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
Authors: 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. 
Published: April 2024

<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>