Warren, Robert S.

Colorectal cancer (CRC) is the third most frequent neoplastic disorder and is a main cause of tumor-related mortality, as many patients progress to stage IV metastatic CRC. Standard care consists of combination chemotherapy (FOLFIRI or FOLFOX). Patients with WT KRAS typing are eligible to receive anti-EGFR therapy combined with chemotherapy. Unfortunately, predicting efficacy of CRC anti-EGFR therapy has remained challenging. Here we uncovered that the EGFR pathway component RasGRP1 acts as a CRC tumor suppressor in the context of aberrant Wnt signaling. We found that RasGRP1 suppresses EGF-driven proliferation of colonic epithelial organoids. Having established that RasGRP1 dosage levels impact biology, we next focused on CRC patients. Mining 5 different data platforms, we establish that RasGRP1 expression levels decrease with CRC progression and predict poor clinical outcome of patients. Last, deletion of 1 or 2 Rasgrp1 alleles made CRC spheroids more susceptible to EGFR inhibition. Retrospective analysis of the CALGB 80203 clinical trial showed that addition of anti-EGFR therapy to chemotherapy significantly improved outcome for CRC patients when tumors expressed low levels of RasGRP1 suppressor. In sum, our data support RasGRP1 as a biomarker in the EGFR pathway that has potential relevance to anti-EGFR therapy for CRC patients.

PurposeThe association of deficient DNA mismatch repair (dMMR) with prognosis in patients with colon cancer treated with adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy remains unknown.Patients and MethodsResected, stage III colon carcinomas from patients (N = 2,686) randomly assigned to FOLFOX ± cetuximab (North Central Cancer Treatment Group N0147 trial) were analyzed for mismatch repair (MMR) protein expression and mutations in BRAFV600E(exon 15) and KRAS (codons 12 and 13). Association of biomarkers with disease-free survival (DFS) was determined using Cox models. A validation cohort (Cancer and Leukemia Group B 88903 trial) was used.ResultsdMMR was detected in 314 (12%) of 2,580 tumors, of which 49.3% and 10.6% had BRAFV600Eor KRAS mutations, respectively. MMR status was not prognostic overall (adjusted hazard ratio [HR], 0.82; 95% CI, 0.64 to 1.07; P = .14), yet significant interactions were found between MMR and primary tumor site (Pinteraction= .009) and lymph node category (N1 v N2; Pinteraction= .014). Favorable DFS was observed for dMMR versus proficient MMR proximal tumors (HR, 0.71; 95% CI, 0.53 to 0.94; P = .018) but not dMMR distal tumors (HR, 1.71; 95% CI, 0.99 to 2.95; P = .056), adjusting for mutations and covariates. Any survival benefit of dMMR was lost in N2 tumors. Mutations in BRAFV600E(HR, 1.37; 95% CI, 1.08 to 1.70; P = .009) or KRAS (HR, 1.44; 95% CI, 1.21 to 1.70; P < .001) were independently associated with worse DFS. The observed MMR by tumor site interaction was validated in an independent cohort of stage III colon cancers (Pinteraction= .037).ConclusionThe prognostic impact of MMR depended on tumor site, and this interaction was validated in an independent cohort. Among dMMR cancers, proximal tumors had favorable outcome, whereas distal or N2 tumors had poor outcome. BRAF or KRAS mutations were independently associated with adverse outcome.