3557 Background: Anti-EGFR (cetuximab, panitumumab) plus doublet chemotherapy is the first line standard of care for metastatic MSS left-sided RAS/RAF WT colorectal cancer (CRC). However, anti-EGFR clinical efficacy is limited by intrinsic and acquired resistance. Defining anti-EGFR intrinsic resistance mutations could improve patient selection for anti-EGFR treatment while defining anti-EGFR acquired resistance mutations could enable early detection of resistance via liquid biopsy. Methods: The intrinsic resistance cohort consisted of 163 metastatic MSS RAS/RAF WT colon adenocarcinoma patients treated in the first line with anti-EGFR with a DNA-seq sample collected before treatment (Tempus xT or xF). We screened mutations for anti-EGFR intrinsic resistance defined as HR > 2 for PFS via univariate CoxPH models. The anti-EGFR acquired resistance cohort consisted of 228 MSS CRC patients with a DNA-seq sample (xT or xF) within 12 months prior to and 0.5-24 months post treatment. We defined acquired resistance mutations as those significantly enriched post-treatment vs pre-treatment via McNemar test. An anti-VEGF acquired resistance cohort of 748 MSS CRC patients was used as a control. Enrichment of targetable gene fusions post-treatment was assessed via Wilcoxon test. FDR < 0.05 was considered significant. Results: The screen for intrinsic resistance mutations returned a single significant hit of PIK3CA non-exon 9 mutations (~3%, p < 0.01), while PTEN deletions (~2%), which are functionally similar, were also associated with shorter PFS but did not reach significance (p=0.08). PIK3CA non-exon 9 mutation or PTEN deletion were detected in ~5% of patients (n=9) and were associated with shorter PFS (HR = 3.6, 95% CI: 1.7-7.6, p < 0.001) and OS (HR = 2.6, 95% CI: 1.03-6.5, p < 0.05). Median PFS and OS were 6 and 14 months for patients with these resistance alterations, versus 11 and 29 months for non-altered patients. In a CoxPH model including age, sex, sidedness, and collection procedure, these alterations maintained a significant association with PFS (HR =5.2, 95% CI: 2.2-12.4, p < 0.01) but not OS (HR=2.7, 95% CI: 0.9-8.9, p=0.08). Analysis of acquired resistance to anti-EGFR treatment yielded significant mutation hits— KRAS, NRAS, EGFR , and MAP2K1— as well as significant enrichment of targetable fusions ( BRAF, FGFR, NTRK, ALK, ROS1, RET, NRG1 ). No mutations or fusions were observed to be associated with anti-VEGF acquired resistance. Conclusions: Patients harboring PIK3CA non-exon 9 mutation or PTEN deletion displayed intrinsic resistance to anti-EGFR therapy despite being RAS/RAF WT and may be offered anti-EGFR therapy per oncology guidelines. This small underrepresented subset of patients may not benefit from anti-EGFR therapy. Prospective clinical validation will be needed to determine if this subset of PI3K pathway alterations has utility in optimizing first line therapy selection.
Maxwell et al. (Wed,) studied this question.