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

Abstract

Purpose: Several uncommon genomic alterations beyond RAS and BRAFV600E mutations drive primary resistance to anti-epidermal growth factor receptors (EGFRs) in metastatic colorectal cancer (mCRC). Our PRESSING panel (including PIK3CA exon 20/AKT1/PTEN mutations, ERBB2/MET 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.

Materials and methods: 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 NTRKs, ERBB3, NF1, MAP2K1/2/4, AKT2 pathogenic mutations; PTEN/NF1 loss; ERBB3, FGFR2, IGF1R, KRAS, ARAF, and AKT1-2 amplification; and EGFR rearrangements. These were collectively associated with outcomes in patients with hyperselected disease, ie, RAS/BRAF wild-type, PRESSING-negative, and microsatellite stable.

Results: 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% v 13%; P = .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 v 12.8 months, adjusted hazard ratio 4.19 [95% CI, 2.58 to 6.79]; median overall survival: 22.6 v 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.

Conclusion: Negative ultraselection warrants further investigation with the aim of maximizing the benefit of EGFR blockade strategies in patients with RAS and BRAF wild-type, microsatellite stable mCRC.

FIG 1.

Heat map showing the genomic profiles according to the presence or absence of PRESSING2 alterations. Patients in the two groups were ordered according to PFS. amp, amplification; fs, frameshift; PFS, progression-free survival; rearr, rearrangements; SNV, single-nucleotide variant.

FIG 2.

Kaplan-Meier curves of (A and C) PFS and (B and D) OS according to the presence or absence of PRESSING2 alterations in the entire study population and in patients receiving first-line anti–EGFR-based therapy. OS, overall survival; mOS, median overall survival; mPFS, median progression-free survival; NA, not assessable; PFS, progression-free survival.

FIG 3.

Kaplan-Meier estimates for (A) PFS and (B) OS in the four subgroups of patients identified by the combination of primary tumor sidedness and PRESSING2 status. OS, overall survival; mOS, median overall survival; mPFS, median progression-free survival; NA, not assessable; PFS, progression-free survival; ref, reference.