Chemotherapy in Luminal Breast Cancer: Who Benefits? Kathy Albain, MD Loyola University Chicago Stritch School of Medicine, Director, Breast Clinical Research Program, Cardinal Bernardin Cancer Center, Loyola University Medical Center Chicago, IL Advisory Board Member: Genomic Health Chemotherapy In Early Stage Luminal Breast Cancer Who Benefits? Kathy S. Albain, MD, FACP Professor of Medicine Loyola University Chicago Stritch School of Medicine Cardinal Bernardin Cancer Center (kalbain@lumc.edu) Controversy in Early Breast Cancer Clinical Practice: Chemotherapy Benefit in Luminal (ER+) Disease Mixed Messages Message Yes! Message No! Benefit to all women whose recurrence risk justifies adjuvant ant chemotherapy Not all women have added benefit to endocrine therapy despite higher risk of recurrence K Albain, SABCS 2011 Webcast 12/6 1
Confounding Factors in the Treatment of ER+ (Luminal) Early Breast Cancer Heterogeneity: ER level, Ki67, intrinsic subtype (luminal A/B, HER2 enriched or not), multigene assay categories De novo resistance (prior to adjuvant ET) Secondary resistance (develops during adjuvant ET) Cross-talk with other pathways Variable chemotherapy sensitivity/resistance Heterogeneity most likely explains controversy across trials of efficacy of adjuvant anthracyclines and taxanes (or not) and differential effect of same regimen by age This Presentation Summary of recent (and conflicting) philosophies of the Oxford Overview and St. Gallen in ER+ Role of multigene assays in addressing this controversy: - to select which patients with ER+ disease will benefit from chemotherapy added to endocrine therapy - many assays are prognostic, but will focus only on prediction Implications for clinical practice The EBCTCG Overview and St. Gallen 2
EBCTCG 2007 Update Unselected for HER2 status EBCTCG 2011 Chemotherapy Meta-analysis Summary: Breast Cancer Mortality ER+ and ER poor Trial Grouping RR SE 2p CMF vs no chemo 0.76 (0.05) <0.0001 CAF vs no chemo 0.64 (0.09) 09) <0.00010001 4AC/EC vs no chemo 0.78 (0.09) 0.01 4AC vs CMF 0.98 (0.05) 0.67 CAF/CEF vs 4AC 0.78 (0.06) 0.0004 Anthra then T vs shorter anthra 0.86 (0.04) 0.0005 Anthra + taxane vs expanded anthracycline alone 0.94 (0.06) 0.33 Lancet Dec 6, 2011 ER+ Anthra/CMF plus ET vs ET Control Age < 55 Age 55-69 EBCTCG Lancet Dec 6, 2011 3
Anthracyclines vs No Chemotherapy by Subsets of ER+ EBCTCG Lancet Dec 6, 2011 What We Learn from the New EBCTCG 2011 Chemotherapy Overview in ER+ Disease Major benefit overall to anthracyclines and taxanes, reducing breast cancer mortality by about 1/3 (the same as in ER-poor disease) No apparent heterogeneity by age, grade, T size, nodes, presence of tamoxifen - when factors generally considered one at a time Even in strongly ER+ disease, chemotherapy impacted outcome, though not to the same extent as in less strongly ER+ disease in the largest trial S8814 which had heterogeneity K Albain, SABCS 2011 Webcast 12/6 SWOG 8814 CAF-Tam vs Tamoxifen Recurrences Only ER 10-99 fm/mg ER100+ Interaction p = 0.04 Peto R, Personal Communication, 2011 4
