Expression of the DNA repair gene MLH1 correlates with survival in patients who have resected pancreatic cancer and have received adjuvant chemoradiation

NRG Oncology RTOG Study 9704

Yaacov R. Lawrence, Jennifer Moughan, Anthony M. Magliocco, Alexander C. Klimowicz, William F. Regine, Rex B. Mowat, Thomas A. Dipetrillo, William Small, Jeffry P. Simko, Talia Golan, Kathryn A. Winter, Chandan Guha, Christopher H. Crane, Adam P. Dicker

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

BACKGROUND: The majority of patients with pancreatic cancer who undergo curative resection experience rapid disease recurrence. In previous small studies, high expression of the mismatch-repair protein mutL protein homolog 1 (MLH1) in pancreatic cancers was associated with better outcomes. The objective of this study was to validate the association between MLH1 expression and survival in patients who underwent resection of pancreatic cancer and received adjuvant chemoradiation. METHODS: Samples were obtained from the NRG Oncology Radiation Therapy Oncology Group 9704 prospective, randomized trial (clinicaltrials.gov identifier NCT00003216), which compared 2 adjuvant protocols in patients with pancreatic cancer who underwent resection. Tissue microarrays were prepared from formalin-fixed, paraffin-embedded, resected tumor tissues. MLH1 expression was quantified using fluorescence immunohistochemistry and automated quantitative analysis, and expression was dichotomized above and below the median value. RESULTS: Immunohistochemical staining was successfully performed on 117 patients for MLH1 (60 and 57 patients from the 2 arms). The characteristics of the participants who had tissue samples available were similar to those of the trial population as a whole. At the time of analysis, 84% of participants had died, with a median survival of 17 months. Elevated MLH1 expression levels in tumor nuclei were significantly correlated with longer disease-free and overall survival in each arm individually and in both arms combined. Two-year overall survival was 16% in patients who had low MLH1 expression levels and 53% in those who had high MLH1 expression levels (P<.0001 for both arms combined). This association remained true on a multivariate analysis that allowed for lymph node status (hazard ratio, 0.41; 95% confidence interval, 0.27-0.63; P<.0001). CONCLUSIONS: In the current sample, MLH1 expression was correlated with long-term survival. Further studies should assess whether MLH1 expression predicts which patients with localized pancreatic cancer may benefit most from aggressive, multimodality treatment.

Original languageEnglish (US)
JournalCancer
DOIs
StateAccepted/In press - 2017

Fingerprint

Pancreatic Neoplasms
DNA Repair
Survival
Proteins
MutL Protein Homolog 1
Radiation Oncology
DNA Mismatch Repair
Paraffin
Formaldehyde
Disease-Free Survival
Neoplasms
Radiotherapy
Multivariate Analysis
Fluorescence
Lymph Nodes
Immunohistochemistry
Confidence Intervals
Staining and Labeling
Recurrence
Population

Keywords

  • Adjuvant
  • Adjuvant
  • Biomarkers
  • Chemotherapy
  • Clinical trial phase 3
  • MutL protein homolog 1 (MLH1)
  • Pancreatic neoplasms
  • Radiotherapy
  • Tumor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Expression of the DNA repair gene MLH1 correlates with survival in patients who have resected pancreatic cancer and have received adjuvant chemoradiation : NRG Oncology RTOG Study 9704. / Lawrence, Yaacov R.; Moughan, Jennifer; Magliocco, Anthony M.; Klimowicz, Alexander C.; Regine, William F.; Mowat, Rex B.; Dipetrillo, Thomas A.; Small, William; Simko, Jeffry P.; Golan, Talia; Winter, Kathryn A.; Guha, Chandan; Crane, Christopher H.; Dicker, Adam P.

In: Cancer, 2017.

