Update on the Practical Management of HER2-Positive Breast Cancer

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1 Update on the Practical Management of HER2-Positive Breast Cancer Antonio C. Wolff, MD, FACP Breast Cancer Program Easy Questions from Joyce HER2 testing and equivocal results TCH vs ACTH options Subcentimeter HER2+ breast cancer A few extra background slides at the end of the slide set San Diego, Aug Disclosure Slide Genentech provides funding to Johns Hopkins to support an early phase clinical trial that has Dr. Wolff as site PI HER2 Testing circa MMXI Goals and outcomes from the ASCO/CAP efforts Standardization versus confusion? Are things better? Lessons from the cooperative group trials Round-Robin exercise by NCCTG/BCIRG/NSABP Ring study data in ALTTO Dr. Wolff is not a pathologist and (hopefully) does not pretend to come across as one Current Assumptions on Benefit from HER2-Targeted Therapy in HER2 Normal Disease Metastatic setting Trastuzumab most likely no benefit Low/medium-level evidence from CALGB 9840 and various phase II trials Lapatinib definitely no benefit High-level evidence from phase III paclitaxel ± lapatinib Adjuvant setting Trastuzumab benefit?? Low-level evidence from 1 st generation trials Ongoing trial NSABP B47 Lapatinib no data HER2 Testing (Dis)Concordance in Adjuvant Trastuzumab Trials Concordance Central vs Local Lab (circa 2006) N9831 IHC 3+ (HercepTest) FISH + (PathVysion) JNCI 2002 (total n = 119) ASCO 2004 (total n = 976) 74% 79.5% 67% 85% JCO 2006 (total n = 2535) 82% (false pos 18%) 88% (false pos 12%) Magnitude of false-neg HER2 testing unclear but real 1

2 ASCO/CAP HER2 Testing Guideline & 1. What is the optimal testing algorithm for the assessment of HER2 status? 2. What strategies can help ensure optimal performance, interpretation, and reporting of established assays? Guideline appendices: Appendix C: Evidence of HER2 Status and Trastuzumab Benefit Appendix D: Evidence of HER2 Testing Variation Appendix E: Tissue Handling Requirements and Control Materials Appendix F: Statistical Requirements for Assay Validation Appendix G: Interpretation Criteria & Test Reporting Appendix H: Regulatory Requirements for Laboratories Appendix I: International External QA Initiatives 2 nd most downloaded JCO article in 2007, > 1000 citations since Arch Path Lab Med 13:18, Jan 2007 & JCO 25:118, Jan guideline JCO 25:4021, Sep letter to the editor, reply to Raji and to Nielsen et al JCO 27:e153, Oct letter to the editor, reply to G. Sauter et al ASCO/CAP HER2 and ER/PgR Jan Clinical Notice JCO Apr letter to the editor American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer Antonio C. Wolff, M. Elizabeth H. Hammond, Jared N. Schwartz, Karen L. Hagerty, D. Craig Allred, Richard J. Cote, Mitchell Dowsett, Patrick L. Fitzgibbons, Wedad M. Hanna, Amy Langer, Lisa M. McShane, Soonmyung Paik, Mark D. Pegram, Edith A. Perez, Michael F. Press, Anthony Rhodes, Catharine Sturgeon, Sheila E. Taube, Raymond Tubbs, Gail H. Vance, Marc van de Vijver, Thomas M. Wheeler and Daniel F. Hayes 2 nd most downloaded JCO article in 2007, > 1000 PubMed citations since Arch Path Lab Med 13:18, Jan 2007 & JCO 25:118, Jan guideline HER2 Testing Algorithm by IHC HER2 Testing Algorithm by FISH JCO 25:4021, Sep letter to the editor, reply to Raji and to Nielsen et al Arch Path Lab Med 13:18, Jan 2007 & JCO 25:118, Jan guideline Clinical Notice for ASCO/CAP Guideline Recommendations for ER/PgR and HER2 Testing I. Reconciles the two guidelines: Changed cold ischemia time from short to 1h Record time between tissue removal and start of fixation Confirmed fixation time in NBF (formalin) as 6 to 48h < 6h for needle cores not ok; unclear if HER2 ok > 48h Handling of specimens obtained remotely Specimen bisection; record times and fixative used Selection of an optimal sample for testing A preference for core needle biopsies, but pathologists to use discretion in selecting sample for testing 2011 Clinical Notice for ASCO/CAP Guideline Recommendations for ER/PgR and HER2 Testing II. Reminder of the intent behind creating the HER2 equivocal categories: Trigger HER2 reflex testing using another validated assay if the first test equivocal I.e., IHC if an equivocal FISH; FISH if an equivocal IHC provide clinicians and their patients with additional information for clinical decision making. Figs 1 & 2 clearly state that patients with uniform IHC staining between 10-30% or FISH ratio 2.0 were eligible for the trastuzumab adjuvant trials ASCO/CAP HER2 and ER/PgR Jan Clinical Notice JCO Apr letter to the editor ASCO/CAP HER2 and ER/PgR Jan Clinical Notice JCO Apr letter to the editor 2

