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

Hamaya Y, Guarinos C, Tseng-Rogenski SS, Iwaizumi M, Das R, Jover R, Castells A, Llor X, Andreu M, Carethers JM - PLoS ONE (2015)

Bottom Line: 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).There is improved survival for stage II/III CRC patients after adjuvant 5-FU-based chemotherapy regardless of EMAST status.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.

ABSTRACT
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).

No MeSH data available.


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Kaplan-Meier plots of cumulative overall survival in patients treated with and without adjuvant 5-FU chemotherapy.(A) Cumulative overall survival of all patients without MSI-H (P = 0.004, log-rank test). (B) Cumulative overall survival of patients with non-MSI-H EMAST-positive tumors (deficient in hMSH3 function) (P = 0.034, stratified log-rank test). (C) Cumulative overall survival of patient with non-MSI-H, non-EMAST tumors (full competency in DNA mismatch repair function) (P = 0.043, stratified log-rank test).
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pone.0127591.g001: Kaplan-Meier plots of cumulative overall survival in patients treated with and without adjuvant 5-FU chemotherapy.(A) Cumulative overall survival of all patients without MSI-H (P = 0.004, log-rank test). (B) Cumulative overall survival of patients with non-MSI-H EMAST-positive tumors (deficient in hMSH3 function) (P = 0.034, stratified log-rank test). (C) Cumulative overall survival of patient with non-MSI-H, non-EMAST tumors (full competency in DNA mismatch repair function) (P = 0.043, stratified log-rank test).

Mentions: We constructed Kaplan-Meier curves to compare cumulative overall survival in patients treated with and without adjuvant 5-FU chemotherapy. Adjuvant 5-FU adjuvant improves overall survival for patients with stage II/III CRC (P = 0.004, log-rank test) (Fig 1A), as has been previously reported [14,19]. We then segregated the data by the CRC EMAST status. As shown in Fig 1B, patients whose cancers demonstrated EMAST (presumed hMSH3-deficient) had improved survival with adjuvant 5-FU therapy (P = 0.034) to the same extent as patients whose cancers did not demonstrate EMAST (MMR-proficient) (P = 0.043) (Fig 1C). Thus, despite the lack of hMSH3 function within the cancer, there is improved survival in stage II/III CRC patients after adjuvant 5-FU chemotherapy regardless of tumor EMAST status.


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

Hamaya Y, Guarinos C, Tseng-Rogenski SS, Iwaizumi M, Das R, Jover R, Castells A, Llor X, Andreu M, Carethers JM - PLoS ONE (2015)

Kaplan-Meier plots of cumulative overall survival in patients treated with and without adjuvant 5-FU chemotherapy.(A) Cumulative overall survival of all patients without MSI-H (P = 0.004, log-rank test). (B) Cumulative overall survival of patients with non-MSI-H EMAST-positive tumors (deficient in hMSH3 function) (P = 0.034, stratified log-rank test). (C) Cumulative overall survival of patient with non-MSI-H, non-EMAST tumors (full competency in DNA mismatch repair function) (P = 0.043, stratified log-rank test).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440728&req=5

pone.0127591.g001: Kaplan-Meier plots of cumulative overall survival in patients treated with and without adjuvant 5-FU chemotherapy.(A) Cumulative overall survival of all patients without MSI-H (P = 0.004, log-rank test). (B) Cumulative overall survival of patients with non-MSI-H EMAST-positive tumors (deficient in hMSH3 function) (P = 0.034, stratified log-rank test). (C) Cumulative overall survival of patient with non-MSI-H, non-EMAST tumors (full competency in DNA mismatch repair function) (P = 0.043, stratified log-rank test).
Mentions: We constructed Kaplan-Meier curves to compare cumulative overall survival in patients treated with and without adjuvant 5-FU chemotherapy. Adjuvant 5-FU adjuvant improves overall survival for patients with stage II/III CRC (P = 0.004, log-rank test) (Fig 1A), as has been previously reported [14,19]. We then segregated the data by the CRC EMAST status. As shown in Fig 1B, patients whose cancers demonstrated EMAST (presumed hMSH3-deficient) had improved survival with adjuvant 5-FU therapy (P = 0.034) to the same extent as patients whose cancers did not demonstrate EMAST (MMR-proficient) (P = 0.043) (Fig 1C). Thus, despite the lack of hMSH3 function within the cancer, there is improved survival in stage II/III CRC patients after adjuvant 5-FU chemotherapy regardless of tumor EMAST status.

Bottom Line: 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).There is improved survival for stage II/III CRC patients after adjuvant 5-FU-based chemotherapy regardless of EMAST status.

View Article: PubMed Central - PubMed

Affiliation: Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, United States of America.

ABSTRACT
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).

No MeSH data available.


Related in: MedlinePlus