Negative Ultraselection of Patients With <i>RAS</i>/<i>BRAF</i> Wild-Type, Microsatellite-Stable Metastatic Colorectal Cancer Receiving Anti-EGFR-Based Therapy.

Abstract

Several uncommon genomic alterations beyond <i>RAS</i> and BRAFV600E mutations drive primary resistance to anti-epidermal growth factor receptors (EGFRs) in metastatic colorectal cancer (mCRC). Our PRESSING panel (including <i>PIK3CA</i> exon 20/<i>AKT1</i>/<i>PTEN</i> mutations, <i>ERBB2</i>/<i>MET</i> amplifications, gene fusions, and microsatellite instability-high status) represented a paradigm of negative hyperselection with more precise tailoring of EGFR blockade. However, a modest proportion of hyperselected mCRC has intrinsic resistance potentially driven by even rarer genomic alterations. A prospective data set at three Italian Academic Hospitals included 650 patients with mCRC with comprehensive genomic profiling by FoundationOne CDx and treated with anti-EGFRs. PRESSING2 panel alterations were selected on the basis of previous clinico-biologic studies and included <i>NTRKs</i>, <i>ERBB3</i>, <i>NF1</i>, <i>MAP2K1</i>/<i>2</i>/<i>4</i>, <i>AKT2</i> pathogenic mutations; <i>PTEN</i>/<i>NF1</i> loss; <i>ERBB3</i>, <i>FGFR2</i>, <i>IGF1R</i>, <i>KRAS</i>, <i>ARAF</i>, and <i>AKT1-2</i> amplification; and <i>EGFR</i> rearrangements. These were collectively associated with outcomes in patients with hyperselected disease, ie, <i>RAS</i>/<i>BRAF</i> wild-type, PRESSING-negative, and microsatellite stable. Among 162 hyperselected patients, 24 (15%) had PRESSING2 alterations, which were mutually exclusive except in two samples and were numerically higher in right-sided versus left-sided cancers (28% <i>v</i> 13%; <i>P</i> = .149). Independently of sidedness and other factors, patients with PRESSING2-positive status had significantly worse progression-free survival and overall survival compared with PRESSING2-negative ones (median progression-free survival 6.4 <i>v</i> 12.8 months, adjusted hazard ratio 4.19 [95% CI, 2.58 to 6.79]; median overall survival: 22.6 <i>v</i> 49.9 months, adjusted hazard ratio 2.98 [95% CI, 1.49 to 5.96]). The combined analysis of primary tumor sidedness and PRESSING2 status allowed us to better stratify outcomes. Negative ultraselection warrants further investigation with the aim of maximizing the benefit of EGFR blockade strategies in patients with <i>RAS</i> and <i>BRAF</i> wild-type, microsatellite stable mCRC.