Gene Mutation Signals Poor Prognosis for Pancreatic Tumors

Neil Osterweil

October 09, 2015

NASHVILLE, Tennessee — For patients with pancreatic neuroendocrine tumors, the presence of recently identified mutations in two key genes is a prognostic factor for poor outcome, researchers report.

"We found loss of nuclear expression in about 23% of the tumors that we studied, and this loss of expression was associated with worse tumors from the outset," lead investigator Michelle Heayn, MD, a second-year pathology resident at the University of Pittsburgh Medical Center, told Medscape Medical News.

Pancreatic tumors with neuroendocrine histology frequently respond to chemotherapy and have a more favorable prognosis than the more common pancreatic adenocarcinomas. However, the mutations are associated with worse disease-free and disease-specific survival.

The results of the study were presented here at the College of American Pathologists 2015 Meeting.

The mutations — in the alpha-thalassemia mental retardation syndrome X-linked gene (ATRX) and the death-domain-associated protein gene (DAXX) — cause loss of expression of the proteins coded by ATRX and DAXX, Dr Heayn explained.

 
We found loss of nuclear expression in about 23% of the tumors that we studied.
 

To test whether these mutations had any prognostic significance, Dr Heayn and her colleagues used immunolabeling in surgically resected pancreatic neuroendocrine tumors from 303 patients. They then correlated the findings with patient demographics, pathologic features, disease-free survival, and disease-specific survival. Follow-up ranged from 1.6 to 18.8 years.

Of the 303 tumors, 69 (23%) had mutations in one or both genes. Tumors with a gene mutation had a larger mean diameter than tumors with intact gene expression (5.0 vs 2.4 cm), as well as a significantly higher histologic grade, more lymphovascular and perineural invasion, a more advanced T stage, greater lymph node involvement, more synchronous metastases, and more frequent disease recurrence (P < .01 for all comparisons).

In addition, the mutations were associated with shorter mean disease-free survival (5.6 vs 17.2 years; < .01) and shorter mean disease-specific survival (12.5 vs 17.7 years; P = .01).

On multivariate analysis that controlled for patient and tumor factors, the mutations were a significant predictor of shorter disease-free survival (P < .01), independent of tumor size, stage, histology, lymphovascular or perineural invasion, and lymph node status.

Dr Heayn and her colleagues are currently exploring whether there is an association between metastatic pancreatic cancer and these genetic mutations.

Metastatic Pancreatic Cancer

Patients with these mutations in their tumors should be followed more closely for recurrence or disease progression, Dr Heayn said. And in this subset of patients, there is the possibility of new targeted therapies.

These findings are very important, said Safia Salaria, MD, from the Vanderbilt University Medical Center in Nashville.

"There is so much heterogeneity in these tumors, and currently we are just using clinicopathologic features and the WHO-recommended Ki-67 labelling and white count," she told Medscape Medical News.

"If we have something that can be an adjunct to that — immunohistochemistry to determine the loss of these genes — it's definitely going to be something that will help us, especially in low-grade tumors," she explained.

Staining for the expression of the genes could also help pathologists identify patients who are at higher risk for disease recurrence or metastasis but don't have metastases at the time of primary resection, Dr Salaria said.

The study was internally supported. Dr Heayn and Dr Salaria have disclosed no relevant financial relationships.

College of American Pathologists (CAP) 2015 Meeting. Poster 29. Presented October 5, 2015.

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