Abstract 3553: Elevated expression of mismatch repair enzyme MLH1 is associated with prolonged overall survival in resected pancreatic cancer treated with adjuvant chemoradiation, a biomarker analysis of RTOG 9704.
Authors: Lawrence Yaacov Richard , Moughan Jennifer , Magliocco Anthony , Klimowicz Alexander , Regine William F. , Mowat Rex B. , DiPetrillo Thomas A. , Small William , Winter Kathryn , Guha Chandan , Crane Christopher , Dicker Adam P. 
Published: August 2014

Introduction

RTOG 9704 was a randomized phase III trial comparing two different adjuvant protocols in patients with resected pancreatic adenocarcinoma. All patients received concurrent 5FU-radiation (RT) therapy, in addition the control arm received 5FU prior to- and following RT, whereas the experimental arm received gemcitabine. MLH1 loss is associated with treatment resistance and genetic instability in the laboratory. It is hypothesized that tumors with higher levels of MLH1 expression would have a better prognosis.

Methods

A Tissue microarray prepared from paraffin blocks removed at time of operation was examined for MLH1 expression using fluorescence immunohistochemistry and analyzed using automated quantitative analysis software (AQUA) from HistoRx. For the purposes of part of the analysis MLH1 levels were dichotomized above and below the median expression value. Clinical endpoints were disease-free and overall-survival. Statistical techniques included the chi-square, Fisher's exact test and the Kaplan-Meier method. A p-value of &lt;0.01 was considered significant to allow for multiple comparisons.

Results

Of the 451 eligible patients enrolled on the trial, immunohistochemistry staining was successfully performed for 117 patients for MLH1 (60 and 57 from the 2 arms). Characteristics from those with tissue were similar to the trial population as a whole. At the time of analysis 84% of the participants had died, with a median survival of 17 months (min-max: 14 to 21 months). Elevated MLH1 levels in tumor nuclei were correlated with longer disease-free and overall survival in both arms of the trial, both individually and combined. Two year overall survival was 16% in those with low MLH1 levels and 53% for those with high levels, p&lt;0.0001 (both arms combined). This association remained true on multivariate analysis allowing for nodal status (HR=0.41, p&lt;0.0001).

Conclusions

The expression of MLH1 correlates with long-term survival in resected pancreatic cancer treated with post-operative chemoradiation. It is suggested that, following validation, MLH1 be used as stratification markers in future clinical trials of DNA damaging agents in pancreatic cancer.

This project was supported by RTOG grants U10 CA21661, CCOP grant U10 CA37422, and RTOG Biospecimen Resource grant U24 CA114734 from the National Cancer Institute (NCI).

Citation Format: Yaacov Richard Lawrence, Jennifer Moughan, Anthony Magliocco, Alexander Klimowicz, William F. Regine, Rex B. Mowat, Thomas A. DiPetrillo, William Small, Kathryn Winter, Chandan Guha, Christopher Crane, Adam P. Dicker. Elevated expression of mismatch repair enzyme MLH1 is associated with prolonged overall survival in resected pancreatic cancer treated with adjuvant chemoradiation, a biomarker analysis of RTOG 9704. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3553. doi:10.1158/1538-7445.AM2013-3553