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

Purpose: 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.
Experimental Design: We examined differences in oncogenic somatic alterations between metastatic colorectal cancer cohorts demonstrating extremes of survivorship following complete metastasectomy: ≤2-year ( n = 17) and ≥10-year ( n = 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.
Results: In the extremes-of-survivorship cohort, significant co-occurrence of KRAS hotspot mutations and TP53 alterations was observed in ≤2-year survivors ( P < 0.001). When validating these findings in the independent cohort of 935 stage IV patients, incorporation of the cumulative effect of any oncogenic Ras/B-raf (i.e., either KRAS, NRAS , or BRAF ) and TP53 alteration generated three prognostic clusters: (i) TP53 -altered alone (median OS, 132 months); (ii) Ras/B-raf -altered alone (65 months) or Ras/B-raf - and TP53 pan-wild-type (60 months); and (iii) coaltered Ras/B-raf - TP53 (40 months; P < 0.0001). Coaltered Ras/B-raf - TP53 was independently associated with mortality (HR, 2.47; 95% confidence interval, 1.91-3.21; P < 0.001). This molecular profile predicted survival in the second independent cohort of 443 resected stage I-IV patients. Coaltered Ras/B-raf - TP53 was associated with worse OS in patients with liver ( n = 490) and lung ( n = 172) but not peritoneal surface ( n = 149) metastases. Moreover, coaltered Ras/B-raf - TP53 tumors were significantly more likely to involve extrahepatic metastatic sites with limited salvage options.
Conclusions: Genomic analysis of extremes of survivorship following colorectal cancer metastasectomy identifies a prognostic role for coaltered Ras/B-raf - TP53 and its association with distinct patterns of colorectal cancer metastasis.
(©2019 American Association for Cancer Research.)