Research output: Contribution to journalArticle

Lawrence, YR, Moughan, J, Magliocco, AM, Klimowicz, AC, Regine, WF, Mowat, RB, Dipetrillo, TA, Small, W, Simko, JP, Golan, T, Winter, KA, Guha, C, Crane, CH & Dicker, AP 2017, 'Expression of the DNA repair gene MLH1 correlates with survival in patients who have resected pancreatic cancer and have received adjuvant chemoradiation: NRG Oncology RTOG Study 9704', Cancer. https://doi.org/10.1002/cncr.31058
Lawrence, Yaacov R. ; Moughan, Jennifer ; Magliocco, Anthony M. ; Klimowicz, Alexander C. ; Regine, William F. ; Mowat, Rex B. ; Dipetrillo, Thomas A. ; Small, William ; Simko, Jeffry P. ; Golan, Talia ; Winter, Kathryn A. ; Guha, Chandan ; Crane, Christopher H. ; Dicker, Adam P. / Expression of the DNA repair gene MLH1 correlates with survival in patients who have resected pancreatic cancer and have received adjuvant chemoradiation : NRG Oncology RTOG Study 9704. In: Cancer. 2017.
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title = "Expression of the DNA repair gene MLH1 correlates with survival in patients who have resected pancreatic cancer and have received adjuvant chemoradiation: NRG Oncology RTOG Study 9704",
abstract = "BACKGROUND: The majority of patients with pancreatic cancer who undergo curative resection experience rapid disease recurrence. In previous small studies, high expression of the mismatch-repair protein mutL protein homolog 1 (MLH1) in pancreatic cancers was associated with better outcomes. The objective of this study was to validate the association between MLH1 expression and survival in patients who underwent resection of pancreatic cancer and received adjuvant chemoradiation. METHODS: Samples were obtained from the NRG Oncology Radiation Therapy Oncology Group 9704 prospective, randomized trial (clinicaltrials.gov identifier NCT00003216), which compared 2 adjuvant protocols in patients with pancreatic cancer who underwent resection. Tissue microarrays were prepared from formalin-fixed, paraffin-embedded, resected tumor tissues. MLH1 expression was quantified using fluorescence immunohistochemistry and automated quantitative analysis, and expression was dichotomized above and below the median value. RESULTS: Immunohistochemical staining was successfully performed on 117 patients for MLH1 (60 and 57 patients from the 2 arms). The characteristics of the participants who had tissue samples available were similar to those of the trial population as a whole. At the time of analysis, 84{\%} of participants had died, with a median survival of 17 months. Elevated MLH1 expression levels in tumor nuclei were significantly correlated with longer disease-free and overall survival in each arm individually and in both arms combined. Two-year overall survival was 16{\%} in patients who had low MLH1 expression levels and 53{\%} in those who had high MLH1 expression levels (P<.0001 for both arms combined). This association remained true on a multivariate analysis that allowed for lymph node status (hazard ratio, 0.41; 95{\%} confidence interval, 0.27-0.63; P<.0001). CONCLUSIONS: In the current sample, MLH1 expression was correlated with long-term survival. Further studies should assess whether MLH1 expression predicts which patients with localized pancreatic cancer may benefit most from aggressive, multimodality treatment.",
keywords = "Adjuvant, Adjuvant, Biomarkers, Chemotherapy, Clinical trial phase 3, MutL protein homolog 1 (MLH1), Pancreatic neoplasms, Radiotherapy, Tumor",
author = "Lawrence, {Yaacov R.} and Jennifer Moughan and Magliocco, {Anthony M.} and Klimowicz, {Alexander C.} and Regine, {William F.} and Mowat, {Rex B.} and Dipetrillo, {Thomas A.} and William Small and Simko, {Jeffry P.} and Talia Golan and Winter, {Kathryn A.} and Chandan Guha and Crane, {Christopher H.} and Dicker, {Adam P.}",
year = "2017",
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journal = "Cancer",
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TY - JOUR

T1 - Expression of the DNA repair gene MLH1 correlates with survival in patients who have resected pancreatic cancer and have received adjuvant chemoradiation

T2 - NRG Oncology RTOG Study 9704

AU - Lawrence, Yaacov R.

AU - Moughan, Jennifer

AU - Magliocco, Anthony M.

AU - Klimowicz, Alexander C.

AU - Regine, William F.

AU - Mowat, Rex B.

AU - Dipetrillo, Thomas A.

AU - Small, William

AU - Simko, Jeffry P.

AU - Golan, Talia

AU - Winter, Kathryn A.

AU - Guha, Chandan

AU - Crane, Christopher H.

