Harvard Medical School Boston USA Adjuvant Hormonal Therapy for Premenopausal Women OFR 10 Chemotherapyinduced amenorrhea Menopausal status should be defined prior to the initiation of adjuvant chemotherapy ID: 999355
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2. Otto Metzger, MDDana-Farber Cancer InstituteHarvard Medical SchoolBoston, USAAdjuvant Hormonal Therapy for Premenopausal Women
3. OFR ~10%Chemotherapy-induced amenorrheaMenopausal status should be defined prior to the initiation of adjuvant chemotherapy
4. Plan of the Talk Tamoxifen versus AI: Is there room for additional discussion in 2017?What is the real gain with extended endocrine therapy? Do we need molecular tests to identify patients at risk of recurrence beyond year 5?
5. Plan of the Talk Tamoxifen versus AI: Is there room for additional discussion in 2017?What is the real gain with extended endocrine therapy? Do we need molecular tests to identify patients at risk of recurrence beyond year 5?
6. Aromatase Inhibitor Overview Group Tamoxifen versus AIThe Lancet 2015 386, 1341-1352DOI: (10.1016/S0140-6736(15)61074-1) RecurrenceBreast Cancer Mortality
7. Aromatase Inhibitor Overview Group Tamoxifen AI versus AIThe Lancet 2015 386, 1341-1352DOI: (10.1016/S0140-6736(15)61074-1) RecurrenceBreast Cancer Mortality
8. Aromatase Inhibitor Overview Group Subgroup Analysis The Lancet 2015 386, 1341-1352DOI: (10.1016/S0140-6736(15)61074-1)
9. Should we just give upfront AI or sequential strategy to all patients?My personal consideration:AI is not tolerated for a significant proportion of patients with discontinuation rates as high as 40% reported in clinical trialsWe can safely select a subgroup of patients that can be treated with adjuvant tamoxifen So, how can we identify a subset of patients that can be treated with upfront tamoxifen? So Why Bother?
10. BIG 1-98 Analytic Cohort12-year update (Lancet Oncol 2011)2-Arm OptionTamoxifenLetrozoleLetrozoleLetrozoleTamoxifen025YEARSABCDTamoxifenTamoxifenLetrozoleAB4-Arm OptionN=1,828Enrolled1998-2000N=3,094Enrolled1999-2003N=4,922N=911N=917N=1548N=1546Is letrozole superior than TAM in the subsets of LA and LB disease? Is there a preferred regimen for patients diagnosed with invasive lobular carcinoma
11. Disease-free survival
12. Disease-free survival
13. Multivariate Analysis Cox Model for DFS (IPCW)100.51.01.5Lobular LBLobular LADuctal LBDuctal LAHazard Ratio (95% CI) 0.95 (0.76-1.20) 0.64 (0.53-0.79) 0.49 (0.32-0.78) 0.33 (0.21-0.55) Favors LetrozoleFavors Tamoxifen1. Included variables: age, tumor size, nodal status, histological grade, histology, local therapy, subtype (LA/LB) and treatmentTreatment by histology (ductal/lobular), p=0.006Treatment by subtype (LA/LB), p=0.01Interactions
14. 2-Arm OptionTamoxifenLetrozoleLetrozoleLetrozoleTamoxifen025YEARSABCDTamoxifenTamoxifenLetrozoleAB4-Arm OptionN=6,182Enrolled1999-2003N=1548N=1540N=1548*N=1546*612 patients (40%) received letrozole after the tamoxifen arm was unblinded. This presentation is the intellectual property of the author/presenter. Contact ottto_metzger@dfci.harvard.edu for permission to reprintWhat is the impact of tumor cell proliferation on the benefit of AI versus TAM? What be learned from the sequential arms of BIG-198?
