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					Overview of Breast
Cancer Management
Edith A. Perez, MD
Director, Clinical Investigations
Director, Breast Cancer Program
Division of Hematology/Oncology
Mayo Clinic
Jacksonville, Florida
 Incidence of Breast Cancer Compared
 With Other Sites (Women)
                                         Breast                         Uterine corpus
                            160          Lung and bronchus              Ovary
                                         Colon and rectum               Non-Hodgkin’s lymphoma
 Rate per 100,000 Females




                            140
                            120
                            100
                            80
                            60
                            40
                            20
                             0
                                  1975   1980        1985        1990          1995            2000
                                                     Year of Diagnosis

Adapted from Jemal A et al. CA Cancer J Clin. 2004;54:8-29; ACS. Breast Cancer Facts and Figures. 2003.
    Mortality Rate for Breast Cancer
    Compared With Other Sites (Women)
                                           Breast                         Uterus
                               60          Lung and bronchus              Ovary
                                           Colon and rectum               Pancreas
    Rate per 100,000 Females




                               50

                               40

                               30

                               20

                               10

                               0
                                    1975   1980        1985        1990          1995          2000
                                                       Year of Diagnosis

Adapted from Jemal A et al. CA Cancer J Clin. 2004;54:8-29; ACS. Breast Cancer Facts and Figures. 2003.
.
Risk Factors for Breast Cancer
   Personal history of breast                            Childbearing absent or
    cancer or proliferative breast                         delayed until after age
    disease                                                30 years
   Genetic mutations in BRCA1,                           Early menarche/
    BRCA2, and others                                      late menopause
   Positive family history of                            Hormone replacement
    breast or ovarian cancer                               therapy
   History of DES therapy                                High body mass index
    (exposure to estrogen or                              High alcohol intake
    progesterone compounds)
   Prior breast irradiation at
    young age
BRCA1 = breast cancer 1 gene; BRCA2 = breast cancer 2 gene; DES = diethylstilbestrol.
Hollingsworth AB et al. Am J Surg. 2004;187:349-362.
Breast Cancer Risk Assessment:
Interactions Between Risk Factors
   Modified Gail model used by the National Cancer Institute
    and National Surgical Adjuvant Breast and Bowel Project in the
    Breast Cancer Prevention Trial
   Assessment tool analyzes combinations of 7 factors to calculate risk
      History of DCIS, LCIS                                          Age at menarche
      Age (patients ≥35 years)                                       Age at first live
                                                                       birth
      First-degree relatives with breast cancer
                                                                      Ethnicity
      Prior breast biopsies and presence of
       atypical ductal hyperplasia
   Risk of developing breast cancer is indicated by the composite score
    of the relative risk for each factor

DCIS = ductal carcinoma in situ; LCIS = lobular carcinoma in situ.
Gail MH et al. J Natl Cancer Inst. 1989;81:1879-1886.
Factors That Influence Survival
in Breast Cancer Patients
 Age at diagnosis
 Tumor size at diagnosis

    Stage at diagnosis
 Biologic characteristics of the tumor

    Hormone receptor status (less significant)
    HER2



HER2 = human epidermal growth factor receptor 2.
ACS. Breast Cancer Facts and Figures. 2003; Lohrisch C, Piccart M. Clin Breast Cancer.
2001;2:129-135; Michaelson JS et al. Cancer. 2002;95:713-723.
Overview of Stages of Breast Cancer
  Stage I                 Stage II                   Stage III                      Stage IV




  Early disease:          Early disease:         Locally advanced disease:     Advanced (or metastatic)
  Tumor confined to       Tumor >2 cm in         Tumor spread to the           disease:
  the breast              diameter or spread     superficial structures of     Metastases present
  (node-negative)         to movable             the chest wall; involvement   at distant sites such as bone,
                          ipsilateral axillary   of ipsilateral internal       liver, lungs, and brain, and
                          node(s) (node-         mammary lymph nodes           including supraclavicular
                          positive)                                            lymph node involvement



