Systemic therapy for Metastatic Breast Cancer Jo Anne

Systemic therapy for Metastatic Breast Cancer Jo Anne Zujewski, MD National Cancer Institute May 2011

Systemic Treatment Approach for 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 Inhibitors Nonselective Inhibitors Androstenedio ne Testosteron e Estrone Estradiol Federman, DD: The Adrenal. Dale DC, Federman DD, eds. In: Scientific American Medicine. Section 3. Subsection IV. © 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 • 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 • Cyclophosphamide 1959 • Thiotepa 1959 • Vinblastine 1961 • 5 -Fluorouracil 1962 • Doxorubicin 1974

Cytotoxic Drugs: approved in 2 nd-3 rd line Metastatic Breast Cancer after 1994 • • • Paclitaxel Docetaxel 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 HER 2 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 Parameter Herceptin + AC AC Overall Herceptin + Taxol® Taxol CT CT (n = 143) (n = 138) (n = 92) (n = 96) (n = 235) Median TTP (mo) p value 7. 8 6. 1 6. 9 3. 0 7. 4 Median survival (mo) p value 26. 8 18. 4 25. 1 < 0. 001 21. 4 0. 16 Slamon et al. N Engl J Med. 2001; 344: 783. <0. 001 22. 1 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.