1. Current Therapy of Metastatic Breast Cancer Julie R. Gralow, M.D Assistant Professor, Medicine/Oncology University of Washington School of Medicine Fred Hutchinson Cancer Research Center

2. Metastatic Breast Cancer Metastatic breast cancer is generally incurable with current conventional therapyMetastatic breast cancer is generally incurable with current conventional therapy Median survival after development of metastatic breast cancer is 3 yearsMedian survival after development of metastatic breast cancer is 3 years Goals in the treatment of metastatic breast cancer:Goals in the treatment of metastatic breast cancer: –Control and regression of disease –Improvement in quality of life –Prolongation of life –??Cure

3. Metastatic Breast Cancer Choice of treatment is based on several factors:Choice of treatment is based on several factors: –age, menopausal status, performance status –HR status, HER-2 status –disease-free interval from diagnosis or previous treatment –response to previous treatment –presence of life-threatening disease –extent and sites of metastatic disease

4. Hormonal Therapy

5. Hormone Therapy for Metastatic Breast Cancer A reasonable first-line approach for patients with ER/PR positive tumors who do not have lymphangitic lung disease, liver metastasis, or life-threatening, rapidly-progressive disease.A reasonable first-line approach for patients with ER/PR positive tumors who do not have lymphangitic lung disease, liver metastasis, or life-threatening, rapidly-progressive disease. There is little clinical evidence that one form of hormone therapy is more effective than another.There is little clinical evidence that one form of hormone therapy is more effective than another. Selection is generally based on the relative toxicities.Selection is generally based on the relative toxicities.

6. Hormone Therapy for Metastatic Breast Cancer Anti-estrogens: tamoxifen (Nolvadex), toremifene (Fareston)Anti-estrogens: tamoxifen (Nolvadex), toremifene (Fareston) Aromatase inhibitors: ananstrazole (Arimidex), letrozole (Femara), exemestane (Aromasin), aminoglutethamideAromatase inhibitors: ananstrazole (Arimidex), letrozole (Femara), exemestane (Aromasin), aminoglutethamide Progestins: megestrol acetate (Megace), medroxyprogesteroneProgestins: megestrol acetate (Megace), medroxyprogesterone Estrogens: DESEstrogens: DES Androgens: HalotestinAndrogens: Halotestin Medical or surgical oophorectomy: goserelin (Zoladex), leuprolide (Lupron)Medical or surgical oophorectomy: goserelin (Zoladex), leuprolide (Lupron)

7. Aromatase Inhibitors Adrenal Hormones CortisolAndrostenedioneAldosterone Estradiol TestosteroneEstrone

8. Letrozole (Femara) vs. Tamoxifen (Nolvadex) as First-line Treatment of Advanced Breast Cancer R Smith et al, San Antonio 2000 907 postmenopausal breast cancer patients with locally advanced or metastatic breast cancer907 postmenopausal breast cancer patients with locally advanced or metastatic breast cancer –65% ER/PR positive –20% prior anti-estrogen treatment Treatment: Randomized to letrozole 2.5 mg/day vs. tamoxifen 20 mg qdTreatment: Randomized to letrozole 2.5 mg/day vs. tamoxifen 20 mg qd Results: TTPOR Clinical BenefitResults: TTPOR Clinical Benefit Letrozole41 wks30%49% Tamoxifen26 wks20%38% (p=0.0001)(p=0.001)(p=0.001)

9. Pre-Operative Letrozole (Femara) vs. Tamoxifen Ellis et al, San Antonio 2000 337 postmenopausal ER/PR positive breast cancer patients with primary tumors > 2 cm (not a candidate for breast conserving surgery - BCS)337 postmenopausal ER/PR positive breast cancer patients with primary tumors > 2 cm (not a candidate for breast conserving surgery - BCS) Treatment: Letrozole 2.5 mg qd vs. tamoxifen 20 mg qd x 4 monthsTreatment: Letrozole 2.5 mg qd vs. tamoxifen 20 mg qd x 4 months Toxicity: well toleratedToxicity: well tolerated Response:OR RR HER2+ RR HER2- BCSResponse:OR RR HER2+ RR HER2- BCS Letrozole55% 69% 53% 45% Tamoxifen36% 17% 40% 36% (p<0.001) (p=0.022)

10. Chemotherapy

11. Chemotherapy for Metastatic Breast Cancer Optimal agentsOptimal agents Dose intensity, dose densityDose intensity, dose density Treatment schedulesTreatment schedules Monotherapy vs. combination regimensMonotherapy vs. combination regimens Duration of therapyDuration of therapy Addition of biologicsAddition of biologics

