Polymorphisms within Immune Regulatory Pathways Predict Cetuximab Efficacy and Survival in Metastatic Colorectal Cancer Patients

SIMPLE SUMMARY: Cetuximab is an antibody that blocks EGFR signaling and stimulates an immune response against cancer cells. For patients with advanced colorectal cancer, tumor sidedness and RAS mutation status are the primary factors used to select systemic therapy. Additional biomarkers are needed to better predict which patients will benefit from cetuximab-based regimens. The aim of our retrospective study was to assess the predictive and prognostic value of 12 germline single nucleotide polymorphisms in five immune related genes in 924 patients with advanced colorectal cancer undergoing therapy with cetuximab. We identified a CD24 germline genetic variant which independently predicted survival in a discovery cohort and confirmed these findings in a validation cohort. If confirmed in prospective studies, CD24 and other immune related polymorphisms may guide the use of cetuximab in patients with advanced colorectal cancer. ABSTRACT: Cetuximab, an IgG1 EGFR-directed antibody, promotes antibody-dependent cell-mediated cytotoxicity. We hypothesized that single-nucleotide polymorphisms (SNPs) in immune regulatory pathways may predict outcomes in patients with metastatic colorectal cancer treated with cetuximab-based regimens. A total of 924 patients were included: 105 received cetuximab in IMCL-0144 and cetuximab/irinotecan in GONO-ASL608LIOM01 (training cohort), 225 FOLFIRI/cetuximab in FIRE-3 (validation cohort 1), 74 oxaliplatin/cetuximab regimens in JACCRO CC-05/06 (validation cohort 2), and 520 FOLFIRI/bevacizumab in FIRE-3 and TRIBE (control cohorts). Twelve SNPs in five genes (IDO1; PD-L1; PD-1; CTLA-4; CD24) were evaluated by PCR-based direct sequencing. We analyzed associations between genotype and clinical outcomes. In the training cohort; patients with the CD24 rs52812045 A/A genotype had a significantly shorter median PFS and OS than those with the G/G genotype (PFS 1.3 vs. 3.6 months; OS 2.3 vs. 7.8 months) in univariate (PFS HR 3.62; p = 0.001; OS HR 3.27; p = 0.0004) and multivariate (PFS HR 3.18; p = 0.009; OS HR 4.93; p = 0.001) analyses. Similarly; any A allele carriers in the JACCRO validation cohort had a significantly shorter PFS than G/G carriers (9.2 vs. 11.8 months; univariate HR 1.90; p = 0.011; multivariate HR 2.12; p = 0.018). These associations were not demonstrated in the control cohorts. CD24 genetic variants may help select patients with metastatic colorectal cancer most likely to benefit from cetuximab-based therapy.