Coaltered <i>Ras/B-raf</i> and <i>TP53</i> Is Associated with Extremes of Survivorship and Distinct Patterns of Metastasis in Patients with Metastatic Colorectal Cancer.

Abstract

We aimed to investigate genomic correlates underlying extremes of survivorship in metastatic colorectal cancer and their applicability in informing survival in distinct subsets of patients with metastatic colorectal cancer. We examined differences in oncogenic somatic alterations between metastatic colorectal cancer cohorts demonstrating extremes of survivorship following complete metastasectomy: ≤2-year (<i>n</i> = 17) and ≥10-year (<i>n</i> = 18) survivors. Relevant genomic findings, and their association with overall survival (OS), were validated in two independent datasets of 935 stage IV and 443 resected stage I-IV patients. In the extremes-of-survivorship cohort, significant co-occurrence of <i>KRAS</i> hotspot mutations and <i>TP53</i> alterations was observed in ≤2-year survivors (<i>P</i> < 0.001). When validating these findings in the independent cohort of 935 stage IV patients, incorporation of the cumulative effect of any oncogenic <i>Ras/B-raf</i> (i.e., either <i>KRAS, NRAS</i>, or <i>BRAF</i>) and <i>TP53</i> alteration generated three prognostic clusters: (i) <i>TP53</i>-altered alone (median OS, 132 months); (ii) <i>Ras/B-raf</i>-altered alone (65 months) or <i>Ras/B-raf</i>- and <i>TP53</i> pan-wild-type (60 months); and (iii) coaltered <i>Ras/B-raf</i>-<i>TP53</i> (40 months; <i>P</i> < 0.0001). Coaltered <i>Ras/B-raf</i>-<i>TP53</i> was independently associated with mortality (HR, 2.47; 95% confidence interval, 1.91-3.21; <i>P</i> < 0.001). This molecular profile predicted survival in the second independent cohort of 443 resected stage I-IV patients. Coaltered <i>Ras/B-raf</i>-<i>TP53</i> was associated with worse OS in patients with liver (<i>n</i> = 490) and lung (<i>n</i> = 172) but not peritoneal surface (<i>n</i> = 149) metastases. Moreover, coaltered <i>Ras/B-raf</i>-<i>TP53</i> tumors were significantly more likely to involve extrahepatic metastatic sites with limited salvage options. Genomic analysis of extremes of survivorship following colorectal cancer metastasectomy identifies a prognostic role for coaltered <i>Ras/B-raf</i>-<i>TP53</i> and its association with distinct patterns of colorectal cancer metastasis.