What worries me (not just in breast cancer, but in many other diseases) is false-negative subgroup analyses of results that, overall, are highly significant; patients can die from under-useuse as well as from over-use of toxic treatments Sir Richard Peto, Dec 3, 2011 see also Peto R(2011) Br J Cancer 1057-8 BUT for ER+, There are Caveats The Overview Cannot Do Everything! Biologic heterogeneity is real, not fully explored Optimal endocrine therapy not uniformly given Interaction of tamoxifen timing with other factors Selection for more chemosensitive disease within recent trials - earlier trials enriched with indolent (luminal l A) ER+ disease (controls of ET alone or no treatment) Importance of menopausal status, not age; impact of amenorrhea ER level alone, or any other factor considered one at a time, may not be sufficient to define who can avoid, as well as who should definitely have CT HER2 status not available for most trials until recently K Albain, SABCS 2011 Webcast 12/6 Theoretical Spectrum of Sensitivity to Adjuvant Systemic Therapy by Intrinsic Subtypes Hayes DF. J Clin Oncol 2012 (editorial) 5
St. Gallen 2011: Shorthand Determination of Breast Cancer Subtypes Intrinsic Subtype Luminal A Surrogate Definition ER and/or PgR(+), HER2(-) Ki-67 low (<14%)* Luminal B1 ER and/or PgR(+), HER2(-) Ki-67 high Luminal B2 HER2 over-expression ER and/or PgR(+), HER2(+) Any Ki-67 ER and PgR absent, HER2(+) Basal-like Triple negative ductal (not medullary, adenoid cystic) * Using PAM5O cutpoint from Cheang et al. JNCI 2009 Annals Oncol 2011 Subtype Type of therapy Notes Luminal A Luminal B (HER2 negative) Luminal B (HER2 positive) HER2 positive (non luminal) Endocrine therapy alone Cytotoxics + endocrine therapy Cytotoxics + anti-her2 + endocrine therapy Cytotoxics + anti-her2 Few require cytotoxics (e.g. high nodal status). Inclusion and type of cytotoxics may depend on level of endocrine expression, perceived risk and patient preference. No data are available to support the omission of cytotoxics in this group. Patients at very low risk may be observed without treatment Triple negative (ductal) Special histological types * A. Endocrine responsive B. Endocrine non responsive Cytotoxics Endocrine therapy Cytotoxics Annals Oncol 2011 Medullary and apocrine carcinomas may not require any adjuvant cytotoxics (if node negative). The Role of Multigene Assays in Addressing the Controversy 6
21 Gene Recurrence Score (RS) 70 Gene Genomic Grade Other Prognostic Signatures... High Risk Driven by Proliferation Genes Relative Endocrine Resistance Relative Chemo Sensitivity BUT Only RS tested in in phase III trials N0, N+ Modified from C. Sotiriou SABCS 09 and Sotiriou and Pusztai, NEJM 2009 Lot of Help for Prognosis, but Limited Data for Prediction of Chemotherapy Benefit ER+ Validated for Factor or Assay Validated for Prognosis prediction* in trials with ET alone control ER level Yes Yes Estrogen-regulated gene signature Yes N/A Proliferation (Ki67) Yes No HER2 Yes N/A Grade/GGI Yes N/A PAM50/intrinsic subtypes Yes N/A** IHC4 score Yes N/A IHC panel*** Yes N/A 21 gene Yes Yes N0*, N+* 70 gene Yes N/A** * validated in a prospectively planned retrospective study ** but, supportive data exists for predictive utility in population-based nonrandomized or neoadjuvant studies *** including Ki67 index, HER-2, ER, PR K Albain, SABCS 2011 Webcast 12/6 DDFS Low, High Risk: ET versus ET/CT (N0-3+) urvival Percent su DDFS: MammaPrint LOW RISK (n=252) 100 80 60 40 HR 0.26 (0.03 2.02) 20 p=0.20 ET (n=174, 69%) ET+CT (n=78, 31%) 99% 93% urvival Percent su 100 80 60 40 20 DDFS: MammaPrint HIGH RISK (n=289) HR 0.35 (0.17 0.71) p<0.01 ET (n=141, 49%) ET+CT (n=148, 51%) 88% 76% 0 0 1 2 3 4 5 Time in years 0 0 1 2 3 4 5 Time in years ( from a non-randomized data base) Bender, et al. PASCO 2009 7