3 2011 Clinical Notice for ASCO/CAP Guideline Recommendations for ER/PgR and HER2 Testing Jan 2007: Available data from the adjuvant trials at present are insufficient to reliably exclude these patients from therapy with trastuzumab Apr 2011: The Panel did not recommend withholding anti-her2 treatment in those patients with an equivocal HER2 test (or tests) whose results fell within ranges that would have allowed them to be treated in the first generation of adjuvant HER2-targeted trials. Impact of ASCO/CAP Guidelines on HER2 Interpretation in Breast Cancer All Mayo Clinic Rochester cases of invasive breast ca HER2 3+ (HercepTest> 10% cells) between (n =?) 144 had available slides and blocks IHC re-reviewed by 3 pathologists (three cases reclassified as 2+) PathVysion FISH done on remaining 141 cases IHC re-scored and FISH scored using ASCO/CAP parameters IHC n = 141 (%) FISH + (> 2.2) FISH ± ( ) FISH (< 1.8) 2+ (11%-30%) 12 (8.5%) 6 2* (1.8 and 2.1) 4 3+ (31%-50%) 6 (4.3%) (51%-70%) 4 (2.8%) (>70%) 119 (84.4%) all 8 tested** 0 0 *Case #9 had IHC 25% and FISH 1.8 & 1.8; Case #10 had IHC 30% and FISH 2.1 & 1.8 **FISH performed in a sample (8 of 119 cases) with IHC 3+ in > 70% of cells ASCO/CAP HER2 and ER/PgR Jan Clinical Notice JCO Apr letter to the editor Shah et al, Hum Pathol 41:103, 2010 n = 2904 IHC 0 or 1+ (n = 136) 2+ (n = 221) 3+: 10-30% (n = 107) 4.2% 3+: > 30% (n = 2439) 95.8% Reclassification of HER2 IHC and FISH in N9831 using 2007 ASCO/CAP Guideline FISH < 1.8 (n = 218) 66 (48%) 69 (31%) 15 (14%) 68 (3%) FISH (n = 14) 2 (2%) 5 (2%) 1 (1%) 6 (0.2%) FISH > (n = 37) 1.5% 9 (7%) 16 (7%) 0.6% 6 (6%) 0.2% 6 (0.2%) FISH > 2.2 (n = 2539) 98.5% 49 (36%) 125 (57%) 78 (73%) 2287 (94%) Perez et al, SABCS Abstr 701, 2009 FISH not done (n = 95) 10 (7%) 6 (3%) 7 (7%) 72 (3%) HER2 and Chromosome 17 Effect on Patient Outcome in N9831 HRs for trastuzumab benefit (n = 1888) IHC FISH ratio Both 0.45 (all p < ) HER2 amplified/p17 vs HER2 amplified/n17 Similar HR within trastuzumab arm (copy number matters!) HR favors those with p17 within chemo arm Like in HERA ER+ vs ER- patients gained similar reduction in HR, but had lower rate of relapse in early follow-up Endocrine Rx (and accurate determination of ER/PgR status) matters! Perez et al, JCO 28:4307, 2010 Lab Compliance with ASCO/CAP HER2 Testing Guideline Survey submitted in late 2008 with the HER2 IHC immunoproficiency testing program Questions on: Pathology practice characteristics Assay validation using FISH or another IHC assay Pathologist HER2 scoring competency 757 of 907 (83.5%) surveys returned CAP Laboratory Accreditation Program No. of Labs Predictive Marker Proficiency Testing HER2 guideline ER/PgR guideline HER2 IHC HER2 FISH ER Nakhleh et al, Arch Path Lab Med 134:728, 2010 College of American Pathologists

