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

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