EORTC-BIG MINDACT TRIAL 6,600 Women with N0-3+ Completed Accrual 7/2011 Evaluate Clinical-Pathological Risk and 70-Gene Signature Risk 55% N=3300 35% 10% N=600 Clinicalpathological and 70-gene both HIGH risk Discordant cases Clin-Path HIGH 70-gene LOW Clin-Path LOW Clinicalpathological and 70-gene both LOW risk 70-gene HIGH N=2100 R1 Use Clin-Path risk to decide Chemo or not Use 70-gene risk to decide Chemo or not Chemotherapy Potential CT sparing in 20-28% pts Endocrine therapy 21 Gene Recurrence Score Assay: Strongly Predictive in NSABP B-20 (ER+ N0) Distant Recurren nce at 10 Years 0.4 0.3 0.2 0.1 0.0 Tam Tam + Chemo 0 10 20 30 40 50 Recurrence Score Minimal, if any, Chemo Benefit Clear Chemo Benefit Benefit from CMF Sparano, TBCI San Antonio, 2005; Paik JCO 2006 PACCT-1: TAILORx Pre-REGISTER n = 7047 21 Gene RS Assay REGISTER Specimen Banking Results expected in 2014 Secondary Study Group 1 RS < 11 ~29% of Population Primary Study Group RS 11-25 ~44% of Population Secondary Study Group 2 RS > 25 ~27% of Population ARM A Hormonal Therapy Alone RANDOMIZE n = 4390 ARM D Chemotherapy Plus Hormonal Therapy ARM B Hormonal Therapy ARM C Chemotherapy Plus Hormonal Therapy 8
S8814 CAFT vs T ER+ N+ Postmenopausal No benefit to CAF over time if low RS Strong benefit if high RS Disease-Free Survival by Treatment Disease-free survival 0.00 0.25 0.50 0.75 1.00 Low risk (RS < 18) Stratified log-rank p = 0.97 at 10 years Tamoxifen (n=55, 15 events) CAF-T (n=91, 26 events) 0 2 4 6 8 10 Years since registration Disease-Free Survival by Treatment Disease-Free Survival by Treatment Disease-free survival 0.00 0.25 0.50 0.75 1.00 High risk (RS 31) Stratified log-rank p = 0.033 at 10 years Tamoxifen (n=47, 26 events) CAF-T (n=71, 28 events) 0 2 4 6 8 10 Years since registration Disease-free survival 0.00 0.25 0.50 0.75 1.00 Intermediate risk (RS 18-30) Stratified log-rank p = 0.48 at 10 years Tamoxifen (n=46, 22 events) CAF-T (n=57, 20 events) 0 2 4 6 8 10 Years since registration Albain Lancet Oncology 2010 S8814 CAFT vs T Breast Cancer Specific Survival by RS Breast cancer specific survival 0.0 00 0.25 0.50 0.75 1.00 S8814D: BC Specific Survival Low Risk (RS < 18) Treatment Tamoxifen only (n=55; 4 BC deaths) CAF-T (n=91; 10 BC deaths) Stratified log-rank test p = 0.56 at 10 years 0 2 4 6 8 10 Years since registration Breast cancer specific survival 0.0 00 0.25 0.50 0.75 1.00 S8814 E: BC Specific Survival Intermediate Risk (RS 18-30) Treatment Tamoxifen only (n=46; 11 BC deaths) CAF-T (n=57; 10 BC deaths) Stratified log-rank test p = 0.89 at 10 years 0 2 4 6 8 10 Years since registration Breast cancer specific survival 0.00 0.25 0.50 0.75 1.00 S8814 F: BC Specific Survival High Risk (RS 31+) Treatment Tamoxifen only (n=47; 20 BC deaths) CAF-T (n=71; 18 BC deaths) Stratified log-rank test p = 0.033 at 10 years 0 2 4 6 8 10 Years since registration Interaction p = 0.021 Albain, et al. Lancet Oncology 2010 DFS survival hazard ratios (adjusted by number of positive nodes) for chemotherapy benefit by linear RS over time: Modelled HR Estimates All Years First 5 years After 5 years HR 95% CI HR 95% CI HR 95% CI Nodes (4+) 2.44 1.75-3.42 2.49 1.58-3.92 2.37 1.44-3.91 Chemotherapy 1.12 0.61-2.06 1.58 0.66-3.76 0.78 0.34-1.83 at RS=0 RS/50 (50 point 2.71 1.37-5.36 5.77 2.42-13.79 0.92 0.30-2.83 difference) Chemo*RS/50 0.43 0.18-1.01 0.30 0.10-0.89 0.66 0.16-2.82 Interaction 0.053-0.029-0.58 - p-value Nevertheless the cumulative benefit of CAF persists up to 10 years Albain, et al. Lancet Oncol 2010 9
