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Recent Advances in Adjuvant Endocrine Therapy for Early Breast Cancer Ruth M. O’Regan, MD Associate Professor, Hematology and Medical Oncology Emory University.

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Presentation on theme: "Recent Advances in Adjuvant Endocrine Therapy for Early Breast Cancer Ruth M. O’Regan, MD Associate Professor, Hematology and Medical Oncology Emory University."— Presentation transcript:

1 Recent Advances in Adjuvant Endocrine Therapy for Early Breast Cancer Ruth M. O’Regan, MD Associate Professor, Hematology and Medical Oncology Emory University School of Medicine Director, Translational Breast Cancer Research Program Emory Winship Cancer Institute Chair, The Louisa and Rand Glenn Family Chair in Breast Cancer Research Director, Hematology and Medical Oncology Fellowship Program Emory University School of Medicine Atlanta, Georgia Clinical Updates Optimizing Endocrine Therapy for Early Breast Cancer

2 Adjuvant Hormonal Therapy Options for Postmenopausal Patients AI TAM AI All superior to 5 years of TAM but which approach is best? TAMAI ATAC, BIG-1-98 (upfront AI vs TAM) IES, ABCSG, BIG-1-98 (TAM to AI) BIG-1-98, TEAM (AI to TAM) MA.17 Extended AI 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 5 years 84% HR positive 61% Node negative 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 arm ATAC Trialists Lancet Onc 2009

4 Efficacy of Anastrozole vs Tamoxifen in HR+ Patient Population of ATAC Study 9-Year Follow-up AnastrozoleTamoxifen Recurrence 17.0%21.8% HR = 0.76; P =.0001 Distant Recurrence 13.2%15.6% HR = 0.84; P =.022 Contralateral Breast Cancer 2.5%4.2% HR = 0.60; P =.004 Disease-Free SurvivalHR = 0.85; P =.003 Death After RecurrenceHR = 0.90; P =.2 ATAC Trialists Lancet Onc 2009 Significant 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 =.01

5 Death: All Causes HR+ Patients At risk: A T Patients (%) Follow-up time (years) HR+ HR % CI (0.86, 1.11) P-value 0.70 Tamoxifen (T) Anastrozole (A) ATAC Trialists Lancet Onc 2009

6 BIG 1-98 Design Tamoxifen Letrozole TamoxifenLetrozole Tamoxifen RANDOMIZERANDOMIZE 025 YEARS A B C D 2-Arm Option 3/98 to 3/00 1,835 pts 4-Arm Option 9/99-5/03 6,193 pts Mouridsen NEJM 2009

7 Letrozole vs Tamoxifen Disease-free Survival T Percent Alive and Disease-Free Years from Randomization L Yearly DFS % NHR (95% CI)P ( )0.003 No. at Risk Mouridsen NEJM 2009

8 Years from Randomization Proportion Failure (%) L T Cumulative Incidence Breast Cancer Relapse 13.6% 10.2% 8.1% 6.2% 5-year diff (L-T) = -3.4% (S.E. 1.2) cuminc P= Mouridsen NEJM 2009

9 IES: Trial Design Tamoxifen RANDOMIZE RANDOMIZE Exemestane 5,162* Tamoxifen 5,294* Post Treatment Follow-up 10,335 * Diagnosis 2-3 years 2-3 years study treatment Total 5 years endocrine therapy Start of study * Total women years Coombes R Lancet 2007

10 End of treatment End of treatment Exemestane After Tamoxifen Disease Free Survival Year % abs. diff. (95% CI) (1.6 – 4.9)(0.1 – 6.8) ITTER+/Unknown HR=0.75 (95% CI: ) Log-rank test: P= HR=0.76 (95% CI: ) Log-rank test: P= E = 339 / 2296 T = 438 / 2306 E = 354 / 2352 T = 454 / (1.8 – 5.1)(0.1 – 6.9) Coombes Lancet 2007

11 Exemestane After Tamoxifen Overall Survival year % abs. diff. (95% CI) (-0.4 – 1.9)(-1.5 – 3.9) End of treatment End of treatment HR=0.83 (95% CI: ) Log-rank test: P=0.05 E=210 / 2296 T=251 / 2306 HR=0.85 (95% CI: ) Log-rank test: P=0.08 E=222 / 2352 T=261 / 2372 ITT ER+/Unknown (-0.4 – 1.9)(-1.2 – 4.3) Coombes Lancet 2007

