Mismatch-repair deficiency (dMMR) predicts worse chemoresponsiveness but better survival in early-stage colorectal adenocarcinoma. This study examined metastatic colorectal and appendix cancers with and without peritoneal metastasis (PM) in the National Cancer Database (NCDB), hypothesizing that dMMR tumors show better survival.
Stage 4 colon, rectum, and appendix cancers (2010–2016) were identified in the NCDB (including goblet cell carcinoids, excluding neuroendocrine tumors). Stage 4 disease without liver, bone, brain, lung, or distant nodal metastases defined PM. Fisher’s exact tests were used to compare proportions, and Kaplan–Meier analysis was used to evaluate survival.
Of 130,125 stage 4 colon, rectum, and appendix cancers, 27,848 (21.4%) had PM. Appendix primary tumors had PM more commonly than colon or rectum cancer (83.6% vs. 20.6% and 12.1% of stage 4 cases; p < 0.0001). More PM patients had MMR testing than patients with other metastasis (OM) (21.4% vs. 16.1%), and testing increased from 9.6% in 2010 to 26.3% in 2016 (both p < 0.0001). Among the PM patients, MMR testing was least common for appendix cancers (9.0%). When tested, PM patients more often had dMMR (22.9% [1122/4900] vs. 15.4% [2532/16,495] of OM patients; p < 0.0001). Colon primary tumor had dMMR most frequently (25.0% vs. 14.6% and 14.5% for rectal and appendix tumor; p < 0.0001). Most PM patients received chemotherapy (66.2%). Immunotherapy use increased over time (1.1% of PM diagnoses in 2010 vs. 20.8% in 2016). For MMR-tested stage 4 patients, dMMR correlated with worse survival (median OM, 19.7 vs. 23.9 months, p < 0.0001; median PM, 19.9 vs. 24.6 months, p = 0.035).
The NCDB showed dMMR predicting worse survival for stage 4 colorectal cancers with and without PM and dMMR existing in 14.5–25% of tested patients, suggesting that increased attention to MMR testing in stage 4 colorectal and appendix cancers can identify many patients who could potentially benefit from immunotherapy.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Venderbosch S, Nagtegaal ID, Maughan TS, 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;20:5322–30.
Heald B, Plesec T, Liu X, et al. Implementation of universal microsatellite instability and immunohistochemistry screening for diagnosing lynch syndrome in a large academic medical center. J Clin Oncol. 2013;31:1336–40.
Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13.
Sinicrope FA. Evaluating the combination of microsatellite instability and mutation in BRAF as prognostic factors for patients with colorectal cancer. Clin Gastroenterol Hepatol. 2019;17:391–4.
Bedeir A, Krasinskas AM. Molecular diagnostics of colorectal cancer. Arch Pathol Lab Med. 2011;135:578–87.
Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117:4623–32.
Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal cancer prognosis. J Clin Oncol. 2005;23:609–18.
Benedix F, Meyer F, Kube R, et al. Influence of anatomical subsite on the incidence of microsatellite instability, and KRAS and BRAF mutation rates in patients with colon carcinoma. Pathol Res Pract. 2012;208:592–7.
Benson AB, Venook AP, Al-Hawary MM, et al. NCCN guidelines insights: colon cancer, version 2.2018. J Natl Compr Cancer Netw. 2018;16:359–69.
Chicago Consensus Working Group. The Chicago consensus on peritoneal surface malignancies: management of colorectal metastases. Ann Surg Oncol. 2020;27:1761–7.
Taieb J, Le Malicot K, Shi Q, et al. Prognostic value of BRAF and KRAS mutations in MSI and MSS stage III colon cancer. J Natl Cancer Inst. 2017;109:djw272.
Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773–9.
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509–20.
Boyiadzis MM, Kirkwood JM, Marshall JL, Pritchard CC, Azad NS, Gulley JL. Significance and implications of FDA approval of pembrolizumab for biomarker-defined disease. J Immunother Cancer. 2018;6:35.
Esquivel J, Chua TC, Stojadinovic A, et al. Accuracy and clinical relevance of computed tomography scan interpretation of peritoneal cancer index in colorectal cancer peritoneal carcinomatosis: a multi-institutional study. J Surg Oncol. 2010;102:565–70.
