domingo, 24 de julio de 2016

DNA Mismatch Repair Deficiency in Rectal Cancer: Benchmarking Its Impact on Prognosis, Neoadjuvant Response Prediction, and Clinical Cancer Genetics

DNA Mismatch Repair Deficiency in Rectal Cancer: Benchmarking Its Impact on Prognosis, Neoadjuvant Response Prediction, and Clinical Cancer Genetics

DNA Mismatch Repair Deficiency in Rectal Cancer: Benchmarking Its Impact on Prognosis, Neoadjuvant Response Prediction, and Clinical Cancer Genetics

  1. Y. Nancy You
+Author Affiliations
  1. Nicole de Rosa, Miguel A. Rodriguez-Bigas, George J. Chang, Jula Veerapong, Ester Borras, Sunil Krishnan, Brian Bednarski, Craig A. Messick, John M. Skibber, Barry W. Feig, Patrick M. Lynch, Eduardo Vilar, and Y. Nancy You, University of Texas MD Anderson Cancer Center, Houston, TX; Nicole de Rosa, University of Nebraska Medical Center, Omaha, NE; and Jula Veerapong, St Louis University, St Louis, MO.
  1. Corresponding author: Y. Nancy You, MD, MHSc, Department of Surgical Oncology, Familial High-Risk Gastrointestinal Cancer Clinic, University of Texas MD Anderson Cancer Center, 1400 Pressler St, Unit 1484, PO Box 301402, Houston, TX 77230; e-mail: ynyou@mdanderson.org.
  1. Presented in part at the American Society of Clinical Oncology Annual Meeting, June 4-8, 2010, Chicago, IL, and at the Society of Pelvic Surgeons Annual Meeting, July 6-12, 2013, Dusseldorf, Germany.

Abstract

Purpose DNA mismatch repair deficiency (dMMR) hallmarks consensus molecular subtype 1 of colorectal cancer. It is being routinely tested, but little is known about dMMR rectal cancers. The efficacy of novel treatment strategies cannot be established without benchmarking the outcomes of dMMR rectal cancer with current therapy. We aimed to delineate the impact of dMMR on prognosis, the predicted response to fluoropyrimidine-based neoadjuvant therapy, and implications of germline alterations in the MMR genes in rectal cancer.
Methods Between 1992 and 2012, 62 patients with dMMR rectal cancers underwent multimodality therapy. Oncologic treatment and outcomes as well as clinical genetics work-up were examined. Overall and rectal cancer–specific survival were calculated by the Kaplan-Meier method.
Results The median age at diagnosis was 41 years. MMR deficiency was most commonly due to alterations in MSH2 (53%) or MSH6 (23%). After a median follow-up of 6.8 years, the 5-year rectal cancer–specific survival was 100% for stage I and II, 85.1% for stage III, and 60.0% for stage IV disease. Fluoropyrimidine-based neoadjuvant chemoradiation was associated with a complete pathologic response rate of 27.6%. The extent of surgical resection was influenced by synchronous colonic disease at presentation, tumor height, clinical stage, and pelvic radiation. An informed decision for a limited resection focusing on proctectomy did not compromise overall survival. Five of the 11 (45.5%) deaths during follow-up were due to extracolorectal malignancies.
Conclusion dMMR rectal cancer had excellent prognosis and pathologic response with current multimodality therapy including an individualized surgical treatment plan. Identification of a dMMR rectal cancer should trigger germline testing, followed by lifelong surveillance for both colorectal and extracolorectal malignancies. We herein provide genotype-specific outcome benchmarks for comparison with novel interventions.

Footnotes

  • Supported by the University of Texas MD Anderson Cancer Center G.S. Hogan Gastrointestinal Cancer Research Grant (Y.N.Y.); a gift from the Feinberg Family (E.V.); the University of Texas MD Anderson Cancer Center Janice Davis Gordon Memorial Postdoctoral Fellowship in Colorectal Cancer Prevention (E.B.); and U.S. National Institutes of Health/National Cancer Institute University of Texas MD Anderson Cancer Center Core Support Grant No. P30CA016672.
  • Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

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