4 Implementation of ASCO/CAP HER2 Guideline at a Tertiary Center (MDACC) 2006: 1033 core needle biopsies (67% invasive) Average duration of fixation 4h (half submitted after 3 pm) HER2 FISH/IHC concordance at 98% 10.8% of FISH results were inconclusive, but results became informative when additional tissue submitted 2007: 1186 core needle biopsies (68% invasive) Duration of formalin fixation increased to 6h HER2 FISH/IHC concordance increased to 98.5% FISH results inconclusive reduced from 10.8% to 3.4% Costs savings $34,000 40% reduction in need to repeat ER/PgR (38 to 23 cases) Round-Robin Review of HER2 Testing in the Context of Adjuvant Breast Ca Therapy Primary goals Concordance of HER2 results by 3 central labs (NCCTG, BCIRG, and NSABP) Round-robin impact on adjudication HER2 heterogeneity (different blocks, same patient) Secondary goal Impact of trastuzumab in patients with HER2 normal disease by panel adjudicated Round-Robin review Middleton et al, Arch Path Lab Med 133:775, 2009 Perez et al, SABCS Abstr PD10-02, 2011 Methods Blinded Round-Robin exchange of specimens from trials with local & central confirmatory HER2 testing (n = 389) N9831, BCIRG 005, and BCIRG 006 Central IHC/FISH results: HER2 normal: 96 local normal (005) and 62 local + (9831) HER2 positive: 37 +/+, 33 +/-, and 36 -/+ 123 patients with > 1 block (n = 125) No blocks from B31 Methods HercepTest (IHC 3+ in > 10% invasive cells) PathVysion (FISH ratio 2) HER2 status independently determined at each site; discordant cases adjudicated in face-to-face meeting Perez et al, SABCS Abstr PD10-02, 2011 Overall Concordance 96% IHC concordants 97% FISH concordants 4% IHC discordants: 2/3s IHC 2+ 3% FISH discordants: median ratio 1.8 Perez et al, SABCS Abstr PD10-02, 2011 Overall Concordance Round-Robin Conclusions Adjudication improved concordance: IHC from 92% to 96%, FISH from 92% to 97% Heterogeneity within same patient, different block IHC 10%, FISH 5% 96% IHC concordants 97% FISH concordants 4% IHC discordants: 2/3s IHC 2+ 3% FISH discordants: median ratio 1.8 Perez et al, SABCS Abstr PD10-02, 2011 Despite technical standardization, 8% initial discordance among expert pathologists Heterogeneity and/or interpretation Does it justify routine re-testing? No, this heterogeneity was only observed in tumor originally called HER2+! Perez et al, SABCS Abstr PD10-02,

5 ALTTO Central Testing Concordance ALTTO Central Testing Concordance HER2 (Dec 2009) Positive Equivocal/Other Central Testing Local Lab HER2 Eligible HER2 Not Eligible Total IEO 6871 Mayo (FP 14.5%) 24 (FP 5.8%) IEO Mayo Estrogen Receptor (Dec 2009) Local Lab Positive Negative ER-Positive 10% Central Testing ER-Positive 1% and <10% IEO Mayo IEO Mayo 665 (FN 16.1%) 5 (FN 3.4%) 217 (FN 5.3%) 0 (FN 0%) ER-Negative Total 208 (FP 4.2%) 44 (FP 16.2%) Concordance in HER2 Status between ALTTO Central Labs (Ring Study) IEO HER2 IHC Mayo Negative (0-1+) Equivocal (2+) Negative (0-1+) 18 6 Equivocal (2+) -- 1 Concordance in ER Status between ALTTO Central Labs (Ring Study) ER IEO (dual antibody) Mayo (single antibody) ER-negative ER-positive ER-negative ER-positive 5 10 Not evaluable 1 -- IEO HER2 FISH Mayo Not Amplified (<1.8) Equivocal ( ) Not Amplified (<1.8) 22 3 Equivocal ( ) ALTTO Eligibility (both tests) Mayo Not Eligible Eligible Not Eligible IEO Eligible cases were repeated (including all 5 discordants) with Mayo adopting the same ER methodology as IEO ER IEO (dual antibody) Mayo (dual antibody) ER-negative ER-positive ER-negative 3 -- ER-positive -- 8 Assays to Measure HER2 Circa MMXI Immunohistochemistry assays CTA CB11 and 4D5 MoAbs (not commercial) HercepTest A085 polyclonal Ab Pathway CB11 MoAb Fluorescence in situ hybridization assays PathVysion HER2:CEP17 ratio pharmdx kits HER2:CEP17 ratio INFORM kit HER2 gene copy number ISH assays w/o fluorescence SPoT-Light chromogenic ISH EnzMet GenePro silver enhanced ISH Inform Dual ISH two-color chromogenic ISH Functional assays HERmark HER2 total protein and homodimers Gene expression profiling assays Oncotype Dx real time RT-PCR TargetPrint DNA microarray ALTTO Ring Study Conclusion Same test on same tissue = same result 5