12 BIG 1-98 Design Tamoxifen Letrozole TamoxifenLetrozole Tamoxifen RANDOMIZERANDOMIZE 025 YEARS A B C D 2-Arm Option 3/98 to 3/00 1,835 pts 4-Arm Option 9/99-5/03 6,193 pts Mouridsen NEJM 2009

13 BIG 1-98 Sequential Therapy Two Pairwise Comparisons 3 blinded arms Sequential vs letrozole monotherapy Evaluated from randomization Median Follow-up 71 mos. 99% confidence intervals to account for multiple comparisons Letrozole 025 N = 3,094 Letrozole Tamoxifen 025 YEARS N = 3,086 Letrozole Tamoxifen Mouridsen NEJM 2009

14 BIG 1-98 Sequential Treatment Disease-Free Survival Mouridsen NEJM 2009

15 Breast Cancer Events Tam  Let vs Let OverallBy Nodal Status* *42% of the population is node positive; 58% node negative Mouridsen NEJM 2009

16 OverallBy Nodal Status* *42% of the population is node positive; 58% node negative Mouridsen NEJM 2009 Breast Cancer Events Tam  Let vs Let

17 TEAM Trial Upfront AI vs Switching Tamoxifen 20 mg/day (2-3 years) Primary Surgery Jones et al. SABCS Abstract 15. Exemestane 25 mg/day (2-3 years) Exemestane 25 mg/day (5 years) Current analysis (2.75 year follow-up) Primary endpoint: DFS for tamoxifen vs exemestane (2.75 years) Following IES: protocol modified - DFS for exemestane vs tamoxifen→exemestane (5 years) Postmenopausal ER + and/or PgR + invasive breast cancer RANDOMIZERANDOMIZE

18 TEAM Trial Efficacy of Tamoxifen vs Exemestane HR (95% CI)P Value Disease-Free Survival*0.89 ( ).12 Disease-Free Survival (on Study Drug)0.83 ( ).02 Recurrence-Free Survival0.85 ( ).05 Time to Distant Metastases0.81 ( ) <.03 * Events: Exemestane 7% vs tamoxifen 8% Jones et al. SABCS Abstract 15. (n = 9,766)

19 Placebo n = 2,582 Extended Adjuvant Therapy MA.17: Trial Design Tamoxifen Letrozole 2.5 mg daily n = 2,575 Randomization (Disease-free) 5 years early adjuvant 5 years extended adjuvant Node(–) 2,581 Node(+) 2,370 Follow-up 30 months Goss JCO 2008

20 Extended Adjuvant Therapy Letrozole After 5 Years of TAM DFS * Distant * DFS OS Node– pts Node+ pts HR=0.61* ( ) HR=0.45* ( ) HR=0.63 ( ) HR=0.53* ( ) HR=1.52 ( ) HR=0.61* ( ) *Statistically significant benefit of LET.  A similar reduction in local recurrences, new primaries, and distant recurrences occurred in node-positive and node-negative patients Goss et al JNCI 2005

21 Ongoing First Generation AI Adjuvant Trials BIG 1-98 (BIG FEMTA) NSABP B33 IES Trial ITA Tamoxifen Anastrozole Placebo Letrozole Exemestane MA.17 ATAC 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 approach But 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 Questions Can 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)?

24 Copyright ©2003 by the National Academy of Sciences ER+ Cancers Are Heterogenous in Outcome Sorlie et al PNAS 2003 ER +

25 Efficacy of Tamoxifen Varies in ER+ Cancers Low Risk (RS<18) N Int Risk (RS 18-30) N Interaction P = 0.06 High Risk (RS≥31) N Years DRFS Placebo Tamoxifen Years DRFS Placebo Tamoxifen Years DRFS Placebo Tamoxifen Paik et al SABCS 2004 TAM-resistant

26 Correlation Between Recurrence Score and Intrinsic Subtype Recurrence Score Luminal A (n = 123) Luminal B (n = 55) Low621 Intermediate254 High3650 Fan et al NEJM 2006

