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

2. Systemic Treatment Approach for Metastatic Breast Cancer Metastatic Breast Cancer  Limited metastases (bone & soft tissue) Positive hormone receptors Positive hormone receptors Hormone responsive Hormone responsive Disease-free interval  2 years Disease-free interval  2 years  Limited metastases (bone & soft tissue) Positive hormone receptors Positive hormone receptors Hormone responsive Hormone responsive Disease-free interval  2 years Disease-free interval  2 years  Extensive disease or visceral crisis Negative hormone receptors Negative hormone receptors No response to hormones No response to hormones  Extensive disease or visceral crisis Negative hormone receptors Negative hormone receptors No response to hormones No response to hormones Hormonal Therapy ChemotherapyChemotherapy ResponseResponse No response No progression Progression of disease If disease progresses, second-line hormonal therapy If disease progresses, second-line hormonal therapy Second-line chemotherapy

3. Hormone positive post-menopausal Metastatic Breast Cancer First line Second line Third line Fourth line Chemotherapy Antiestrogen or Nonsteroidal Aromatase Inhibitor (AI) Nonsteroidal AI or Antiestrogen Steroidal AI Progestin Fifth line Androgen if response No Response

4. 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

5. 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

6.   Selective Versus Nonselective Aromatase Inhibition               

7. Nonselective Aromatase Inhibitors: Limitations Affect steroid hormones other than estrogen— causing adrenal insufficiencyAffect steroid hormones other than estrogen— causing adrenal insufficiency Require concomitant steroid replacement therapyRequire concomitant steroid replacement therapy Low specificityLow specificity Moderate potencyModerate potency Other side effects—CNS effects, skin toxicities, etcOther side effects—CNS effects, skin toxicities, etc

8. Aromatase Inhibitors NonselectiveNonselective –Aminoglutethimide (competitive) SelectiveSelective –Competitive– Noncompetitive (nonsteroidal)(steroidal) »Anastrozole Exemestane »Letrozole Formestane »Vorozole »Fadrozole

9. At least as effective as tamoxifen (time to progression and objective response)At least as effective as tamoxifen (time to progression and objective response) Fewer thromboembolic eventsFewer 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 tamoxifenFirst 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 Anastrozole as First-Line Therapy for Advanced Breast Cancer: Summary

10. Systemic Treatment Approach for Metastatic Breast Cancer Metastatic Breast Cancer  Limited metastases (bone & soft tissue) Positive hormone receptors Positive hormone receptors Hormone responsive Hormone responsive Disease-free interval  2 years Disease-free interval  2 years  Limited metastases (bone & soft tissue) Positive hormone receptors Positive hormone receptors Hormone responsive Hormone responsive Disease-free interval  2 years Disease-free interval  2 years  Extensive disease or visceral crisis Negative hormone receptors Negative hormone receptors No response to hormones No response to hormones  Extensive disease or visceral crisis Negative hormone receptors Negative hormone receptors No response to hormones No response to hormones Hormonal Therapy ChemotherapyChemotherapy ResponseResponse No response No progression Progression of disease If disease progresses, second-line hormonal therapy If disease progresses, second-line hormonal therapy Second-line chemotherapy

11. Cytotoxic Therapy: Metastatic Breast Cancer FDA approved drugs before 1994 Methotrexate1953Methotrexate1953 Cyclophosphamide1959Cyclophosphamide1959 Thiotepa1959Thiotepa1959 Vinblastine1961Vinblastine1961 5-Fluorouracil19625-Fluorouracil1962 Doxorubicin1974Doxorubicin1974

12. Cytotoxic Drugs: approved in 2nd-3rd line Metastatic Breast Cancer after 1994 Paclitaxel 1994Paclitaxel 1994 Docetaxel 1996Docetaxel 1996 Capecitabine 1998Capecitabine 1998 Capecitabine + Docetaxel 2001Capecitabine + Docetaxel 2001 Abraxane 2005Abraxane 2005 Ixabepilone 2007Ixabepilone 2007

13. Biological targeted therapy for Metastatic breast cancer Trastuzumab 1998Trastuzumab 1998 Lapatinib 2006Lapatinib 2006

14. Herceptin (Trastuzumab) Study Design Chemotherapy (AC or Paclitaxel) Herceptin loading: 4 mg/kg weekly: 2 mg/kg  Chemotherapy Alone Patients with untreated MBC HER2 overexpression 2+ 3+

15. Time to Progression (Months) Proportion Progression-Free 0510152025 0.0 0.2 0.4 0.6 0.8 1.0 Herceptin Time to Progression Herceptin Control 

16. Herceptin Overall Survival All Patients

17. Herceptin + Herceptin + Herceptin + ACAC Taxol ® TaxolCTCT Parameter (n = 143)(n = 138)(n = 92)(n = 96) (n = 235) (n = 234) Median TTP (mo) 7.86.16.93.07.44.6 p value < 0.001 <0.001 < 0.001 Median survival (mo) 26.821.422.118.425.120.3 p value 0.16 0.17 0.046 SubstrataOverall Trastuzamab Pivotal Trial: Efficacy Summary Slamon et al. N Engl J Med. 2001;344:783.

18. Metastatic breast cancer Balance the side effects of the treatment with the symptom relief obtained with chemotherapy: no survival advantageBalance the side effects of the treatment with the symptom relief obtained with chemotherapy: no survival advantage

19. Metastatic breast cancer Use of sequential single agent sequential chemotherapy is recommended unless a clinical need for a rapid responseUse of sequential single agent sequential chemotherapy is recommended unless a clinical need for a rapid response »Brachial plexopathy »Painful liver disease »Lymphangic lung disease

20. Her-2 directed therapy Trastuzumab has controlled disease in HER-2 positive patients for longer period of time than in the pre- trastuzumab eraTrastuzumab has controlled disease in HER-2 positive patients for longer period of time than in the pre- trastuzumab era Her-2 directed therapy is continuousHer-2 directed therapy is continuous Metastatic disease can be controlled with chemotherapy plus her-2 directed therapy; but not cured.Metastatic disease can be controlled with chemotherapy plus her-2 directed therapy; but not cured.