1. METASTATIC DISEASE IN BREAST CANCER Mario Alberto Vásquez-Chaves, MD MsC Tokyo Women´s Medical University June 2011

2. WHAT IS METASTATIC BRCA? Anything more distant than ipsilateral Axillar or Internal mammary LNs may PRESENT with distant mets may RECURR outside of this area

3. INCIDENCE Between 5-10% metastatic at diagnosis Majority = women relapsing with metastatic disease Roughly 40,000 women die each year from metastatic BrCa

4. SITES OF METASTASES Bones Liver Lungs Brain Peritoneal LAD Skin

5. SURVIVAL WITH MBRCA Can be few months to years ( Vogel et al, Cancer, 1992) 15 - 90+ months Depends on sites involved and rate of tumor progression Volume of disease Nonvisceral vs visceral Receptor status (?HER2) Response to Rx Yamamoto et al, JCO, 1998

6. MEDIAN OVERALL SURVIVAL ~ 2 years (26 months, Vogel JCO, 1992) Stage5 yr OS Colon Ca 5 yr OS BrCa NSCLCa I70%88%40% II60%79%23% III47%54-55%8-9% IV6%18-19%2% NCDB, Five Year Survival Table for Cases Diagnosed in 1998 and 1999

7. CLINICAL VIGNETTE 64 yo F presents with new dry cough, progressive over last several weeks Stage IIB infiltrating ductal, HR+,HER2- diagnosed in 2002 S/p lumpectomy, AC x4, XRT and 5 yrs of AI 40 pack-yr history Work up reveals….

9. SUSPECTED RECURRENCE…. Establish diagnosis ? Need to biopsy 13-40% discordance in receptor status between primary tumor and metastasis Restage CBC, LFTs, imaging

10. DIAGNOSIS ESTABLISHED…. Estimate prognosis Burden and location of mets Estimate likelihood of response to Rx Disease free interval Tumor factors Establish goals of therapy

11. CURRENT TREATMENT PHILOSOPHY MACROmetastasis = expression of systemic disease Locoregional therapy Appropriate if impending local complication Palliative benefit Generally, no improvement in survival Systemic medical therapy backbone of Rx

12. GOALS OF SYSTEMIC THERAPY Controlling disease Palliation Prolong survival ==> no prospective randomized clinical trials showing therapy extends survival over BSC “Cure” Greenberg et al, JCO, 1996 1581 pts with met BrCa CR with therapy = 16% Alive and still in CR at 5 yrs = 1.6%

13. “TREATABLE BUT NOT CURABLE” Prolong survival with as few symptoms and side effects as possible…. Data where available, often no head-to-head trials of the multiple therapies…. OS remains gold standard

14. SYSTEMIC THERAPIES Bisphosphonates Endocrine therapies HER2 targeted therapies Conventional chemotherapy (cytotoxics) Other biologics Toxicity

15. BISPHOSPHONATES Reduction of bony complications (Thierhault et al, JCO, 1999) 1)Which agent? Zolendronate, pamidronate 2)When to start? 1 st met, 1 st bony met…. 3)Timing? q4wks, q3mos…. 4)When to stop??

16. ENDOCRINE THERAPY

17. PREDICTIVE FACTORS, RESPONSE TO HORMONAL THERAPY (TAMOXIFEN, ARIMIDEX) McGuire et al, BCRT, 1987 ERPR Odds Response -- < 10% +-25% -+50% ++75%

18. AGENTS Ovarian ablation/suppression Hormone withdrawal SERMs Tamoxifen  Toremifene Aromatase inhibitors  Steroidal: exemestane  Non-steroidals: anastrozole, letrozole Estrogen receptor down-regulators Androgens/estrogens/progestins  Megesterol acetate

19. ENDOCRINE THERAPY 1) Which patients? Low risk pt (HR-?) How likely to respond? 10-40% RR, SD 20-30% For how long? Response duration variable 2) When to use? Used early: low toxicity, good chance of response Wilcken N, Hornbuckle J, Ghersi D. Cochrane Database of Systematic Reviews 2003

20. ENDOCRINE THERAPY 3) What to use? PRE: Tam vs ovarian suppression vs ??? POST: AI > Tam for RR, OS, TTP (11% benefit in relative HR, Mauri, JCNI, 2006) 2 nd line: evidence for tam, fulvestrant, another AI 3rd, 4th….. ??? 4) Combinations? ET combos: tam+ovarian ablation, no study for AI + Tam in metastatic disease ET + cytotoxics: likely no survival benefit (Fossati et al, JCO, 1998 )

