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Journal Article

RAS/RAF co-mutation and ERBB2 copy number modulates HER2 heterogeneity and responsiveness to HER2-directed therapy in colorectal cancer

Purpose: ERBB2 amplified colorectal cancer (CRC) 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. CRC 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). Multi-site HER2 immunohistochemistry and genomic profiling were performed to understand HER2 intratumoral and interlesional heterogeneity. The impact of concurrent RAS co-mutations on the effectiveness of HER2-directed therapies were studied in isogenic CRC cell lines and xenografts.

Results: ERBB2 amplifications are enriched in left-sided CRC. 20% of ERBB2 amplified CRCs have co-occurring oncogenic RAS/RAF alterations. While RAS/RAF wild-type CRC typically have clonal ERBB2 amplification, CRCs 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 CRC 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 co-altered CRC.

Conclusions: Co-occurring RAS/RAF alterations define a unique subtype of ERBB2 amplified CRC 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 CRC is warranted.

Harshabad Singh
Pranshu Sahgal
Kevin Kapner
Steven M Corsello
Hersh Gupta
Rahul Gujrathi
Yvonne Y Li
Andrew D Cherniack
Raquelle El Alam
Joseph Kerfoot
Elizabeth Andrews
Annette Lee
Chetan Nambiar
Alison M Hannigan
Joshua Remland
Lauren Brais
Meghan E Leahy
Douglas A Rubinson
Benjamin L Schlechter
Matthew Meyerson
Yanan Kuang
Cloud P Paweletz
Jessica K Lee
Julia C F Quintanilha
Andrew J Aguirre
Kimberly J Perez
Brandon M Huffman
Humberto Rossi
Thomas A Abrams
Sheheryar Kabraji
Livio Trusolino
Andrea Bertotti
Ewa T Sicinska
Aparna R Parikh
Brian M Wolpin
Alexa B Schrock
Marios Giannakis
Kimmie Ng
Jeffrey A Meyerhardt
Jason L Hornick
Nilay S Sethi
James M Cleary
Journal Name
Clinical Cancer Research
Publication Date
February 12, 2024
American Association for Cancer Research