Breast Cancer Hormonal Therapy

What’s New with Hormonal Agents in Breast Cancer? Robin O’Brien BScPharm PharmD BCOP BC Cancer Agency Nov 2003 Goals • review hormonal therapy • what’s new? – which SERM for prevention? – tamoxifen or an aromatase inhibitor for adjuvant therapy … or both? – role of LHRH analogues? – fulvestrant for palliative therapy? Good News: Decreased Mortality www.cancer.ca Bad News: Increased Incidence www.cancer.ca Increased Incidence in Postmenopausal Women Only Incidence Mortality Age 70+ Age 50-69 Age 25-49 No Change Case 1 Brenda is bothered by troublesome hot flashes that wake her up at night. She is considering using estrogen replacement therapy but is worried about her risk of developing breast cancer. She also wonders about breast cancer prevention. Role of Hormones in Breast Cancer > estrogen declared a carcinogen (Dec. 2000) - endometrial and breast cancers > estrogen acts as fertilizer for breast cancer - tumour initiation and promotion > cancer risk related to lifetime estrogen exposure > estrogen & progesterone receptors found on tumours > combined estrogen + progesterone  cancer risk > Women’s Health Initiative study terminated Estrogen Replacement Limit to short-term management of hot flashes. Continuous progestin appears safer than cyclic. NCI Risk Assessment Tool www.bcra.nci.nih.gov/brc/ > > > > > > Risk Factors age age at first menses age at first live birth mother or sister(s) with breast cancer previous biopsies atypical hyperplasia on biopsy Primary Prevention: bcra.nci.nih.gov Prevention • • • • • • avoid exogenous estrogens have a large family early breast feed include soy products in diet avoid alcohol optimize weight SERMs for Primary Prevention Selective Estrogen Receptor Modulators > tamoxifen – anti-estrogenic in breast tissue - estrogenic in endometrium, may cause cancer - reduced ER(+) tumours by 49% in prevention trial > raloxifene - tamoxifen analogue, no effect on endometrium - reduced ER(+) tumours by 76% in MORE osteoporosis trial - not recommended for prevention outside of clinical trials - not recommended for women with a history of breast cancer Canadian Task Force on Preventive Health Care 5% risk warrants tamoxifen x 5 years Canadian Guidelines Can Med Assoc J 2001;164:1681 Prevention Bottom Line • avoid exogenous estrogen • avoid alcohol, optimize weight • 5% 5-year risk warrants tamoxifen x 5 years Case 2 Susan has just completed adjuvant chemotherapy. Her physician recommends tamoxifen x 5 years but she has heard that aromatase inhibitors are “leading edge”. She wonders if she should be offered another option. Adjuvant Treatment surgery +/- radiation +/- chemotherapy ER(+) or PR(+) Tamoxifen x 5 years Low Risk High Risk Tamoxifen contraindicated and postmenopausal ER(-)PR(-) no further treatment no further treatment Letrozole x ? years Anastrozole x 5 years International Consensus Risk Assessment Minimal - Low Risk Avg. - High Risk Tumour Size HR Status Grade 2cm (+) ve 1  35 years (-) ve > 2cm (-) ve 2-3 <35 years (+) ve Age Lymph Node J Clin Oncol 2001;19:3817. 5-year Outcomes Stage I small primary II regional spread % of Cases 40 40 % DFS 70-90 50-70 % Survival 96 78 III locally advanced IV metastatic 15 5 20-30 0-10 n/a 21 Adjuvant Hormones > not a cure, reduces recurrence risk if HR (+) > hot flashes most common side effect > tamoxifen x 5 years - gold standard for HR (+) tumours - may cause endometrial cancer, thromboembolism > aromatase inhibitors (anastrozole, letrozole) > > > > anastrozole x 5 years instead of tamoxifen letrozole x 5 years following tamoxifen women must be postmenopausal may cause arthritis, arthralgias, myalgias Estrogen Pathway Cholesterol Progesterone DHEA Androstenedione Testosterone Aromatase Aromatase Estrone Estradiol Sites of Aromatase Activity Clemens M, Goss P. NEJM 2001;344:276-85. NEJM 348:2432. ATAC: Anastrozole vs Tamoxifen as Adjuvant Therapy (early results) Objective Method Result Conclusion Disease-free survival (DFS), safety A vs. T vs. A+T x 5 y adjuvant therapy for breast cancer in postmenopausal women. Multicentre, randomized, double-blind, n=9366. Interim analysis at median FU=33 months. DFS: anastrozole superior (except with chemo and radiation) Contralateral cancers: anastrozole superior - DFS, tolerability: anastrozole superior - Bone density: tamoxifen superior - Cognition: need longer follow-up - Overall survival difference: need longer follow-up Lancet 2002;359:2131-9. ATAC Early Results 100 80 60 % Event 40 Free Anastrozole Tamoxifen/A+T 20 0 6 12 18 24 30 Months 36 42 Number Needed to Treat NNT to prevent 1 additional recurrence over tamoxifen = 50 Incremental cost to prevent 1 additional recurrence over tamoxifen = $420,000 Letrozole after Tamoxifen Adjuvant Therapy (early results) Objective Method Result Conclusion Disease-free survival (DFS), contralateral cancers with letrozole 2.5 mg vs placebo x 5 years following tamoxifen adjuvant therapy in postmenopausal women. Multicentre, randomized, double-blind, n=5187. Interim analysis at median FU=29 months. DFS, contralateral cancers: letrozole superior Tolerability: hot flashes, arthritis, arthralgias, myalgias - DFS, contralateral cancers: letrozole superior - Bone density: need longer follow-up, use calcium and vit D - Overall survival difference: need longer follow-up - Optimal duration of therapy: unknown NEJM 2003;349(19). Adjuvant Exemestane NSABP clinical trial testing exemestane after 5-years tamoxifen recently terminated following letrozole results. Adjuvant Bottom Line • tamoxifen remains the gold standard • anastrozole an option if tamoxifen contraindicated • letrozole after 5-years tamoxifen an option if high risk Case 3 Laura has metastatic breast cancer that responded to an aromatase inhibitor for almost a year but is now progressing. She is wondering about treatment options with other hormonal agents. Palliative Treatment Stage IV: Distant Metastases bisphosphonate if bone metastases Indolent Disease premenopausal postmenopausal Aggressive Disease anthracycline? HER2 (+) hormones trastuzumab + chemotherapy HER2 (-) chemotherapy supportive care LHRH analogue chemotherapy Palliative Hormones LHRH analogue if premenopausal adjuvant tamoxifen? none or > 1 year ago < 1 year ago or anastrozole or tamoxifen? fulvestrant? or megestrol exemestane testosterone letrozole Line 1, 2 tamoxifen 3, 4, 5 6 Fulvestrant via Special Access Programme • efficacy equivalent to anastrozole – 250 mg IM once monthly ($175 US) – studied in postmenopausal women • pure antiestrogen, no agonist activity – blocks and downregulates ER and PR • no known interactions, 3A4 substrate Bottom Line • adjuvant tamoxifen remains gold standard • adjuvant aromatase inhibitors an option for postmenopausal women • palliative LHRH analogues an option for premenopausal women • palliative fulvestrant available via SAP Avoid Hormonal NHPs aletris alfalfa anise B-sitosterols bitter melon black cohosh blue cohosh chasteberry DHEA dong quai EPO fennel flaxseed Flor*Essence ginseng licorice milk thistle raspberry leaf red clover resveratrol scarlet pimpernel soy supps wild yam Take Home Message • adjuvant tamoxifen remains the gold standard • aromatase inhibitors are an option for postmenopausal women • fulvestrant is available through SAP