6 Easy Questions from Joyce Joint Analysis NCCTG 9831/NSABP B-31 HER2 testing and equivocal results TCH vs ACTH options Subcentimeter HER2+ breast cancer Perez et al, JCO 2011 Trials of One Year of Trastuzumab Lessons from First Generation Trials Trial Strategy DFS HR B-31/ N9831 HERA BCIRG 006 BCIRG 006 N9831 PACS04 AC-Tx ± concurrent T Chemo ± sequential T AC-Tx ± concurrent T AC-Tx vs TCb-T AC-Tx ± sequential T FEC or ED ± sequential T 0.48 (2005) 0.64 (2007) (2005) 0.96 X-over to trastuz. 20.9% 52% DFS HR OS HR Reference 0.52 (2011) 0.76 (2011) 1.6% - 1.6% NS 0.61 (2011) 0.85 NS (2011) Romond 2005, Perez 2011 Smith 2007, Gianni 2011 Slamon 2009 (third abstract) Slamon 2009 (third abstract) Perez 2005 & 2009 (abstracts) - - NS Spielmann 2009 Trastuzumab works, whether concomitantly, sequentially, or late after cross-over Cardiac toxicity is less with a non-anthracycline, but not prohibitive with concomitant Symptomatic CHF in B31/N9831 was 0.5% (AC) vs 2% (AC-TH) and 86% (31 of 36) had complete or partial resolution (Russell, JCO 2010) However, there is indirect evidence that a concomitant approach and that includes an anthracycline may be superior Trials like ALTTO and TEACH will refine our approach to HER2-positive disease Easy Questions from Joyce Approach to Adjuvant Therapy Decisions HER2 testing and equivocal results TCH vs ACTH options Subcentimeter HER2+ breast cancer Since 2005 Largely based on anatomy Nodal status Tumor size (Endocrine Rx added if ER+) Greater focus on biologic subtype ER+, HER2- HER2+ Triple negative Does anatomy (tumor burden) matter in the biologic era? Adapted from Eric Winer 6

7 Ten Year Outcome of Node-Negative, LVI Negative Early Breast Cancer: Site of First Relapse by Tumor Size T1a-b HER2+ MDACC (n = 97) Relapses in patients who did not receive systemic adjuvant therapy; n=1187 No. of patients (%) Local Regional Distant Tumor size (cm) relapse relapse relapse Cohort 1: cm 40 (9.3%) 9 (2.1%) 41 (9.5%) Cohort 2: cm 45 (8.9%) 17 (3.4%) 81 (16%) Cohort 3: cm 27 (11%) 15 (6.0%) 63 (25%) Distant metastasis as first site of relapse becomes increasingly more frequent as primary tumor size increases Chia et al, J Clin Oncol 22:1630, 2004 Gonzalez-Anguloet al, J Clin Oncol 27:5700, 2009 T1a-b HER2+ IEO (n = 150) Eligibility Requirements for Adjuvant Trastuzumab Trials Trial Eligibility Requirements NSABP B-31 Node-positive disease N-9831 Node-positive disease OR High-risk node-negative disease: tumor 2 cm and ER- or PRpositive, or tumor 1cm and ER- and PR-negative HERA BCIRG 006 Node-positive disease OR Node-negative disease with tumor 1cm Node-positive disease OR Node-negative disease AND one of the following risk factors: tumor >2cm, ER- and PR-negative, grade 2-3, or age <35 Curigliano et al, J Clin Oncol 27:5693, 2009 FinHER Node-positive disease OR Node-negative disease with tumor 2 cm and PR-negative The Limbo Game BINV-7, HER2+/ER- Key Issues in HER2 Therapy Testing Standardization Tissue handling, assays, and interpretation Guidelines are living documents Choice of regimen Sequential or concomitant, A or not, long or short? How low is too low? Size matters Reasonable for T1b, but stretching if T1a NCCN v It Takes a Village 7

