• Jashodeep Datta, J Joshua Smith, Walid K Chatila, John C McAuliffe, Cyriac Kandoth, Efsevia Vakiani, Timothy L Frankel, Karuna Ganesh, Isaac Wasserman, Marla Lipsyc-Sharf, Jose Guillem, Garrett M Nash, Philip B Paty, Martin R Weiser, Leonard B Saltz, Michael F Berger, William R Jarnagin, Vinod Balachandran, T Peter Kingham, Nancy E Kemeny, Andrea Cercek, Julio Garcia-Aguilar, Barry S Taylor, Agnes Viale, Rona Yaeger, David B Solit, Nikolaus Schultz, and Michael I D'Angelica.
• Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. jash.datta@med.miami.edu dangelim@mskcc.org smithj5@mskcc.org.
• Clin Cancer Res. 2020 Mar 1; 26 (5): 1077-1085.

PurposeWe 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 DesignWe 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.ResultsIn 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.ConclusionsGenomic 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.

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