DNA Mismatch Repair Deficiency Linked To ‘Remarkably Good’ PDAC Survival

Treatment for pancreatic ductal carcinoma patients with DNA mismatch repair deficiency should be given in the context of favourable biology and life expectancy

medwireNews: Study findings highlight the unusually good prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) who have DNA mismatch repair deficiency (dMMR).

Writing in a letter to JAMA Surgery, the researchers describe “remarkably good outcomes” for the 10 patients who showed evidence of dMMR from a hospital cohort of 821 individuals with PDAC. Seven of the 10 patients had pathogenic germline mutations to MLH1 or MSH2 and eight had a history of Lynch syndrome-associated malignancy.

After a median of 93.1 months of follow-up, 5-year overall survival (OS) was 100% for the six patients who presented with localised disease and underwent pancreatoduodenectomy or distal pancreatectomy alongside adjuvant or neoadjuvant chemotherapy or chemoradiotherapy.

This compares with a 25% rate for 5-year OS previously reported in one of the largest randomised trials of surgery plus adjuvant chemotherapy to date, say Y Nancy You, from the University of Texas MD Anderson Cancer Center in Houston, USA, and co-authors.

The remaining four patients had metastatic disease at the time of diagnosis and were treated with chemotherapy; their median OS was 16.5 months, with a 5-year OS rate of 25%. By contrast, in trials of FOLFIRINOX and gemcitabine regimens, PDAC patients have achieved a median OS of 11.1 months and 6.8 months, respectively, the researchers observe.

“These findings confirm those of previous studies, which suggested superior outcomes in patients with dMMR malignant neoplasms, presumably related to a more robust tumor-infiltrating immune response,” write Y Nancy You et al.

The researchers now recommend that PDAC diagnosis in patients with tumours associated with Lynch syndrome should “prompt dedicated tumor and germline genetic testing” and that treatment should be given “in the context of these patients’ favorable tumor biological characteristics and life expectancy.”

Noting that dMMR status in colorectal cancer has been linked to response to treatment, including checkpoint inhibitor therapy, the authors conclude: “Ongoing clinical trials in patients with PDAC and mutations in DNA damage-repair genes, such as BRCA, PALB2, ATM, and MMR, hold promise for more effective targeted treatment options.

“Given the clinical significance of the findings reported herein, routine screening of PDAC specimens for dMMR may be indicated and should be the focus of future investigations.”

Reference

Cloyd JM, Katz MHG, Wang H, et al.Clinical and genetic implications of DNA mismatch repair deficiency in patients with pancreatic ductal adenocarcinoma. JAMA Surg; Advance online publication 9 August 2017. doi:10.1001/jamasurg.2017.2631

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