27 Oncotype DX 21 Gene Recurrence Score (RS) Assay PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 INVASION Stromolysin 3 Cathepsin L2 HER2 GRB7 HER2 BAG1GSTM1 Reference Beta-actin GAPDH RPLPO GUS TFRC CD68 16 Cancer and 5 Reference Genes From 3 Studies CategoryRS (0 – 100) Low riskRS < 18 Int riskRS ≥ 18 and < 31 High riskRS ≥ 31 Paik et al NEJM 2004

28 Poor Outcome for Patients with HER2+ MBC Treated with Endocrine Agents Alone AgentClinical BenefitPFS Anastrozole28%2.4 months Letrozole29%3.0 months Kaufmann ESMO 2006, Johnston SABCS 2008 *PFS in first-line aromatase inhibitor trials ranges from 9 to 11 months

29 Cui, X. et al. J Clin Oncol; 23: Overall Survival According to Tumor Receptor Status in Women Treated with Tamoxifen PR is prognostic or predictive for patients treated with tamoxifen

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 ER PR HER2 LUM A LUM B Low Ki-67 High Ki-67 Hormone-sensitive Hormone-resistant RS

32 Copyright ©2003 by the National Academy of Sciences Luminal B Cancers Most Likely to Relapse in First 5 Years Sorlie et al PNAS 2003

33 Goss et al. J Clin Oncol; 2007 Disease free survivalDistant disease free survival LUMINAL B LUMINAL A ER+PR- ER+PR+ Extended Adjuvant Therapy is Beneficial in Luminal A But Not B Cancers (using PR as a surrogate)?

34 ATAC Trial: Disease-free Survival HR+ patients Patients (%) At risk: A T 13.9% 16.4% 25.8% 29.9% Tamoxifen (T) Anastrozole (A) HR+ HR % CI (0.76, 0.94) P-value Follow-up time (years) Absolute difference2.5%4.1% HR, hazard ratio; CI, confidence interval ATAC Trialists Lancet Onc 2008

35 Aromatase Inhibitor vs Tamoxifen?  TransATAC is a subset of patients from the ATAC trial in whom tumor blocks are available for molecular profiling  21-gene recurrence score performed (n = 1,308)  None of these patients received chemotherapy  Will 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 Results Node- (N=872)Node+ (N=306) % pts9-year DR rate% pts9-year DR rate Low RS <1859%4%52%17% Int RS %12%31%28% High RS ≥ 3015%25%17%49% High vs. Low RS: HR 5.2 Int vs. Low RS: HR 2.5 High vs. Low RS: HR 2.7 Int vs. Low RS: HR 1.8 P<.001 for RS in predicting time to distant recurrence (DR) in N+ and N- patients 21-gene Recurrence Score To Predict Risk of Distant Recurrence In Patients Treated With Anastrozole or Tamoxifen

37 All Patients, Int. RS (n=229) All Patients, Low RS (n=513) All Patients, High RS (n=130) All Patients (n = 872) All Anastrozole (n = 440) Anastrozole, Low RS (n=268) Anastrozole, High RS (n=60) Anastrozole, Int. RS (n=112) Percent with Distant Recurrence at 9 Years Node Negative # of events Percent with Distant Recurrence at 9 Years Tamoxifen, Low RS ( n=245 ) Tamoxifen, High RS ( n=70 ) Tamoxifen, Int. RS ( n=117 ) All Tamoxifen (n = 432) Dowsett, SABCS 2008, Abstract 53

38 Percent with Distant Recurrence at 9 Years All Patients, Int. RS (n=94) All Patients, Low RS (n=160) All Patients, High RS (n=52) All Patients (n = 306) All Anastrozole (n = 154) Anastrozole, Low RS (n=81) Anastrozole, High RS (n=26) Anastrozole, Int. RS (n=47) # of events Tamoxifen, Low RS (n=79) Tamoxifen, High RS (n=26) Tamoxifen, Int. RS (n=47) All Tamoxifen (n = 152) Percent with Distant Recurrence at 9 Years Node Positive Dowsett, SABCS 2008, Abstract 53

39 Summary Postmenopausal Patients  Available data suggests that upfront AI approach is optimal for unselected ER+ breast cancers  But luminal A and B are clearly different and may need different therapeutic approaches  Luminal A (low RS):  May do fine with tamoxifen or sequencing approach  Require extended adjuvant therapy?  Luminal B (high RS):  Five years of treatment probably sufficient  AIs may be better in some patients (or they could be hormone- refractory)