12. Chemotherapy for Metastatic Breast Cancer Anthracyclines: doxorubicin (Adriamycin), epirubicin (Ellence), mitoxantrone, liposomal formulations (Doxil)Anthracyclines: doxorubicin (Adriamycin), epirubicin (Ellence), mitoxantrone, liposomal formulations (Doxil) Taxanes: paclitaxel (Taxol), docetaxel (Taxotere)Taxanes: paclitaxel (Taxol), docetaxel (Taxotere) Vinca alkaloids: vinblastine (Velban), vinorelbine (Navelbine)Vinca alkaloids: vinblastine (Velban), vinorelbine (Navelbine) Alkylating agents: cyclophosphamide, melphalan, thiotepa, cisplatin, carboplatinAlkylating agents: cyclophosphamide, melphalan, thiotepa, cisplatin, carboplatin Antimetabolites: 5-FU, methotrexate, gemcitabine (Gemzar), capecitabine (Xeloda)Antimetabolites: 5-FU, methotrexate, gemcitabine (Gemzar), capecitabine (Xeloda) Topoisomerase inhibitors: etoposide (VP-16)Topoisomerase inhibitors: etoposide (VP-16)

13. Capecitabine (Xeloda) Selective tumor-activated fluoropyrimidineSelective tumor-activated fluoropyrimidine FDA-approved in U.S. 1998FDA-approved in U.S. 1998 Oral agentOral agent Activity observed in breast and colon cancersActivity observed in breast and colon cancers No alopecia, minimal myelosuppressionNo alopecia, minimal myelosuppression

14. A Multicenter Phase II Trial of Capecitabine (Xeloda) in Paclitaxel (Taxol)-Refractory Metastatic Breast Cancer Blum, ASCO 1998 Patients: 163 paclitaxel-resistant breast cancer patients, 2-3 prior regimensPatients: 163 paclitaxel-resistant breast cancer patients, 2-3 prior regimens Treatment: Capecitabine 2510 mg/m2/day divided bid given for 2 out of 3 weeksTreatment: Capecitabine 2510 mg/m2/day divided bid given for 2 out of 3 weeks Toxicity: Grade 3/4 diarrhea (14%), hand-foot syndrome (10%)Toxicity: Grade 3/4 diarrhea (14%), hand-foot syndrome (10%) Response: 20% response rate (3 CRs), median duration of response 8.1 months, TTP 93 daysResponse: 20% response rate (3 CRs), median duration of response 8.1 months, TTP 93 days

15. A Randomized Phase II Trial of Capecitabine (Xeloda) vs. CMF as First Line Chemotherapy of Breast Cancer in Women Aged > 55 Years O’Shaughnessy, ASCO 1998 Patients: 95 untreated stage IV breast cancer patients > 55Patients: 95 untreated stage IV breast cancer patients > 55 Treatment: Capecitabine 2510 mg/m2/day divided bid 2 out of 3 weeks vs. CMFTreatment: Capecitabine 2510 mg/m2/day divided bid 2 out of 3 weeks vs. CMF

16. A Randomized Phase II Trial of Capecitabine (Xeloda) vs. CMF as First Line Chemotherapy of Breast Cancer in Women Aged > 55 Years O’Shaughnessy, ASCO 1998 Grade 3/4 toxicity:Grade 3/4 toxicity: – Hand-foot syndrome: Capecitabine 16%, CMF 0% –Diarrhea: Capecitabine 8%, CMF 3% –Myelosuppression: Capecitabine 20%, CMF 47% Results:Results: –Response rate: Capecitabine 25%, CMF 16% –Median TTP: Capecitabine 132 days, CMF 94 days

17. Docetaxel (Taxotere) +/- Capecitabine (Xeloda) in Stage IV Breast Cancer O’Shaughnessy et al, San Antonio 12/00 Patients: 511 stage IV breast cancer patients, s/p anthracyclinePatients: 511 stage IV breast cancer patients, s/p anthracycline Treatment: Docetaxel 100 mg/m2 q3 wks vs. docetaxel 75 mg/m2 q3 wks plus capecitabine 2500 mg/m2 days 1-14Treatment: Docetaxel 100 mg/m2 q3 wks vs. docetaxel 75 mg/m2 q3 wks plus capecitabine 2500 mg/m2 days 1-14

18. Docetaxel (Taxotere) +/- Capecitabine (Xeloda) in Stage IV Breast Cancer O’Shaughnessy et al, San Antonio 12/00 Toxicity: T alone: more neutropenia, myalgia, arthralgia. T/X: more diarrhea, stomatitis, nausea, vomiting, hand/foot syndromeToxicity: T alone: more neutropenia, myalgia, arthralgia. T/X: more diarrhea, stomatitis, nausea, vomiting, hand/foot syndrome Results: T/X TResults: T/X T Overall survival 14.4 mo11.2 mop=0.0159 1 year survival56.7%46.2%n.s. OR 41.6%29.7p=0.06 TTP6.1 mo4.2 mop=0.0001