Greene FL et al, eds. AJCC Cancer Staging Handbook from the AJCC Cancer Staging Manual. 2003.
TNM Staging in Breast Cancer
Provides information about:            Overall    T Category    N Category      M Category
                                       Stage        (tumor)      (nodes)       (metastases)
 Tumor size
                                      Stage 0         Tis            N0             M0
 Node involvement                     Stage I        T1             N0             M0
    Whether the cancer               Stage IIA       T0             N1             M0
     has spread to the                                T1             N1             M0
                                                      T2             N0             M0
     lymph nodes of the
     breast (axilla, internal         Stage IIB       T2             N1             M0
                                                      T3             N0             M0
     mammary,
                                     Stage IIIA       T0             N2             M0
     supraclavicular,                                 T1             N2             M0
     intramammary)                                    T2             N2             M0
                                                      T3             N1             M0
 Metastasis
                                                      T3             N2             M0
    Whether the tumor has           Stage IIIB       T4           Any N            M0
     spread to other parts           Stage IIIC     Any T            N3             M0
     of the body                      Stage IV      Any T          Any N            M1
 Tis = tumor in situ.
 Greene FL et al, eds. AJCC Cancer Staging Handbook from the AJCC Cancer Staging Manual. 2003.
Breast Cancer Treatment:
TNM Stage 0
Objective: To reduce the risk of invasive breast cancer and achieve local
control of carcinoma and decrease risk of death
Surveillance                     Physical examination
(LCIS, DCIS)                     Mammogram; MRI in some cases
Surgery                          Lumpectomy
(DCIS)                              If DCIS in 1 area
                                 Mastectomy
                                    If DCIS in 2 areas
                                    If multifocal or “large”
Radiotherapy                     Usually (not always) accompanies
(DCIS)                            lumpectomy
Hormonal therapy                 In selected ER-positive cases; for 5 years
(DCIS)                            to lower cancer risk
LCIS = lobular carcinoma in situ; DCIS = ductal carcinoma in situ; MRI = magnetic
resonance imaging; ER = estrogen receptor.
ACS. Available at:
www.cancer.org/docroot/CRI/content/CRI_2_4_4X_Breast_Cancer_Treatment_by_ stage_5.asp. 2003.
Breast Cancer Treatment:
TNM Stages I and II
Objective: To eradicate local disease by direct localized action on the breast
and axillary lymph nodes (when appropriate)
    Breast conservation surgery              Lumpectomy or quadrantectomy
    Radiotherapy                             Axillary dissection
                                             Affected breast, chest wall
    Adjuvant chemotherapy                    Combination chemotherapy
                                                  3-6 months
    Adjuvant hormonal therapy                Premenopausal
                                                Tamoxifen   if ER-positive
                                             Postmenopausal
                                                Tamoxifen   and/or aromatase inhibitor

ACS. Available at:
www.cancer.org/docroot/CRI/content/CRI_2_4_4X_Breast_Cancer_Treatment_by_Stage_5.asp. 2003.
.
Breast Cancer Treatment:
TNM Stage III
Objective: To achieve local control, prevent metastases, and extend overall
survival through aggressive treatment
Surgery                                      Mastectomy or lumpectomy
Radiotherapy                                 Chest wall, regional nodes
Adjuvant/neoadjuvant                         Combination chemotherapy
chemotherapy                                      4-6 months
Hormonal therapy                             Benefit if tumor ER-positive and/or
                                              PR-positive




ER = estrogen receptor; PR = progesterone receptor.
ACS. Available at:
www.cancer.org/docroot/CRI/content/CRI_2_4_4X_Breast_Cancer_Treatment_by_Stage_5.asp. 2003.
Breast Cancer Treatment:
TNM Stage IV
Objective: To improve symptoms, prolong survival, and enhance quality of life

