Role of Genomic Profiling in (Minimally) Node Positive Breast Cancer

Role of Genomic Profiling in (Minimally) Node Positive Breast Cancer Kathy S. Albain, MD, FACP Professor of Medicine Dean s Scholar Loyola University Chicago Stritch School of Medicine Cardinal Bernardin Cancer Center kalbain@lumc.edu

DISCLOSURE Advisory board honorarium - Genomic Health Inc - nanostring Technologies - biotheranostics, Inc. Research collaborations - Agendia - Genomic Health Inc Research funding - National Cancer Institute - Breast Cancer Research Foundation

Breast Cancer Evolution of Genomic Profiling THEN Simply breast cancer ER(+), ER (-) ER(+) HER2(-) ER(-) HER2(+) ER(+) HER2(+) ER(-) HER2(-) If ER(+) and HER2(-), either: High grade/prolif, Low ER level or Low grade/prolif, High ER level Multigene Assays Molecular (intrinsic) Subtypes Albain, KS. St. Gallen 2013 NOW Whole genome/next gen sequencing

How Subtyping/Genomic Profiling Helps Prognostic information Trajectory of recurrence events Prediction of systemic treatment benefit - Chemotherapy, endocrine therapy, anti-her - Specific drug selection Paradigm shift: use multigene assays to better define biology in individual patients - Give chemotherapy when we did not before (low stage/small tumors but adverse biology) - Avoid chemotherapy compared to the past (higher stage/n+ but favorable/indolent biology)

Molecular Intrinsic Subtypes, Multigene Assays and Prediction of Chemotherapy Benefit ER+ HER2- Node+

ER+ Anthra/CMF plus ET vs ET Control* Age < 55 Age 55-69 *Mostly larger N0 or N+ accrued to these trials EBCTCG Lancet Dec 6, 2011

Lot of Help for Prognosis, but Limited Data for Prediction of Chemotherapy Benefit ER+ Selected Factors/Assays Validated for Prognosis Validated for 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 ** supportive data exists for predictive utility in population-based nonrandomized or neoadjuvant studies *** including Ki67 index, HER-2, ER, PR K Albain, SABCS 2012

SWOG 8814 N+ CAF-T vs T ER 10-99 fm/mg ER100+ Interaction p = 0.04 Albain, KS. St. Gallen 2013 Peto R, Personal Communication, 2011

Disease-free survival S8814: One Grouping of Standard Markers was Predictive: No DFS Benefit from CAF if Central IHC HER2- and ER Level High* Disease-free survival HER2 Negative and ER Allred 7-8 HER2 Positive or ER Allred <7 0.00 0.25 0.50 0.75 1.00 Stratified log-rank p = 0.81 at 10 years Tamoxifen (n=57, 20 events) CAF-T (n=85, 30 events) 0 2 4 6 8 10 Years since registration 0.00 0.25 0.50 0.75 1.00 Stratified log-rank p = 0.011 at 10 years Tamoxifen (n=73, 36 events) CAF-T (n=112, 39 events) 0 2 4 6 8 10 Years since registration *Interaction p=0.052; if add mitotic grade, p=0.024 Albain, et al. Lancet Oncology 2010

HER2 Positive Proportion 0.0 0.2 0.4 0.6 0.8 1.0 Proportion 0.0 0.2 0.4 0.6 0.8 1.0 HER2 Negative Proportion Proportion 0.0 0.2 0.4 0.6 0.8 1.0 CALGB 9344/INT 0148: No Paclitaxel Benefit ER+HER2- Exploratory DFS Analysis by Estrogen Receptor n = 1322, Node+ ER Negative ER Positive 0.0 0.2 0.4 0.6 0.8 1.0 Paclitaxel No paclitaxel 0 2 4 6 8 10 Years No Paclitaxel Paclitaxel 0 2 4 6 8 10 Years Paclitaxel Paclitaxel No paclitaxel No paclitaxel 0 2 4 6 8 10 0 2 4 6 8 10 Years Years Hayes DF, et al. NEJM 2006

Many Assays, Same Answer? prognostic, but are they predictive?) (Clearly Assay Favorable Biology* More Aggressive Biology** Intrinsic subtype (cdna arrays, frozen tissue) PAM 50 intrinsic ROR, (paraffin, nanostring) IHC shorthand binary cutpoints St Gallen 13 (ER, PR, HER2, Ki67) 21 gene RS assay (OncotypeDX) 70 gene assay (MammaPrint) Luminal A Luminal A Luminal A-like Lower scores Low risk category Luminal B Luminal B Luminal B-like Higher scores High risk category * Relatively chemotherapy resistant; **Relatively chemotherapy sensitive Albain, KS. St. Gallen 2013