S1007 RxPONDER Schema Node-positive (1-3 nodes) HR-positive and HER2-negative breast cancer (N= 8,800) Patients consent to study-sponsored sponsored RS testing, discussion of potential trials, tumor tissue submission and linkage to cancer registry data (N= 600) RS already Available Physician and patients discuss randomization knowing the RS STEP 1 REGISTRATION Tumor tissue submission for RS STEP 2 REGISTRATION RANDOMIZATION RS > 25 (N= 3,800) Discuss alternative trials for high risk patients RECURRENCE SCORE RS < 25 N= 5,600 Physician and patients discuss randomization knowing the RS Refuse Accept STEP 2 REGISTRATION/ RANDOMIZATION N= 4,000 Randomization stratified by 1. RS 0-13 vs. 14-25 2. Menopausal status 3. Axillary node dissection vs. Sentinel node biopsy N= 2,000 Chemotherapy; appropriate endocrine therapy N= 2,000 No Chemotherapy; appropriate endocrine therapy N= 1,600 Record chosen therapy and followed for vital status through cancer registry Medical Oncology Investigators: Gonzalez-Angulo A-M, PI; Hortobagyi G; Albain K S1007 RxPONDER Accrual 8/24/12 Registration 1 (goal 9400) 1290 Registration 2 (goal 4000) 288 Chemotherapy + endocrine therapy 292 Endocrine therapy alone Variable Pathologic Complete Remission Rates with Chemotherapy before Surgery by Intrinsic Subtype Subtype Percent pcr Luminal A 0 Luminal B 19% HER2 39% Basal-like 73% Claudin low 39% C. Perou, 9 th International Congress on the Future of Breast Cancer, 2010 10
No pcrs if Good 70-Gene Signature Straver, et al. Breast Cancer Res Treat 2009 Pathologic CRs not Observed in Lower 21 Gene Recurrence Scores in Neoadjuvant Study (incl. N+, taxanes) Gianni, L. et al. J Clin Oncol; 23:7265-7277 2005 NSABP Planned Phase III Neoadjuvant TAILORx for Level 1 Evidence HR+/Her-2 2 Neg. Breast Cancer Needing Neo Rx to Achieve BCT Core Biopsy p yfor Gene Expression Profile (RS) < 11 11-25 > 25 Neoadjuvant Hormonal Tx Randomize Neoadjuvant Chemotherapy Neoadjuvant Hormonal Tx Neoadjuvant Chemotherapy SURGERY Endpoints: Clinical Response, BCT, RCB, pcr PI: H. Bear 11
Neoadjuvant Meta-analysis: analysis: Canonical Pathways Associated with pcr Differ by Subtype All ER-/HER2- HER2+ ER+/HER2- Ignatiadis et al J Clin Oncol 2012; slide modified from AM Gonzalez-Angulo Future Directions and the Patient in Our Office Today SWOG Phase III adjuvant endocrine therapy + everolimus/placebo in high-risk, node-positive, hormone receptor-positive, positive, HER2-neu normal breast cancer Node-positive HR-positive and HER2-negative breast cancer Number of positive nodes? 1-3 positive Patients consent to study-sponsored sponsored RS testing if not already done 4+ positive RS 25 RECURRENCE SCORE evaluated Low risk 1-3 positive nodes and RS 25 RS > 25 Adjuvant or neoadjuvant chemotherapy 1-3 positive nodes and RS > 25 or 4+ positive nodes all RS RANDOMIZATION Chemotherapy vs. No Chemotherapy Chemotherapy; endocrine therapy No Chemotherapy; endocrine therapy RANDOMIZATION Post-chemotherapy (stratification by number of lymph nodes and timing of chemotherapy) Everolimus vs. Placebo Everolimus + Endocrine Therapy Placebo + Endocrine Therapy Current RxPONDER trial S1007 New adjuvant trial 12
S8814 (INT0100) DFS by RS and Nodal Status at 5,10 Years Ten Years Five Years DFS Event by 10 Year rs (%) 30 40 50 60 70 80 0 10 20 90 100 Tam alone; 4+ nodes CAF-T; 4+ Nodes Tam alone; 1-3 nodes CAF-T; 1-3 Nodes DFS Event by 5 Years (%) 30 40 50 60 70 0 10 20 80 90 100 Tam alone; 4+ nodes CAF-T; 4+ Nodes Tam alone; 1-3 nodes CAF-T; 1-3 Nodes 0 5 10 15 20 25 30 35 40 45 50 Recurrence Score 0 5 10 15 20 25 30 35 40 45 50 Recurrence Score Albain, et al. Lancet Oncology 2010 ATAC by Recurrence Score The Challenge of Tumor Burden Dowsett et al. J Clin Oncol 2010 It s time to give prospective (clinical trial) attention to biologically indolent but higher clinical risk luminal breast cancer However you want to define it High ER level/low prolif, low RS, good risk 70 gene, luminal A, etc These patients should probably not be entered within trials testing cytotoxic therapy, or else agents with novel mechanisms of action need to be added to standard therapy New trial designs needed for them, especially with higher risk Pay attention to the lesson of S8814: overall positive benefit to anthracyclines added to tamoxifen, but a sizable subgroup in the trial did not appear to benefit 13
