Abstract 1705P
Background
HER2-positive metastatic colorectal cancer (mCRC) is a distinct subtype for which HER2-targeted therapy is established. HER2 intratumoral heterogeneity (ITH), containing two types of heterogeneity–genetic heterogeneity (GH, a mixture of HER2 positive and negative tumor cells) and non-genetic heterogeneity (NGH, a mixture of HER2 positive tumor cells and amplified HER2 gene tumor cells without HER2 protein expression)– is a predictor of response to HER2-targeted treatment in breast cancer (BC). Here, using samples with mCRC, we evaluated the diagnostic accuracy of the Gene-Protein Assay (GPA), an assay assessing HER2 ITH by a combined HER2 immunohistochemistry (IHC) and bright-field HER2 in situ hybridization (ISH) on the same tissue section, and the frequency of HER2 ITH and heterogeneous patterns.
Methods
Tissue samples from patients with mCRC (n = 122) screened for TRIUMPH, a phase II trial of pertuzumab plus trastuzumab for HER2-positive mCRC, but not selected for the actual study, were assessed for the HER2 ITH status. HER2 status was originally assessed with IHC and fluorescence ISH (FISH). HER2 status and ITH were evaluated with the GPA. HER2 positive was defined as HER2 IHC 3+ or IHC 2+ and HER2/CEP17 ≥ 2.0 over 10% tumor cells. ITH was defined the presence of different HER2 status in >50% of tumor cells.
Results
HER2 GPA demonstrated that 37 samples (30.3%) were HER2 positive and 85 samples (69.7%) were HER2 negative. The positive percent agreement, negative percent agreement of GPA compared to IHC/FISH were 97.3% and 100%, respectively. Eight of 37 HER2 positive samples (21.6%) had a HER2 ITH. HER2 ITH was more frequently observed in IHC 2+ samples than that in IHC 3+ samples (60.0% vs. 15.6%, p=0.06). Among eight samples with HER2 ITH, GH and NGH were observed with 6 (75.0%) and 2 (25.0%) samples, respectively. There were no HER2 negative samples with HER2 gene amplification.
Conclusions
In mCRC, HER2 GPA could evaluate HER2 status accurately and HER2 ITH patterns with a high frequency of GH compared to BC, in which GH is observed in about 25%. It is the first study to confirm HER2 GH and NGH patterns in mCRC using GPA. The impact of mCRC HER2 ITH on HER2-targeted treatment will be assessed with the data of the TRIUMPH study.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Kushiro Rosai Hospital.
Funding
Roche Diagnostics.
Disclosure
K. Sawada: Financial Interests, Personal, Invited Speaker: Ono, Chugai, Daiichi Sankyo, Lilly, Asahi-Kasei, Merck, Takeda, Taiho. H. Nitta: Financial Interests, Personal, Full or part-time Employment: Roche Diagnostics K.K. W. Okamoto: Financial Interests, Personal, Invited Speaker: Chugai Pharma, Ono Pharmaceutical, Bristol Myers Squibb Japan, Yakult Honsha, Lilly Japan, Thermo Fisher Scientific, Takeda, Novartis, Taiho Pharmaceutical; Financial Interests, Personal, Expert Testimony, 03/2022: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Janssen Oncology. H. Taniguchi: Financial Interests, Personal, Invited Speaker: Ono, Takeda, Eli Lilly, Chugai, Taiho, Merck Biopharma; Financial Interests, Institutional, Invited Speaker: Takeda, Ono, Daiichi Sankyo. H. Hara: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Boehringer Ingelheim, Dainippon Sumitomo; Financial Interests, Personal, Invited Speaker: Daiichi Sankyo, MSD, Ono, Bayer, Chugai, Kyowa Hakko Kirin, Lilly, Merck Biopharma, Sanofi, Taiho, Takeda, Yakult; Financial Interests, Institutional, Invited Speaker: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Janssen, Merck Biopharma, MSD, Ono, Taiho. T. Kato: Financial Interests, Personal, Invited Speaker: Chugai Pharmaceutical Co., Ltd., Eli Lilly and Company, Ono Pharmaceutical Co., Takeda Pharmaceutical Company Limited, Asahikasei; Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical Co. T. Nishina: Financial Interests, Personal, Invited Speaker: Taiho pharmaceutical, Ono pharmaceutical, Bristol Myers Squibb; Financial Interests, Institutional, Invited Speaker: MSD, Daiichi Sankyo, Ono pharmaceutical, Bristol Myers Squibb, Astellas. T. Ohta: Financial Interests, Personal, Invited Speaker: Bristol Myers Squibb Japan, Chugai Pharma, Teijin Pharma, Takeda Pharmaceutical Company Limited., Taiho Pharmaceutical Co., Ltd., Eisai Co., Ltd., Yakult Honsha; Financial Interests, Personal and Institutional, Invited Speaker: Takeda Pharmaceutical Company Limited. T. Esaki: Financial Interests, Personal, Invited Speaker: Chugai, Taiho, EP force, MSD, Daiichi Sankyo, Eli Lilly, Ono; Financial Interests, Institutional, Research Grant: MSD, Novartis, Ono, Nihon Kayaku, IQVIA, Daiichi Sankyo, Chugai, Syneos Health Clinical, Pfizer, Dainippon Sumitomo, Quintiles, Eli Lilly, Parexel, Astellas, Astellas Amgen Biopharma; Financial Interests, Institutional, Funding: Taiho, Chugai, Nihon Kayaku. T. Yoshino: Financial Interests, Personal, Invited Speaker: Chugai, Merck Biopharma, Bayer, Ono, MSD; Financial Interests, Institutional, Invited Speaker: Ono, Sanofi, Daiichi Sankyo, Chugai, Pfizer; Financial Interests, Institutional, Research Grant: Taiho, MSD, Ono, Amgen, Genomedia, Sysmex, Daiichi Sankyo, Chugai, Boehringer Ingelheim. S. Fujii: Financial Interests, Personal, Research Grant: Roche Diagnostics K.K., Daiichi Sankyo Co Ltd., Genomedia Inc.; Financial Interests, Personal, Invited Speaker: Roche Diagnostics K.K., MSD K.K.; Financial Interests, Personal, Advisory Board: Daiichi Sankyo Co Ltd., Agilent Technologies Inc. All other authors have declared no conflicts of interest.