19. Paclitaxel (Taxol) Plus Carboplatin First-line Therapy in Metastatic Breast Cancer (NCCTG 953252) Perez et al, Cancer 2000 Patients: 50 evaluable patientsPatients: 50 evaluable patients –No prior therapy for metastatic disease Treatment: Paclitaxel 200 mg/m2 over 3-hrs and carboplatin AUC 6 q3 wksTreatment: Paclitaxel 200 mg/m2 over 3-hrs and carboplatin AUC 6 q3 wks

20. Paclitaxel (Taxol) Plus Carboplatin as First-line Therapy in Metastatic Breast Cancer (NCCTG) Perez et al, Cancer 2000 Toxicity:Toxicity: –grade 3-4 neutropenia: 82% –febrile neutropenia: 0 –grade 3 neuropathy: 16% Results:Results: –OR: 62%; CR: 16%; PR: 46% –Median TTP: 7.3 mo –12 mo survival estimate: 72%

21. UW Docetaxel (Taxotere)/Vinorelbine (Navelbine) Regimen Gralow et al, ASCO 2000 Patients: Stage IV breast cancer, s/p anthracyclinePatients: Stage IV breast cancer, s/p anthracycline –Prior taxane 45% –Concurrent trastuzumab (Herceptin) 31% Treatment:Treatment: –Docetaxel 60 mg/m2 day 1 –Vinorelbine 27.5 mg/m2 days 8+15 –G-CSF days 2-21

22. UW Docetaxel (Taxotere)/Vinorelbine (Navelbine) Regimen Gralow et al, ASCO 2000 ToxicityToxicity –6/39 grade 4 neutropenia, 3/39 febrile neutropenia, 5/39 treated for infection, 1/39 grade 4 thrombocytopenia –Grade 3/4 non-hematologic toxicities: 1 case each of grade 3 stomatitis, diarrhea, neuropathy ResponseResponse –OR 59.4% (22/37) –CR 29.7% (11/37)

23. Biological Therapy

24. HER-2 in Breast Cancer HER-2 growth factor receptor nucleus cell division ligand cancer cell

25. Trastuzumab (Herceptin) Anti-HER-2 Antibody BREAST CANCER CELL HER-2

26. Trastuzumab (Herceptin) Derived from murine 4D5 antibodyDerived from murine 4D5 antibody 95% humanized recombinant molecule95% humanized recombinant molecule Targets ECD of HER2 growth factor receptorTargets ECD of HER2 growth factor receptor Anti-proliferative to HER2+ cell linesAnti-proliferative to HER2+ cell lines Enhances antibody dependent cellular toxicityEnhances antibody dependent cellular toxicity Not immunogenicNot immunogenic

27. Trastuzumab (Herceptin) Plus Chemotherapy in Metastatic Breast Cancer Slamon et al, NEJM 2001 31 month follow-up31 month follow-up AC+HACT+HT CR8%4%8%2% PR48%38%34%15% OR56%42%41%17% Duration9.1 mo6.710.54.5 p<0.001 TTP7.8 mo6.16.93.0 p<0.001 Survival 26.8 mo21.4 22.118.4 p=0.16

28. Trastuzumab (Herceptin) Cardiotoxicity H AC+HAC T+HT Any Dysfunction 7% 28%7% 11%1% Class III-IV 5% 19%3% 4%1% Class III-IV 6% 0% after rx 94% of pts in H-only trial had received an anthracycline Only correlated risk factor: age (not corrleated with anthracycline dose, prior XRT, HER-2 expression level)

29. Future Applications of Trastuzumab (Herceptin): Proposed and Ongoing Studies New treatment combinationsNew treatment combinations Earlier stage breast cancerEarlier stage breast cancer Easier routes and schedules of administrationEasier routes and schedules of administration Lower levels of HER-2 expressionLower levels of HER-2 expression Other tumor typesOther tumor types

30. Anti-Cancer Treatment Strategies Cytotoxic drugsCytotoxic drugs –new analogs, classes, molecules Hormonal AgentsHormonal Agents Drug resistance modulatorsDrug resistance modulators Immunologic approachesImmunologic approaches –Antibodies, immunoconjugates, fusion proteins, vaccines Growth factor directedGrowth factor directed –HER-2, EGFR, hormonal receptors, mammastatin, osteoclast

31. Anti-Cancer Treatment Strategies Signal transduction inhibitorsSignal transduction inhibitors –Tyrosine kinase, farnesyl transferase Angiogenesis inhibitorsAngiogenesis inhibitors Apoptosis inducers (SAANDS)Apoptosis inducers (SAANDS) Inhibition of the metastatic cascadeInhibition of the metastatic cascade –Adhesion molecules, matrix metalloprotease inhibitors Gene therapyGene therapy