Synapse - Coaltered Ras/B-raf and TP53 is associated with extremes of survivorship and distinct patterns of metastasis in patients with metastatic colorectal cancer

Coaltered Ras/B-raf and TP53 is associated with extremes of survivorship and distinct patterns of metastasis in patients with metastatic colorectal cancer Journal Article

Authors:	Datta, J.; Smith, J. J.; Chatila, W. K.; McAuliffe, J. C.; Kandoth, C.; Vakiani, E.; Frankel, T. L.; Ganesh, K.; Wasserman, I.; Lipsyc-Sharf, M.; Guillem, J.; Nash, G. M.; Paty, P. B.; Weiser, M. R.; Saltz, L. B.; Berger, M. F.; Jarnagin, W. R.; Balachandran, V.; Kingham, T. P.; Kemeny, N. E.; Cercek, A.; Garcia-Aguilar, J.; Taylor, B. S.; Viale, A.; Yaeger, R.; Solit, D. B.; Schultz, N.; D'Angelica, M. I.
Article Title:	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.
Keywords:	survival; recurrence; microsatellite instability; outcomes; prognostic role; hepatic resection; colon-cancer; liver metastases; defines; apc mutations
Journal Title:	Clinical Cancer Research
Volume:	26
Issue:	5
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2020-03-01
Start Page:	1077
End Page:	1085
Language:	English
ACCESSION:	WOS:000518188000012
DOI:	10.1158/1078-0432.Ccr-19-2390
PROVIDER:	wos
PMCID:	PMC7056517
PUBMED:	31719050
Notes:	Article -- Source: Wos