15. LA-like Ductal LB-like DuctalThis presentation is the intellectual property of the author/presenter. Contact ottto_metzger@dfci.harvard.edu for permission to reprintInvasive Ductal CarcinomaDisease-free survival by LA and LB subtypes
16. Points for consideration:Classic clinico-pathologic features can be used to identify indolent tumors that could be treated with upfront tamoxifenThere might be a potential for the use of genomic tests in the identify “indolent” tumorsHow can we use this information in our clinical practice?
17. Very high and very low risk levels are informativeUltralowThreshold
18. Stockholm STO 3 phase III postmenopausal N0 <3 cm validates ultralow risk (IDLE, indolent lesions of epithelial origin)SABCS 2016 PD7-01
19. TAILORx trial first report: N0, ER+, HER2-negative 21 gene Recurrence Score <11, endocrine therapy aloneSparano J et al. NEJM 2015
20. 01020304050607080901009-Years Risk of Distant Recurrence (%) 0 5 10 15 20 25 30 35 40 45 50Recurrence ScoreNodeNegative1-3 Positive Nodes4+ Positive Nodes95%CIMeanTransATAC Low incidence of distant recurrence at 9 years for those with very low RS levels even in the subset of 1-3 positive nodes
21. Node positivity does not necessarily imply the need for upfront AIMetzger et al. Unpublished data
22. Plan of the Talk Tamoxifen versus AI: Is there room for additional discussion in 2017?What is the real gain with extended endocrine therapy? Do we need molecular tests to identify patients at risk of recurrence beyond year 5?
23. 1. Goss PE et al, J Natl Cancer Inst 2005;97:1262–71. 2. Mamounas EP et al., J Clin Oncol 2008;26:1965-1971. 3. Jakesz et al., J Natl Cancer Inst. 2007 Dec 19;99(24):1845-53. 4. Davies C et al., Lancet. 2013 ;381(9869):805-16. 5. Gray et al., J Clin Oncol 31, 2013 (suppl; abstr 5). 6. Goss PE et al., N Engl J Med. 2016Extended Endocrine Therapy
24. New Data From SABCS 2016Results from 3 extended AI randomized studies presented at SABCS 2016In all 3 studies, primary analyses demonstrated no statistically significant benefit in DFS from extending AI therapy in post-menopausal patients. Of note, results from B-42 and DATA were generally similar to previous extended endocrine therapy trials (~3-4% absolute benefit)1. Mamounas E et al, 2016 SABCS. 2. Tjan-Heijnen VC et al, 2016 SABCS. 3. Block EJ et al, 2016 SABCSNSABP B-42DATAIDEALPopulation3966 patients who completed 5 years of AI or up to 3 years TAM followed by AI (for a total of 5 years)1912 patients who completed 2-3 years of Tamoxifen1824 patients who completed 5 years of TamoxifenTreatment5y AI vs Placebo3y AI vs 6y AI2.5y AI vs 5y AIHR0.85 (0.73 – 0.999)0.79 (0.62-1.02)0.96 (0.76-1.20)DFS84.7% (5 years AI) vs 81.3% (Placebo)83.1% (6 years AI) vs 79.4% (3 years AI)87.9% (5 years AI) vs 88.4% (2.5 years AI)P valueP=0.048 (n.s.)P=0.07 (n.s.)P=0.7 (n.s.)Note, there was a statistically significant benefit in terms of prevention of distant recurrence(1.9% absolute benefit, P=0.03)Discontinuation of AIs in all these trials was ~40% in the extended period
25. NSABP B-42Letrozole X 5 yrsPlacebo X 5 yrsPostmenopausal Pts with ER+ or PR+ Breast CancerStage I, II, or IIIa invasive BC at diagnosisDisease-free After 5 Years of Endocrine TherapyStratification:Pathological nodal status (Negative, Positive)Prior adjuvant TAM (Yes, No)Lowest BMD T score: spine, hip, femur (>-2.0, ≤ -2.0 SD)AI X 5 yrsorR AI to Complete 5 yrs TAM X < 3 yrs