Low RN, Barone RM. Combined diffusion-weighted and gadolinium-enhanced MRI can accurately predict the peritoneal cancer index preoperatively in patients being considered for cytoreductive surgical procedures. Ann Surg Oncol. 2012;19:1394–401.
Jacobson R, Sherman SK, Dahdaleh F, Turaga KK. Peritoneal metastases in colorectal cancer. Ann Surg Oncol. 2018;25:2145–51.
Xue L, Hyman NH, Turaga KK, Eng OS. Peritoneal metastases in colorectal cancer: biology and barriers. J Gastrointest Surg. 2019;24:720–7.
Chicago Consensus Working Group. The Chicago consensus on peritoneal surface malignancies: management of appendiceal neoplasms. Ann Surg Oncol. 2020;27:1753–60.
Tseng J, Bryan DS, Poli E, Sharma M, Polite BN, Turaga KK. Under-representation of peritoneal metastases in published clinical trials of metastatic colorectal cancer. Lancet Oncol. 2017;18:711–2.
Surgeons ACo. NCDB participant user file: citing data from the NCDB. 2020. Retrieved 19 Feb 2020 at http://ncdbpuf.facs.org/node/412.
Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time. Control Clin Trials. 1996;17:343–46.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B Methodol. 1995;57:289–300.
Benedix F, Kube R, Meyer F, et al. Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum. 2010;53:57–64.
Yahagi M, Okabayashi K, Hasegawa H, Tsuruta M, Kitagawa Y. The worse prognosis of right-sided compared with left-sided colon cancers: a systematic review and meta-analysis. J Gastrointest Surg. 2016;20:648–55.
Franko J, Shi Q, Meyers JP, et al. Prognosis of patients with peritoneal metastatic colorectal cancer given systemic therapy: an analysis of individual patient data from prospective randomised trials from the Analysis and Research in Cancers of the Digestive System (ARCAD) database. Lancet Oncol. 2016;17:1709–19.
Charlton ME, Kahl AR, Greenbaum AA, et al. KRAS testing, tumor location, and survival in patients with stage IV colorectal cancer: SEER 2010–2013. J Natl Compr Cancer Netw. 2017;15:1484–93.
Shaikh T, Handorf EA, Meyer JE, Hall MJ, Esnaola NF. Mismatch repair deficiency testing in patients with colorectal cancer and nonadherence to testing guidelines in young adults. JAMA Oncol. 2018;4:e173580.
Kim SH, Shin SJ, Lee KY, et al. Prognostic value of mucinous histology depends on microsatellite instability status in patients with stage III colon cancer treated with adjuvant FOLFOX chemotherapy: a retrospective cohort study. Ann Surg Oncol. 2013;20:3407–13.
Stein A, Strong E, Clark Gamblin T, et al. Molecular and genetic markers in appendiceal mucinous tumors: a systematic review. Ann Surg Oncol. 2020;27:85–97.
Lenz HJ, Ou FS, Venook AP, et al. Impact of consensus molecular subtype on survival in patients with metastatic colorectal cancer: results from CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2019;37:1876–85.
Koopman M, Kortman GA, Mekenkamp L, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer. 2009;100:266–73.
Blaker H, Alwers E, Arnold A, et al. The association between mutations in BRAF and colorectal cancer-specific survival depends on microsatellite status and tumor stage. Clin Gastroenterol Hepatol. 2019;17:455–62.
Cohen R, Rousseau B, Vidal J, Colle R, Diaz LA Jr, Andre T. Immune checkpoint inhibition in colorectal cancer: microsatellite instability and beyond. Target Oncol. 2020;15:11–24.
This work was supported by NIH T32#CA078586 (SKS).
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Sherman, S.K., Schuitevoerder, D., Chan, C.H.F. et al. Metastatic Colorectal Cancers with Mismatch Repair Deficiency Result in Worse Survival Regardless of Peritoneal Metastases. Ann Surg Oncol (2020). https://doi.org/10.1245/s10434-020-08733-x