@article{1c276e656e4f46f3a80e866b9e2a0caa,
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 ¼ 17) and ≽10-year (n ¼ 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 ¼ 490) and lung (n ¼ 172) but not peritoneal surface (n ¼ 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.",
author = "Jashodeep Datta and {Joshua Smith}, J. and Chatila, {Walid K.} and McAuliffe, {John C.} and Cyriac Kandoth and Efsevia Vakiani and Frankel, {Timothy L.} and Karuna Ganesh and Isaac Wasserman and Marla Lipsyc-Sharf and Jose Guillem and Nash, {Garrett M.} and Paty, {Philip B.} and Weiser, {Martin R.} and Saltz, {Leonard B.} and Berger, {Michael F.} and Jarnagin, {William R.} and Vinod Balachandran and {Peter Kingham}, T. and Kemeny, {Nancy E.} and Andrea Cercek and Julio Garcia-Aguilar and Taylor, {Barry S.} and Agnes Viale and Rona Yaeger and Solit, {David B.} and Nikolaus Schultz and D'Angelica, {Michael I.}",
note = "Funding Information: This work was supported by the NCI at the NIH (P30 CA008748 to J.J. Smith); The American Society of Colon and Rectal Surgeons Career Development Award (to J.J. Smith); Roslyn Faculty Research Award (to J.J. Smith); American Society of Colon and Rectal Surgeons Limited Project Grant to (J.J. Smith); Franklin Martin MD Faculty Research Fellowship from the American College of Surgeons to (J.J. Smith); the Wasserman Colon/Rectal Cancer Fund to (J.J. Smith); and the Colorectal Cancer Alliance and the Chris4Life Research Award and in part by a Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (grant number: SU2C-AACR-DT22-17). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. Funding Information: J.J. Smith reports receiving other remuneration from Intuitive Surgical Inc. and Guardant Health. C. Kandoth holds ownership interest (including patents) in Massive Bio, Inc. M.F. Berger is an employee/paid consultant for Roche. A. Cercek is an employee/paid consultant for Bayer and Proteus and reports receiving commercial research grants from Seattle Genetics. J. Garcia-Aguilar reports receiving speakers bureau honoraria from Intuitive Medical, Ethicon, and Medtronic. B.S. Taylor reports receiving commercial research grants from Genentech and is an unpaid consultant/ advisory board member for Boehringer Ingelheim. R. Yaeger is an employee/paid consultant for Array BioPharma and reports receiving commercial research grants from Array BioPharma and Novartis Pharmaceuticals. D.B. Solit is an employee/paid consultant for Pfizer, Loxo Oncology, Illumina, Vivideon Therapeutics, and Lilly Oncology. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research Inc.. All rights reserved.",
year = "2020",
month = mar,
day = "1",
doi = "10.1158/1078-0432.CCR-19-2390",
language = "English (US)",
volume = "26",
pages = "1077--1085",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "5",
}