8 Bioinformaticians Thank you Breast Cancer Black Box Extra Slides Oncologists I simply misremembered it wrong. Rep. Mark Kirk (R-IL), Friday, Jun Demographics and Accreditation Information Parameters Response Type of Institution that performs IHC (n = 748).Private, non profit / public hospital 347 (46%) / 106 (14%).Reference IHC lab 56 (8%) 450 beds or less (n = 519) 436 (64%) No pathology residency (n= 748) 562 (75%) Type of Cancer Center (n = 384).ACS Commission on Cancer 251 (65%).NIH-designated 37 (10%).Self-designated 94 (25%) Lab accreditation (n = 733).CAP 614 (84%).State 44 (6%).JCAHO 39 (5.3%) Competency assessment of pathologists? (n = 704) 639 (90%) yes Nakhleh et al, Arch Path Lab Med 134:728, 2010 Where is HER2 Testing Done? Parameters Response How is HER2 IHC done? (n = 735).interpret slides stained in-house 598 (81%).interpret slides stained at outside lab 132 (19%) Use quantitative computer image analysis? (n = 739).Yes 242 (33%).No 497 (67%) Where is FISH test performed? (n= 746).in-house 169 (23%).outside lab 577 (77%) Nakhleh et al, Arch Path Lab Med 134:728, 2010 Tissue Fixation and Specimen Handling Parameters Response How are late Thu and Fri specimens handled? (n = 727).Process/embed tissue on weekends, fixation max 48h 435 (59%).No special procedures or Other 177 (24%).FISH on all cases fixed > 48h 46 (6%).FISH if IHC neg on cases fixed > 48h 46 (6%).Breast surgeries no longer done late Thu and Fri 23 (3%) How is fixation time described in path report? (n = 725)*.Time of fixation not included 206 (28%).No. of hours stated 197 (27%).Standard disclaimer that compliant with 6-48h 175 (24%).No. of hours approximated using various methods 68 (9%).Statement added only if not compliant 36 (5%) *Significantly more likely to report if accredited by CAP than others Nakhleh et al, Arch Path Lab Med 134:728, 2010 Technical Variability Frequency of ER neg by Day of Surgery n = 5077 ( ) 40% 35% Age adjusted p value= % 23.6% 25% 20.4% 20% 15% 10% 5% 0% Sun Thu Fri & Sat 7 hospitals within Intermountain Healthcare Nkoy, Hammond, Rees, et al. Arch Path Lab Med, 134:606,

9 Outcome After Mastectomy for T1N0 Cancer Tumor size (cm) # of patients Recurrence 1 st decade Recurrence after 1 st decade Total Recurrence < 1 cm (12%) cm (26%) Size was most important predictor of outcome Other histologic factors had little influence on prognosis if < 1cm Ipsilateral breast recurrence not a confounding factor Diagnosed pre-1970 (prior to mammography) Rosen et al, JCO 7:1239, 1989 Node-Negative Early Breast Cancer: Overall Survival by Tumor Grade Overall survival Cohort 1: cm Grade 1 Grade 2 Grade Survival time (years) Chia et al, J Clin Oncol 22:1630, 2004 Adjuvant Trastuzumab Data Efficacy Adjuvant Trastuzumab Data Cardiac Toxicity Time to First LVEF Drop 10% and to < 50% Herceptin Product Information, FDA Oct 2010 Herceptin Product Information, FDA Oct 2010 Adjuvant Trastuzumab Data Outcome as a Function of HER2 Status ALTTO Central Pathology Ring Study Objective: To assess whether the central lab results can be duplicated in the other central lab Method: IEO and Mayo exchanged 30 cases that discordant in each central lab (local pos/central neg) for re-testing HER2 local pos/central neg: 20 IEO, 5 Mayo Re-test IHC (HercepTest) and FISH (PathVysion) ER local pos/central neg: 5 IEO, 20 Mayo ER local neg/central pos: 5 IEO, 5 Mayo Re-test IHC according to own method Herceptin Product Information, FDA Oct

10 Time-Dependent Effects of Adjuvant Rx SEER Jatoi I et al, J Clin Oncol 2011;29:1 10