COLORECTAL CANCER: Mutations in TP53 and RAS/BRAF show utility as prognostic markers, with co-mutated tumours showing the worst outcomes.

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March 16, 2020

SCIENTIFIC

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

Abstract

Purpose:

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.

Experimental Design:

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.

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: (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.

Conclusions:

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.

https://clincancerres.aacrjournals.org/content/early/2019/11/12/1078-0432.CCR-19-2390