Presentation on theme: "Recent Advances in Adjuvant Endocrine Therapy for Early Breast Cancer"— Presentation transcript:
1 Recent Advances in Adjuvant Endocrine Therapy for Early Breast Cancer Clinical UpdatesOptimizing Endocrine Therapy for Early Breast CancerRecent Advances in Adjuvant Endocrine Therapy for Early Breast CancerRuth M. O’Regan, MDAssociate Professor, Hematology and Medical OncologyEmory University School of MedicineDirector, Translational Breast Cancer Research ProgramEmory Winship Cancer InstituteChair, The Louisa and Rand Glenn Family Chair in Breast Cancer ResearchDirector, Hematology and Medical Oncology Fellowship ProgramAtlanta, Georgia
2 Adjuvant Hormonal Therapy Options for Postmenopausal Patients AIATAC, BIG-1-98 (upfront AI vs TAM)IES, ABCSG, BIG-1-98 (TAM to AI)TAMAIBIG-1-98, TEAM (AI to TAM)AITAMMA.17ExtendedAITAMAIAll superior to 5 years of TAM but which approach is best?ATAC Trialists Lancet Onc 2008, Mouridsen NEJM 2009, Goss JCO 2008,Coombes R Lancet 2007, Jakesz R JNCI 2007
3 ATAC Recruitment July 1996 – March 2000 Median follow-up 100 months Tamoxifen (n = 3,116)Surgery+/- RT+/- Chemo (20%)Anastrozole (n = 3,125)Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm84% HR positive61% Node negative5 yearsATAC Trialists Lancet Onc 2009
4 Efficacy of Anastrozole vs Tamoxifen in HR+ Patient Population of ATAC Study 9-Year Follow-upAnastrozoleTamoxifenRecurrence17.0%21.8%HR = 0.76; P = .0001Distant Recurrence13.2%15.6%HR = 0.84; P = .022Contralateral Breast Cancer2.5%4.2%HR = 0.60; P = .004Disease-Free SurvivalHR = 0.85; P = .003Death After RecurrenceHR = 0.90; P = .2Significant long-term carryover effect for anastrozole:- Absolute difference in recurrence increased from 2.8% after 5 years to 4.8% after 9 years- Hazard ratio anastrozole vs tamoxifen for years 5-9 = 0.75; P = .01ATAC Trialists Lancet Onc 2009
5 Death: All Causes HR+ Patients 3030252015105HR0.9795% CI(0.86, 1.11)P-value0.70HR+2520Tamoxifen (T) Anastrozole (A)15105123456789Follow-up time (years)At risk: A TATAC Trialists Lancet Onc 2009
6 BIG 1-98 Design R A N D O M I Z E A Tamoxifen B Letrozole C Tamoxifen 2-Arm Option3/98 to 3/001,835 ptsBLetrozole4-Arm Option9/99-5/036,193 ptsCTamoxifenLetrozoleDLetrozoleTamoxifen25YEARSMouridsen NEJM 2009
7 Letrozole vs Tamoxifen Disease-free SurvivalYearlyDFS %97.797.695.193.490.589.086.884.684.081.4T2040608010012345Percent Alive and Disease-FreeYears from RandomizationLNHR (95% CI)P80100.81 ( )0.003No. atRisk40034007389238962964292612611238892866567544Mouridsen NEJM 2009
8 Cumulative Incidence Breast Cancer Relapse 205-year diff (L-T) = -3.4%(S.E. 1.2) cuminc P=0.000213.6%15TL108.1%Proportion Failure (%)10.2%56.2%12345Years from RandomizationMouridsen NEJM 2009
9 IES: Trial Design RANDOMI ZE Exemestane 5,162* Post Treatment Follow-up10,335*TamoxifenTamoxifen5,294*2-3 years study treatment2-3 yearsStart of studyDiagnosisTotal 5 years endocrine therapy* Total women yearsCoombes R Lancet 2007
12 BIG 1-98 Design A B C D R A N D O M I Z E Tamoxifen 2-Arm Option 3/98 to 3/001,835 ptsBLetrozoleCTamoxifenLetrozole4-Arm Option9/99-5/036,193 ptsDLetrozoleTamoxifen25YEARSMouridsen NEJM 2009
13 BIG 1-98 Sequential Therapy Two Pairwise Comparisons Letrozole3 blinded armsSequential vs letrozole monotherapyEvaluated from randomizationMedian Follow-up 71 mos.99% confidence intervals to account for multiple comparisonsN = 3,094TamoxifenLetrozole25LetrozoleN = 3,086LetrozoleTamoxifen25YEARSMouridsen NEJM 200913
14 BIG 1-98 Sequential Treatment Disease-Free Survival Mouridsen NEJM 200914
15 Breast Cancer Events TamLet vs Let OverallBy Nodal Status**42% of the population is node positive; 58% node negativeMouridsen NEJM 200915
