array-
comparative genomic hybridization. Telomerase activity was found to be higher in the higher grades
(Grade II and III) compared with the lower grade (Grade I). The average mRNA expression of TRF1 and
POT1 was lower in the tumor ssues than in the normal ssues. Tankyrase 1 mRNA expression showed a
grade-dependent increase in tumor tissues and its expression was also high in estrogen and
progesterone negative tumors. The data support the notion that telomere dysfunction might be of value
as a marker of aggressiveness of the tumors in breast cancer pa ents. (c) 2008 Wiley-Liss, Inc.
Genes Chromosomes Cancer. 2008 Aug 21
PMID: 18720522



70- Differential patterns of allelic loss in estrogen receptor-positive infiltrating
lobular and ductal breast cancer

Loo LW, Ton C, Wang YW, Grove DI, Bouzek H, Vartanian N, Lin MG, Yuan X, Lawton TL, Daling JR,
Malone KE, Li CI, Hsu L, Porter PL.

                                                                                                    55
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA.

The two main histological types of infiltrating breast cancer, lobular (ILC) and the more common ductal
(IDC) carcinoma are morphologically and clinically distinct. To assess the molecular alterations
associated with these breast cancer subtypes, we conducted a whole-genome study of 166 archival
estrogen receptor (ER)-posi ve tumors (89 IDC and 77 ILC) using the Affymetrix GeneChip(R) Mapping
10K Array to identify sites of loss of heterozygosity (LOH) that either distinguished, or were shared by,
the two phenotypes. We found single nucleotide polymorphisms (SNPs) of high-frequency LOH (>50%)
common to both ILC and IDC tumors predominately in 11q, 16q, and 17p. Overall, IDC had a slightly
higher frequency of LOH events across the genome than ILC (frac onal allelic loss = 0.186 and 0.156). By
comparing the average frequency of LOH by chromosomal arm, we found IDC tumors with significantly
(P < 0.05) higher frequency of LOH on 3p, 5q, 8p, 9p, 20p, and 20q than ILC tumors. We iden fied
additional chromosomal arms differentiating the subtypes when tumors were stratified by tumor size,
mito c rate, or DNA content. Of 5,754 informa ve SNPs (>25% informa vity), we iden fied 78 and 466
individual SNPs with a higher frequency of LOH (P < 0.05) in ILC and IDC tumors, respec vely.
Hierarchical clustering of these 544 SNPs grouped tumors into four major groups based on their pa erns
of LOH and retention of heterozygosity. LOH in chromosomal arms 8p and 5q was common in higher
grade IDC tumors, whereas ILC and low-grade IDC grouped together by virtue of LOH in 16q. Published
2008 Wiley-Liss, Inc.



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Genes Chromosomes Cancer. 2008 Aug 21
PMID: 18720524

71- Glycodelin reduces breast cancer xenograft growth in vivo.

Hautala LC, Koistinen R, Seppälä M, Bützow R, Stenman UH, Laakkonen P, Koistinen H.

Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Biomedicum Helsinki,
University of Helsinki, Helsinki, Finland.

Malignant growth is characterized by loss of cell differentiation, uncontrolled proliferation and
resistance to apoptosis. Many tumor suppressor genes that protect cells against malignant
transformation regulate cell differentiation. Here, we show for the first time that glycodelin, a
differentiation-related protein, reduces breast cancer tumor growth in vivo. We found that glycodelin
cDNA-transfected MCF-7 breast cancer cells showed a differen ated phenotype and produced smaller
tumors in mouse mammary fat pads compared with control-transfected cells. Glycodelin-induced
differentiation was associated with reduced expression of oncogenes and increased expression of tumor
suppressor genes. Our results suggest that glycodelin acts as a tumor suppressor in breast cancer. This
may explain its reported associa on with a more favorable prognosis in some cancers. (c) 2008 Wiley-
Liss, Inc.

PMID: 18720404

                                                                                                      56
Int J Cancer. 2008 Aug 20.




72- Vitamin D receptor polymorphisms (FokI, BsmI) and breast cancer risk:
association replication in two case-control studies within French Canadian
population.

Sinotte M, Rousseau F, Ayotte P, Dewailly E, Diorio C, Giguere Y, Berube S, Brisson J.

M Sinotte, Departement de medecine sociale et preventive, Universite Laval, Unite de recherche en
sante des populations, Centre hospitalier affilie universitaire de Quebec, Quebec, Canada.

Vitamin D has been associated with reduced breast cancer risk. We studied the association of two VDR
gene SNPs (FokI and BsmI) with breast cancer risk in two independent case-control studies carried out in
the same population. The modifying effect of family history of breast cancer on this relation was also
evaluated. The first and second studies included 718 (255 cases/463 controls) and 1596 (622 cases/974
controls) women recruited in Quebec City, Canada. FokI and BsmI genotypes were assessed. Relative
risks of breast cancer were estimated by multivariate logistic regression. Compared to homozygotes for



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the F allele (FF genotype), FokI ff homozygotes had a higher breast cancer risk (study 1: OR=1.22,
95%CI=0.76-1.95, study 2: OR=1.44, 95%CI=1.05-1.99 and combined studies: OR=1.33, 95%CI=1.03-
1.73). Significant interac ons were observed between FokI and family history of breast cancer in the two
studies as well as in the combined analysis (P interac on=0.031, 0.050, and 0.0059 respec vely). Among
women without family history, odds ra os were 1.00, 1.27 (95%CI=1.02-1.58) and 1.57 (95%CI=1.18-
2.10) respec vely for FF, Ff and ff carriers (Ptrend=0.0013). BsmI Bb+bb genotypes were associated with
a weak non significant increased risk in the two studies (combined OR=1.22, 95%CI=0.95-1.57) without
interaction with family history. Results support the idea that vitamin D, through its signalling pathway,
can affect breast cancer risk. They also suggest that variability in observed associations between VDR
FokI and breast cancer from different studies may partly be explained by the proportion of study
subjects with a family history of breast cancer.
Endocr Relat Cancer. 2008 Aug 21.
PMID: 18719092



73- Elevated free IGF-II levels in localized, early-stage breast cancer in women.

Espelund U, Cold S, Frystyk J, Orskov H, Flyvbjerg A.

U Espelund, Medical Research Laboratories, Clinical Institute and Dept. M (Diabetes and Endocrinology),
Aarhus University Hospital, Aarhus, Denmark.


                                                                                                      57
Objective. Epidemiological studies imply an association between circulating insulin-like growth factor I
(IGF-I) and breast cancer, whereas the role of IGF-II, which also acts on the IGF-I receptor, is less settled.
This study investigates the association between IGF-II and breast cancer in patients with localized
disease. Design. The participants were women with well-characterized, early stage, localized breast
cancer (n=43) and matched healthy women (n=38), from whom fas ng serum levels of IGF-related
peptides were measured. Results. In patients, mean free IGF-II was increased (+57%, P<0.001) in spite of
reduced total IGF-II levels (-12%, P=0.003) as compared to controls. Similar changes were seen in free
IGF-I (+28%, P=0.004) and total IGF-I (-16% P=NS). Pro-IGF-II and IGF binding protein 1 (IGFBP-1) were
unchanged. IGFBP-2 was reduced by 22% in the pa ents (P=0.004). Pa ents showed reduced IGFBP-3
protease activity and accordingly increased levels of intact IGFBP-3, whereas total IGFBP-3 was
unchanged. Conclusion. Women with localized, early-stage breast cancer show elevated circulating free
IGF-I and -II, reduced total IGF-II and alterations in IGFBPs. The changes observed despite minimal
cancer disease suggest a role for the circulating IGF-system in the progression of breast cancer in
women.
Eur J Endocrinol. 2008 Aug 21.
PMID: 18719053



74- Regulation of the Warburg effect in early-passage breast cancer cells.


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Robey IF, Stephen RM, Brown KS, Baggett BK, Gatenby RA, Gillies RJ.

Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA. robeyi@email.arizona.edu

Malignancy in cancer is associated with aerobic glycolysis (Warburg effect) evidenced by increased
trapping of [(18)F]deoxyglucose (FdG) in pa ents imaged by positron emission tomography (PET).
[(18)F]deoxyglucose uptake correlates with glucose transporter (GLUT-1) expression, which can be
regulated by hypoxia-inducible factor 1 alpha (HIF-1alpha). We have previously reported in established
breast lines that HIF-1alpha levels in the presence of oxygen leads to the Warburg effect. However,
glycolysis and GLUT-1 can also be induced independent of HIF-1alpha by other factors, such as c-Myc
and phosphorylated Akt (pAkt). This study investigates HIF-1alpha, c-Myc, pAkt, and aerobic glycolysis in
low-passage breast cancer cells under the assumption that these represent the in vivo condition better
than established lines. Similar to in vivo FdG-PET or primary breast cancers, rates of glycolysis were
diverse, being higher in cells expressing both c-Myc and HIF-1alpha and lower in cell lines low or
negative in both transcription factors. No correlations were observed between glycolytic rates and pAkt
levels. Two of 12 cell lines formed xenogra s in mice. Both were posi ve for HIF-1alpha and
phosphorylated c-Myc, and only one was positive for pAkt. Glycolysis was affected by pharmacological
regulation of c-Myc and HIF-1alpha. These findings suggest that c-Myc and/or HIF-1alpha ac vi es are
both involved in the regulation of glycolysis in breast cancers.



                                                                                                           58
Neoplasia. 2008 Aug;10(8):745

PMID: 18670636



75- Genome-wide linkage scan in Dutch hereditary non-BRCA1/2 breast cancer
families iden fies 9q21-22 as a puta ve breast cancer suscep bility locus.

Oldenburg RA, Kroeze-Jansema KH, Houwing-Duistermaat JJ, Bayley JP, Dambrot C, van Asperen CJ,
van den Ouweland AM, Bakker B, van Beers EH, Nederlof PM, Vasen H, Hoogerbrugge N, Cornelisse CJ,
Meijers-Heijboer H, Devilee P.

Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Breast cancer accounts for over 20% of all female cancers. A positive family history remains one of the
most important risk factors for the disease, with first-degree relatives of patients having a twofold
elevated risk. Known breast cancer suscep bility genes such as BRCA1 and BRCA2 explain only 20-25%
of this risk, suggesting the existence of other breast cancer susceptibility genes. Here, we report the
results of a genome-wide linkage scan in 55 high-risk Dutch breast cancer families with no mutations in
BRCA1 and BRCA2. Twenty-two of these families were also part of a previous linkage study by the Breast



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Cancer Linkage Consor um. In addi on, we performed CGH analyses in 61 tumors of these families and
31 sporadic tumors. Three regions were iden fied with parametric HLOD scores >1, and three with
nonparametric LOD scores >1.5. Upon further marker genotyping for the candidate loci, and the
addi on of another 30 families to the analysis, only the locus on chromosome 9 (9q21-22, marker
D9S167) remained significant, with a nonparametric mul point LOD score of 3.96 (parametric HLOD
0.56, alpha = 0.18). With CGH analyses we observed preferen al copy number loss at BAC RP11-276H19,
containing D9S167 in familial tumors as compared to sporadic tumors (P < 0.001). Five candidate genes
were selected from the region around D9S167 and their coding regions subjected to direct sequence
analysis in 16 probands. No clear pathogenic muta ons were found in any of these genes. (c) 2008
Wiley-Liss, Inc.
Genes Chromosomes Cancer. 2008 Jul 28.
PMID: 18663745

76- Mul ple loci with different cancer specifici es within the 8q24 gene desert.

Ghoussaini M, Song H, Koessler T, Al Olama AA, Kote-Jarai Z, Driver KE, Pooley KA, Ramus SJ, Kjaer SK,
Hogdall E, DiCioccio RA, Whittemore AS, Gayther SA, Giles GG, Guy M, Edwards SM, Morrison J,
Donovan JL, Hamdy FC, Dearnaley DP, Ardern-Jones AT, Hall AL, O'Brien LT, Gehr-Swain BN, Wilkinson
RA, Brown PM, Hopper JL, Neal DE, Pharoah PD, Ponder BA, Eeles RA, Easton DF, Dunning AM; UK
Genetic Prostate Cancer Study Collaborators/British Association of Urological Surgeons' Section of
Oncology; UK ProtecT Study Collaborators.


                                                                                                     59
Bollina P, Bonnington S, Cooper D, Doble A, Doherty A, Durkan G, Elliott E, Gillatt D,
Herbert P, Holding P, Howson J, Jones M, Kockelbergh R, Kynaston H, Lennon T, Lyons
N, Leung H, Moody H, Powell P, Prescott S, Thompson P.

Cancer Research UK Department of Oncology, University of Cambridge, Strangeways Research
Laboratory, Worts Causeway, CB1 8RN, Cambridge, UK. maya@srl.cam.ac.uk

Recent studies based on genome-wide association, linkage, and admixture scan analysis have reported
associa ons of various gene c variants in 8q24 with suscep bility to breast, prostate, and colorectal
cancer. This locus lies within a 1.18-Mb region that contains no known genes but is bounded at its
centromeric end by FAM84B and at its telomeric end by c-MYC, two candidate cancer susceptibility
genes. To inves gate the associa ons of specific loci within 8q24 with specific cancers, we genotyped
the nine previously reported cancer-associated single-nucleotide polymorphisms across the region in
four case-control sets of prostate (1854 case subjects and 1894 control subjects), breast (2270 case
subjects and 2280 control subjects), colorectal (2299 case subjects and 2284 control subjects), and
ovarian (1975 case subjects and 3411 control subjects) cancer. Five different haplotype blocks within
this gene desert were specifically associated with risks of different cancers. One block was solely
associated with risk of breast cancer, three others were associated solely with the risk of prostate
cancer, and a fifth was associated with the risk of prostate, colorectal, and ovarian cancer, but not
breast cancer. We conclude that there are at least five separate functional variants in this region.
J Natl Cancer Inst. 2008 Jul 2;100(13):962-6.


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PMID: 18577746



77- Imagable 4T1 model for the study of late stage breast cancer.

Tao K, Fang M, Alroy J, Sahagian GG.

BACKGROUND: The 4T1 mouse mammary tumor cell line is one of only a few breast cancer models with
the capacity to metastasize efficiently to sites affected in human breast cancer. Here we describe two
4T1 cell lines modified to facilitate analysis of tumor growth and metastasis and evaluation of gene
function in vivo. New information regarding the involvement of innate and acquired immunity in
metastasis and other characteristics of the model relevant to its use in the study of late stage breast
cancer are reported.

 METHODS: The lines were engineered for stable expression of firefly luciferase to allow tracking and
quantitation of the cells in vivo. Biophotonic imaging was used to characterize growth and metastasis of
the lines in vivo and an improved gene expression approach was used to characterize the basis for the
metastatic phenotype that was observed.

RESULTS: Growth of cells at the primary site was biphasic with metastasis detected during the second
growth phase 5-6 weeks a er introduction of the cells. Regression of growth, which occurred in weeks


                                                                                                      60
3-4, was associated with extensive necrosis and infiltra on of leukocytes. Biphasic tumor growth did not
occur in BALB/c SCID mice indicating involvement of an acquired immune response in the effect.
Hematopoiesis in spleen and liver and elevated levels of circula ng leukocytes were observed at week 2
and increased progressively un l death at week 6-8. Gene expression analysis revealed an associa on of
several secreted factors including colony stimulatory factors, cytokines and chemokines, acute phase
proteins, angiogenesis factors and ECM modifying proteins with the 4T1 metasta c phenotype. Signaling
pathways likely to be responsible for production of these factors were also identified.

 CONCLUSIONS: The production of factors that stimulate angiogenesis and ECM modification and induce
hematopoiesis, recruitment and ac va on of leukocytes suggest that 4T1 tumor cells play a more direct
role than previously appreciated in orchestrating changes in the tumor environment conducive to tumor
cell dissemination and metastasis. The new cell lines will greatly facilitate the study of late stage breast
and preclinical assessment of cancer drugs and other therapeutics particularly those targeting immune
system effects on tumor metastasis.
BMC Cancer. 2008 Aug 9;8(1):228
PMID: 18691423



78- Genetic Counseling and Testing for Common Hereditary Breast Cancer
Syndromes. A Paper from the 2007 William Beaumont Hospital Symposium on


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Molecular Pathology.

Allain DC.

From the Clinical Cancer Genetics Program and the Human Cancer Genetics Program, Department of
Internal Medicine, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio
State University, Columbus, Ohio.

