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 Lung and bronchus Colon and rectum Uterine corpus Ovary Non-Hodgkin’s lymphoma 160 140 120 100 80 Rate per 100,000 Females 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 Lung and bronchus Colon and rectum Uterus Ovary Pancreas 60 50 40 Rate per 100,000 Females 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. .
Childbearing absent or delayed until after age 30 years Early menarche/ late menopause Hormone replacement therapy High body mass index High alcohol intake Risk Factors for Breast Cancer • Personal history of breast cancer or proliferative breast disease • Genetic mutations in BRCA1, BRCA2, and others • Positive family history of breast or ovarian cancer • History of DES therapy (exposure to estrogen or 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 (patients ≥35 years) • First-degree relatives with breast cancer • 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 • Age at menarche • Age at first live birth • Ethnicity 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: Tumor confined to the breast (node-negative) Early disease: Tumor >2 cm in diameter or spread to movableipsilateral axillarynode(s) (node-positive) Locally advanced disease:Tumor spread to thesuperficial structures ofthe chest wall; involvementof ipsilateral internal mammary lymph nodes Advanced (or metastatic) disease: Metastases presentat distant sites such as bone, liver, lungs, and brain, and including supraclavicular 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: • Tumor size • Node involvement • Whether the cancer has spread to the lymph nodes of the breast (axilla, internal mammary, supraclavicular, intramammary) • Metastasis • Whether the tumor has spread to other parts of the body 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 • Physical examination • Mammogram; MRI in some cases • Lumpectomy • If DCIS in 1 area • Mastectomy • If DCIS in 2 areas • If multifocal or “large” • Usually (not always) accompanies lumpectomy • In selected ER-positive cases; for 5 years to lower cancer risk Surveillance(LCIS, DCIS) Surgery(DCIS) Radiotherapy(DCIS) Hormonal therapy(DCIS) 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) • Lumpectomy or quadrantectomy • Axillary dissection • Affected breast, chest wall • Combination chemotherapy • 3-6 months • Premenopausal • Tamoxifen if ER-positive • Postmenopausal • Tamoxifen and/or aromatase inhibitor Breast conservation surgery Radiotherapy Adjuvant chemotherapy Adjuvant hormonal therapy 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 • Chest wall, regional nodes • Combination chemotherapy • 4-6 months • Benefit if tumor ER-positive and/or PR-positive Radiotherapy Adjuvant/neoadjuvant chemotherapy Hormonal therapy 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 • Used in selected cases to relieve symptoms • Used in selected cases to relieve symptoms and control local disease • Primary therapy; single-agent or combination chemotherapy • HER2-positive • ER-positive and/or PR-positive Surgery Radiotherapy Chemotherapy Monoclonal antibody Hormonal therapy 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 • Antiestrogens • Tamoxifen • Toremifene • Surgery • Radiation (infrequently used) • LHRH analogs • Goserelin • Aromatase inhibitors • Anastrozole • Exemestane • Letrozole • Estrogen receptor antagonist • Fulvestrant Estrogen receptor blockade Hormonal ablation Estrogen synthesis suppression Estrogen receptor downregulation 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 Ovarian ablation Gonadotropins(FSH+LH) Anti-estrogens Premenopausal Ovary LHRHanalogs Prolactin Growth hormone Pituitary gland Corticosteroids Aromataseinhibitors LHRH (hypothalamus) Pre-/post-menopausal Adrenalglands 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 improvement in disease-free and overall survival Addition of tamoxifen, aromatase inhibitors Adjuvant CAF, CEF Adjuvant AC, EC, FEC 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 (%) ³85 (n = 42) 65-84 (n = 94) 65 (n = 71) Control (n = 179) 100 100 80 80 60 60 Probability of Relapse-Free Survival (%) Probability of Overall Survival (%) 40 40 20 20 0 0 0 0 5 10 15 20 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 Reduction 15% Delay 7 days RDI <85% ARDI<85%* 100 98 98 97 90 80 75 72 70 68 60 Percent (%) 65 64 58 56 40 37 34 30 30 31 31 28 29 20 27 25 15 14 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 1010 108 106 104 102 100 1012 1010 108 106 104 102 100 Cell Number 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 *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