126P - Genomic landscape and prognostic impact of HER2 low-expressing tumors

Background

There is evolving evidence that HER2 low-expressing (1+/2+ IHC) tumors may respond to novel anti-HER2-based therapies. We evaluated the frequency and prognostic impact of HER2 expression and its association with ERBB2 genomic alterations in a large database of molecularly profiled tumors from real-world patients (pts).

Methods

A wide range of tumor types (N = 88,535) underwent HER2 immunohistochemistry (IHC), next-gen sequencing (NGS) of DNA (592-gene or whole exome) and RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). ERBB2 copy number amplification was determined by calculating the average depth of sample & sequencing depth of each exon in comparison to a pre-calibrated reference value. Copy number >6 was classified as amplified (amp). ERBB2 variants (SNV/indels) were classified according to the American College of Medical Genetics and Genomics (ACMG) standards. Cohorts were stratified by IHC HER2 values of 0 (non-expressors), 1+, 2+, or 3+ and compared with ERBB2 alterations using χ² where applicable. For overall survival (OS) analysis, hazard ratios (HR) were calculated for IHC 1, 2, and 3 vs. IHC 0.

Results

Cancer (Ca) subtypes with at least 5 samples were evaluated. High prevalence of ERBB2 amp was observed in head & neck Ca (20%) among HER2 (1+) pts and in cervical Ca (57%) among HER2 (2+) pts. High prevalence of ERBB2 mutations was observed in cholangiocarcinoma (5.6%) among HER2 (1+) pts and in small intestine Ca (9.6%) among HER2 (2+) pts. Prevalence of ERBB2 alterations and its association with HER2 IHC are listed in the table. Median OS for HER2 (3+, 2+, 1+, and 0+) pts was 30.6, 26.9, 26.5 and 23 months, respectively. HR for OS for HER2 (3+, 2+ and 1+ compared to 0+) was 0.80, 0.89 and 0.90 respectively (p

Conclusions

Significant associations between ERBB2 alterations and HER2 low-expressing tumors were observed. High prevalence of ERBB2 alterations was observed in some uncommonly tested tumors. Median OS of HER2 low-expressors was better than non-expressors in this heterogenous group.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

CARIS and Medical College of Wisconsin.

Funding

Has not received any funding.

Disclosure

A. Shreenivas: Financial Interests, Institutional, Advisory Board: Taiho; Financial Interests, Institutional, Research Grant: Natera; Non-Financial Interests, Other, Investigator: Target Cancer Foundation. A. Elliott: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. T. Corbiere: Financial Interests, Personal and Institutional, Full or part-time Employment: Caris Life Science. H. Chen: Financial Interests, Speaker, Consultant, Advisor: Jazz Pharmaceuticals, Biologic dynamics. B. George: Financial Interests, Personal, Invited Speaker, consultant: Ipsen, Taiho Oncology, AstraZeneca; Financial Interests, Personal, Advisory Board, consultant: Roche; Financial Interests, Personal, Other, consultant: Genentech, Foundation Medicine; Financial Interests, Personal, Invited Speaker: France Foundation; Financial Interests, Personal, Stocks/Shares: xbiotech; Financial Interests, Institutional, Local PI, research support: Genentech, Hoffman La Roche, Taiho Oncology, Mirati therapeutics, BMS, Carsgen, Helix biopharma, Tvardi therapeutics, Pfizer, Glyconex, Faeth therapeutics, Biontech, Transcenta. M. Kamgar: Financial Interests, Institutional, Research Grant: Cornerstone pharmaceuticals, OneCell. A. Desai: Financial Interests, Advisory Board: Foundation one, Janssen, Amgen, AstraZeneca. J. Xiu: Financial Interests, Personal, Full or part-time Employment, Employment: Caris Life Sciences. E.S. Antonarakis: Financial Interests, Institutional, Advisory Board: Orion; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Clovis, MacroGenics, Merck, Novartis, Seagen; Non-Financial Interests, Principal Investigator: Orion; Non-Financial Interests, Advisory Role: Aadi Bioscience, Amgen, AstraZeneca, Bayer, Blue Earth Diagnostics, Curium, EcoR1, Hookipa Pharma, Janssen, Lilly, Menarini Silicon Biosystems, Merck, Pfizer, Sanofi, Tango Therapeutics, Tempus, z-Alpha, Orion. R. Kurzrock: Financial Interests, Personal, Other, Dr. Kurzrock has received consultant and/or speaker fees and/or advisory board/consultant for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Inc., Biological Dynamics, Caris, Datar Cancer Genetics, Daiichi Sankyo, Eisai, EOM Pharmaceuticals, Iylon, LabCorp, Lanuaria, Merck, NeoGenomics, Neomed, Pfizer, Precirix, Prosperdtx, Regeneron, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech.: Biological Dynamics, Caris, Datar Cancer Genetics, Daiichi Sankyo, Eisai, OM Pharmaceuticals, Iylon, LabCorp, Lanuaria, Merck, NeoGenomics, Neomed, Pfizer, Precirix, Prosperdtx, Regeneron, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech, AstraZeneca, Bicara Therapeutics, Inc.; Financial Interests, Personal, Other, Dr. Kurzrock has an equity interest in CureMatch Inc.; serves on the Board of CureMatch and CureMetrix, and is a co-founder of CureMatch.: CureMatch, CureMetrix; Financial Interests, Institutional, Other, Dr. Kurzrock has received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, and TopAlliance and from the NCI.: Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech; Financial Interests, Institutional, Research Grant, Dr. Kurzrock has received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, and TopAlliance and from the NCI.: Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, and TopAlliance and from the NCI. All other authors have declared no conflicts of interest.