The impact of molecular and mismatch repair status on the survival outcomes of surgically treated patients with colorectal peritoneal metastases



      Stratification of patients with colorectal peritoneal metastases (CRPM) using RAS/BRAF mutational status may refine patient selection for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). This study aimed to analyse the association of RAS/BRAF status and their variants, with clinicopathological variables and survival outcomes in patients who have undergone CRS ± HIPEC.


      A single centre, peritonectomy database was interrogated for patients with CRPM who underwent peritonectomy procedures between 2010 and 2020.


      During the study period, 174 patients were included. Molecular status was obtained on 169 patients, with 68 (40.5%) KRAS, 25 (14.8%) BRAF and 6 (3.6%) NRAS mutations detected. Patients with BRAF mutations were more likely to be mismatch repair deficient (dMMR) (BRAF 20%, KRAS 4.4%, wild type 8.6%, p = 0.015). Most common BRAF and KRAS variants were, V600E (80%) and G12D (39.7%), respectively. BRAF V600E was independently associated with worse overall (median: 28 months, multivariate: HR 2.29, p = 0.026) and disease-free survival (median: 8 months, multivariate: HR 1.8, p = 0.047). KRAS G12V was a strong prognostic factor associated with disease-free survival (median: 9 months, HR 2.63, p = 0.016). dMMR patients (14/161, 8.7%) exhibited worse median overall survival compared to those with proficient MMR (dMMR 27 months, pMMR 29 months p = 0.025).


      This study highlights the importance of molecular analysis in CRPM stratification. BRAF V600E mutations predict poor outcomes post CRS and HIPEC and may help refine patient selection for this procedure. Molecular analysis should be performed preoperatively to characterise prognosis and guide perioperative therapeutic options.


