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% 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