Surgery                                         Used in selected cases to relieve
                                                 symptoms
Radiotherapy                                    Used in selected cases to relieve
                                                 symptoms and control local
                                                 disease
Chemotherapy                                    Primary therapy; single-agent or
                                                 combination chemotherapy
Monoclonal antibody                             HER2-positive
Hormonal therapy                                ER-positive and/or
                                                 PR-positive


ACS. Available at:
www.cancer.org/docroot/CRI/content/CRI_2_4_4X_Breast_Cancer_Treatment_by_Stage_5.asp. 2003.
Local Therapy: Major Surgical
Treatment Options for Breast Cancer
   Local therapy provides adequate control of locoregional disease
      Includes surgery and radiation therapy
   Surgery
      Mastectomy
         Modified radical with sentinel lymph node evaluation
         Radical or total mastectomy with sentinel lymph node
           evaluation
         May include breast reconstruction
      Breast-conserving surgery
         Wide local excision
         Quadrantectomy
         Lumpectomy
         Includes axillary dissection if disease is invasive

ACS. Available at: www.cancer.org/docroot/CRI/content/CRI_2_4_4X_Surgery_5.asp. 2003.
Complications Following Breast
Cancer Surgery
   Lymphedema
      May occur in 10% to 30% of women undergoing
       axillary dissection
      Reduced to 3% in patients undergoing sentinel
       node biopsy alone
   Numbness
   Reduced shoulder mobility
   Psychosocial impact of mastectomy
   Phantom breast sensations
ACS. Available at: www.cancer.org/docroot/NWS/content/NWS_3_1x_New_Procedure_Reduces_
Risk_of_ Lymphedema_After_Breast_Cancer_Surgery.asp, 2001; Rowland JH et al. J Natl Cancer Inst.
2000;92:1422-1429; Staps T et al. Cancer. 1985;56:2898-2901.
Local Therapy: Radiotherapy
in Breast Cancer
   Adjuvant radiotherapy in ESBC
      Reduces risk of recurrence
      May improve survival
   Radiotherapy in MBC
      Relieves symptoms such as pain, for example
       in patients with bone and brain metastases,
       while not effecting a cure


ESBC = early-stage breast cancer; MBC = metastatic breast cancer.
Cairncross JG et al. Ann Neurol. 1980;7:529-541; Coia LR. Int J Radiat Oncol Biol Phys. 1992;23:
229-238; Early Breast Cancer Trialists’ Collaborative Group. N Engl J Med. 1995;333:1444-1455;
Harris S. Int J Clin Pract. 2001;55:609-612.
Radiotherapy for Breast Cancer:
Methods of Delivery
   External beam radiation
      Most common method
      Typically, radiation is delivered to entire breast
   Partial-breast irradiation, including brachytherapy
      Radioactive seeds or pellets placed internally
       near the site of the tumor for local effect
      Can deliver high dose-rate radiation, allowing
       for a shorter treatment regimen compared to
       traditional radiotherapy

Gordils-Perez J et al. Clin J Oncol Nurs. 2003;7:629-636.
Partial-Breast Irradiation
for Early-Stage Breast Cancer
   Recent trial compared partial-breast to whole-
    breast irradiation
   199 patients with ESBC
      Breast-conserving surgery
   Median follow-up of 65 months
   Compared to matched controls, recurrence rate
    was similar (1% vs 1%; P = .65)
   Partial-breast irradiation has 5-year local control
    rates comparable to those for whole-breast
    radiation therapy while sparing normal tissues
Vicini FA et al. J Natl Cancer Inst. 2003;95:1205-1210.
Currently Available Systemic
Therapies for Breast Cancer
     Hormonal
     Chemotherapy
     Targeted
     Clinical trials provide support for optimal
      implementation of the above therapies in
      patients with breast cancer
Hormone Therapy Options
for Breast Cancer
Mechanism                                              Options
Estrogen receptor blockade                                 Antiestrogens
                                                              Tamoxifen
                                                              Toremifene
Hormonal ablation                                          Surgery
                                                           Radiation (infrequently used)
                                                           LHRH analogs
                                                              Goserelin
Estrogen synthesis suppression                             Aromatase inhibitors
                                                              Anastrozole
                                                              Exemestane
                                                              Letrozole
Estrogen receptor downregulation                           Estrogen receptor antagonist
                                                              Fulvestrant
LHRH = luteinizing hormone-releasing hormone.
Hayes DR, Robertson JFR. In: Robertson JFR et al, eds. Endocrine Therapy of Breast Cancer. 2002.
Leake R. Endocrine-Related Cancer. 1997;4:289-296; NCI. Available at:
www.cancer.gov/clinicaltrials/results/fulvestrant0802.
Hormonal Environment
of the Breast
                              Gonadotropins                                Ovarian ablation
                                (FSH+LH)
                                                                     Anti-
                                                                   estrogens
                 Premenopausal
                                                  Ovary
                    LHRH
                   analogs                          Prolactin
                                                 Growth hormone

                          Pituitary gland            Corticosteroids
      LHRH                                                             Aromatase
  (hypothalamus)      Pre-/post-                Adrenal                inhibitors
                     menopausal                 glands      Androgens


                                   ACTH                     Progesterone
                                                                Peripheral conversion
FSH = follicle-stimulating hormone; LHRH = luteinizing hormone-releasing hormone;
ACTH = adrenocorticotropic hormone.
Osborne CK. N Engl J Med. 1998;339:1609-1618; Masamura S et al. Breast Cancer Res Treat.
1995;33:19-26.
Evolution of Systemic Adjuvant
Chemotherapy for Early-Stage
Breast Cancer
                                    Mastectomy alone

                                       Adjuvant CMF
                                                                             Progressive
       Addition of                  Adjuvant CAF, CEF                       improvement
       tamoxifen,                                                          in disease-free
       aromatase                Adjuvant AC, EC, FEC                         and overall
        inhibitors                                                             survival
                                     Adjuvant AC +T


               Dose-dense AC + T                   TAC
Bonadonna G et al. N Engl J Med. 1995;332:901-906; Citron ML et al. J Clin Oncol. 2003;21:
1431-1439; Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998;351:1451-1467;
Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998;352:930-942; Henderson IC et al.
J Clin Oncol. 2003;6:976-983; Nabholtz JM et al. ASCO 2002; Orlando, Fla. Presentation.
Preferred Chemotherapy Regimens for
Management of Metastatic Breast Cancer
   Single-agent options for women with recurrent
    or metastatic breast cancer
      Anthracyclines (doxorubicin or epirubicin)
      Taxanes (paclitaxel or docetaxel)
      Capecitabine
      Others not approved by regulatory agencies
         Vinorelbine           Irinotecan
   Combination options for women with recurrent
    or metastatic breast cancer
      CAF/FAC                 AT              Docetaxel/capecitabine
      FEC                     CMF             Paclitaxel/gemcitabine
      AC, EC                                   Paclitaxel (or docetaxel)/
                                                 carboplatin with trastuzumab
NCCN. Breast Cancer: Clinical Practice Guidelines in Oncology. V.1.2004. Available at: www.nccn.org.
Single-Agent vs Combination
Chemotherapy in Metastatic
Breast Cancer
    Optimal treatment for metastatic breast cancer
     remains controversial
    Combination therapy is a good option for patients
     with symptomatic, metastatic breast cancer
    Recent trials show that newer drug combinations
     improve outcomes with manageable safety profiles
    Sequential therapy may be appropriate for patients
     with indolent disease or nonvisceral metastatic
     breast cancer

Biganzoli L et al. Curr Opin Obstet Gynecol. 2004;16:37-41;
Miles D et al. Oncologist. 2002;7(suppl 6):13-19.
Adjuvant Chemotherapy for Early-Stage
Breast Cancer Improves Outcomes
            The Milan Study: Relapse-Free and Overall Survival With CMF
                                               20-year follow-up (N = 386)                         Optimal Dose (%)
                                                                                                       85 (n = 42)
                                                                                                       65-84 (n = 94)
                            100                                                      100               65 (n = 71)
Relapse-Free Survival (%)