26. LetrozolePlacebo1008060402000 2 4 6 7 8 Years After RandomizationDisease-Free SurvivalLetrozole 1959 1813 1644 1225 216Placebo 1964 1814 1639 1208 210HR=0.85 (0.73-0.999) P = 0.048 84.7% 81.3%# Events292339NSABP B-42: Disease-Free Survival*P-value did not reach statistical significance level of 0.0418
27. LetrozolePlaceboCumulative Incidence of DR1210864200 2 4 6 7 8 5.8% 3.9%HR=0.72 (0.53-0.97) P=0.03Years After Randomization # Pts # Events 731964 102NSABP B-42:Cumulative Incidence of Distant Recurrence
28. 80% power to detect an increase in 3-year adapted Disease-Free Survival (aDFS) from 90% to 94%, i.e., a hazard ratio (HR) of 0.60 and a significance level of 0.05Accounting for 10% drop-out: 950 patients per group to be included (n=1912 patients actually included)Minimum follow-up: ≥6 years after randomization, i.e., ≥ 3 years of adapted follow-up (last patient included in August 2009)DATA Study DesignStratificationNodal statusER/PR status HER2 statusTamoxifen duration6 years anastrozole1 mg daily3 years anastrozole1 mg daily Postmenopausal at randomizationER+ and/or PR+ No sign of disease recurrenceM0 breast cancer After 2-3 years adjuvant tamoxifen
29. San Antonio Breast Cancer Symposium, December 6-10, 2016adapted Disease-Free Survival (aDFS) N=16606-year Anastrozole(N=827)3-year Anastrozole(N=833)5-y aDFS (%)83.179.4HR (95% CI)0.79 (0.62 – 1.02) P-value0.073-year aDFS: 90.7% vs. 88.9%
30. San Antonio Breast Cancer Symposium, December 6-10, 2016N=5976-year Anastrozole(N=293)3-year Anastrozole(N=286)5-y aDFS (%)86.075.9HR (95% CI)0.58 (0.39 – 0.89)P-value0.01aDFS if ER+ and PR+, HER2-, pN+, Chemo+
31. DFS 5 years2.5y: 88.4% 5y: 87.9% HR: 0.96 (0.76-1.20) P-value: 0.70 IDEAL Study
32. Plan of the Talk Tamoxifen versus AI: Is there room for additional discussion in 2017?What is the real gain with extended endocrine therapy? Do we need molecular tests to identify patients at risk of recurrence beyond year 5?
33. NODAL STATUS IS AN IMPORTANT PROGNOSTIC INDICATOR Saphner et al. JCO 1996
34. H.Pan for EBCTCG, ASCO 2106What is the risk of distant recurrence for T1 N0 and T2 N0 ?
35. H.Pan for EBCTCG, ASCO 2106
36. H.Pan for EBCTCG, ASCO 2106
37. Limitations of Oxford Overview DataOld studiesLack of detailed information on biomarker dataLarger clinico-pathologic variables (?)Can we do better in identifying those less likely to recur using classic clinico-pathologic variables alone?
38. Preliminary Results from ATAC – Clinical Treatment ScoreNode: 0 = Negative1 = 1 positive2 = 2-3 positive3 = 4-9 positive4 = >9 positiveSize: Continuous(if >50 then = 50)Grade: 0 = Grade 11 = Grade 22 = Grade 3Endocrine Rx0 = Tamoxifen1 = AnastrozoleAge: ContinuousLow risk <1% DR/yr; intermediate risk 1-2% DR/yr; high risk >2%/yr 0255075100Distant recurrence free (%)1157938853747648318High12231047987893803426Intermediate19591757167415811449777LowNumber at risk5678910Follow-up time [years]LowIntermediateHigh2.4%7.5%20.6%Hazard ratioReference3.40 (2.31-5.00)9.39 (6.65-13.28)DRs 5-10yr39 77 181Courtesy from Mitch Dowsett
39. Can we take advantage of genomic signatures to identify those at risk of disease recurrence beyond year 5? Can we use genomic tests to identify those more likely to benefit from extended endocrine therapy?
