Synapse - Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy

Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy Journal Article

Authors:	Cercek, A.; Dos Santos Fernandes, G.; Roxburgh, C. S.; Ganesh, K.; Ng, S.; Sanchez-Vega, F.; Yaeger, R.; Segal, N. H.; Reidy-Lagunes, D. L.; Varghese, A. M.; Markowitz, A.; Wu, C.; Szeglin, B.; Sauvé, C. E. G.; Salo-Mullen, E.; Tran, C.; Patel, Z.; Krishnan, A.; Tkachuk, K.; Nash, G. M.; Guillem, J.; Paty, P. B.; Shia, J.; Schultz, N.; Garcia-Aguilar, J.; Diaz, L. A.; Goodman, K.; Saltz, L. B.; Weiser, M. R.; Smith, J. J.; Stadler, Z. K.
Article Title:	Mismatch repair-deficient rectal cancer and resistance to neoadjuvant chemotherapy
Abstract:	PURPOSE: Evaluate response of mismatch repair-deficient (dMMR) rectal cancer to neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: dMMR rectal tumors at Memorial Sloan Kettering Cancer Center (New York, NY) were retrospectively reviewed for characteristics, treatment, and outcomes. Fifty patients with dMMR rectal cancer were identified by IHC and/or microsatellite instability analysis, with initial treatment response compared with a matched MMR-proficient (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), six (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 with 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 with enrichment of germline MSH2 and MSH6 mutations when compared with 193 patients with Lynch syndrome-associated colon cancer (MSH2, 57% vs 36%; MSH6, 17% vs 9%; P < 0.003). 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 Lynch syndrome in patients with dMMR rectal cancer. ©2020 American Association for Cancer Research.
Journal Title:	Clinical Cancer Research
Volume:	26
Issue:	13
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2020-07-01
Start Page:	3271
End Page:	3279
Language:	English
DOI:	10.1158/1078-0432.Ccr-19-3728
PUBMED:	32144135
PROVIDER:	scopus
PMCID:	PMC7348681
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85087209387&doi=10.1158%2f1078-0432.CCR-19-3728&partnerID=40&md5=3cf156a9f1d5c8d18c60c4f532460b2f
Notes:	Article -- Export Date: 3 August 2020 -- Source: Scopus