Data from <i>RAS/RAF</i> Comutation and <i>ERBB2</i> Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer

• DOI: 10.1158/1078-0432.c.7181326.v1
• Publication Date: 2024-04-15T07:23:31Z
• Authors: 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. Schle...; Matthew Meyerson; Yanan Kuang; Cloud P. Paweletz; Jessica K. Lee; Julia C.F. Quinta...; 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. Meyerh...; Jason L. Hornick; Nilay S. Sethi; James M. Cleary

<div>AbstractPurpose:<p><i>ERBB2</i>-amplified colorectal cancer is a distinct molecular subtype with expanding treatments. Implications of concurrent oncogenic <i>RAS/RAF</i> alterations are not known.</p>Experimental Design:<p>Dana-Farber and Foundation Medicine Inc. Colorectal cancer cohorts with genomic profiling were used to identify <i>ERBB2</i>-amplified cases [Dana-Farber, <i>n</i> = 47/2,729 (1.7%); FMI, <i>n</i> = 1857/49,839 (3.7%)]. Outcomes of patients receiving HER2-directed therapies are reported (Dana-Farber, <i>n</i> = 9; Flatiron Health-Foundation Medicine clinicogenomic database, FH-FMI CGDB, <i>n</i> = 38). Multisite HER2 IHC and genomic profiling were performed to understand HER2 intratumoral and interlesional heterogeneity. The impact of concurrent <i>RAS</i> comutations on the effectiveness of HER2-directed therapies were studied in isogenic colorectal cancer cell lines and xenografts.</p>Results:<p><i>ERBB2</i> amplifications are enriched in left-sided colorectal cancer. Twenty percent of <i>ERBB2</i>-amplified colorectal cancers have co-occurring oncogenic <i>RAS/RAF</i> alterations. While <i>RAS/RAF</i> WT colorectal cancers typically have clonal <i>ERBB2</i> amplification, colorectal cancers with co-occurring <i>RAS/RAF</i> alterations have lower level <i>ERRB2</i> amplification, higher intratumoral heterogeneity, and interlesional <i>ERBB2</i> discordance. These distinct genomic patterns lead to differential responsiveness and patterns of resistance to HER2-directed therapy. <i>ERBB2</i>-amplified colorectal cancer with <i>RAS/RAF</i> alterations are resistant to trastuzumab-based combinations, such as trastuzumab/tucatinib, but retain sensitivity to trastuzumab deruxtecan in <i>in vitro</i> and murine models. Trastuzumab deruxtecan shows clinical efficacy in cases with high-level <i>ERBB2-</i>amplified <i>RAS/RAF</i> coaltered colorectal cancer.</p>Conclusions:<p>Co-occurring <i>RAS/RAF</i> alterations define a unique subtype of <i>ERBB2</i>-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 <i>ERBB2</i>-amplified colorectal cancer is warranted.</p></div>