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Researchers ID Pancreatic Cancer Mutations with Ties to Treatment, Prognosis

NEW YORK (GenomeWeb) – A study appearing online today in Nature Communications suggests mutations in tumor samples and circulating tumor DNA (ctDNA) can inform treatment options and anticipated outcomes for individuals with pancreatic ductal adenocarcinoma.

Johns Hopkins University's Victor Velculescu and colleagues from the US and Denmark used exome or targeted sequencing to profile mutation patterns in more than 100 pancreatic ductal adenocarcinoma tumors. Analyzing the sequences alongside patients' clinical data, they uncovered alterations associated with improved survival outcomes as well as mutations that may be clinically actionable.

The genetic glitches also served as signposts that helped the team detect ctDNA in blood samples from a subset of patients at the time of their diagnoses. Meanwhile, the reappearance of ctDNA following surgery offered an early window into disease recurrence.

"Taken together, these analyses provide predictors of clinical outcome in pancreatic cancer and have implications for personalized therapeutic intervention in these patients," Velculescu and his co-authors wrote.

The researchers used the Illumina HiSeq 2000 or 2500 instruments to sequence protein-coding sequences in matched tumor and normal samples for 24 pancreatic ductal adenocarcinoma patients that were captured with Agilent's SureSelect version 4 kit.

They also did targeted sequencing on another 77 pancreatic ductal adenocarcinoma tumors, focusing on 116 suspicious genes.

As found in past pancreatic cancer studies, the team saw recurrent mutations in KRAS, TP53, SMAD4, and other cancer driver genes. Pancreatic ductal adenocarcinoma tumors were also marked by more-frequent-than-usual glitches in genes related to chromatin regulation — alterations that appeared to coincide with better disease outcomes.

In particular, the team saw a jump in survival amongst the 20 percent of individuals whose tumors contained alterations affecting chromatin regulatory genes such as MLL, MLL2, MLL3, and ARID1A.

Whereas the median survival time for patients lacking MLL, MLL2, or MLL3 mutations was just over 15 months, for example, the researcher noted that 79 percent of individuals with glitches in these genes survived beyond the study's median of 32 months follow-up time.

The researchers also uncovered potentially targetable mutations in more than one-third of the cases considered, including alterations in genes such as ERBB2, AKT1, AKT2, MDM2, PIK3CA, or BRCA2 that have been deemed clinically actionable in ongoing pancreatic cancer trials or prior clinical trials focused on other conditions.

For the 51 individuals with localized pancreatic ductal adenocarcinoma who provided blood samples for the study, the researchers were able to pick up ctDNA by liquid biopsy some 43 percent of the time using digital PCR-based methods.

The team saw potential ties between the presence of this ctDNA at the time of diagnosis and subsequent disease progression. Likewise, the persistence or reappearance of tumor sequences in the blood after tumor resection tended to herald poorer patient outcomes.

In the average individual with recurrent disease, the researchers detected ctDNA roughly three months after surgery. In contrast, standard computed tomography imaging picked up the recurrent cases roughly 9.6 months post-surgery, more than half a year later than with the method used by Velculescu and his colleagues.

The study's authors cautioned that they may have missed some genetic glitches owing to factors such as low allele frequencies, tumor purity problems, or small plasma samples. Even so, they argued that the new analysis provides a look at mutation patterns that may help in better understanding and treating pancreatic ductal adenocarcinoma. 

"These analyses suggest future efforts to evaluate more intensive therapies for patients without MLL alterations or with detectable ctDNA after surgical resection," the team concluded, "as well as interventional clinical trials based on actionable alterations observed in pancreatic cancer patients."