40 Premenopausal Patients Tamoxifen for 5 years is standard of care SOFT trial is evaluating ovarian suppression plus tamoxifen vs exemestane Should 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 patients Endocrine-responsive (ER and/or PR positive) No chemotherapy except neoadjuvant Treatment duration: 3 years Tamoxifen 20 mg daily Zoledronic acid 4 mg q6mo Anastrozole 1 mg daily Anastrozole mg daily Zoledronic acid 4 mg q6mo Surgery (+ RT) Goserelin 3.6 mg q28d RANDOMIZATIONRANDOMIZATION Gnant et al NEJM 2009

42 Primary Endpoint: Disease-free Survival Zoledronic Acid vs No Zoledronic Acid Time since randomization, mont h s Disease-free survival, % No. of Hazard ratio (95% CI) events vs No ZOLP value ZOL (0.46 to 0.91).011 No ZOL83 42 Gnant et al NEJM 2009

43 Primary Endpoint: Disease-free Survival Anastrozole vs Tamoxifen Time since randomization, months Disease-free survival, % Follow-up 60 months SOFT study continues to accrue Gnant et al NEJM 2009

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 Goetz J Clin Oncol 23: , 2005 Disease FreeOverall Survival Hot flashes 36/177 Hot flashes 0/13

47 CYP2D6 as Predictive Marker as Prognostic Marker in the ABCSG-8 Trial NCYP2D6: PMCYP2D6: IM Tamoxifen (5 years)673.83, P= , P =.689 Tam to Ana (5 years)551.02, P = , P =.538 Tamoxifen (years 3-5)552.81, P = , P =.431 Anastrozole (years 3-5)310.71, P = , P =.269 CYP2D6 and risk of breast event relative to extensive metabolizers (EM) Goetz, SABCS 2008, Abstract 57 ABCSG-8 : TAM vs TAM followed by anastrozole

48 Risk of Breast Cancer Recurrence in Women Initiating Tamoxifen With CYP2D6 Inhibitors Aubert et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA508). Retrospective cohort analysis of medical and pharmacy claims from the Medco Health Solutions integrated database Primary endpoint: hospitalization for breast cancer (event-free survival) Median duration of overlap between CYP2D6 inhibitors and tamoxifen: 287 days Weak CYP2D6 inhibitor therapy use or without overlap with tamoxifen Moderate-severe CYP2D6 inhibitor use with tamoxifen (n = 945) (n = 359) (n = 1,659) Eligibility: Continuous eligibility 6 mos. prior to tamoxifen initiation Tamoxifen naïve (6 mos. negative history) Tamoxifen duration ≥ 24 mos. Medication possession ratio of ≥ 0.7 No CYP2D6 inhibitor therapy (n = 355)

49 Risk of Breast Cancer Recurrence in Women Initiating Tamoxifen With CYP2D6 Inhibitors Aubert et al. J Clin Oncol 2009; 27 (suppl): 18s (abstract CRA508). Concomitant use of tamoxifen with moderate-severe CYP2D6 inhibitors significantly increases the risk of breast cancer recurrence Moderate-potent SSRIs double the risk of recurrence, while weak SSRIs were not associated with increased risk N Breast cancer recurrence HR*P value No CYP2D6 inhibitors9457.5%reference Moderate/severe CYP2D6 inhibitors 40714%1.92 ( ).0002 SSRIs Weak1379%1.07 ( ).677 Moderate/potent21316%2.20 ( ).0002 * HR relative to no CYP2D6 inhibitor group

50 Summary Premenopausal Patients  Available data do not support a role for ovarian ablation with an AI  However, trials have not taken into account the luminal subtypes  CYP2D6 data is compelling and should be looked at in patients on the SOFT trial  Until then the role of CYP2D6 testing remains unclear since we do not have data on how to treat poor metabolizers

51 Conclusions HR+ cancers are clearly heterogeneous with divergent outcomes Need to identify robust predictive factors for both luminal A and B cancers Essential to establish molecular differences between luminal subtypes so that novel therapeutic approaches can be developed


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