RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer.

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.

The prognostic value of invariant chain (Ii) and Her-2/neu expression in curatively resected colorectal cancer.

BACKGROUND: Current methods to predict outcome for patients with curatively resected colorectal cancer are not ideal. The combined use of molecular markers and clinicopathologic features may better identify patients who are at risk for recurrence. The Her-2/neu and invariant chain molecules may be important in cancer development and progression, but their usefulness as clinical predictors of outcome in colorectal cancer has not been well studied. METHODS: We used immunohistochemistry to determine the expression of Her-2/neu, invariant chain, p27, and p53 in primary tumor samples from 156 patients with curatively resected stage I-III colorectal cancer. The association between expression and clinical outcomes was assessed by univariate and multivariate analysis. RESULTS: Her-2/neu expression was detected in only 24% of cases, and high levels of invariant chain were detected in only 15%. Although patients whose tumors overexpressed Her-2/neu survived longer than those with non-overexpressing tumors, neither Her-2/neu nor invariant chain were independently associated with survival. Consistent with previous reports, high p27 expression was associated with improved outcome, whereas overexpression of p53 was associated with worse outcome. CONCLUSIONS: Our study did not reveal a statistically significant association between Her-2/neu or invariant chain expression and clinical outcomes in patients with curatively resected colorectal cancer. However, the data suggest that Her-2/neu could be a favorable prognostic variable. Because of the low frequency of Her-2/neu expression, larger numbers of patients need to be studied for this question to be adequately answered.