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        • Flood M.
        • Narasimhan V.
        • Waters P.
        • et al.
        Survival after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: a systematic review and discussion of latest controversies.
        Surgeon. 2021; 19: 310-320
        • Froysnes I.S.
        • Larsen S.G.
        • Spasojevic M.
        • Dueland S.
        • Flatmark K.
        Complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastasis in Norway: prognostic factors and oncologic outcome in a national patient cohort.
        J Surg Oncol. 2016; 114: 222-227
        • Passot G.
        • Vaudoyer D.
        • Villeneuve L.
        • et al.
        What made hyperthermic intraperitoneal chemotherapy an effective curative treatment for peritoneal surface malignancy: a 25-year experience with 1,125 procedures.
        J Surg Oncol. 2016; 113: 796-803
        • Wong J.S.M.
        • Tan G.H.C.
        • Chia C.S.
        • Ong J.
        • Ng W.Y.
        • Teo M.C.C.
        The importance of synchronicity in the management of colorectal peritoneal metastases with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.
        World J Surg Oncol. 2020; 18: 10
        • Baratti D.
        • Kusamura S.
        • Iusco D.
        • et al.
        Postoperative complications after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy affect long-term outcome of patients with peritoneal metastases from colorectal cancer: a two-center study of 101 patients.
        Dis Colon Rectum. 2014; 57: 858-868
        • Hentzen J.
        • Rovers K.P.
        • Kuipers H.
        • et al.
        Impact of synchronous versus metachronous onset of colorectal peritoneal metastases on survival outcomes after cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC): a multicenter, retrospective, observational study.
        Ann Surg Oncol. 2019; 26: 2210-2221
        • Narasimhan V.
        • Britto M.
        • Pham T.
        • et al.
        Evolution of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: 8-year single-institutional experience.
        Dis Colon Rectum. 2019; 62: 1195-1203
        • Narasimhan V.
        • Tan S.
        • Kong J.
        • et al.
        Prognostic factors influencing survival in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for isolated colorectal peritoneal metastases: a systematic review and meta-analysis.
        Colorectal Dis. 2020; 22: 1482-1495
        • Khosravi-Far R.
        • Der C.J.
        The Ras signal transduction pathway.
        Cancer Metastasis Rev. 1994; 13: 67-89
        • Heinemann V.
        • von Weikersthal L.F.
        • Decker T.
        • et al.
        FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial.
        Lancet Oncol. 2014; 15: 1065-1075
        • Van Cutsem E.
        • Lenz H.J.
        • Kohne C.H.
        • et al.
        Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer.
        J Clin Oncol. 2015; 33: 692-700
        • Renaud S.
        • Romain B.
        • Falcoz P.E.
        • et al.
        KRAS and BRAF mutations are prognostic biomarkers in patients undergoing lung metastasectomy of colorectal cancer.
        Br J Cancer. 2015; 112: 720-728
        • Vauthey J.N.
        • Zimmitti G.
        • Kopetz S.E.
        • et al.
        RAS mutation status predicts survival and patterns of recurrence in patients undergoing hepatectomy for colorectal liver metastases.
        Ann Surg. 2013; 258 (discussion 626-617): 619-626
        • Tonello M.
        • Baratti D.
        • Sammartino P.
        • et al.
        Microsatellite and RAS/RAF mutational status as prognostic factors in colorectal peritoneal metastases treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).
        Ann Surg Oncol. 2021;
        • Andre T.
        • Shiu K.K.
        • Kim T.W.
        • et al.
        Pembrolizumab in microsatellite-instability-high advanced colorectal cancer.
        N Engl J Med. 2020; 383: 2207-2218
        • Sinicrope F.A.
        • Shi Q.
        • Allegra C.J.
        • et al.
        Association of DNA mismatch repair and mutations in BRAF and KRAS with survival after recurrence in stage III colon cancers : a secondary analysis of 2 randomized clinical trials.
        JAMA Oncol. 2017; 3: 472-480
        • Venderbosch S.
        • Nagtegaal I.D.
        • Maughan T.S.
        • et al.
        Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies.
        Clin Cancer Res. 2014; 20: 5322-5330
        • Quenet F.
        • Elias D.
        • Roca L.
        • et al.
        Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial.
        Lancet Oncol. 2021; 22: 256-266
        • Jones J.C.
        • Renfro L.A.
        • Al-Shamsi H.O.
        • et al.
        (Non-V600) BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer.
        J Clin Oncol. 2017; 35: 2624-2630
        • Baratti D.
        • Kusamura S.
        • Niger M.
        • et al.
        Prognostic impact of primary side and RAS/RAF mutations in a surgical series of colorectal cancer with peritoneal metastases.
        Ann Surg Oncol. 2021; 28: 3332-3342
        • Graf W.
        • Cashin P.H.
        • Ghanipour L.
        • et al.
        Prognostic impact of BRAF and KRAS mutation in patients with colorectal and appendiceal peritoneal metastases scheduled for CRS and HIPEC.
        Ann Surg Oncol. 2020; 27: 293-300
        • van de Vlasakker V.C.J.
        • Lurvink R.J.
        • Cashin P.H.
        • et al.
        The impact of PRODIGE 7 on the current worldwide practice of CRS-HIPEC for colorectal peritoneal metastases: a web-based survey and 2021 statement by Peritoneal Surface Oncology Group International (PSOGI).
        Eur J Surg Oncol. 2021; 47: 2888-2892
        • Verwaal V.J.
        • van Ruth S.
        • de Bree E.
        • et al.
        Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer.
        J Clin Oncol. 2003; 21: 3737-3743
        • Rieser C.J.
        • Jones H.
        • Hall L.B.
        • et al.
        Definition and prediction of early recurrence and mortality following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: towards predicting oncologic futility preoperatively.
        Ann Surg Oncol. 2021; 28: 9116-9125
        • Kopetz S.
        • Grothey A.
        • Yaeger R.
        • et al.
        Encorafenib, binimetinib, and cetuximab in BRAF V600e-mutated colorectal cancer.
        N Engl J Med. 2019; 381: 1632-1643
        • Tabernero J.
        • Grothey A.
        • Van Cutsem E.
        • et al.
        Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600e-mutant metastatic colorectal cancer: updated survival results and subgroup Analyses from the BEACON study.
        J Clin Oncol. 2021; 39: 273-284
        • Morris V.K.
        • Parseghian C.M.
        • Escano M.
        • et al.
        Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable, BRAFV600E metastatic colorectal cancer.
        J Clin Oncol. 2022; 40 (12): 12
        • Zhou S.L.
        • Xin H.Y.
        • Sun R.Q.
        • et al.
        Association of KRAS variant subtypes with survival and recurrence in patients with surgically treated intrahepatic cholangiocarcinoma.
        JAMA Surg. 2022; 157: 59-65
        • Nassar A.H.
        • Adib E.
        • Kwiatkowski D.J.
        Distribution of KRAS (G12C) somatic mutations across race, sex, and cancer type.
        N Engl J Med. 2021; 384: 185-187
        • Overman M.J.
        • McDermott R.
        • Leach J.L.
        • et al.
        Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study.
        Lancet Oncol. 2017; 18: 1182-1191
        • Klingbiel D.
        • Saridaki Z.
        • Roth A.D.
        • Bosman F.T.
        • Delorenzi M.
        • Tejpar S.
        Prognosis of stage II and III colon cancer treated with adjuvant 5-fluorouracil or FOLFIRI in relation to microsatellite status: results of the PETACC-3 trial.
        Ann Oncol. 2015; 26: 126-132
        • Ooki A.
        • Akagi K.
        • Yatsuoka T.
        • et al.
        Combined microsatellite instability and BRAF gene status as biomarkers for adjuvant chemotherapy in stage III colorectal cancer.
        J Surg Oncol. 2014; 110: 982-988
        • Smith C.G.
        • Fisher D.
        • Claes B.
        • et al.
        Somatic profiling of the epidermal growth factor receptor pathway in tumors from patients with advanced colorectal cancer treated with chemotherapy +/- cetuximab.
        Clin Cancer Res. 2013; 19: 4104-4113
        • Larsen S.G.
        • Goscinski M.A.
        • Dueland S.
        • et al.
        Impact of KRAS, BRAF and microsatellite instability status after cytoreductive surgery and HIPEC in a national cohort of colorectal peritoneal metastasis patients.
        Br J Cancer. 2021;
        • Boland C.R.
        • Goel A.
        Microsatellite instability in colorectal cancer.
        Gastroenterology. 2010; 138: 2073-2087 e2073
        • Fabrizio D.A.
        • George Jr., T.J.
        • Dunne R.F.
        • et al.
        Beyond microsatellite testing: assessment of tumor mutational burden identifies subsets of colorectal cancer who may respond to immune checkpoint inhibition.
        J Gastrointest Oncol. 2018; 9: 610-617
        • Koopman M.
        • Kortman G.A.
        • Mekenkamp L.
        • et al.
        Deficient mismatch repair system in patients with sporadic advanced colorectal cancer.
        Br J Cancer. 2009; 100: 266-273
        • Fujiyoshi K.
        • Yamamoto G.
        • Takahashi A.
        • et al.
        High concordance rate of KRAS/BRAF mutations and MSI-H between primary colorectal cancer and corresponding metastases.
        Oncol Rep. 2017; 37: 785-792