16 Breast Cancer Events TamLet vs Let OverallBy Nodal Status**42% of the population is node positive; 58% node negativeMouridsen NEJM 2009
17 TEAM Trial Upfront AI vs Switching PostmenopausalER+ and/or PgR+ invasive breast cancerCurrent analysis(2.75 year follow-up)RANDOMIZETamoxifen20 mg/day (2-3 years)Exemestane 25 mg/day(2-3 years)Primary SurgeryExemestane 25 mg/day(5 years)Primary endpoint: DFS for tamoxifen vs exemestane (2.75 years)Following IES: protocol modified - DFS for exemestane vs tamoxifen→exemestane (5 years)Jones et al. SABCS Abstract 15.1717
18 TEAM Trial Efficacy of Tamoxifen vs Exemestane HR (95% CI)P ValueDisease-Free Survival*0.89 ( ).12Disease-Free Survival (on Study Drug)0.83 ( ).02Recurrence-Free Survival0.85 ( ).05Time to Distant Metastases0.81 ( )< .03* Events: Exemestane 7% vs tamoxifen 8%Jones et al. SABCS Abstract 15.
19 Extended Adjuvant Therapy MA.17: Trial Design Randomization(Disease-free)Letrozole 2.5 mg dailyn = 2,575TamoxifenPlacebon = 2,5825 years early adjuvant5 years extended adjuvantNode(–) 2,581Node(+) 2,370Follow-up 30 monthsGoss JCO 2008
20 Extended Adjuvant Therapy Letrozole After 5 Years of TAM DFS*Distant* DFSOSNode–ptsNode+HR=0.61*( )HR=0.45*( )HR=0.63( )HR=0.53*( )HR=1.52( )( )*Statistically significant benefit of LET.A similar reduction in local recurrences, new primaries, and distant recurrences occurred in node-positive and node-negative patientsGoss et al JNCI 2005
21 Ongoing First Generation AI Adjuvant Trials BIG 1-98 (BIG FEMTA)NSABP B33IES TrialITATamoxifenAnastrozolePlaceboLetrozoleExemestaneMA.17ATAC Trialists Lancet Onc 2008, Mouridsen NEJM 2009, Goss JCO 2008,Coombes R Lancet 2007, Jakesz R JNCI 2007
22 Upfront vs Sequencing Approach? BIG-1-98 suggests that an upfront AI may be superior to a TAM-AI sequencing approachBut patients seem to do just as well with an AI followed by TAM (unclear what clinical relevance this has)Major issue is the fact that ER-positive cancers are not all the same and therefore one size may not fit all
23 Key QuestionsCan we use biomarkers/molecular profiling to decide how to treat patients with ER+ cancers?Do all or just a subset of ER+ cancers require more than 5 years of endocrine treatment?Can we use biomarkers/molecular profiling/pharmacogenomics to individualize endocrine therapy (AI vs TAM)?
25 Efficacy of Tamoxifen Varies in ER+ Cancers 24681416Years0.00.20.40.60.81.0DRFSPlaceboTamoxifen121024681416Years0.00.20.40.60.81.0DRFSPlaceboTamoxifen1210Low Risk (RS<18)Int Risk (RS 18-30)N171142N8569High Risk (RS≥31)N997924681416Years0.00.20.40.60.81.0DRFSPlaceboTamoxifen1210TAM-resistantInteraction P = 0.06Paik et al SABCS 2004
26 Correlation Between Recurrence Score and Intrinsic Subtype Luminal A(n = 123)Luminal B(n = 55)Low621Intermediate254High3650Fan et al NEJM 2006
27 Oncotype DX 21 Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 StudiesPROLIFERATIONKi-67STK15SurvivinCyclin B1MYBL2ESTROGENERPRBcl2SCUBE2GSTM1BAG1INVASIONStromolysin 3Cathepsin L2CD68CategoryRS (0 – 100)Low riskRS < 18Int riskRS ≥ 18 and < 31High riskRS ≥ 31ReferenceBeta-actinGAPDHRPLPOGUSTFRCHER2GRB7Paik et al NEJM 2004
28 Poor Outcome for Patients with HER2+ MBC Treated with Endocrine Agents Alone Clinical BenefitPFSAnastrozole28%2.4 monthsLetrozole29%3.0 months*PFS in first-line aromatase inhibitor trials ranges from 9 to 11 monthsKaufmann ESMO 2006, Johnston SABCS 2008
29 PR is prognostic or predictive for patients treated with tamoxifen Overall Survival According to Tumor Receptor Status in Women Treated with TamoxifenPR is prognostic or predictive for patients treated with tamoxifenCui, X. et al. J Clin Oncol; 23:
30 Disease-free Survival by Ki-67 LI in BIG-1-98 (Letrozole and Tamoxifen) 1,252 (47%) expressed Ki-67 LI > 11% (high)Viale G et al. SABCS 2007 Abs 64.