21. HR+ AND HER2+ Conflicting evidence….. TanDem Study Median OS 28.5 months A+H 25.1 months A-->H 17.2 months A alone Clemens et al, ASCO Breast 2007, #231

22. HER2 TARGETED THERAPIES

23. PREDICTIVE FACTORS HER2 status RR Clinical Benefit IHC 3+ 35%48% IHC 2+ 0%7% Vogel et al, JCO, 2002

24. HER2 TARGETED AGENTS Trastuzumab (humanized, monoclonal Ab) Lapatinib (small molecule, tyrosine kinase inhibitor [TKI] of EGFR and HER2) Pertuzumab (monoclonal Ab, blocks dimerization of HER2/3) CI-1033, pan-HER TKI

25. TRASTUZUMAB Can use with or without chemo Monotherapy: RR close to 30%, clinical benefit rate close to 50% (Vogel et al, JCO, 2002) Combination: up to 63% RR, TTP 9 mos for docetaxel + tras, minimal add’l toxicity (Esteva et al, JCO, 2002) When to stop? Slamon et al, NEJM, 2001

26. LAPATINIB Capecitabine/lapatinib vs monotherapy RR 22% vs 14%, p = 0.09 TTP 8.4 vs 4.3 mos, p <0.0001 OS not sig Pts progressing on trastuzumab combined with capecitabine Other combinations? Monotherapy 1st line: RR 24%, TTF 16.1 wks (Gomez et al, JCO, 2007) Geyer et al, NEJM, 2006

27. CHEMOTHERAP Y

28. ESTABLISHED AGENTS Anthracyclines (doxorubicin, mitoxantrone, liposomal doxorubicin) Anti-mitotics (taxanes, vinorelbine, ixabepilone) Anti-metabolites (5FU, capecitabine, methotrexate) Alkylators (cis/carboplatin) Gemcitabine Etoposide

29. CHEMOTHERAPY 1) Which patients? 2) When? Consider if (NCCN consensus-based): Visceral disease with symptoms Patients failing ET Hormone receptor negative Rapidly progressing?

30. COMBINATION VS SEQUENTIAL Trial/DrugsRROSToxicity GP vs P (n = 529) Albain et al, JCO, 2008 40 vs 22% p<0.0001 18.6 vs 15.8 mos p = 0.0489 G4 neutropenia 47.9 vs 11.5%; QoL p = NS ECOG 1193 (n=739) AP vs A vs P Sledge et al, JCO, 2003 47% vs 36% vs 34% p = NS 22 vs 18.9 vs 22.2 p = NS Fact-B, no significant differences Fossati et al, JCO, 1998  over 31,000 women  nearly 200 RCTs n = 996 HR 0.82 Not available

31. SINGLE AGENTS What to use first? No studies to suggest optimal sequence What dose? No advantage to higher dose Schedule? Weekly vs q3Wks, esp for taxanes (CALGB 9840) How likely to respond? First line, RR 30-50% Continuous vs intermittent? PFS prolonged, but probably not OS (Muss et al, NEJM 1991)

32. BEVACIZUMAB: MOVING PAST CYTOXIC COMBINATIONS….

33. E2100 Paclitaxel/bev vs paclitaxel wkly (first-line) PFS 11.8 vs 5.9 mos OS 26.7 vs 25.2 mos (NS) RR 36% vs 21% Grade 3+ CVAs 1.9% Miller et al, NEJM 2007

34. BEVACIZUMAB AVADO study (ASCO 2008) Doce/bev 15 or 7.5 vs docetaxel q3wk alone RR 63.1% vs 55.2% vs 44.4% PFS: 8.8 vs 8.7 vs 8.0 mos HER2+ patients? (phase II, Pegram SABCS 2006) Dose? When to stop? 2nd line? (Miller et al, JCO, 2005) Combinations? (Xcalibur trial, RIBBON-1 and 2)

35. SUMMARY Choose therapy MOST likely to work with LEAST toxicity Monitor pt for response and toxicity When to stop actively treating the cancer in mBrCa??? Return to our patient: Visceral mets Symptomatic ER+PR+ HER2- What’s the right therapy choice?

36. THANKS A LOT