Systemic therapy for Metastatic Breast Cancer Jo Anne Zujewski, MD National Cancer Institute May 2011 Systemic Treatment Approach for Metastatic Breast Cancer Metastatic Breast Cancer Limited metastases (bone & soft tissue) Extensive disease or visceral crisis • Positive hormone receptors • Negative hormone receptors • Hormone responsive • No response to hormones • Disease-free interval 2 years Hormonal Therapy Response No response If disease progresses, second-line hormonal therapy Chemotherapy No progression Progression of disease Second-line chemotherapy Hormone positive post-menopausal Metastatic Breast Cancer First line Second line Antiestrogen or Nonsteroidal Aromatase Inhibitor (AI) Nonsteroidal AI or Antiestrogen if response Third line Steroidal AI if response Fourth line Progestin if response Fifth line Androgen No Response Chemotherapy Hormonal Therapies: Metastatic Breast Cancer • tamoxifen 20 mg po daily • anastrozole 1 mg po daily, letrozole 2.5 mg or exemestane 25 mg (post-menopausal) • Fulvestrant (500 mg IM load then 250 mg IM) • megace 40 mg po 4 x daily • aminoglutethemide 250 mg po 4 x daily with hydrocortisone (post-menopausal) • luteinizing hormone releasing analog 7.5 mg depot every 28 days (pre-menopausal) • oophorectomy Tamoxifen in Metastatic Breast Cancer Response Rates: • All women: 16-52% (CR+PR) • Postmenopausal women – 30-40%: unselected women – 50%: ER+ disease – 60-70%: ER+/PR+ disease • Premenopausal women – 20-45% – Efficacy equivalent to oophorectomy Selective Versus Nonselective Aromatase Inhibition Cholesterol Multiple steps involving P-450 enzymes and production of steroid intermediates Aldostero ne Cortisol Selective Inhiitors Nonselective Inhiitors Androstenedio ne Testosteron e Estrone Estradiol Federman, DD: The Adrenal. Dale DC, Federman DD, eds. In: Scientific American Medicine. Section 3. Susection I. 1997 Scientific American Inc. All rights reserved. Nonselective Aromatase Inhibitors: Limitations • Affect steroid hormones other than estrogen— causing adrenal insufficiency • Require concomitant steroid replacement therapy • Low specificity • Moderate potency • Other side effects—CNS effects, skin toxicities, etc Aromatase Inhibitors • Nonselective –Aminoglutethimide (competitive) • Selective –Competitive – Noncompetitive (nonsteroidal) (steroidal) »Anastrozole • Exemestane »Letrozole • Formestane »Vorozole »Fadrozole Anastrozole as First-Line Therapy for Advanced Breast Cancer: Summary • At least as effective as tamoxifen (time to progression and objective response) • Fewer thromboembolic events • First aromatase inhibitor to demonstrate at least equivalence to tamoxifen— compared with previous studies using fadrozole and formestane— both had lower antitumor activity compared to tamoxifen Systemic Treatment Approach for Metastatic Breast Cancer Metastatic Breast Cancer Limited metastases (bone & soft tissue) Extensive disease or visceral crisis • Positive hormone receptors • Negative hormone receptors • Hormone responsive • No response to hormones • Disease-free interval 2 years Hormonal Therapy Response No response If disease progresses, second-line hormonal therapy Chemotherapy No progression Progression of disease Second-line chemotherapy Cytotoxic Therapy: Metastatic Breast Cancer FDA approved drugs before 1994 • • • • • • Methotrexate 1953 Cyclophosphamide1959 Thiotepa 1959 Vinblastine 1961 5-Fluorouracil 1962 Doxorubicin 1974 Cytotoxic Drugs: approved in 2nd-3rd line Metastatic Breast Cancer after 1994 • • • • • • Paclitaxel Docetaxel Capecitabine Capecitabine + Docetaxel Abraxane Ixabepilone 1994 1996 1998 2001 2005 2007 Biological targeted therapy for Metastatic breast cancer • Trastuzumab • Lapatinib 1998 2006 Herceptin (Trastuzumab) Study Design Chemotherapy (AC or Paclitaxel) 469 Herceptin loading: 4 mg/kg weekly: 2 mg/kg Chemotherapy Alone Patients with untreated MBC HER2 overexpression 2+ 3+ 1.0 0.8 p < 0.001 0.6 Herceptin 0.2 0.4 Control 0.0 Proportion Progression-Free Herceptin Time to Progression 0 5 10 15 20 Time to Progression (Months) 25 Herceptin Overall Survival All Patients Trastuzamab Pivotal Trial: Efficacy Summary Substrata Herceptin + AC AC Parameter (n = 143) Median TTP (mo) p value 7.8 Median survival (mo) p value 26.8 (n = 138) Overall Herceptin + Taxol® Taxol Herceptin + CT CT (n = 92) (n = 96) (n = 235) 6.1 < 0.001 6.9 3.0 7.4 21.4 22.1 18.4 25.1 0.16 Slamon et al. N Engl J Med. 2001;344:783. <0.001 0.17 (n = 234) 4.6 < 0.001 20.3 0.046 Metastatic breast cancer • Balance the side effects of the treatment with the symptom relief obtained with chemotherapy: no survival advantage Metastatic breast cancer • Use of sequential single agent sequential chemotherapy is recommended unless a clinical need for a rapid response »Brachial plexopathy »Painful liver disease »Lymphangic lung disease Her-2 directed therapy • Trastuzumab has controlled disease in HER-2 positive patients for longer period of time than in the pretrastuzumab era • Her-2 directed therapy is continuous • Metastatic disease can be controlled with chemotherapy plus her-2 directed therapy; but not cured.