Article ; Online: RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research
2024 Volume 30, Issue 8, Page(s) 1669–1684
Abstract: Purpose: ERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments. Implications of concurrent oncogenic RAS/RAF alterations are not known.: Experimental design: Dana-Farber and Foundation Medicine Inc. Colorectal ... ...
| Abstract | Purpose: ERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments. Implications of concurrent oncogenic RAS/RAF alterations are not known. Experimental design: Dana-Farber and Foundation Medicine Inc. Colorectal cancer cohorts with genomic profiling were used to identify ERBB2-amplified cases [Dana-Farber, n = 47/2,729 (1.7%); FMI, n = 1857/49,839 (3.7%)]. Outcomes of patients receiving HER2-directed therapies are reported (Dana-Farber, n = 9; Flatiron Health-Foundation Medicine clinicogenomic database, FH-FMI CGDB, n = 38). Multisite HER2 IHC and genomic profiling were performed to understand HER2 intratumoral and interlesional heterogeneity. The impact of concurrent RAS comutations on the effectiveness of HER2-directed therapies were studied in isogenic colorectal cancer cell lines and xenografts. Results: ERBB2 amplifications are enriched in left-sided colorectal cancer. Twenty percent of ERBB2-amplified colorectal cancers have co-occurring oncogenic RAS/RAF alterations. While RAS/RAF WT colorectal cancers typically have clonal ERBB2 amplification, colorectal cancers with co-occurring RAS/RAF alterations have lower level ERRB2 amplification, higher intratumoral heterogeneity, and interlesional ERBB2 discordance. These distinct genomic patterns lead to differential responsiveness and patterns of resistance to HER2-directed therapy. ERBB2-amplified colorectal cancer with RAS/RAF alterations are resistant to trastuzumab-based combinations, such as trastuzumab/tucatinib, but retain sensitivity to trastuzumab deruxtecan in in vitro and murine models. Trastuzumab deruxtecan shows clinical efficacy in cases with high-level ERBB2-amplified RAS/RAF coaltered colorectal cancer. Conclusions: Co-occurring RAS/RAF alterations define a unique subtype of ERBB2-amplified colorectal cancer that has increased intratumoral heterogeneity, interlesional discordance, and resistance to trastuzumab-based combinations. Further examination of trastuzumab deruxtecan in this previously understudied cohort of ERBB2-amplified colorectal cancer is warranted. |
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| MeSH term(s) | Humans ; Animals ; Mice ; DNA Copy Number Variations ; Gene Amplification ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/genetics ; Colorectal Neoplasms/metabolism ; Receptor, ErbB-2/metabolism ; Trastuzumab/pharmacology ; Trastuzumab/therapeutic use ; Treatment Outcome ; Mutation |
| Chemical Substances | Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK) ; ERBB2 protein, human (EC 2.7.10.1) |
| Language | English |
| Publishing date | 2024-02-12 |
| Publishing country | United States |
| Document type | Journal Article |
| ZDB-ID | 1225457-5 |
| ISSN | 1557-3265 ; 1078-0432 |
| ISSN (online) | 1557-3265 |
| ISSN | 1078-0432 |
| DOI | 10.1158/1078-0432.CCR-23-2581 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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