AU - Dicker, Adam P.

PY - 2017

Y1 - 2017

N2 - BACKGROUND: The majority of patients with pancreatic cancer who undergo curative resection experience rapid disease recurrence. In previous small studies, high expression of the mismatch-repair protein mutL protein homolog 1 (MLH1) in pancreatic cancers was associated with better outcomes. The objective of this study was to validate the association between MLH1 expression and survival in patients who underwent resection of pancreatic cancer and received adjuvant chemoradiation. METHODS: Samples were obtained from the NRG Oncology Radiation Therapy Oncology Group 9704 prospective, randomized trial (clinicaltrials.gov identifier NCT00003216), which compared 2 adjuvant protocols in patients with pancreatic cancer who underwent resection. Tissue microarrays were prepared from formalin-fixed, paraffin-embedded, resected tumor tissues. MLH1 expression was quantified using fluorescence immunohistochemistry and automated quantitative analysis, and expression was dichotomized above and below the median value. RESULTS: Immunohistochemical staining was successfully performed on 117 patients for MLH1 (60 and 57 patients from the 2 arms). The characteristics of the participants who had tissue samples available were similar to those of the trial population as a whole. At the time of analysis, 84% of participants had died, with a median survival of 17 months. Elevated MLH1 expression levels in tumor nuclei were significantly correlated with longer disease-free and overall survival in each arm individually and in both arms combined. Two-year overall survival was 16% in patients who had low MLH1 expression levels and 53% in those who had high MLH1 expression levels (P<.0001 for both arms combined). This association remained true on a multivariate analysis that allowed for lymph node status (hazard ratio, 0.41; 95% confidence interval, 0.27-0.63; P<.0001). CONCLUSIONS: In the current sample, MLH1 expression was correlated with long-term survival. Further studies should assess whether MLH1 expression predicts which patients with localized pancreatic cancer may benefit most from aggressive, multimodality treatment.

AB - BACKGROUND: The majority of patients with pancreatic cancer who undergo curative resection experience rapid disease recurrence. In previous small studies, high expression of the mismatch-repair protein mutL protein homolog 1 (MLH1) in pancreatic cancers was associated with better outcomes. The objective of this study was to validate the association between MLH1 expression and survival in patients who underwent resection of pancreatic cancer and received adjuvant chemoradiation. METHODS: Samples were obtained from the NRG Oncology Radiation Therapy Oncology Group 9704 prospective, randomized trial (clinicaltrials.gov identifier NCT00003216), which compared 2 adjuvant protocols in patients with pancreatic cancer who underwent resection. Tissue microarrays were prepared from formalin-fixed, paraffin-embedded, resected tumor tissues. MLH1 expression was quantified using fluorescence immunohistochemistry and automated quantitative analysis, and expression was dichotomized above and below the median value. RESULTS: Immunohistochemical staining was successfully performed on 117 patients for MLH1 (60 and 57 patients from the 2 arms). The characteristics of the participants who had tissue samples available were similar to those of the trial population as a whole. At the time of analysis, 84% of participants had died, with a median survival of 17 months. Elevated MLH1 expression levels in tumor nuclei were significantly correlated with longer disease-free and overall survival in each arm individually and in both arms combined. Two-year overall survival was 16% in patients who had low MLH1 expression levels and 53% in those who had high MLH1 expression levels (P<.0001 for both arms combined). This association remained true on a multivariate analysis that allowed for lymph node status (hazard ratio, 0.41; 95% confidence interval, 0.27-0.63; P<.0001). CONCLUSIONS: In the current sample, MLH1 expression was correlated with long-term survival. Further studies should assess whether MLH1 expression predicts which patients with localized pancreatic cancer may benefit most from aggressive, multimodality treatment.

KW - Adjuvant

KW - Adjuvant

KW - Biomarkers

KW - Chemotherapy

KW - Clinical trial phase 3

KW - MutL protein homolog 1 (MLH1)

KW - Pancreatic neoplasms

KW - Radiotherapy

KW - Tumor

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U2 - 10.1002/cncr.31058

DO - 10.1002/cncr.31058

M3 - Article

JO - Cancer

JF - Cancer

SN - 0008-543X

ER -