Theoretical Spectrum of Sensitivity to Adjuvant Systemic Therapy by Intrinsic Subtypes Hayes DF. J Clin Oncol 2012 (editorial)

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 Albain, KS. SABCS 2012

Percent survival Percent survival DDFS Low, High Risk: ET versus ET/CT (N0-3+) DDFS: MammaPrint LOW RISK (n=252) DDFS: MammaPrint HIGH RISK (n=289) 100 80 60 40 ET (n=174, 69%) ET+CT (n=78, 31%) 99% 93% 100 80 60 40 ET (n=141, 49%) ET+CT (n=148, 51%) 88% 76% 20 HR 0.26 (0.03-2.02) p=0.20 20 HR 0.35 (0.17-0.71) p<0.01 0 0 1 2 3 4 5 Time in years 0 0 1 2 3 4 5 Time in years ( a non-randomized data base) From Knauer et al. Breast Cancer Res Treat 2010; Albain KS. SABCS 2012

No pcr if Low Risk/Favorable Biology by PAM50 Intrinsic Subtype/Multigene Assays Higher Risk - 6 Studies Study Assay pcr Result Straver, et al. 2009 70-gene signature (MammaPrint) None if good prognosis signature Parker, et al. 2009 ROR Score by PAM50 None/very few low score Cheung, Perou et al. 2011 Intrinsic subtypes PAM50 Very low if Luminal A Gluck, et al. 2012 70-gene plus subtyping (MammaPrint, BluePrint) 6% Luminal A, 11% Luminal B Gianni, et al. 2005 21-gene RS (Oncotype Dx) None if RS < 27 Chang, et al. 2008 21-gene RS (Oncotype Dx) None if RS < 26 Albain, KS. St. Gallen 2013

Disease-free survival Disease-free survival 0.00 0.25 0.50 0.75 1.00 Disease-free survival 0.00 0.25 0.50 0.75 1.00 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 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 High risk (RS 31) Intermediate risk (RS 18-30) Stratified log-rank p = 0.033 at 10 years Stratified log-rank p = 0.48 at 10 years Tamoxifen (n=47, 26 events) CAF-T (n=71, 28 events) Tamoxifen CAF-T (n=46, 22 events) (n=57, 20 events) 0 2 4 6 8 10 Years since registration 0 2 4 6 8 10 Years since registration Albain Lancet Oncology 2010

0 0 10 20 30 40 50 60 70 80 90 100 DFS Event by 5 Years (%) 10 20 30 40 50 60 70 80 90 100 S8814 (INT0100) DFS by RS and Nodal Status at 5,10 Years Ten Years Five Years Tam alone; 4+ nodes CAF-T; 4+ Nodes Tam alone; 1-3 nodes CAF-T; 1-3 Nodes 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

S8814 Ten-Year Breast Cancer Specific Survival by RS and Treatment RS Group Tamoxifen (95% CI) CAF-T (95% CI) Low (<18) 92% (79%-97%) 87% (76%-93%) Intermediate (18-30) 70% (50%-83%) 81% (67%-89%) High ( 31) 54% (38%-68%) 73% (60%-82%) Albain et al. Lancet Oncology 2010

Breast cancer specific survival 0.00 0.25 0.50 0.75 1.00 S8814 CAFT vs T Breast Cancer Specific Survival by RS 0.00 0.25 0.50 0.75 1.00 Breast cancer specific survival 0.00 0.25 0.50 0.75 1.00 S8814 D: BC Specific Survival Low Risk (RS < 18) S8814 E: BC Specific Survival Intermediate Risk (RS 18-30) 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 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 S8814 F: BC Specific Survival High Risk (RS 31+) Interaction p = 0.021 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 Albain, et al. Lancet Oncology 2010

Remarkably Similar Significant Interaction between Chemotherapy Benefit and Recurrence Score in B20 and S8814 Variable/Study Tamoxifen Tamoxifen + Chemotherapy 10 yr DRFS B20 N0* Low Recurrence Score 97% 93% High Recurrence Score 60% 73% 10 yr BCSS S8814 N+** Low Recurrence Score 93% 88% High Recurrence Score 54% 73% * Paik S, et al. J Clin Oncol 2006; interaction p = 0.038 **Albain KS, et al. Lancet Oncol 2010; interaction p = 0.021 Albain, KS. SABCS 2012

