Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy

Cercek, A. et al. (2020) Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy. Clinical Cancer Research, 26(13), pp. 3271-3279. (doi: 10.1158/1078-0432.CCR-19-3728) (PMID:32144135) (PMCID:PMC7348681)

Abstract

Purpose: Evaluate response of mismatch repair deficient (dMMR) rectal cancer to neoadjuvant chemotherapy. Experimental Design: dMMR rectal tumors at Memorial Sloan Kettering were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty dMMR rectal cancer patients were identified by immunohistochemistry and/or microsatellite instability analysis, with initial treatment response compared to a matched pMMR rectal cancer cohort. Germline and somatic mutation analyses were evaluated. Patient-derived dMMR rectal tumoroids were assessed for chemotherapy sensitivity. Results: Of 21 patients receiving neoadjuvant chemotherapy (fluorouracil/oxaliplatin), 6 (29%) had progression of disease. In comparison, no progression was noted in 63 pMMR rectal tumors (P = 0.0001). Rectal cancer dMMR tumoroids reflected this resistance to chemotherapy. No genomic predictors of chemotherapy response were identified. Of 16 patients receiving chemoradiation, 13 (93%) experienced tumor downstaging; one patient had stable disease, comparable to 48 pMMR rectal cancers. Of 13 patients undergoing surgery, 12 (92%) had early-stage disease. Forty-two (84%) of the 50 patients tested positive for Lynch syndrome (LS) with enrichment of germline MSH2 and MSH6 mutations when compared to 193 LS-associated colon cancer patients (MSH2, 57% vs 36%; MSH6, 17% vs 9%; P < .003). Conclusions: Over one-fourth of dMMR rectal tumors treated with neoadjuvant chemotherapy exhibited disease progression. Conversely, dMMR rectal tumors were sensitive to chemoradiation. MMR status should be performed upfront in all locally advanced rectal tumors with careful monitoring for response on neoadjuvant chemotherapy and genetic testing for LS in dMMR rectal cancer patients.

• Item Type: Articles
• Additional Information: This research was funded in part through the Romeo Milio Lynch Syndrome Foundation, the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, the Robert and Kate Niehaus Center for Inherited Cancer Genomics, the Fieldstone Family Fund, a Stand Up to Cancer Colorectal Cancer Dream Team Translational Research Grant (SU2C-AACR-DT22-17) (Stand Up to Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, a scientific partner of SU2C), and the National Institutes of Health Cancer Center Support Grant P30 CA008748. J.J.S. is supported by the American Society of Colon and Rectal Surgeons Career Development Award, the Joel J. Roslyn Faculty Research Award, the American Society of Colon and Rectal Surgeons Limited Project Grant, the Memorial Sloan Kettering Department of Surgery Junior Faculty Award, and the John Wasserman Colon and Rectal Cancer Fund. J.J.S. is also supported by the Colorectal Cancer Alliance and the Chris4Life Research Award.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Roxburgh, Professor Campbell
• Authors: Cercek, A., Dos Santos Fernandes, G., Roxburgh, C. S.D., Ganesh, K., Ng, S. Y., Sanchez-Vega, F., Yaeger, R., Segal, N. H., Reidy, D. L., Varghese, A., Markowitz, A. J., Wu, C., Szeglin, B. C., Sauve, C., Salo-Mullen, E., Tran, C., Patel, Z., Krishnan, A., Tkachuk, K., Nash, G. M., Guillem, J. G., Paty, P. B., Shia, J., Schultz, N., Garcia-Aguilar, J., Diaz Jr., L. A., Goodman, K., Saltz, L. B., Weiser, M. R., Smith, J. J., and Stadler, Z. K.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Clinical Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 1078-0432
• ISSN (Online): 1557-3265
• Published Online: 06 March 2020
• Copyright Holders: Copyright © 2020 American Association for Cancer
• First Published: First published in Clinical Cancer Research 26(13):3271-3279
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher