Early breast updates

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  • 1.Early Breast Cancer Updates

2. WhyEffect of adjuvant therapy : adjuvant hormonal with Tam. (ER +ve) 40% decrease in risk of recurrence by 5 years. 34% decrease in br. cancer mortality by 5 years. adjuvant polychemotherapy . < 50 years old: 10% decrease in br. cancermortality by 15 years. 50-69 years old: 3% decrease in risk of br.cancer mortality by 15 yearsMeta-analyses of adjuvant therapies for women with early breast cancer: the Early Breast Cancer Trialists Collaborative Group overview Annals of Oncology17 (Supplement 10): x59x62, 2006. 3. Outline Molecular Classification. Adjuvant Chemotherapy. Adjuvant Hormonal. Adjuvant Targeted Therapy. Neoadjuvant therapy. 4. Molecular Classification: Early EBC was 2 groups only Now we reached to more recent approachutilizing both TNM staging Plus ER/PR statusand Her2 status. Dividing EBC into 4 maingroupsNode ve Node +veLuminal AER ++ Luminal BER +Her 2 +veTriple veBasal likevirulent 5. Disease outcome in subgroups 6. What are the lessons we achievedfrom molecular classification Lumina A: more benefit in hormonal and lessin chemo. Luminal B: grey zone: chemo, hormonaland/or Her 2 blockade (Luminal B2) Her 2 +ve: benefit from single and morerecently dual Her 2 blockade + chemo Triple negative: the hidden mystery, rapidresponse to chemo, but still survive poor. 7. Prognostic and Predictive markers:are we there yet? In the last decade, advances in gene expression profilingdramatically changed our understanding of genomic andtranscriptomic landscape of breast cancer, withimproved our ability to prognosticate behavior andresponse to treatment. Traditional prognostic factors: Tumor size, Nodalstatus, Histological grade ER/PR status , Her 2 statusand age. Multiparametric tools have been developed toimprove the predictive value of those factors TNM stagingNottingham Prognostic indexAdjuvant online ( http://www.adjuvantonline.com) 8. Prognostic multigene classifiers in routineclinical practice: among the them, the top 3 assays incurrent clinical decision making are Oncotype Dx, the 21 gene assay.Mammaprint the 70 gene signature of Vant veer.PAM50 clinically updated version of intrinsic subtypes.Why Oncotype Dx in EBC: Use paraffin embaded fixed materials Prognostic Predictive value for the value of chemo in those of HR+ve. Her 2-ve, -ve Node Validated in randomized trail : NSABP B14, B20 9. The Oncotype DX 16 BREAST CANCER RELATED GENESEstrogenERPRBcl2SCUBE2ProliferationKi-67STK15SurvivinCyclin B1MYBL2HER2GRB7HER2InvasionStromelysin 3Cathepsin L2OthersCD68GSTM1BAG1 5 REFERENCE GENESBeta-actin GAPDH RPLPO GUS TFRCPaik S, et al. N Engl J Med. 2004;351:2817-2826. 10. The Oncotype DX Recurrence Score is correlated withdistant recurrence rate at 10 years, hormone therapybenefit, and chemotherapy benefit. Low risk is up to 17 Intermediate risk 18-30 High risk > 30 Validation: a study was performed to clinically validate theprespecified 21-gene RT-PCR assay and Recurrence Scorealgorithm as a predictor of the prospectively definedprimary endpoint of distant recurrence-free survival innode-negative, estrogen receptorpositive patients treatedwith tamoxifen from the large multicenter study NSABP -B14. 