40. Smoothed hazard rates for RS, IHC4 and ROR in TransATAC over 10 years(Node negative and positive combined) Sestak et al 2013, JNCI, 105, 1504-11
41. What is the additional prognostic value of signatures to clinical variables? SignatureInformation includedClinical Treatment Score (CTS)Nodal status, grade, tumour size, age, treatmentImmunohistochemical markers (IHC4)ER, PgR, Ki67, HER2Oncotype Recurrence Score (RS)21 genes (oestrogen, proliferation, invasion, HER2 genes)Breast Cancer Index (BCI)H/I and 5 proliferation genes (Molecular Grade Index)Prosigna (ROR)46 genes, proliferation score, tumour size(EU cut-offs from transATAC for N- and N+)EndoPredict (EPclin)12 genes (proliferation, differentiation, oestrogen); nodal status and tumour sizeSestak et al SABCS 2016
42. Prognostic value years 5-10 – node-negative (n=591; 34 events) Likelihood Ratio χ2EPclinIHC4CTSRORRSBCILikelihood Ratio ∆χ2EPclinIHC4RORRSBCI% Improvement20.0%67.5%11.4%111.0%62.0%**
43. Prognostic value years 5-10 – node-positive (n=227; 31 events)Likelihood Ratio χ2EPclinIHC4CTSRORRSBCILikelihood Ratio ∆χ2EPclinIHC4RORRSBCI% Improvement7.5%11.3%6.9%25.6%27.5%**
44. Do we have a Genomic Tool able to Predict the benefit of Endocrine Therapy?
45. BCI Predictive (H/I) Results: MA.17 RCT CohortIn patients with High H/I, extended letrozole reduced recurrence rate significantly from 27% to 10.5% (P=0.007)No significant reduction in patients with Low H/I (P=0.35)P=0.007Recurrences (%)16.5% absolute benefitNo significant benefitP=0.35Sgroi et al, J Natl Cancer Inst. 2013;105:1036-1042
46. Summary of BCI Predictive (H/I) Validation DataH/I shown to be a significant predictor of endocrine benefit in 3 randomized trial cohortsStudy CohortTreatmentPredictive analysisInteraction P valueStockholm (n=600)1Adjuvant tamoxifen vs untreatedH/I High HR: 0.35 (0.19-0.65); p=0.0005H/I Low HR: 0.67 (0.36-1.24), p=0.20.003TransATAC (n=665)2Adjuvant anastrozole vs tamoxifenH/I High HR: 0.51 (0.27-0.97); p=0.04H/I Low HR: 1.33 (0.65-2.71), p=0.40.004MA.17(n=249)3Extended letrozole vs placeboH/I High OR: 0.33 (0.15-0.73); p=0.006H/I Low OR: 0.58 (0.25-1.36), p=0.210.03Results suggest generalizability as an endocrine response biomarker1. Zhang Y, et al. Clin Cancer Res. 2013;19(15):4196-205. 2. Sgroi D, et al. Lancet Oncol. 2013 Oct;14(11):1067-76. 3. Sgroi et al, J Natl Cancer Inst. 2013;105:1036-1042
47. Take Home MessagesTumor burden (i.e. tumor size and nodal status) reliably identify those more likely to recur between years 0-5 and 5-10Genomic tools add prognostic value to clinical variables particularly in the node-negative subsetWe should be careful when evaluating the additional value of genomic signatures if the “genomic algorithms” include tumor size and nodal statusBCI provides predictive information as an endocrine response biomarker
48. ConclusionsAdjuvant Tamoxifen for low-risk patients may be as good as AIHigh-risk patients (defined by tumor burden) are the ones more likely to benefit from 10 years of adjuvant endocrine therapyBCI predictive value should be explored in a prospective and large phase III clinical trial focused on patients with intermediate to low tumor burden for which the value of extended endocrine therapy is not so clear
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