Throughout the past 15 years, the iden fica on of several genes associated with hereditary breast
cancer has fueled the growth of clinical genetic counseling and testing services. In addition, increased
knowledge of the genetic and molecular pathways of the known hereditary breast cancer genes, as well
as an increased understanding of the impact of testing on individuals has added to the ability to identify,
manage, and provide psychosocial support for mutation carriers. This review provides an overview of
the clinical features, cancer risks, causative genes, and management for hereditary breast and ovarian
cancer syndrome, Cowden syndrome, and Li-Fraumeni syndrome. This article summarizes the genetic
counseling process and genetic test result interpretation, including a review of the key elements
involved in the provision of risk assessment and informed consent, as well as a review of the risks,
benefits, and limitations of cancer susceptibility genetic testing.
J Mol Diagn. 2008 Aug 7.
PMID: 18687797



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79- Silencing of transforming growth factor-beta1 in situ by RNA interference for
breast cancer: implications for proliferation and migration in vitro and metastasis
in vivo.

Moore LD, Isayeva T, Siegal GP, Ponnazhagan S.

Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0007,
USA.

PURPOSE: Overexpression of transforming growth factor (TGF)-beta has been implicated in promoting
immune suppression, tumor angiogenesis, tumor cell migration, and invasion in many cancers, including
carcinoma of the breast. Thus, targeted down-regulation of TGF-beta1 expression in breast cancer in situ
and determination of its implications would provide new treatment approaches for disease
management.

EXPERIMENTAL DESIGN: Small interfering RNA constructs targeting TGF-beta1 were validated and used
to develop clonal derivatives of the metastatic breast cancer cell line MDA-MB-435. The cells were used
in several in vitro analyses, including migration, invasion, 3-(4,5-dimethylthiazol-2-yl)-2,5-
diphenyltetrazolium bromide, apoptosis, and signaling assays. A wound-healing assay was used to
determine migration of the cells in culture and a Boyden chamber transwell assay was used for invasion.



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Further, the clones were used in an in vivo mouse model for the kinetics of tumor growth and gene
expression in the primary site and in lungs upon metastasis.

RESULTS: Inhibition of TGF-beta1 expression in MDA-MB-435 cells showed a 35% decrease in migra on
and a 55% decrease in invasion in vitro, with a 50% increase in prolifera on and no effect on apoptosis.
In vivo analysis indicated a 90% decrease in the number of mice bearing macroscopic lung metastases;
however, the primary tumors did not show any difference in the growth kinetics when compared with
the parental MDA-MB-435 cells. Analysis of TGF-beta signaling pathways in the clonal derivatives
showed a decrease in Smad2 ac va on and an increase in AKT and extracellular signal-regulated kinase
activation. Interestingly, analysis of TGF-beta receptor expression showed a decrease in both receptor I
and II expression in TGF-beta1 silenced cells. These results suggest that inhibi on of TGF-beta1 ligand
may act as a negative feedback loop to disrupt the function of all TGF-beta isoforms.

CONCLUSIONS: Therapies targeting the TGF-beta signaling pathway may be more effective in late-stage
disease to prevent organ metastasis but not primary tumor formation and may be combined with other
tumor-targeted therapies normally limited by increased circulating TGF-beta levels.
Clin Cancer Res. 2008 Aug 1;14(15):4961-70.
PMID: 18676771

80- Prognos c significance of CD55 expression in breast cancer.

Ikeda J, Morii E, Liu Y, Qiu Y, Nakamichi N, Jokoji R, Miyoshi Y, Noguchi S, Aozasa K.

                                                                                                      62
Department of Pathology, Graduate School of Medicine, Osaka University, Yamada-oka 2-2, Suita 565-
0871, Japan.

PURPOSE: Our recent study revealed that CD55-high population in breast cancer cell line was resistant
to apoptosis and formed colonies in vitro more efficiently than CD55-low population. The present study
was conducted to examine whether CD55-high population in breast cancer cell line possesses higher
tumorigenic poten al in vivo and presence of CD55-high cells in breast cancer affects clinicopathologic
behavior of patients.

 EXPERIMENTAL DESIGN: CD55-high and CD55-low population was sorted from breast cancer cell line,
injected into immunodeficient mice, and the resultant tumor volume was measured. CD55 expression
was immunohistochemically examined in clinical samples from 74 cases with breast cancers, and cases
with >1% of tumor cells showing high level of CD55 expression were categorized as CD55 high.

 RESULTS: The xenotransplanted tumor volume derived from CD55-high population was significantly
larger than that from CD55-low popula on. Fi y (67.6%) of 74 cases of breast cancer were CD55-high. A
significant correla on was observed between CD55-high character and relapse rate (P < 0.001).
Univariate analysis showed that tumor size (P = 0.005) and CD55 expression (P = 0.005) were
unfavorable prognostic factors. Mul variate analysis revealed that the tumor size (P = 0.013) and CD55
expression (P = 0.011) were independent prognos c factors.



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CONCLUSIONS: CD55 play an important role in tumorigenesis of breast cancer, and presence of small
population of cells with strong CD55 expression would be sufficient to predict poor prognosis of
patients.
Clin Cancer Res. 2008 Aug 1;14(15):4780-6.           PMID: 18676748




81- Small is beautiful: microRNAs and breast cancer-where are we now?

Verghese E, Hanby A, Speirs V, Hughes T.

Leeds Teaching Hospital NHS Trust, UK.

MicroRNAs are a recently discovered class of small regulatory RNAs that influence the stability and
translational efficiency of target mRNAs. They have been implicated in an increasing number of
biological processes, including neoplasia. Recent studies have shown an involvement for these
regulatory molecules in breast cancer. For example, miRNA profiling studies have identified microRNAs
that are deregulated in breast cancer. Furthermore, functional studies have uncovered their roles in
breast cancer as both tumour suppressor genes (eg miR-335) and oncogenes (eg miR-21). miRNAs
deregulated in breast cancer influence the translational regulation of well-established regulatory
molecules, such as oestrogen receptor-alpha, which is regulated by miR-206, and novel cancer-related

                                                                                                     63
molecules whose functions are not yet fully understood.. Here we present an overview of our current
understanding of miRNA in breast cancer. Copyright (c) 2008 Pathological Society of Great Britain and
Ireland. Published by John Wiley & Sons, Ltd.
J Pathol. 2008 Jul;215(3):214-21 .
PMID: 18446835



82- BRCA1 muta ons in Algerian breast cancer patients: high frequency in young,
sporadic cases.

Uhrhammer N, Abdelouahab A, Lafarge L, Feillel V, Ben Dib A, Bignon YJ.
Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, 58 rue Montalembert, 63011
Clermont-Ferrand, France.

Breast cancer rates and median age of onset differ between Western Europe and North Africa. In
Western popula ons, 5 to 10 % of breast cancer cases can be a ributed to major genetic factors such as
BRCA1 and BRCA2, while this a ribu on is not yet well defined among Africans. To help determine the
contribu on of BRCA1 muta ons to breast cancer in a North African popula on, we analysed genomic
DNA from breast cancer cases ascertained in Algiers.Both familial cases (at least three breast cancers in



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the same familial branch, or two with one bilateral or diagnosed before age 40) and sporadic cases less
than 38 years of age were studied. Complete sequencing plus quan ta ve analysis of the BRCA1 gene
was performed. 9.8 % (5/51) of early-onset sporadic and 36.4 % (4/11) of familial cases were found to be
associated with BRCA1 muta ons. This is in contrast 10.3 % of French HBOC families exhibi ng a BRCA1
mutation. One muta on, c.798_799delTT, was observed in two Algerian families and in two families
from Tunisia, suggesting a North African founder allele. Algerian non-BRCA1 tumors were of significantly
higher grade than French non-BRCA tumors, and the age at diagnosis for Algerian familial cases was
much younger than that for French non-BRCA familial cases. In conclusion, we observed a much higher
frequency of BRCA1 muta ons among young breast cancer pa ents than observed in Europe, sugges ng
biological differences and that the inclusion criterea for analysis in Western Europe may not be
applicable for the Northern African population.
Int J Med Sci. 2008 Jul 8;5(4):197-202.
PMID: 18645608

83- A six-gene signature predicting breast cancer lung metastasis.

Landemaine T, Jackson A, Bellahcène A, Rucci N, Sin S, Abad BM, Sierra A, Boudinet A, Guinebretière
JM, Ricevuto E, Noguès C, Briffod M, Bièche I, Cherel P, Garcia T, Castronovo V, Teti A, Lidereau R,
Driouch K.

Centre René Huguenin, Fédération Nationale des Centres de Lutte Contre le Cancer and Institut National
de la Sante et de la Recherche Medicale, U735, Saint-Cloud, France.