S1007 RxPONDER Schema Node-positive (1-3 nodes) HR-positive and HER2-negative breast cancer (N= 8,800) Patients consent to study-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 (N= 3,800) Discuss alternative trials for high risk patients RECURRENCE SCORE RS > 25 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: Gralow J, Hortobagyi G, Albain K

S1007 RxPONDER Accrual as of 2/28/14* Registration 1 (goal 9400) 4599 Registration 2 (goal 4000) - 2272 1139 Chemotherapy + endocrine therapy 1133 Endocrine therapy alone *Now excluding 1 microscopic node

It s time to give prospective (clinical trial) attention to biologically indolent but higher clinical risk ER+ breast cancer not (or incompletely) responsive to chemotherapy 10 20 30 40 50 60 70 80 90 100 0 However you want to define it high ER level/low prolif, low RS, good risk 70 gene, luminal A, etc 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 Albain, KS. St. Gallen 2013 Albain, et al. Lancet Oncol 2010 and Dowsett et al. J Clin Oncol 2010

Approaches to Improve Outcome for Bad Stage but Indolent or Unique Biology Enhance chemotherapy benefit by adding agents that inhibit specific targets Add novel agents to endocrine therapy to shut down bypass signaling pathways that drive tumor growth (in addition to, or even instead of chemotherapy) Identify new targets (e.g., AR, PgR, Notch/stem cell) Focus on late relapses/tumor dormancy Albain, KS. Miami 2014

SWOG S8814 N+ ER+ Next Phase Whole transcriptome expression analyses on stored RNA using next generation sequencing techniques Identify novel genes not identified in the research leading 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) Albain, KS. Miami 2014

S1207 Phase III adjuvant endocrine therapy + everolimus/placebo in high-risk, node-positive, hormone receptor-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 RS testing if not already done 4+ positive RS 25 RANDOMIZATION Chemotherapy vs. No Chemotherapy RECURRENCE SCORE evaluated Low risk 1-3 positive nodes and RS 25 RS > 25 Chemotherapy; endocrine therapy No Chemotherapy; endocrine therapy Current RxPONDER trial S1007 Adjuvant or neoadjuvant chemotherapy RANDOMIZATION Post-chemotherapy (stratification by number of lymph nodes and timing of chemotherapy) Everolimus vs. Placebo 1-3 positive nodes and RS > 25 or 4+ positive nodes all RS (n = 3500) New adjuvant trial Everolimus + Endocrine Therapy Placebo + Endocrine Therapy

SWOG 8814 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 at RS=0 RS/50 (50 point difference) 1.12 0.61-2.06 1.58 0.66-3.76 0.78 0.34-1.83 2.71 1.37-5.36 5.77 2.42-13.79 0.92 0.30-2.83 Chemo*RS/50 0.43 0.18-1.01 0.30 0.10-0.89 0.66 0.16-2.82 Interaction p-value 0.053-0.029-0.58 - Nevertheless the cumulative benefit of CAF persists up to 10 years Albain, et al. Lancet Oncol 2010

Prediction of Late Relapse (beyond 5 years) High Risk ER+ N0/N+ PAM50 ROR (nanostring) EndoPredict Score (8 genes) Breast Cancer Index (BCI) an algorithmic combination of - HOXB13/IL17BR ratio (H/I) - Molecular Grade Index GOAL: Select candidates for prolonged endocrine therapy and/or addition of targeted therapy Albain, KS. Miami 2014

Distant Metastasis-free Survival (MFS) by EndoPredict Risk Groups EndoPredict assesses prognosis of of patients on ET, captures late events Dubsky P et al. Ann Oncol 2013;24:640-647

Genomic Profiling (Minimally) Positive Nodes There is no difference in chemotherapy predictive utility for high risk N0 versus N+ Large prospective trials will confirm role in high risk N0 and N1-3+ (MINDACT, TAILORx and RxPONDER S1007 Sadly, no prospective trials will be done in 4+ nodes Will you accept the N1-3+ outcome from S1007 to inform decision-making for 4+? Easier to accept once novel strategies employed for high risk but indolent biology scenarios Albain, KS. Miami 2014

Clinical Parameters + Multigene Assays Have High Overlap and Imperfectly Predict Outcome/Resistance Need to Capture and Target the Biology of Pathway Activation Multigene assays, molecular subtypes (21 gene, 70 gene, PAM50 ROR, etc) Clinical-pathologic parameters (T, N, ER, PgR, HER2, Ki67, grade, IHC4) Pathway Activation (phosphorylation and other PTMs, mutations) Fuqua S, Albain K. 2013