11. Distant recurrence over time10-Year rate of recurrence =6.8%*95% CI: 4.0%, 9.6%0 2 4 6 8 10 12 14 160%10%20%30%40%50%60%70%80%90%100%ProportionwithoutdistantrecurrenceRS < 18, n = 338RS 18-30, n = 149RS 31, n = 181All Patients, n = 668P < 0.00110-Year rate of recurrence =14.3%95% CI: 8.3%, 20.3%10-Year rate of recurrence =30.5%*95% CI: 23.6%, 37.4%Oncotype DX Clinical Validation: NSABP B-14, Distant RecurrencePaik S, et al. N Engl J Med. 2004;351:2817-2826. 12. Oncotype DX Clinical Validation: NSABPB-20 Objective: Prospectively determine therelationship between Recurrence Score resultand chemotherapy benefit in node-negative,ER+ patientsRandomizedTam + MFTam + CMFTamPaik S, et al. J Clin Oncol. 2006;24:3726-3734. 13. absolute benefitfrom tamoxifen +chemotherapyN EventsAll patientsTamoxifen + chemotherapyTamoxifen4242273331 P = 0.02RS 18-30Tamoxifen + chemotherapyTamoxifen894594 P = 0.39RS < 18Tamoxifen + chemotherapyTamoxifen21813584 P = 0.61N EventsRS 18-30Tamoxifen + chemotherapyTamoxifen894594 P = 0.39PATIENTS WITH HIGH RS28% absolute benefit fromtamoxifen +chemotherapyRS 31Tamoxifen + chemotherapyTamoxifen117471318 P < 0.0012 4 6 8 10 12YearsProportionwithoutdistantrecurrencePaik S, et al. J Clin Oncol. 2006;24:3726-3734. 14. Adjuvant Chemotherapy 15. The Oxford OverviewEarly Breast Cancer TrialistsCollaborative Group(EBCTCG) The most comprehensive analysis of the adjuvantsettings 1984, 1990, 1995, 2000, 2005/6, 2010 2010: cover more than 100,000 patients among 123randomised trails, published 2012, postulating 3questions to be answered in meta-analysis Benefit of polychemotherapy Vs non. Benefit of anthracycline (A) vs CMF. Benefit of Taxane + (A) vs (A) alone. 16. Polychemotherapy versusNo chemotherapy10y results in 23500 women 17. RRs were 069 (SE 004) for distant recurrence RRs were 073 (SE 003, 1=703) for any recurrence. RRs 079 (SE 004, 1=337) for breast cancer mortality. the proportional effects of anthracycline based regimens onbreast cancer outcomes did not depend much on age, nodalstatus, ER status, or, if ER-positive, on endocrine therapy,age, nodal status, tumor differentiation, or ER level 18. Anthracycline regimensvsstandard CMF10y results in 22000 women 19. Almost equal 4 AC, vs CMF. 20. shows results from the trials with anthracycline dose per cycle atleast 60 mg/m2 doxorubicin or 90 mg/m2 epirubicin and withcumulative anthracycline dosage more than 240 mg/m2doxorubicin or 360 mg/m2 epirubicin. RRs were 089 for recurrence. RRs were 080 for breast cancer mortalityANTHRACYCLINEMORE 21. Taxane + Anthracycline regimens vsAnthracycline regimens5y results in 44000 women 22. Recurrence RRs were 0.85. Mortality RRs were 0.87.T+AVssameA5 y results 23. 5 years results Recurrence RRs were 0.83. Mortality RRs were 0.86.T+AVsmoreA 24. Adjuvant Hormonal 25. Estrogen and Breast CancerEstrogenCellGrowthandDivisionEstrogenReceptorSERMS, SERDSAromataseinhibitors, ovariansuppression 26. Endocrine Therapy in Breast Cancer Selective Estrogen Receptor Modulators tamoxifen toremifene raloxifene Aromatase inhibitors (postmenopausal) anastrozole letrozole exemestane Medical or surgical oophorectomy (premenopausal) Selective Estrogen Receptor Downregulators fulvestrant Others: Progestins, Estrogens, Androgens 27. Selective Estrogen Receptor ModulatorsEBCTCG 2000 (Oxford Overview)Tamoxifen vs. Nil: Disease-free SurvivalER Negative ER