                                                                                                       Control (n = 179)




                                                              Overall Survival (%)
                             80                                                      80




                                                                Probability of
     Probability of




                             60                                                      60

                             40                                                      40

                             20                                                      20

                              0                                                        0
                                  0   5   10      15     20                                0   5     10      15     20
                                                  Years After Mastectomy
   Adapted from: Bonadonna G et al. N Engl J Med. 1995;332:901-906.
Reduced Dose Intensity* in Early-
Stage Breast Cancer Chemotherapy
              120       Delay  7 days                  Reduction  15%                          RDI <85%            ARDI<85%*

              100
                                                                  98                       98
                                                             97
                                                                       90
               80
Percent (%)




                                                                                                     72 75 70
                                                   68
               60                                                                     64                                       65
                                              58
                                                                                                                          56
               40
                                    34                                                                               37
                            30 30        31             28                  31                  29
               20                                                                27                             25
                    14 15
                0
                     AC21            CAF21               CAF28               CMF21               CMF28          Overall
               N=     6849               2794                1244                5172                3839            19,898
*Relative dose intensity (RDI) adjusted to a standard doxorubicin/cyclophosphamide (AC) regimen.
Lyman GH et al. J Clin Oncol. 2003;21:4524-4531; Lyman GH et al. ASCO 2004; New Orleans, La.
Abstract 776.
Dose-Dense or Frequent Chemotherapy
for Breast Cancer Reduces Time
Between Cycles
                        Standard dose                      Dose-dense

                 1012                               1012

                 1010                               1010
   Cell Number




                 108                                108

                 106                                106

                 104                                104

                 102                                102

                 100                                100
                         0    8   16       24              0     8      16   24
                                        Time (weeks)
Norton L. Semin Oncol. 1997;24(4 suppl 10):S10-3–S10-10.
Summary of Research on Adjuvant
Chemotherapy for Early-Stage
Breast Cancer
   Adjuvant chemotherapy improves survival in ESBC
   Improved survival outcomes demonstrated with
    an RDI >85% in 1 retrospective analysis with CMF
   Regimens containing an anthracycline and/or
    a taxane show improved outcomes
      Strong data in node-positive breast cancer
   A study of a dose-dense approach (chemotherapy
    Q2W with prophylactic G-CSF support) has
    also demonstrated benefit in disease-free and
    overall survival
RDI = relative dose intensity; ESBC = early-stage breast cancer; CMF =
cyclophosphamide/methotrexate/fluorouracil; G-CSF = granulocyte colony-stimulating factor.
Targeted Therapy Options
for Breast Cancer
      Mechanism                                        Examples
      HER2 inhibitor family                               Antibodies
                                                             Trastuzumab
                                                          Small molecules
                                                             Gefitinib
                                                             Erlotinib*
                                                             Lapafarnib*
      Angiogenesis inhibitor                              Antibodies
                                                             Bevacizumab*
*Investigational agents. HER2 = human epidermal growth factor receptor 2.
Goldman B. J Natl Cancer Inst. 2003;95:1744-1746; Gefitinib [package insert]. 2003; NCCN. Breast
Cancer. Clinical Practice Guidelines in Oncology. V.1.2004. Available at: www.nccn.org; Normanno N
et al. Endocrine-Related Cancer. 2003;10:1-21; US FDA. Available at:
www.fda.gov/bbs/topics/NEWS/2004/NEW01027.html; Perez E. ASCO 2004; New Orleans, La.
Presentation.
Conclusions
   Although the incidence of breast cancer is increasing,
    mortality has decreased over the past 2 decades
   Advances in conventional therapies include less radical
    surgical techniques and reduced radiation fields
   Cytotoxic chemotherapy advances include improved types,
    dosing, and scheduling
   Improvements have also been made in hormonal therapy
   Newer targeted therapies are further advancing
    the care of patients with breast cancer
   Treatment regimens are becoming more individualized

				
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