                                                                                                        64
The lungs are a frequent target of metastatic breast cancer cells, but the underlying molecular
mechanisms are unclear. All existing data were obtained either using statistical association between
gene expression measurements found in primary tumors and clinical outcome, or using experimentally
derived signatures from mouse tumor models. Here, we describe a distinct approach that consists of
using tissue surgically resected from lung metastatic lesions and comparing their gene expression
profiles with those from nonpulmonary sites, all coming from breast cancer patients. We show that the
gene expression profiles of organ-specific metastatic lesions can be used to predict lung metastasis in
breast cancer. We iden fied a set of 21 lung metastasis-associated genes. Using a cohort of 72 lymph
node-nega ve breast cancer pa ents, we developed a 6-gene prognostic classifier that discriminated
breast primary cancers with a significantly higher risk of lung metastasis. We then validated the
predic ve ability of the 6-gene signature in 3 independent cohorts of breast cancers consis ng of a total
of 721 pa ents. Finally, we show that the signature improves risk stratification independently of known
standard clinical variables and a previously established lung metastasis signature based on an
experimental breast cancer metastasis model.
Cancer Res. 2008 Aug 1;68(15):6092-9.

PMID: 18676831

84- Circulating tumor cells in breast cancer: methodology and clinical
repercussions.


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Gasent Blesa JM, Alberola Candel V, Esteban González E, Vidal Martínez J, Gisbert Criado R, Provencio
Pulla M, Laforga Canales J, Pachmann K.
Hospital General Universitari Marina Alta, Dènia, Alacant, Spain. joanmagasent@telefonica.net

Breast cancer is the most common type of cancer among women, and clinicians have long recognized its
heterogeneity. Its detection and treatment in early stages allow for reduction of mortality. Despite the
advances and new strategies for combining surgical, radiotherapy, and chemotherapy options, however,
the percentage of patients developing metastases and advanced stages remains high. Even though
serum tumor markers have been used for the early diagnosis of metastases, their systematic
determination has not had an effect on survival. Methods that are more reliable are needed to detect
metastases earlier than with the common clinical methods and thus start treatment before overt
relapse. Early indicators of response or resistance to treatment are also an issue in clinical practice.
Imaging techniques are time consuming, and it is difficult to detect changes that indicate response
limited to therapy, and approaches to defining changes in tumor mass are time and resource consuming.
In contrast, detection of circulating tumor cells (CTC) could be a useful tool in early detection of relapse
and response to systemic chemotherapy. Extremely sensitive techniques are available that are easily
applied to peripheral blood samples, which might provide enormous research possibilities in this area.
Clin Transl Oncol. 2008 Jul;10(7):399-406.
PMID: 18628068


                                                                                                         65
                                     Screening & Risk factors



85- Geriatric screening and preventive care.

Spalding MC, Sebesta SC.

Department of Family and Community Medicine, Texas Tech University Health Sciences Center at El
Paso, El Paso, Texas 79924, USA.

Preventive health care decisions and recommendations become more complex as the population ages.
The leading causes of death (i.e., heart disease, malignant neoplasms, cerebrovascular disease, and
chronic lower respiratory disease) among older adults mirror the actual causes of death (i.e., tobacco
use, poor diet, and physical inactivity) among persons of all ages. Many aspects of mortality in older
adults are modifiable through behavior change. Pa ents 65 years and older should be counseled on
smoking cessation, diets rich in healthy fats, aerobic exercise, and strength training. Other types of
preventive care include aspirin therapy; lipid management; and administration of tetanus and
diphtheria, pneumococcal, and influenza vaccines. Although cancer is the second leading cause of death
in pa ents 65 years and older, a survival benefit from cancer screening is not seen unless the patient's



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life expectancy exceeds five years. Therefore, it is best to review life expectancy, functionality, and
comorbidities with older patients when making cancer screening recommendations. Other
recommended screenings include abdominal aor c aneurysm for men 65 to 75 years of age, breast
cancer for women 40 years and older with a life expectancy greater than five years, and colorectal
cancer for men and women 50 years and older with a life expectancy greater than five years.
Am Fam Physician. 2008 Jul 15;78(2):206-15.
PMID: 18697503



86- Epidemiology, genetics, and risk evaluation of postmenopausal women at risk
of breast cancer.

Vogel VG.

Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine,
Pittsburgh, PA, USA. vvogel@magee.edu

Breast cancer risk factors have been studied for the past three decades, and the single most important
risk factor is age. Hormonally linked adult reproductive and anthropometric risk factors contribute to the
etiology of postmenopausal breast cancer. The risk of breast cancer increases among women older than
50 years of age who have benign breast disease, especially those with atypical ductal or lobular

                                                                                                       66
hyperplasia. Lobular carcinoma in situ increases risk significantly, as do a family history of breast cancer
in first-degree rela ves and the presence of BRCA1 or BRCA2 muta ons. Diet, exercise, and
environmental factors play a very small role in overall risk. Mammographic breast density increases
relative risk fivefold among women with the highest density, and breast cancer risk is two to three times
greater in women with elevated serum levels of estradiol or testosterone. Multivariate risk models allow
determination of composite relative risks and cumulative lifetime risk, although improved models for
African American women are required. For postmenopausal women, newer risk models are being
developed and validated that include age, breast density, race, ethnicity, family history of breast cancer,
a previous breast biopsy, body mass index, age at onset of natural menopause, hormone therapy, and
previous false-positive mammography. A simpler model that includes only age, breast cancer in first-
degree relatives, and previous breast biopsy performs well for estrogen receptor-positive breast cancer
in postmenopausal women. As many as 10 million women in the United States are at increased risk, and
clinicians are obligated to identify these women and manage their risk appropriately.
Menopause. 2008 Jul-Aug;15(4 Suppl):782-9.
PMID: 18596599



87- 2008 update of the guideline: early detec on of breast cancer in Germany.

Albert US, Altland H, Duda V, Engel J, Geraedts M, Heywang-Köbrunner S, Hölzel D, Kalbheim E, Koller


www.vancls.info
M, König K, Kreienberg R, Kühn T, Lebeau A, Nass-Griegoleit I, Schlake W, Schmutzler R, Schreer I,
Schulte H, Schulz-Wendtland R, Wagner U, Kopp I.

Faculty of Medicine, Philipps-University, Marburg, Germany, albertu@med.uni-marburg.de.

INTRODUCTION: The goal of the 2008 updated guideline: early detec on of breast cancer in Germany is
to support physicians as well as healthy and affected women in the decision-making process involved in
the diagnostic chain for the early detection of breast cancer by providing them with evidence- and
consensus-based recommenda ons. The updated guideline replaces the guideline issued in 2003.

MATERIALS AND METHODS: The guideline forms the basis for developing an effective and efficient
national early breast cancer detection program that meets the standards set by the Council of Europe
and WHO for cancer control programs. The guideline presents the current, evidence- and consensus-
based state of scientific knowledge in a multidisciplinary approach for the entire diagnostic chain,
consisting of history taking and risk consultation, information on health behavior, clinical breast
examination, diagnostic imaging, image-guided percutaneous tissue-acquisition techniques, open
surgical excisional biopsy and pathomorphological tissue evaluation. The guideline recommends a set of
quality indicators to assure resource availability, performance quality and outcomes enhancing total
quality management for early breast cancer diagnosis.




                                                                                                         67
CONCLUSION: Currently, early detection of breast cancer offers the most promising possibility to
optimize the diagnosis and treatment of breast cancer and, as a result, reduce breast cancer mortality
and improve health related quality of life in women.
J Cancer Res Clin Oncol. 2008 Jul 26.
PMID: 18661152



88- A family history of breast cancer will not predict female early onset breast
cancer in a population-based setting.

de Bock GH, Jacobi CE, Seynaeve C, Krol-Warmerdam EM, Blom J, van Asperen CJ, Cornelisse CJ, Klijn
JG, Devilee P, Tollenaar RA, Brekelmans CT, van Houwelingen JC.

Department of Epidemiology, Groningen University Medical Center, Groningen, The Netherlands.
g.h.de.bock@epi.umcg.nl

BACKGROUND: An increased risk of breast cancer for relatives of breast cancer patients has been
demonstrated in many studies, and having a relative diagnosed with breast cancer at an early age is an
indication for breast cancer screening. This indication has been derived from estimates based on data
from cancer-prone families or from BRCA1/2 muta on families, and might be biased because BRCA1/2


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mutations explain only a small proportion of the familial clustering of breast cancer. The aim of the
current study was to determine the predictive value of a family history of cancer with regard to early
onset of female breast cancer in a population based setting.

 METHODS: An unselected sample of 1,987 women with and without breast cancer was studied with
regard to the age of diagnosis of breast cancer.

