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

Abstract

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.

Figure 1:

A. CONSORT diagram of selection of extreme outlier test set (n=35) investigating molecular profile associated with extremes of survivorship in resected colorectal liver metastasis (CRLM); B. (Upper) OncoPrint representation of the 14 most frequently altered genes in ≤2-year and ≥10-year survivorship cohorts following CRLM resection. Types of gene alteration grouped by putative driver mutations, variants of undetermined significance (VUS), or structural alterations are shown in the adjoining color legend. Somatic alteration frequencies in recurrently altered genes corresponding to specific genes are shown in the adjacent histograms. (Lower) Proportion of patients in ≤2-year and ≥10-year survivorship cohorts with co-occurrent KRAS-TP53 alterations, KRAS alterations alone, TP53 alterations alone, or non-KRAS/non-TP53 alterations.

Figure 2:

A. Stratification of MSKCC validation cohort (n=935) of metastatic CRC patients by presence or absence of co-occurrent KRAS and TP53 alterations; B. Further prognostic refinement by stratification of validation cohort (n=935) by co-occurrence of KRAS and TP53 alterations, singly altered KRAS or TP53, and non-KRAS/non-TP53 alterations; C. Recapitulation of the prognostic performance of this molecular profile in mCRC patients with liver as first site of metastasis (n=490). Number at risk at each time point indicated in adjoining risk table; D. OncoPrint representation of the 13 most frequently altered genes in ≤2-year (n=167) and ≥8-year (n=69) survivorship cohorts in the MSKCC validation cohort. Types of gene alteration grouped by putative driver mutations or structural alterations are shown in the adjoining color legend.

Figure 3:

A. Stratification of MSKCC validation cohort (n=935) by co-occurrence of Ras/B-raf (i.e., any alterations in KRAS, BRAF, or NRAS) and TP53 alterations, Ras/B-raf alterations alone, TP53 alterations alone, and non-Ras/B-raf/non-TP53 alterations. Number at risk at each time point indicated in adjoining risk table; B. Forest plot indicating Cox proportional-hazards model for overall survival; bar-and-whisker plot depicts hazard ratio and 95% confidence interval, with corresponding p-values shown alongside.

Figure 4:

Prognostic relevance of co-occurrent Ras/B-raf and TP53 alterations in metastatic CRC patients with: A. (from left to right) Liver, lung, and peritoneal surface as first site of metastasis. Number at risk at each time point indicated in adjoining risk table. B. Sankey diagram illustrating relative flow of first site of metastasis from respective genomic subgroups in metastatic CRC: TP53-altered alone (n=370), Ras/B-raf-altered alone (n=173), and co-altered Ras/B-raf-TP53 (n=355). Peritoneal surface refers to peritoneum, ovary, or omentum.