Pancreatic cancer therapy sheds light on the disease’s ties to BRCA mutation

When most people hear about BRCA genes, they immediately think about how inherited mutations in those genes – BRCA1 and BRCA2 – have been linked with higher risk of breast and ovarian cancer.

Yet researchers have long known that several cancers other than breast and ovarian are associated with harmful mutations in BRCA1 and BRCA2, including fallopian tube cancer, prostate cancer and pancreatic cancer.

Now a new study, presented at the American Society for Clinical Oncology’s annual meeting in Chicago on Sunday, describes a treatment approach specifically for patients with metastatic pancreatic cancer who had a BRCA1 or BRCA2 mutation.

“This was an important biomarker-driven study for the field,” said Dr. Diane Simeone, director of the Pancreatic Cancer Center at NYU Langone Health’s Perlmutter Cancer Center in New York, who was not involved in the study.

“If you just take a germline BRCA2 mutation carrier, even someone who doesn’t have a family history of pancreatic cancer, the lifetime risk of that individual getting pancreatic cancer is about 6% to 7% and that’s something that doesn’t really get discussed,” she said. “If you have a family member with pancreatic cancer and a BRCA mutation then those are the kinds of individuals that really need to be seen in our high-risk screening clinics.”

The study, which published in the New England Journal of Medicine, found that among patients with a germline BRCA mutation and metastatic pancreatic cancer, being treated with a therapy called olaparib had a reduced risk of disease progression or death.

Last year, the US Food and Drug Administration approved olaparib for the maintenance treatment of adult patients with BRCA-mutated advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who have completely or partially responded to first-line platinum-based chemotherapy.

The new study involved 154 patients whose pancreatic cancer had not progressed while being previously treated with a platinum-based chemotherapy. Between 2015 and this year, those patients were randomly assigned to either receive olaparib as a type of maintenance care or to receive a placebo.

Two years into the study, the researchers found that 22.1% of the patients in the olaparib group versus 9.6% of patients in the placebo group did not see their disease progress.

“Patients received platinum-based chemotherapy immediately before maintenance olaparib; therefore, the combined first-line platinum-based chemotherapy and maintenance olaparib strategy resulted in a progression-free survival of more than 1 year among patients,” the researchers wrote in the study.

This is significant because pancreatic cancer is usually diagnosed at later stages which, in turn, results in a poor prognosis for patients.

Some adverse events that occurred with the treatment were fatigue, nausea, anemia, abdominal pain, diarrhea, constipation, vomiting or back pain, but no adverse events resulted in death. Only 6% of patients in the olaparib group and 2% in the placebo group discontinued the trial due to an adverse event.

Cancer itself is a genetic disease in that it is caused by certain changes to genes that control the way our cells grow, divide and function. Meanwhile, BRCA mutations impair proteins in the body that help repair damaged DNA, putting the body at risk of cancer.

So “if you have someone who has a BRCA mutation, they can’t fix damaged DNA as well as those with normal BRCA. The mutation puts the patient at higher risk of cancer,” said Dr. Otis Brawley, Bloomberg distinguished professor of oncology and epidemiology at Johns Hopkins University in Baltimore, who was not involved in the study.

“Platinum-based therapy damages DNA and helps to kill cancer cells. Many cancer cells develop alternative ways to repair the damage caused by our therapy,” he said. “But if you take out another additional way that the cell can fix DNA – so two mechanisms of fixing DNA are now impaired – and you give a chemotherapy drug that damages DNA, you actually kill more cancer cells. That’s why it makes sense and they’ve done it proof of principle in this clinical trial.”

As more patients utilize genetic testing, Simeone believes we may identify “greater numbers of pancreatic cancer patients with these kinds of mutations,” she said. “Germline testing is now recommended in all patients who present with pancreatic cancer, according to new guidelines.”

In general, according to the National Cancer Institute, because harmful BRCA mutations still are relatively rare, most experts agree that testing for mutations in individuals who do not have cancer should be performed only when there has been a family history of BRCA mutations.