COLORECTAL CANCER: Mutations in TP53 and RAS/BRAF show utility as prognostic markers, with co-mutated tumours showing the worst outcomes.
Co-Altered Ras/B-raf and TP53 is Associated with Extremes of Survivorship and Distinct Patterns of Metastasis in Metastatic Colorectal Cancer
Patients American Association for Cancer Research, November 12, 2019
We aimed to investigate genomic correlates underlying extremes of survivorship in metastatic colorectal cancer (CRC) and their applicability in informing survival in distinct subsets of metastatic CRC patients.
We examined differences in oncogenic somatic alterations between metastatic CRC 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.
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: (1) TP53-altered alone (median OS 132m); (2) Ras/B-raf-altered alone (65m) or Ras/B-raf- and TP53 pan-wildtype (60m); and (3) co-altered Ras/B-raf-TP53 (40m; P<0.0001). Co-altered Ras/B-raf-TP53 was independently associated with mortality (HR 2.47, 95%CI 1.91-3.21, P<0.001). This molecular profile predicted survival in the second independent cohort of 443 resected stage I-IV patients. Co-altered 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, co-altered Ras/B-raf-TP53 tumors were significantly more likely to involve extrahepatic metastatic sites with limited salvage options.
Genomic analysis of extremes of survivorship following CRC metastasectomy identifies a prognostic role for co-altered Ras/B-raf-TP53 and its association with distinct patterns of CRC metastasis.