SWOG S8814 Next Phase Whole transcriptome expression analyses on stored RNA using next generation sequencing techniques Identify novel genes not identified in the research hleading up to the 21 gene RS assay Prognosis in patients treated with tamoxifen alone and CAF followed by tamoxifen Prediction of CAF benefit Identify candidate genes and pathways that can be tested further in other trials such as S1007 (RxPONDER) Highlights of early TCGA findings using 500 tumors 1. Basal like tumors form a distinct subtype by gene expression, DNA methylation, protein patterns, and by microrna expression profiling (75% of Triple negative breast cancers are of the Basal like subtype) 2. The 10 most frequently mutated genes in ER+/HER2 tumors occur within a diversity of pathways and includes PIK3CA(48%), TP53(20%), MAP3K1(18%), GATA3(14%), CDH1(9%), MLL3(8%), MAP2K4(6%), PTEN(5%), RUNX1(4%) and AKT1(3%). 3. DNA methylation analysis identifies Basal like tumors as showing a hypo methylation phenotype and asubset of Luminal B cases as having frequent promoter CpG island hyper methylation phenotype. 4. Integrated pathway analyses identifies distinct mechanisms of PIK3CA pathway activation by subtype 5. Complex and numerous DNA copy number changes are associated with the Basal like, HER2 enriched, and LumB subtypes, and are independent predictors of poor outcomes 6. HER2+ tumors are molecularly heterogeneous and tumors that are clinical HER2+ AND HER2 enriched subtype appear to show activation of HER2 and HER1 signaling Slide courtesy C. Perou 2/2012 Chemotherapy for Early Stage ER+ BC* - Mixed Messages, Both True! Message Summary Yes EBCTCG 2011! Anthra, taxane major and durable benefits overall and for major subsets No Biologic heterogeneity defined by multigene assays cannot be ignored Consistent evidence across studies New tactics needed to identify and treat the chemo-insensitive cohort *Excluding very small N0, or small HER2+ tumors 14
My View Need to put into practice now our new knowledge about tumor biology in ER+ disease, while not ignoring the real benefit of chemotherapy in many women with ER+ disease. Limitations in defining the chemo-resistant group by onefactor-at-a-time analyses however you choose to do it with combination of factors, the result seems to be the same there is a group that does not benefit regardless of risk. Results have been consistent and support the hypotheses being studied in the 3 large prospective trials In the meantime, we need to be vigilant to neither overtreat or undertreat with chemotherapy and multigene assays can provide additional guidance and should be offered to all women who would consider chemotherapy. SUMMARY Modern adjuvant/neoadjuvant chemotherapy benefits patients with luminal breast cancer in general (2011 Oxford Overview) However, across all risk levels, biologic subtypes of ER+ disease differ widely in degree of chemotherapy sensitivity Avoidance of chemotherapy is justified in HER2 non-enriched subgroups that are highly endocrine responsive with low proliferation (variably defined by low 21 gene RS, luminal A, low risk 70 gene) High risk scenarios with this biologic profile require alternate strategies to increase cure rates Thank You for Inviting Me! 15