RESULTS: The risk of early-onset breast cancer was increased when there were: (1) at least 2 cases of
female breast cancer in first-degree rela ves (yes/no; HR at age 30: 3.09; 95% CI: 128-7.44), (2) at least 2
cases of female breast cancer in first or second-degree rela ves under the age of 50 (yes/no; HR at age
30: 3.36; 95% CI: 1.12-10.08), (3) at least 1 case of female breast cancer under the age of 40 in a first- or
second-degree relative (yes/no; HR at age 30: 2.06; 95% CI: 0.83-5.12) and (4) any case of bilateral
breast cancer (yes/no; HR at age 30: 3.47; 95%: 1.33-9.05). The posi ve predic ve value of having 2 or
more of these characteris cs was 13% for breast cancer before the age of 70, 11% for breast cancer
before the age of 50, and 1% for breast cancer before the age of 30.

CONCLUSION: Applying family history related criteria in an unselected population could result in the
screening of many women who will not develop breast cancer at an early age.
BMC Cancer. 2008 Jul 23;8:203.        PMID: 18651949




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89- Health beliefs and breast self-examination in a sample of Turkish nursing
students and their mothers.

Kara B, Acikel CH.
Department of Internal Medicine Nursing, School of Nursing, Gulhane Military Medical Academy,
Ankara, Turkey.

Aim. To describe health beliefs and breast self-examination practice of Turkish female nursing students
and their mothers. Background. Breast cancer is the most frequently diagnosed cancer and the second
leading cause of cancer deaths among Turkish women. Breast self-examination is one of the primary
methods for early detection of breast cancer in asymptomatic women.

Design. The study was designed as a cross-sectional and comparative survey. The data were obtained
from 392 par cipants, including female nursing students (n = 196) and their mothers (n = 196) in Ankara,
Turkey.

 Methods. Data were collected by using a personal data form and the Champion's Health Belief Model
Scale. Descriptive statistics, paired samples t-test, chi-square test, reliability analysis, Pearson
correlation coefficients and logistic regression analysis were conducted.

Results. The percentage of nursing students who performed breast self-examination regularly was



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statistically higher than that of their mothers. The scores of health motivation, benefits and confidence
were significantly higher in nursing students. The mothers' perceived susceptibility and barriers were
significantly higher than their daughters. The frequency of breast self-examination practice was affected
by the level of education, the mother's or daughter's monthly performance of breast self-examination
and the level of perceived barrier to breast self-examination.
Conclusions. There were differences in health beliefs related to breast self-examination and its practice
between nursing students and their mothers. The results of this study showed that monthly
performance of breast self-examination was more common among women who graduated from high
school and university, whose mother or daughter performed breast self-examination regularly every
month and those with lower levels of perceived barriers. Relevance to clinical practice. It is essential
that nurses be aware of the factors that contribute to monthly performance of breast self-examination.
Cultural factors should be considered in planning educational programmes about breast self-
examination practice. Interventions should be designed to enhance nursing students' proficiency in
performing breast self-examination.
J Clin Nurs. 2008 Jul 17.
PMID: 18647200



90- Risk factors for late relapse and death in patients with early breast cancer.

C GK, M B, B Z.

                                                                                                       69
Adjuvant treatments reduce the risk for recurrence and death from breast cancer; but even 10-15 years
after diagnosis, these risks persist. The aim of our study was to identify prognostic factors for relapse
and death in the second decade after primary surgery. Patients with early breast cancer treated from
1983-1987 (n=1035) were included. Pa ents' characteristics, tumor prognostic factors, treatments, data
on recurrence and death were obtained from patients' charts and our cancer registry. Median follow-up
was 17 (1-23) years. At 10 years a er surgery, 515 (49.8%) pa ents were alive and of them 432 (41.7%)
were relapse-free. Of the 432 pa ents being alive and relapse-free at 10 years 153 (35.4%) had an event
therea er, of them 38 (25%, 9% of all) had a relapse of breast cancer. For this period only the presence
of lymphovascular invasion (LVI) and positive estrogen receptors (ER) were found as independent
unfavorable prognostic factors for relapse-free (HR 2.09, p=0.007; HR 1.50, p=0.021, respec vely) and
overall survival (HR 2.15, p=0.006; HR 1.41, p=0.05, respec vely) while tumor size, grade and nodal
status had no prognostic significance. Positive ER and LVI are independent prognostic factors for relapse
and death in the second decade after surgery in patients with early breast cancer. Key words: breast
cancer, estrogen receptors, late relapse, lymphovascular invasion.
Neoplasma. 2008;55(5):416-20.
PMID: 18665752



91- Interventions to increase recommendation and delivery of screening for


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breast, cervical, and colorectal cancers by healthcare providers systematic reviews
of provider assessment and feedback and provider incentives.

Sabatino SA, Habarta N, Baron RC, Coates RJ, Rimer BK, Kerner J, Coughlin SS, Kalra GP,
Chattopadhyay S; Task Force on Community Preventive Services.Collaborators (17)

Fielding JE, Rimer BK, Abraido-Lanza A, Calonge N, Clymer J, Glanz K, Goetzel RZ,

CDC Division of Cancer Prevention and Control, National Center for Chronic Disease Prevention and
Health Promotion, Atlanta, Georgia, USA. SSabatino@cdc.gov

Most major medical organizations recommend routine screening for breast, cervical, and colorectal
cancers. Screening can lead to early detection of these cancers, resulting in reduced mortality. Yet not
all people who should be screened are screened, either regularly or, in some cases, ever. This report
presents results of systematic reviews of effectiveness, applicability, economic efficiency, barriers to
implementation, and other harms or benefits of two provider-directed intervention approaches to
increase screening for breast, cervical, and colorectal cancers. These approaches, provider assessment
and feedback, and provider incentives encourage providers to deliver screening services at appropriate
intervals. Evidence in these reviews indicates that provider assessment and feedback interventions can
effectively increase screening by mammography, Pap test, and fecal occult blood test. Health plans,
healthcare systems, and cancer control coalitions should consider such evidence-based findings when

                                                                                                       70
implementing interventions to increase screening use. Evidence was insufficient to determine the
effectiveness of provider incentives in increasing use of any of these tests. Specific areas for further
research are suggested in this report, including the need for additional research to determine whether
provider incentives are effective in increasing use of any of these screening tests, and whether
assessment and feedback interventions are effective in increasing other tests for colorectal cancer (i.e.,
flexible sigmoidoscopy, colonoscopy, or double-contrast barium enema).
Am J Prev Med. 2008 Jul;35(1 Suppl):S67-74.
PMID: 18541190



92- Client-directed interventions to increase community access to breast, cervical,
and colorectal cancer screening a systematic review.

Baron RC, Rimer BK, Coates RJ, Kerner J, Kalra GP, Melillo S, Habarta N, Wilson KM, Chattopadhyay S,
Leeks K; Task Force on Community Preventive Services.Collaborators (17)

ielding JE, Rimer BK, Abraido-Lanza A, Calonge N, Clymer J, Glanz K, Goetzel RZ,

Community Guide Branch, National Center for Health Marketing, CDC, Atlanta, Georgia, USA.
rbaron@cdc.gov



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Most major medical organizations recommend routine screening for breast, cervical, and colorectal
cancers. Screening can lead to early detection of these cancers, resulting in reduced mortality. Yet not
all people who should be screened are screened, either regularly or, in some cases, ever. This report
presents the results of systematic reviews of effectiveness, applicability, economic efficiency, barriers to
implementation, and other harms or benefits of interventions designed to increase screening for breast,
cervical, and colorectal cancers by increasing community access to these services. Evidence from these
reviews indicates that screening for breast cancer (by mammography) has been increased effectively by
reducing structural barriers and by reducing out-of pocket client costs, and that screening for colorectal
cancer (by fecal occult blood test) has been increased effectively by reducing structural barriers.
Additional research is needed to determine whether screening for cervical cancer (by Pap test) can be
increased by reducing structural barriers and by reducing out-of-pocket costs, whether screening for
colorectal cancer (fecal occult blood test) can be increased by reducing out-of-pocket costs, and
whether these interventions are effective in increasing the use of other colorectal cancer screening
procedures (i.e., flexible sigmoidoscopy, colonoscopy, double contrast barium enema). Specific areas for
further research are also suggested in this report.
Am J Prev Med. 2008 Jul;35(1 Suppl):S56-66.
PMID: 18541188




                                                                                                         71
                                         Supportive care
93- Treatment-Related Symptom Clusters in Breast Cancer: A Secondary Analysis.

