484P - Multi-platform characterization of HER2 expression in triple-negative breast cancer

Background

To improve quantification methods of antibody drug conjugate (ADC) targets, it is critical to understand differences in expression across assays. Here we report HER2 expression per local (L-IHC) and central (C-IHC) IHC, RNA sequencing (seq), and copy number amplification (CNA) by exome seq in patients (pts) with TNBC using matched tumor samples over time.

Methods

Pts were identified from an institutional database of pts who underwent surgery for stage I-III TNBC, and a prospective biopsy protocol for pts who developed metastatic TNBC. Samples were collected at diagnosis (DX), residual disease (RD) post-neoadjuvant therapy (if applicable) and recurrence (M). Clinical pathology records were reviewed for L-IHC; slides were blindly reviewed by a pathologist for C-IHC. HER2 IHC was classified as HER2-0 if IHC 0, and HER2-low if 1+ or 2+/ISH non-amplified. RNA expression was quantified using log2p1-transformed and normalized transcripts per million. Normal subtype samples were excluded.

Results

L-IHC and C-IHC were available in 96 samples (28 DX, 11 RD, 57 M) from 61 pts (Table). HER2-low prevalence was 25.0% (24/96) per L-IHC and 35.4% (34/96) per C-IHC. Discrepant HER2 category was observed in 16.7% of samples (16/96). In 67 samples with L-IHC and RNA seq, ERBB2 expression was higher in HER2-low (n=21) vs HER2-0 (n=46) groups (p=0.03). A similar trend in ERBB2 expression was observed with C-IHC (p=0.32). HER2-enriched (HER2E) subtype was present in 23.8% (5/21) of HER2-low vs 6.5% (3/46) of HER2-0 tumors (p=0.10). Basal subtype was 71.4% (15/21) in HER2-low vs 89.1% (41/46) in HER2-0 tumors (p=0.09). Among 17 paired DX/RD and M, 6 pairs had change in L-IHC with no difference in ERBB2 expression (p=0.83). Of 90 samples with L-IHC and exome seq, none had ERBB2 CNA. Table: 484P

Distribution of HER2 C-IHC and intrinsic subtype (research-based PAM50) according to HER2 L-IHC in samples from pts with TNBC. Discordant HER2-low and HER2-0 cases are highlighted in bold

Conclusions

Most discrepant cases between L-IHC and C-IHC resulted in change from HER2-0 to HER2-low. Correlation between HER2 IHC and gene expression was observed in TNBC pts. HER2E subtype was numerically more prevalent in HER2-low vs HER2-0 tumors.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Dana-Farber Cancer Institute.

Funding

AstraZeneca, Komen, Breast Cancer Alliance.

Disclosure

A.C. Garrido-Castro: Financial Interests, Institutional, Funding, Research funding: AstraZeneca, Daiichi Sankyo, Gilead Sciences, Merck, Zenith Epigenetics, Bristol Myers Squibb, Novartis; Other, Travel to scientific meeting: Roche/Genentech. J. Gomez Tejeda Zanudo: Financial Interests, Personal, Stocks or ownership: CNCR, IDNA, IBB, XBI, Adaptive Biotechnologies, 2seventy bio, Bluebird bio. E..T. Richardson: Financial Interests, Personal, Full or part-time Employment, Current employment: Merck. A.M. Barkell: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. T.A. King: Financial Interests, Personal, Advisory Board: Exact Sciences; Financial Interests, Personal, Speaker, Consultant, Advisor: Exact Sciences. E.A. Mittendorf: Financial Interests, Personal, Advisory Board: Merck, BioNTech, AstraZeneca; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Institutional, Research Grant, I have a grant from SU2C funded by Roche/Genentech that supports the conduct of a clinical trial: Roche/Genentech; Financial Interests, Institutional, Coordinating PI, Gillead provides clinical trial support to my institution for a study that I am the PI on: Gillead; Financial Interests, Personal, Steering Committee Member: Roche/Genentech, BMS; Non-Financial Interests, Member of Board of Directors: American Society of Clinical Oncology; Non-Financial Interests, Advisory Role, I serve in an advisory role as a Komen Scholar: Komen for the Cure. D. Carroll: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad board participant/consultant: 4D Pharma, ARC Therapeutics, Daiichi Sankyo, Eisai, Genentech/Roche, Gilead, Novartis, Sanofi, SeaGen; Financial Interests, Personal, Other, Consulting: Aadi BioPharma; Financial Interests, Personal, Advisory Board, Ad board participation: Artios, Incyte Corp, Beyond Springs; Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly; Financial Interests, Personal, Advisory Board, Advisory Board participation: Bayer, Infinity Therapeutics, Myovant, OncXerna, Umoja Biopharma, Zentalis, Zetagen; Financial Interests, Personal, Other, Consultant: Blueprint Medicines; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, Ellipses Pharma, Mersana Therapeutics; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Advisory Board, Advisory Board participation/consulting: Menarini/Stemline; Financial Interests, Personal, Advisory Board, Ad Board participant/consultant: Merck; Financial Interests, Personal, Advisory Board, Ad board participant/Consultant: Pfizer; Financial Interests, Personal, Advisory Board, Advisory board participation: Reveal Genomics; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks; Financial Interests, Personal, Advisory Board, Advisory board/consulting: Jazz Pharma; Financial Interests, Institutional, Funding, And steering committing: AstraZeneca; Financial Interests, Institutional, Funding, And steering committee: Eli Lilly; Financial Interests, Institutional, Funding: Pfizer, Sanofi, SeaGen, Odonate, Cyclacel, Exelixis, Bristol Myers Squibb, Eisai, Merck, Novartis; Financial Interests, Personal and Institutional, Steering Committee Member: CytomX; Financial Interests, Institutional, Funding, and steering committee: Gilead, Genentech/Roche; Financial Interests, Institutional, Local PI: Stemline/Menarini. E.C. De Bruin: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. N.U. Lin: Financial Interests, Personal, Advisory Board, Ad board participation: Seattle Genetics, Daiichi Sankyo, Prelude Therapeutics; Financial Interests, Personal, Advisory Board, Ad board/Steering Committee participation; consultant: AstraZeneca; Financial Interests, Personal, Other, Consultant: Denali Therapeutics, Blueprint Medicines, Janssen, Affinia Therapeutics; Financial Interests, Personal, Advisory Board, Ad board/Steering committee participation: Olema Pharmaceuticals; Financial Interests, Personal, Other, High level Consulting: Artera Inc.; Financial Interests, Personal, Other, Steering committee: Stemline/Menarini; Financial Interests, Personal, Other, Consulting: Voyager Therapeutics; Financial Interests, Personal, Royalties, Royalties for book chapter(s): Up to Date; Financial Interests, Institutional, Funding, Trial funding to institute (and steering committee): Olema Pharmaceuticals, AstraZeneca, Seattle Genetics; Financial Interests, Institutional, Funding, Trial funding to institute: Zion Pharmaceuticals; Financial Interests, Institutional, Funding, trial funding to institute: Pfizer, Genentech. All other authors have declared no conflicts of interest.