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Published on: July 17, 2019
RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in
Harshabad Singh1, Pranshu Sahgal1,2, Kevin Kapner1
1Dana-Farber Brigham and Women's Cancer Center, Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
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.
Insights
ERBB2-amplified colorectal cancer with RAS/RAF alterations shows resistance to trastuzumab but remains sensitive to trastuzumab deruxtecan. This finding highlights a distinct molecular subtype with unique treatment implications for colorectal cancer patients.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- ERBB2-amplified colorectal cancer (CRC) is a distinct molecular subtype with emerging therapeutic options.
- The impact of concurrent oncogenic RAS/RAF alterations on ERBB2-amplified CRC treatment outcomes remains largely unknown.
Purpose of the Study:
- To investigate the implications of concurrent oncogenic RAS/RAF alterations in ERBB2-amplified colorectal cancer.
- To understand the differential responsiveness and resistance patterns to HER2-directed therapies in this specific CRC subtype.
Main Methods:
- Genomic profiling of large CRC cohorts (Dana-Farber, Foundation Medicine Inc.) to identify ERBB2-amplified cases.
- Analysis of patient outcomes receiving HER2-directed therapies.
- Assessment of HER2 intratumoral and interlesional heterogeneity using IHC and genomic profiling.
- In vitro and xenograft studies using isogenic CRC cell lines to evaluate the impact of RAS comutations on therapy effectiveness.
Main Results:
- ERBB2 amplifications are more frequent in left-sided CRC.
- Approximately 20% of ERBB2-amplified CRCs harbor co-occurring RAS/RAF alterations.
- Colorectal cancers with RAS/RAF alterations exhibit lower-level ERBB2 amplification, increased intratumoral heterogeneity, and interlesional ERBB2 discordance compared to RAS/RAF wild-type cases.
- ERBB2-amplified CRC with RAS/RAF alterations demonstrated resistance to trastuzumab-based combinations (e.g., trastuzumab/tucatinib) but retained sensitivity to trastuzumab deruxtecan in preclinical models.
- Trastuzumab deruxtecan showed clinical efficacy in patients with high-level ERBB2-amplified, RAS/RAF-coaltered CRC.
Conclusions:
- Concurrent RAS/RAF alterations define a unique subtype of ERBB2-amplified CRC characterized by increased heterogeneity and resistance to certain HER2-targeted therapies.
- Trastuzumab deruxtecan represents a promising therapeutic option for ERBB2-amplified colorectal cancer with co-occurring RAS/RAF alterations.
- Further clinical investigation of trastuzumab deruxtecan in this understudied CRC cohort is warranted.
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