Kim HJ, Barsevick AM, Tulman L, McDermott PA.

University of Ulsan (H.-J.K.), Ulsan, South Korea; and Fox Chase Cancer Center (A.M.B.), and School of
Nursing (L.T.) and Graduate School of Education (P.A.M.), University of Pennsylvania, Philadelphia,
Pennsylvania, USA.

This study investigated treatment-related symptom clusters and the influence of selected
demographic/clinical variables on symptom clustering in breast cancer patients across a treatment
trajectory. A secondary analysis of 282 breast cancer pa ents receiving chemotherapy or radiotherapy
was done to determine the clustering of oncologic treatment-related symptoms at selected time points
of treatment. Two distinct clusters were identified: a psychoneurological cluster and an upper
gastrointestinal cluster. The clustering of symptoms was generally stable across the treatment
trajectory. The clustering, however, was weaker when the time lapse after the completion of treatment
became longer. Demographic and clinical variables did not significantly influence symptom clustering.
Psychoneurological symptoms had a tendency to occur together across the treatment trajectory, as did
upper gastrointestinal symptoms. Effective symptom assessment/management strategies need to take


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into account this co-occurrence of symptoms. The findings from this study underscore the need for
further investigation of the common biological basis of symptoms to attain more effective management
of multiple symptoms.
J Pain Symptom Manage. 2008 Aug 19.
PMID: 18718735



94- A couple-based intervention for female breast cancer.

Baucom DH, Porter LS, Kirby JS, Gremore TM, Wiesenthal N, Aldridge W, Fredman SJ, Stanton SE, Scott
JL, Halford KW, Keefe FJ.

Department of Psychology, UNC-Chapel Hill, Chapel Hill, NC, USA.

Objective: Although women's breast cancer affects both women and their male partners, as well as their
relationships, few interventions have been developed to work with couples confronting breast cancer.
The current investigation presents the pilot results from a new couple-based intervention program for
breast cancer that teaches couples how to minimize negative effects and maximize positive functioning
during this difficult time.




                                                                                                         72
Method: In this pilot study, 14 couples in which the wife had early stage breast cancer were randomly
assigned to one of the two treatment conditions: Couple-based relationship enhancement (RE) or
treatment-as-usual (TAU).

Results: The results from this study suggest that compared with couples receiving treatment-as-usual,
both women and men in the RE condition experienced improved functioning on individual psychological
variables as well as relationship functioning at pos est and 1-year follow-up. In addition, women in RE
show fewer medical symptoms at both time periods.

Conclusions: In this pilot study, the couple-based intervention, RE, has shown promise in improving
individual, medical, and relationship functioning for couples in which the woman is facing breast cancer,
and therefore merits further inves ga on on a larger scale. Copyright (c) 2008 John Wiley & Sons, Ltd.
Psychooncology. 2008 Aug 13.
PMID: 18702064



95- Patterns of Dementia Diagnosis in Surveillance, Epidemiology, and End Results
Breast Cancer Survivors Who Use Chemotherapy.

Heck JE, Albert SM, Franco R, Gorin SS.



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Department of Epidemiology, Columbia University, New York, New York, USA.

OBJECTIVES: To determine patterns of dementia diagnosis seen after chemotherapy treatment. DESIGN:
Using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, International
Classification of Diseases, Ninth Revision (ICD-9) diagnoses of demen a occurring in the years after
breast cancer diagnosis were examined.

SETTING: The SEER program collects information from population-based tumor registries in seven
metropolitan areas (San Francisco and Oakland, Detroit, Atlanta, Seattle, Los Angeles County, San Jose
and Monterey Counties, and the greater California area) and eight states (Connecticut, Iowa, New
Mexico, Utah, Hawaii, Kentucky, New Jersey, and Louisiana). PARTICIPANTS: Eighteen thousand three
hundred sixty women diagnosed with Stage II, III, or IV breast cancer.

MEASUREMENTS: Using validated ICD-9 diagnoses of demen a, the occurrence of demen a and other
cognitive impairment in the years after breast cancer diagnosis in women who received chemotherapy
was compared with that of women who did not. To account for group differences, propensity score
analysis was used to balance the differences in groups before treatment. Risk of dementia was
calculated using Cox proportional hazards modeling.

 RESULTS: There were significant differences at baseline between individuals who received and did not
receive chemotherapy. In the first few years after breast cancer diagnosis, dementia was more common
in women who had not had chemotherapy, probably reflecting group differences at baseline. In the

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longer term, diagnoses of dementia were more common in women who had chemotherapy treatment
(hazard ra o=1.20, 95% confidence interval=1.08-1.33).

 CONCLUSION: These findings suggest the possibility of severe cognitive changes associated with
chemotherapy, particularly over the long term.
J Am Geriatr Soc. 2008 Aug 4.
PMID: 18691280



96- Managed care enrollment and chronically disabled women with breast cancer.

Habermann EB, Virnig BA, Durham SB, Baxter NN.

Division of Health Policy and Management, School of Public Health, University of Minnesota, 420
Delaware St SE, MMC 729, Minneapolis, MN 55455, USA. butz0030@umn.edu

OBJECTIVE: To assess whether managed care enrollment or healthcare utilization level among women
enrolled in Medicare because of disability affects stage at diagnosis and treatment of breast cancer.

STUDY DESIGN: Retrospective study using the Surveillance, Epidemiology, and End Results-Medicare



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database. We compared breast cancer stage at diagnosis and treatment among women with disabilities
enrolled in Medicare managed care versus fee-for-service (FFS) Medicare. Women enrolled in FFS
Medicare were classified into levels of healthcare u liza on during the 6 to 18 months before breast
cancer diagnosis.

METHODS: Controlling for confounders, we used regression models to determine the effects of
managed care enrollment and healthcare utilization level on earlier stage at diagnosis and treatment of
breast cancer.

 RESULTS: Disabled patients enrolled in FFS Medicare without contact with the healthcare system and
those with fewer than 12 physician visits during the 6 to 18 months before breast cancer diagnosis were
more likely than disabled patients enrolled in Medicare managed care to be diagnosed as having breast
cancer at a late stage. There was no difference between women enrolled in Medicare managed care
versus women enrolled in FFS Medicare having at least 12 physician visits during the 12-month period.
Breast cancer treatment for women with disabilities did not vary across managed care enrollment or
healthcare utilization level.

CONCLUSION: Managed care enrollment or increased contact with healthcare providers could result in
earlier stage at breast cancer diagnosis.
Am J Manag Care. 2008 Aug;14(8):514

PMID: 18690767



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97- Home-based lymphedema treatment in patients with cancer-related
lymphedema or noncancer-related lymphedema.

Ridner SH, McMahon E, Dietrich MS, Hoy S.

School of Nursing, Vanderbilt University, Nashville, TN, USA. sheila.ridner@vanderbilt.edu

PURPOSE/OBJECTIVES: To compare treatment protocol adherence, satisfaction, and perceived changes
in emotional and functional status between patients with lymphedema with and without cancer using
the home-based Flexitouch (Tactile Systems Technology, Inc.) system for lymphedema self-care.
DESIGN: Quasi-experimental, pre- and post-test design.

SETTING: Private homes in the continental United States and Alaska. SAMPLE: 155 community-dwelling
individuals with lymphedema: 93 with cancer-related lymphedema and 62 with noncancer-related
lymphedema.

METHODS: A survey was completed before use of the Flexitouch system. Participants received in-home
education about device use, safety precautions, and the two-phase therapy protocol. A post-therapy
survey was completed during the maintenance phase of the protocol.

MAIN RESEARCH VARIABLES: Use of the Flexitouch system, treatment protocol adherence, participant



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satisfaction, and emotional and functional status.

FINDINGS: Participants without cancer were more adherent to the prescribed protocol. Both groups
were satisfied with the system, perceived it to be effective, and reported improvement in physical and
emotional status. Participants' use of professional manual lymphatic drainage (MLD) therapy, self-MLD,
and bandaging declined after they initiated use of the Flexitouch system.

CONCLUSIONS: Patients using the Flexitouch system were satisfied with the device and perceived it to
be beneficial in management of their lymphedema.

 IMPLICATIONS FOR NURSING: Patients using the Flexitouch system should be assessed for adherence to
the prescribed treatment protocol and use of other self-care treatments. Healthcare professionals
should facilitate communication among members of the lymphedema treatment team and the patient
when problems are noted.
Oncol Nurs Forum. 2008 Jul;35(4):671-80.
PMID: 18591171

98- Postlymphadenectomy complications and quality of life among breast cancer
patients in Brazil.