31 Possible Surrogate Markers for Hormone Resistance LUM A LUM BERPRHER2RSLow Ki High Ki-67Hormone-sensitive Hormone-resistant
33 Extended Adjuvant Therapy is Beneficial in Luminal A But Not B Cancers (using PR as a surrogate)?ER+PR-LUMINAL BER+PR+LUMINAL ADisease free survivalDistant disease free survivalGoss et al. J Clin Oncol; 2007
35 Aromatase Inhibitor vs Tamoxifen? TransATAC is a subset of patients from the ATAC trial in whom tumor blocks are available for molecular profiling21-gene recurrence score performed (n = 1,308)None of these patients received chemotherapyWill 21-gene recurrence score be prognostic for post-menopausal patients treated with anastrozole?Can the recurrence score define a group of patients who would do just as well with tamoxifen?Dowsett, SABCS 2008, Abstract 53
36 21-gene Recurrence Score To Predict Risk of Distant Recurrence In PatientsTreated With Anastrozole or TamoxifenResultsNode- (N=872)Node+ (N=306)% pts9-year DR rateLow RS <1859%4%52%17%Int RS 18-3026%12%31%28%High RS ≥ 3015%25%49%High vs. Low RS: HR 5.2Int vs. Low RS: HR 2.5High vs. Low RS: HR 2.7Int vs. Low RS: HR 1.8P<.001 for RS in predicting time to distant recurrence (DR) in N+ and N- patientsDowsett, SABCS 2008, Abstract 533636
37 Percent with Distant Recurrence at 9 Years Node Negative# of eventsAll Patients, Low RS (n=513)20All Patients, Int. RS (n=229)24All Patients, High RS (n=130)28All Patients (n = 872)72Tamoxifen, Low RS (n=245)8Tamoxifen, Int. RS (n=117)12Tamoxifen, High RS (n=70)21All Tamoxifen (n = 432)41Anastrozole, Low RS (n=268)12Anastrozole, Int. RS (n=112)12Anastrozole, High RS (n=60)7All Anastrozole (n = 440)31Dowsett, SABCS 2008,Abstract 5310203040506070Percent with Distant Recurrence at 9 Years37
38 Percent with Distant Recurrence at 9 Years Node Positive# of eventsAll Patients, Low RS (n=160)25All Patients, Int. RS (n=94)25All Patients, High RS (n=52)24All Patients (n = 306)74Tamoxifen, Low RS (n=79)11Tamoxifen, Int. RS (n=47)13Tamoxifen, High RS (n=26)11All Tamoxifen (n = 152)35Anastrozole, Low RS (n=81)14Anastrozole, Int. RS (n=47)12Anastrozole, High RS (n=26)13All Anastrozole (n = 154)39Dowsett, SABCS 2008,Abstract 5310203040506070Percent with Distant Recurrence at 9 Years38
39 Summary Postmenopausal Patients Available data suggests that upfront AI approach is optimal for unselected ER+ breast cancersBut luminal A and B are clearly different and may need different therapeutic approachesLuminal A (low RS):May do fine with tamoxifen or sequencing approachRequire extended adjuvant therapy?Luminal B (high RS):Five years of treatment probably sufficientAIs may be better in some patients (or they could be hormone-refractory)
40 Premenopausal Patients Tamoxifen for 5 years is standard of careSOFT trial is evaluating ovarian suppression plus tamoxifen vs exemestaneShould we evaluate CYP2D6 in premenopausal patients and what should we do if they are poor metabolizers?
