GICS 2009: DNA Mismatch Repair Plays Role in Pancreatic Cancer Outcomes

Roxanne Nelson

January 19, 2009

January 19, 2009 (San Francisco, California) — Genetic variations in DNA mismatch repair are associated with tumor response to preoperative therapy, tumor respectability, and overall survival in patients with pancreatic cancer treated with gemcitabine.

According to new data presented here at the 2009 Gastrointestinal Cancers Symposium, single-nucleotide polymorphisms (SNPs) of MMR genes have the potential to predict clinical response to gemcitabine-based therapy and serve as prognostic markers for tumor respectability and overall survival in patients with resectable pancreatic cancer.

Pancreatic cancer patients pose a conundrum for those of us who treat them.

"This research really exemplifies the goals for where we want the future to be in gastrointestinal cancer research and treatment," said Jennifer Obel, MD, assistant professor of medicine at Feinberg School of Medicine, Northwestern University, in Chicago, Illinois. "Pancreatic cancer patients pose a conundrum for those of us who treat them. We know that the majority of those who undergo surgery and chemotherapy for cure will recur and die of the disease within 5 years."

Overall survival in older studies, where patients underwent surgery without adjuvant chemotherapy, is 10% at 5 years, explained Dr. Obel, who was not involved in the study. More recent data show that the overall survival rate has increased to 20% at 5 years among patients who receive gemcitabine.

"Identifying panels of genetic mutations, such as in this study, can help identify poor response to therapy," she said. "If we are able to do this and validate the data, we can avoid aggressive therapy in patients who are unlikely to benefit from it."

Highly Lethal Disease

Pancreatic cancer is the fourth leading cause of cancer death in both men and women; it is a highly lethal disease. "The best hope for a patient is tumor resection, but only 20% are diagnosed at a stage early enough for resection," said study author Donghui Li, PhD, from the University of Texas MD Anderson Cancer Center, in Houston. "But even then, 30% of patients with resectable tumors do not benefit because of relapse or metastasis. Identifying these patients remains a clinical challenge."

Gemcitabine is the standard therapy now for the treatment of pancreatic cancer, but factors influencing individual response to gemcitabine are not well defined. Response to drugs varies considerably because of genetic variations in drug metabolism or cellular responses to the drug, such as DNA repair. Previous studies have suggested that DNA mismatch repair plays a role in cellular response to gemcitabine-induced DNA damage, Dr. Li explained.

Based on this information, Dr. Li and colleagues sought to determine whether genetic variations in DNA mismatch repair are associated with clinical outcome in pancreatic cancer patients treated with gemcitabine.

Unfavorable Genotypes Identified

The study was conducted in 154 patients with potentially resectable pancreatic adenocarcinoma who had received preoperative gemcitabine-based treatment. The researchers evaluated 15 SNPs from 8 MMR genes (EXO1, MLH1, MSH2, MSH3, MSH6, PMS1, TREX1, and TP73) to determine mismatch repair genes and evaluate their association with tumor response to therapy, tumor resectability, and overall survival.

Of the 154 patients, 109 underwent tumor resection. All of the patients were enrolled in 2 phase 2 clinical trials for preoperative gemcitabine-based chemoradiation at MD Anderson from 1999 to 2006, and associations of genotypes with tumor response to therapy, margin-negative tumor resection, and overall survival were evaluated using logistic regression and Cox proportional regression models.

Multivariable models identified a number of genotypes as significant predictors for tumor response to therapy, tumor resectability, and overall survival. As an example, said Dr. Li, patients with the TP73 GG genotype had a response rate of 94% to preoperative chemoradiotherapy. In contrast, patients with the GA/AA genotype had a 73% response, which is a 20% difference. A total of 81% of the patients with favorable genotypes underwent margin-negative tumor resection, compared with 52% of the patients with more unfavorable genotypes.

"When we compared the median survival time, it was 25.5 months for the 'good' genotype carriers and 7.4 months for the 'bad' genotype carriers," she said.

They also observed that TREX1 EX14-460C>T and TP73 Ex2+4G>A genotypes were significant predictors for tumor response, MLH1 IVS12- 169C>T and TP73 were significant predictors for tumor resectability, and EXO1 R354H, TREX1, and TP73 were significant predictors for overall survival in multivariable models, including all clinical factors and genotypes examined.

Combined Genotype Effect Seen

A strong combined genotype effect on each clinical end point was seen. "Some genotypes had nonsignificant weak effects, but when we combined the genotypes together, a strong combined genotype effect was detected," said Dr. Li. "The median survival time decreased as the number of variant genotypes increased."

As an example, 20 of the 25 patients with 0 or 1 adverse genotypes were still alive, but the median survival time could not be calculated. However, those with 2 adverse genotypes had a median survival of 36 months. Survival time decreased to 23.9 months among patients with 3 adverse genotypes, and declined to only 8.3 months among those with 6 or 7 adverse genotypes.

SNPs of MMR genes have a potential value as predictors for clinical response to gemcitabine-based therapy and as prognostic markers for tumor resectability and overall survival in this population. "But these observations need to be confirmed in separate patient populations and, if confirmed, these markers can be applied in future individualized cancer therapy," said Dr. Li.

Dr. Li has disclosed no relevant financial relationships.

2009 Gastrointestinal Cancers Symposium (GICS): Abstract 118. Presented January 16, 2009


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