Paim CR, de Paula Lima ED, Fu MR, de Paula Lima A, Cassali GD.



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Federal University of Minas Gerais, Brazil.

This descriptive, cross-sec onal, correla onal study with a convenience sample of 96 women treated
for breast cancer at an outpatient service in Brazil was designed to investigate postlymphadenectomy
complications after axillary lymph node dissection (ALND) and sentinel lymph node biopsy and
explore the associative relationships between the complications and quality of life. Clinical
evaluations using perimetry, goniometry, and muscle strength test were used to evaluate the
complications. Pain and quality of life were assessed by the Short-Form McGill Pain Questionnaire and
the Functional Assessment of Cancer Therapy-Breast. All participants had at least one complication.
Incidence was higher for pain (57%), impaired shoulder strength (57%), and fibrosis (54%), followed by
impaired shoulder range of mo on (46%) and lymphedema (17%). The incidence of impaired shoulder
flexion (P = .01) and lymphedema (P = .002) was higher in ALND group. Winged scapula (8.4%) only
occurred in the ALND group. Quality of life was significantly correlated with pain (r = -0.53, P = .000)
and impaired shoulder strength in flexion (r = 0.4; P = .000) and abduc on (r = -0.5, P = .000). Future
studies are needed to prospectively investigate the onset of the complications and identify
appropriate interventions to promote quality of life in women treated for breast cancer.
Cancer Nurs. 2008 Jul-Aug;31(4):302-9; quiz 310-1
PMID: 18600117




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                                       Nucleare medicine


99- Preoperative Staging of Large Primary Breast Cancer With
[18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography
Compared With Conventional Imaging Procedures.

Fuster D, Duch J, Paredes P, Velasco M, Muñoz M, Santamaría G, Fontanillas M, Pons F.

Nuclear Medicine Department, Hospital Clínic de Barcelona, Barcelona, Spain.

PURPOSE: To evaluate the u lity of positron emission tomography (PET) and [(18)F]fluorodeoxyglucose
in the initial staging of large primary breast tumors.

PATIENTS AND METHODS: This prospective study was approved by the ethics committee, and all
pa ents gave their informed consent before enrollment. Sixty consecu ve pa ents with large (> 3 cm)
primary breast cancer diagnosed by clinical examination and breast magnetic resonance imaging (MRI)
were entered onto the study. The mean age was 57 +/- 13 years. Chest computed tomography (CT), liver
ultrasonography, bone scan, and PET/CT were performed in all patients. All findings were histologically


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confirmed, and/or at least 1 year of follow-up was required. Correlation between parameters was
calculated using Pearson's correla on coefficient. P < .05 was considered sta s cally significant.

RESULTS: Primary tumor was identified by both PET/CT and MRI in all patients. Multifocal and/or
mul centric tumors were found in 19 pa ents by MRI. Axillary lymph node metastases were found in 20
of 52 pa ents. Extra-axillary metastatic lymph nodes were also found in three patients. One patient
showed an infiltrated lymph node in the contralateral axilla. The sensitivity and specificity for PET/CT to
detect axillary lymph nodes metastases were 70% and 100%, respec vely. PET/CT diagnosed all extra-
axillary lymph nodes. The overall sensitivity and specificity of PET/CT in detecting distant metastases
were 100% and 98%, respec vely; whereas the sensi vity and specificity of conven onal imaging were
60% and 83%, respec vely. PET led to a change in the ini al staging in 42% of patients.

CONCLUSION: PET/CT underestimates locoregional lymph node staging in large primary breast cancer
patients. PET/CT is a valuable tool to discard unsuspected extra-axillary lymph nodes and distant
metastases.
J Clin Oncol. 2008 Aug 11.
PMID: 18695254



100- [18F]FDG and [18F]FLT uptake in human breast cancer cells in rela on to the
effects of chemotherapy: an in vitro study.

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Direcks WG, Berndsen SC, Proost N, Peters GJ, Balzarini J, Spreeuwenberg MD, Lammertsma AA,
Molthoff CF.

Department of Nuclear Medicine & PET Research, VU University Medical Centre, P.O. Box 7057, 1007
MB Amsterdam, The Netherlands.

Increased 2'-deoxy-2'-[18F]fluoro-D-glucose (FDG) uptake is the most commonly used marker for
positron emission tomography in oncology. However, a prolifera on tracer such as 3'-deoxy-3'-
[18F]fluorothymidine (FLT) might be more specific for cancer. 3'-deoxy-3'-[18F]fluorothymidine uptake is
dependent on thymidine kinase 1 (TK) ac vity, but the effects of chemotherapeu c agents are
unknown. The aim of this study was to characterise FDG and FLT uptake mechanisms in vitro before and
a er exposure to chemotherapeu c agents. The effects of 5-fluorouracil (5-FU), doxorubicin and
paclitaxel on FDG and FLT uptake were measured in MDA MB231 human breast cancer cells in rela on
to cell cycle distribution, expression and enzyme activity of TK-1. At IC50 concentra ons, 5-FU resulted
in accumula on in the G1 phase, but doxorubicin and paclitaxel induced a G2/M accumula on.
Compared with untreated cells, 5-FU and doxorubicin increased TK-1 levels by >300. At 72 h, 5-FU
decreased FDG uptake by 50% and FLT uptake by 54%, whereas doxorubicin increased FDG and FLT
uptake by 71 and 173%, respec vely. Paclitaxel increased FDG uptake with >100% a er 48 h, whereas
FLT uptake hardly changed. In conclusion, various chemotherapeutic agents, commonly used in the



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treatment of breast cancer, have different effects on the time course of uptake of both FDG and FLT in
vitro. This might have implications for interpretation of clinical findings.
Br J Cancer. 2008 Aug 5;99(3):481-7
PMID: 18665170



101- Comparison of FDG PET and MRI for evaluating the tumor extent of breast
cancer and the impact of FDG PET on the systemic staging and prognosis of
patients who are candidates for breast-conserving therapy.

Uematsu T, Kasami M, Yuen S.

Department of Breast Imaging and Breast Intervention, Breast Center, Shizuoka Cancer Center Hospital,
Naga-izumi, Shizuoka, 411-8777, Japan, t.uematsu@scchr.jp.

BACKGROUND: FDG PET has not yet found a role in the clinical evaluation of the tumor extent of breast
cancer. FDG PET has been reported to be useful for evaluating the prognoses of breast cancer patients
with more accuracy than conventional imaging modalities. The purpose of this study was to compare
the accuracy of FDG PET and MRI for the preoperative assessment of the tumor extent of breast cancer,
for evaluating the impact of FDG PET on systemic staging, and also for predicting the prognosis of
patients who are candidates for breast-conserving therapy.

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 METHODS: The study was a prospec ve series of 23 breasts with breast cancer that underwent both
FDG PET and MRI before surgery. Systemic staging with FDG PET was also performed. The correlation
between the results of these examinations and histological findings was thus examined. The maximum
standardized uptake value (SUVmax) of the tumors was investigated in association with the patient
prognoses.

RESULTS: When evalua ng the local tumor extent, the accuracy of FDG PET (43.5%) was significantly
lower than that of MRI (91%) (P < 0.001). The sensi vity, specificity, and accuracy of FDG PET regarding
the nodal status were 60, 94, and 87%, respec vely. No pa ents demonstrated any distant metastasis,
whereas FDG PET gave a false positive in one patient. The mean follow-up period was 61 months. The
SUVmax value of the worse prognosis patient group was significantly higher than that of the good
prognosis pa ent group (P = 0.032).

CONCLUSIONS: FDG PET is not a breast imaging modality for evaluating the local tumor extent, but it is
useful for predicting the prognoses of patients who are candidates for breast-conserving therapy.
Breast Cancer. 2008           PMID: 18663562



102- Breast Cancer Staging in a Single Session: Whole-Body PET/CT
Mammography.


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Heusner TA, Kuemmel S, Umutlu L, Koeninger A, Freudenberg LS, Hauth EA, Kimmig KR, Forsting M,
Bockisch A, Antoch G.

Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen,
University at Duisburg-Essen, Essen, Germany; 2Department of Gynecology and Obstetrics, University
Hospital Essen, University at Duisburg-Essen, Essen, Germany; and 3Department of Nuclear Medicine,
University Hospital Essen, University at Duisburg-Essen, Essen, Germany.

Our objective was to compare the diagnostic accuracy of an all-in-one protocol of whole-body (18)F-FDG
PET/CT and integrated (18)F-FDG PET/CT mammography with the diagnostic accuracy of a multimodality
algorithm for initial breast cancer staging.