41 Randomized Trial in Premenopausal Patients With HR+ Breast Cancer 1,803 premenopausal breast cancer patientsEndocrine-responsive (ER and/or PR positive)No chemotherapy except neoadjuvantTreatment duration: 3 yearsTamoxifen 20 mg dailyZoledronic acid 4 mg q6moAnastrozole 1 mg dailyAnastrozole mg dailySurgery(+ RT)Goserelin3.6 mg q28dRANDOMIZATIONGnant et al NEJM 2009
42 Zoledronic Acid (ZOMETA®) Preclinical Profile Primary Endpoint: Disease-free Survival Zoledronic Acid vs No Zoledronic Acid100908070605040302010122436487284Time since randomization, monthsDisease-free survival, %No. of Hazard ratio (95% CI) events vs No ZOL P valueZOL (0.46 to 0.91) .011No ZOL 83Gnant et al NEJM 20094242
43 Primary Endpoint: Disease-free Survival Anastrozole vs Tamoxifen Zoledronic Acid (ZOMETA®) Preclinical ProfilePrimary Endpoint: Disease-free Survival Anastrozole vs TamoxifenFollow-up 60 months1009080706050Disease-free survival, %4030No. of Hazard ratio (95% CI) events vs TAM P valueANA (0.78 to 1.53) .593TAM 65201012243648607284Time since randomization, monthsSOFT study continues to accrueGnant et al NEJM 20094343
44 Metabolism of Tamoxifen Jin et al JNCI 97: 30-39, 2005
45 CYP2D6 Genetic Variations Caucasians and Western Europeans:1-2% have multiple copies (Ultra-rapids = UM)70% have two wild type alleles (Extensive = EM)20% have one variant (CYP2D6*4) allele (Intermediate = IM)~8% have two variant alleles (Poor = PM)CYP2D6 is responsible for the conversion of tamoxifen to its most abundant active metabolite: endoxifen
46 Kaplan Meier Plots For Patient By CYP2D6*4 Genotype Disease FreeOverall SurvivalHot flashes36/1770/13Goetz J Clin Oncol 23: , 2005
47 CYP2D6 as Predictive Marker as Prognostic Marker in the ABCSG-8 Trial ABCSG-8 : TAM vs TAM followed by anastrozoleCYP2D6 and risk of breast event relative to extensive metabolizers (EM)NCYP2D6: PMCYP2D6: IMTamoxifen (5 years)673.83, P= .0170.87, P = .689Tam to Ana (5 years)551.02, P = .9850.81, P = .538Tamoxifen (years 3-5)2.81, P = .0810.75, P = .431Anastrozole (years 3-5)310.71, P = .7820.57, P = .269Goetz, SABCS 2008, Abstract 574747
48 Risk of Breast Cancer Recurrence in Women Initiating Tamoxifen With CYP2D6 Inhibitors Eligibility:Continuous eligibility 6 mos. prior to tamoxifen initiationTamoxifen naïve (6 mos. negative history)Tamoxifen duration ≥ 24 mos.Medication possession ratio of ≥ 0.7No CYP2D6 inhibitor therapy(n = 945)Weak CYP2D6 inhibitor therapy use or without overlap with tamoxifen(n = 355)Moderate-severe CYP2D6 inhibitoruse with tamoxifen(n = 359)(n = 1,659)Retrospective cohort analysis of medical and pharmacy claims from the Medco Health Solutions integrated databasePrimary endpoint: hospitalization for breast cancer (event-free survival)Median duration of overlap between CYP2D6 inhibitors and tamoxifen: 287 daysAubert et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA508).
49 Risk of Breast Cancer Recurrence in Women Initiating Tamoxifen With CYP2D6 Inhibitors HR*P valueNo CYP2D6 inhibitors9457.5%referenceModerate/severe CYP2D6 inhibitors40714%1.92 ( ).0002SSRIsWeak1379%1.07 ( ).677Moderate/potent21316%2.20 ( )* HR relative to no CYP2D6 inhibitor groupConcomitant use of tamoxifen with moderate-severe CYP2D6 inhibitors significantly increases the risk of breast cancer recurrenceModerate-potent SSRIs double the risk of recurrence, while weak SSRIs were not associated with increased riskAubert et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA508).
50 Summary Premenopausal Patients Available data do not support a role for ovarian ablation with an AIHowever, trials have not taken into account the luminal subtypesCYP2D6 data is compelling and should be looked at in patients on the SOFT trialUntil then the role of CYP2D6 testing remains unclear since we do not have data on how to treat poor metabolizers
51 ConclusionsHR+ cancers are clearly heterogeneous with divergent outcomesNeed to identify robust predictive factors for both luminal A and B cancersEssential to establish molecular differences between luminal subtypes so that novel therapeutic approaches can be developed