Positive5 years of adjuvanttamoxifen becamestandard in ER+ patientstamoxifennilER status matters!!5 yrs15 yrs 28. Aromatase InhibitorsAdrenal HormonesCortisol Androstenedione AldosteroneEstradiolTestosteroneEstroneAromatase inhibitors blockpost-menopausal estrogenproductionAnastrozoleLetrozoleExemestane 29. Adjuvant Aromatase InhibitorsAIs asInitial TherapyAIs After2-3 Yrs of TAMAIs After5 Years of TAMTAM X 5 YrsAI X 5 Yrs TAM X 2-3 AI X 2-3TAM X 5 YrsTAM X 5 YrsPLAC X 5 YrsAI X 5 YrsThree StrategiesSurvival benefit for AIarmATAC and BIG1-98 studiesReduction in recurrences 30. Upfront Use of Aromatase Inhibitors vs. TamoxifenATAC Trial: Anastrozole vs. TamoxifenHowell A et al, Lancet 365:60-62, 2005BIG 1-98 Trial: Letrozole vs. TamoxifenThurlimann B et al, NEJM 353: 2747-57, 200568 months follow-up:17% relative reduction in events for A vs T(3% absolute difference)26 months follow-up:19% relative reduction in events for L vs. T(3% absolute difference) 31. Extended Adjuvant Hormonal Therapy TrialsMA17 Trial: Letrozole vs. Placebo After Completing 5Years of TamoxifenGoss P et al, J Natl Cancer Inst 97: 1262-71, 200530 months of follow-up:42% decrease in breast cancer eventsNode positive patients show statistically significantimprovement in survival 32. Letrozole +Zoledronic Acid 4 mgq6mLetrozole + Delayed*Zoledronic Acid 4 mgq6mStage I-IIIa breast cancer Postmenopausal oramenorrheic due tocancer treatment ER+ and/or PgR+ T-score -2 SD N = 1065Treatment duration 5 yrsDe Boer R, et al. SABCS 2011. Abstract S1-3.ZO-FAST: 5-Yr Final AnalysisTreatment duration 5 yrs 33. ZO-FAST: Conclusions Immediate initiation of ZOL at start of letrozolesignificantly prolonged DFS vs delayed initiationof ZOL in postmenopausal women withendocrine-responsive EBC Continued to improve BMD after 5 yrs of follow-up 34% improvement in DFS 34. Adjuvant TargetedTherapy 35. 37HER-2 as a Target for Therapycell divisionHER-2nucleuscancer cellTrastuzumab (Herceptin)Anti-HER-2 AntibodyHER-2 Oncogene: amplified andoverexpressed in 20-25% of breastcancerLapatinib (Tykerb)Dual HER-1/HER-2Tyrosine Kinase Inhibitor 36. Adjuvant trastuzumab trials: >13,000 patientsNCCTG N9831 (USA)HERA (ex-USA) BCIRG 006 (global)NSABP B-31 (USA)Piccart-Gebhart et al 2005;Romond et al 2005;Slamon et al 2006IHC orFISH(n=5090)2 years HerceptinObservationStandardchemotherapy1 year HerceptinIHC orFISH(n=2030)Herceptin 1 yearIHC orFISH(n=3505)Herceptin 1 yearFISH(n=3222)Herceptin 1 yearIHC orFISH(n=5090)Docetaxel Docetaxel + carboplatin Doxorubicin + cyclophosphamide PaclitaxelFISH(n=3222)IHC orFISH(n=3505)IHC orFISH(n=2030)Herceptin1 yrHerceptin1 yrHerceptin1 yrHerceptin1 yrHerceptin2 yrObservation 37. aBased on small subgroups of patients with HER2-positivebreast cancer; brelapse-free survival; V, vinorelbineCEF, cyclophosphamide, epirubicin, 5-fluorouracilDFS benefit across 5 out of 6 trials4234Joensuu et al 2006; Slamon et al 2006Perez et al 2007; Smith et al 2007Spielmann et al 200733Median follow-up, years0 1 2FavoursHerceptinFavours noHerceptinHRDFS benefitB-31 / N9831 ACPHHERA CTxH 1 yearFinHera VH / DHCEFbPACS-04a CTxH 1 yearBCIRG 006 ACDHBCIRG 006 DCarboH 38. 0 1 2FavoursHerceptinFavours noHerceptinHRAdjuvant Trastuzumab trials: proven OS benefitB-31 / N9831 ACPHBCIRG 006 ACDHHERA H 1 yearBCIRG 006 DCarboHFinHer VH / DHa432Median