METHODS: Forty women (mean age, 58.3 y; range, 30.8-78.4 y; SD, 12 y) with suspected breast cancer
were included. For the primary tumor, we compared (18)F-FDG PET/CT mammography versus MRI
mammography; for axillary lymph node status, (18)F-FDG PET/CT versus clinical investigation and
ultrasound; and for distant metastases, (18)F-FDG PET/CT versus a multimodality staging algorithm.
Histopathology and clinical follow-up served as the standard of reference. The Fisher exact test
evaluated the significance of differences (P < 0.05). Altera ons in pa ent management caused by (18)F-
FDG PET/CT were documented.




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RESULTS: No significant differences were found in the detec on rate of breast cancer lesions ((18)F-FDG
PET/CT, 95%; MRI, 100%; P = 1). (18)F-FDG PET/CT correctly classified lesion focality significantly more
o en than did MRI ((18)F-FDG PET/CT, 79%; MRI, 73%; P < 0.001). MRI correctly defined the T stage
significantly more o en than did (18)F-FDG PET/CT (MRI, 77%; (18)F-FDG PET/CT, 54%; P = 0.001). (18)F-
FDG PET/CT detected axillary lymph node metastases in 80% of cases; clinical inves ga on/ultrasound,
in 70%. This difference was not sta s cally significant (P = 0.067). Distant metastases were detected
with (18)F-FDG PET/CT in 100% of cases, and the mul modality algorithm identified distant metastases
in 70%. This difference was not sta s cally significant (P = 1). Three pa ents had extraaxillary lymph
node metastases that were detected only by PET/CT (cervical, retroperitoneal, mediastinal/internal
mammary group). (18)F-FDG PET/CT changed pa ent management in 12.5% of cases.

CONCLUSION: Our data suggest that a whole-body (18)F-FDG PET/CT mammography protocol may be
used for staging breast cancer in a single session. This ini al assessment of the (18)F-FDG PET/CT
protocol indicates similar accuracy to MRI for the detection of breast cancer lesions. Although MRI
seems to be more accurate when assessing the T stage of the tumor, (18)F-FDG PET/CT seems able to
more accurately define lesion focality. Although (18)F-FDG PET/CT mammography was able to detect
axillary lymph node metastases with a high sensitivity, this method cannot soon be expected to replace
the combination of clinical examination, ultrasound, and sentinel lymph node biopsy for axillary
assessment.
J Nucl Med. 2008 Aug;49(8):1215-1222.
PMID: 18632831


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103- Tumor Metabolism and Blood Flow Changes by Positron Emission
Tomography: Relation to Survival in Patients Treated With Neoadjuvant
Chemotherapy for Locally Advanced Breast Cancer.
Dunnwald LK, Gralow JR, Ellis GK, Livingston RB, Linden HM, Specht JM, Doot RK, Lawton TJ, Barlow
WE, Kurland BF, Schubert EK, Mankoff DA.

Divisions of Nuclear Medicine and Medical Oncology and Departments of Bioengineering, Pathology,
and Biostatistics, University of Washington; Seattle Cancer Care Alliance; and Clinical Research Division,
Fred Hutchinson Cancer Research Center, Seattle, WA.

PURPOSE: Patients with locally advanced breast carcinoma (LABC) receive preoperative chemotherapy
to provide early systemic treatment and assess in vivo tumor response. Serial positron emission
tomography (PET) has been shown to predict pathologic response in this setting. We evaluated serial
quantitative PET tumor blood flow (BF) and metabolism as in vivo measurements to predict patient
outcome.

 PATIENTS AND METHODS: Fifty-three women with primary LABC underwent dynamic
[(18)F]fluorodeoxyglucose (FDG) and [(15)O]water PET scans before and at midpoint of neoadjuvant


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chemotherapy. The FDG metabolic rate (MRFDG) and transport (FDG K1) parameters were calculated;
BF was es mated from the [(15)O]water study. Associa ons between BF, MRFDG, FDG K1, and
standardized uptake value and disease-free survival (DFS) and overall survival (OS) were evaluated using
the Cox proportional hazards model.

RESULTS: Pa ents with persistent or elevated BF and FDG K1 from baseline to midtherapy had higher
recurrence and mortality risks than pa ents with reduc ons. In mul variable analyses, BF and FDG K1
changes remained independent prognosticators of DFS and OS. For example, in the association between
BF and mortality, a pa ent with a 5% increase in tumor BF had a 67% higher mortality risk compared
with a pa ent with a 5% decrease in tumor BF (hazard ra o = 1.67; 95% CI, 1.24 to 2.24; P < .001).

CONCLUSION: LABC pa ents with limited or no decline in BF and FDG K1 experienced higher recurrence
and mortality risks that were greater than the effects of clinical tumor characteristics. Tumor perfusion
changes over the course of neoadjuvant chemotherapy measured directly by [(15)O]water or indirectly
by dynamic FDG predict DFS and OS.
J Clin Oncol. 2008 Jul 14
PMID: 18626006

104- Imaging of urokinase-type plasminogen activator receptor expression using a
64Cu-labeled linear peptide antagonist by microPET.



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Li ZB, Niu G, Wang H, He L, Yang L, Ploug M, Chen X.

Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford
University School of Medicine, Stanford, California 94305-5484, USA.

PURPOSE: Malignant tumors are capable of degrading the surrounding extracellular matrix, resulting in
local invasion or metastasis. Urokinase-type plasminogen activator (uPA) and its cell surface receptor
(uPAR) are central molecules in one of the major protease systems involved in extracellular matrix
degradation. Noninvasive imaging of this receptor in vivo with radiolabeled peptides that specifically
target uPAR may therefore be useful to decipher the potential invasiveness of malignant lesions.

EXPERIMENTAL DESIGN: In this study, we developed a (64)Cu-labeled uPAR-binding peptide for positron
emission tomography (PET) imaging. A linear, high-affinity uPAR-binding pep de antagonist AE105 was
conjugated with 1,4,7,10-tetraazadodecane-N,N',N'',N'''-tetraace c acid (DOTA) and labeled with (64)Cu
for microPET imaging of mice bearing U87MG human glioblastoma (uPAR posi ve) and MDA-MB-435
human breast cancer (uPAR negative).

 RESULTS: Surface plasmon resonance measurements show that AE105 with DOTA conjugated at the
alpha-amino group (DOTA-AE105) has high affinity toward uPAR. microPET imaging reveals a rapid and
high accumula on of (64)Cu-DOTA-AE105 in uPAR-posi ve U87MG tumors (10.8 +/- 1.5%ID/g at 4.5
hours, n = 3) but not in uPAR-negative MDA-MB-435 tumors (1.2 +/- 0.6%ID/g at 4.5 hours, n = 3).
Specificity of this peptide-based imaging of uPAR was validated by further control experiments. First, a

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nonbinding variant of AE105 carrying a single amino acid replacement (Trp-->Glu) does not target
U87MG tumors in vivo. Second, targe ng of U87MG tumors by (64)Cu-DOTA-AE105 is specifically
inhibited by a nonlabeled antagonist.

CONCLUSION: The successful demonstra on of the ability of a (64)Cu labeled uPAR-specific probe to
visualize uPAR expression in vivo may allow clinical translation of this class of radiopharmaceuticals for
uPAR-positive cancer detection and patient stratification for uPA/uPAR system-based cancer therapy.
Clin Cancer Res. 2008 Aug 1;14(15):4758-66.
PMID: 18676745



105- F-18 FDG uptake in cutaneous metastases from breast cancer.

Borkar S, Pandit-Taskar N.

Department of Radiology, Nuclear Medicine Service, Memorial Sloan Kettering Cancer Center, New York,
New York 10021, USA. borkars@mskcc.org

Cutaneous metastases from internal malignancies are rare with a reported incidence between 0.7% and
10%. Among all malignancies the highest incidence of cutaneous metastasis is seen in breast cancer. We



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report the detection of distant dermal metastases from breast cancer on F-18 FDG PET imaging. A 73-
year-old woman with metastatic left breast cancer was referred for F-18 FDG PET/CT scan, which
showed multiple FDG avid lesions along cutaneous and subcutaneous nodules in the posterior neck,
bilateral proximal arms, anterior chest wall, and trunk. A punch biopsy of a right lower chest wall lesion
revealed invasive ductal carcinoma involving the deep dermis.
Clin Nucl Med. 2008 Jul;33(7):488-9.
PMID: 18580238




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