Efficacy of Adjuvant 5-Fluorouracil Therapy for Patients with EMAST-Positive Stage II/III Colorectal Cancer

• Published in: PloS one Vol. 10; no. 5; p. e0127591
• Main Authors: Hamaya, Yasushi, Guarinos, Carla, Tseng-Rogenski, Stephanie S, Iwaizumi, Moriya, Das, Ritabrata, Jover, Rodrigo, Castells, Antoni, Llor, Xavier, Andreu, Montserrat, Carethers, John M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.05.2015; Public Library of Science (PLoS)
• Subjects: 5-Fluorouracil; Adjuvant chemotherapy; Adult; Aged; Aged, 80 and over; Analysis; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - adverse effects; Antimetabolites, Antineoplastic - therapeutic use; Cancer therapies; Care and treatment; Chemotherapy; Chemotherapy, Adjuvant; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - mortality; Colorectal Neoplasms - pathology; Cytotoxicity; Càncer; Còlon; Data processing; Defects; Deoxyribonucleic acid; DNA; DNA repair; Drug therapy; Female; Fluorouracil; Fluorouracil - administration & dosage; Fluorouracil - adverse effects; Fluorouracil - therapeutic use; Gastroenterology; Health aspects; Health risks; Hospitals; Humans; Inflammation; Internal medicine; Kaplan-Meier Estimate; Male; Medicine; Metastasis; Microsatellite Repeats; Middle Aged; Mismatch repair; Multivariate analysis; Neoplasm Staging; Oxidative stress; Patients; Proteins; Risk Factors; Survival; Toxicity; Treatment Outcome; Tumors; Young Adult; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0127591

Elevated Microsatellite Alterations at Selected Tetranucleotide repeats (EMAST) is a genetic signature found in up to 60% of colorectal cancers (CRCs) that is caused by somatic dysfunction of the DNA mismatch repair (MMR) protein hMSH3. We have previously shown in vitro that recognition of 5-fluorouracil (5-FU) within DNA and subsequent cytotoxicity was most effective when both hMutSα (hMSH2-hMSH6 heterodimer) and hMutSβ (hMSH2-hMSH3 heterodimer) MMR complexes were present, compared to hMutSα > hMutSβ alone. We tested if patients with EMAST CRCs (hMutSβ defective) had diminished response to adjuvant 5-FU chemotherapy, paralleling in vitro findings. We analyzed 230 patients with stage II/III sporadic colorectal cancers for which we had 5-FU treatment and survival data. Archival DNA was analyzed for EMAST (>2 of 5 markers mutated among UT5037, D8S321, D9S242, D20S82, D20S85 tetranucleotide loci). Kaplan-Meier survival curves were generated and multivariate analysis was used to determine contribution to risk. We identified 102 (44%) EMAST cancers. Ninety-four patients (41%) received adjuvant 5-FU chemotherapy, and median follow-up for all patients was 51 months. Patients with EMAST CRCs demonstrated improved survival with adjuvant 5FU to the same extent as patients with non-EMAST CRCs (P<0.05). We observed no difference in survival between patients with stage II/III EMAST and non-EMAST cancers (P = 0.36). There is improved survival for stage II/III CRC patients after adjuvant 5-FU-based chemotherapy regardless of EMAST status. The loss of contribution of hMSH3 for 5-FU cytotoxicity may not adversely affect patient outcome, contrasting patients whose tumors completely lack DNA MMR function (MSI-H).