Supplementary Table 9 from RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer

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

doi:10.1158/1078-0432.25603618.v1

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Supplementary Table 9 from RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer

journal contribution

posted on 2024-04-15, 07:22 authored by 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

Supplementary Table 9. Statistics from flow sorting for SW480-GFP and -HER2 lines.

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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ARTICLE ABSTRACT

ERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments. Implications of concurrent oncogenic RAS/RAF alterations are not known. 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. 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. 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.