Rachna Shroff, MD, led a landmark study on the use of targeted drugs called PARP inhibitors in pancreatic cancer patients with BRCA mutations.
by Anna C. Christensen, UA Cancer Center
June 15, 2018
TUCSON, Ariz. – A physician-scientist at the University of Arizona Cancer Center investigated a novel treatment for pancreatic cancer patients whose tumors exhibited a harmful genetic mutation. The results, in which a type of drug called a PARP inhibitor showed early promise in treating pancreatic patients with mutations in the BRCA gene, were published online last month in the Journal of Clinical Oncology Precision Oncology.
Pancreatic cancer is predicted to become the second-deadliest cancer by 2020. In most cases, by the time the disease is diagnosed, the cancer has spread beyond the pancreas and cannot be cured with surgery. The cancer’s deadliness is exacerbated by a dearth of treatment options.
“There are two combination chemotherapies that are approved for treating metastatic pancreatic cancer," said Rachna Shroff, MD, the UA Cancer Center’s new section chief of gastrointestinal medical oncology and the study’s principal investigator. “Beyond that, not a lot has been proven to be successful in newly diagnosed patients.”
Pancreatic cancer is often treated with a regimen called FOLFIRINOX, a combination that includes oxaliplatin, a platinum-based chemotherapy that blocks cell division. Tumors can develop resistance to platinum therapies, however, and when traditional chemotherapy fails, few options remain.
“The new frontier for pancreatic cancer is finding ways to target pancreatic cancer outside of traditional chemotherapy,” said Dr. Shroff.
A genetic mutation
Under normal circumstances, a gene called BRCA keeps tumors at bay by repairing damaged DNA. However, a mutation in BRCA causes it to lose its tumor-suppressing abilities, increasing susceptibility to cancer. When Angelina Jolie revealed that her mutated BRCA gene gave her an 87 percent chance of developing breast cancer, the gene became one of the most well-known among the general public.
Some people are born with the BRCA mutation, having inherited it from one or both parents. For others, a glitch in DNA replication might result in cells with defective copies of the gene. People with this type of acquired BRCA mutation are also thought to be at a higher risk for certain cancers.
In addition to its link to breast cancer, the BRCA mutation is associated with ovarian cancer, and the Food and Drug Administration has already approved drugs targeting BRCA-positive breast and ovarian cancers. Researchers hope similar drugs can be developed to treat the 9 percent of pancreatic cancer patients whose tumors have the BRCA mutation.
A targeted approach
Whereas chemotherapy drugs use a "wrecking-ball" approach to attack cancer cells without regard to their underlying genetics, cancer researchers hope for targeted treatments that can zero in like a laser on a tumor cell’s unique molecular features. As genetic analysis becomes more widespread, scientists could begin to identify different subsets of pancreatic cancers, each of which could be targeted by drugs optimized for their unique genetic profiles.
Nine percent of pancreatic cancer patients have a mutation in the BRCA gene, making them one subset that already has been identified.
“This is a very important subset,” said Dr. Shroff. “I don’t think we’ve fully understood how best to serve this population.”
PARP is a protein that repairs damaged DNA in tumor cells, helping cancer to grow. Rucaparib is a PARP inhibitor, a drug that blocks PARP from repairing DNA, thereby killing cancer cells. Because it is effective in breast and ovarian cancers with the BRCA mutation, Dr. Shroff hoped to learn if it would work in pancreatic cancer patients with that mutation as well.
“Cancer cells are rapidly dividing,” Dr. Shroff explained. “This inhibitor targets the enzyme that helps them rapidly divide and grow without errors in DNA replication. PARP is probably one of the few valid targets we have identified in pancreatic cancer.”
Reasons for optimism
The study, which Dr. Shroff led when she was at MD Anderson Cancer Center, was one of a small handful looking at the efficacy of PARP inhibitors in pancreatic cancer patients with the BRCA mutation. A total of 19 patients were enrolled. Participants had locally advanced or metastatic pancreatic cancer, and had received only one or two previous chemotherapy regimens. Some of these patients saw results.
“Patients who did respond responded nicely and for a while,” reported Dr. Shroff. “We had one complete response — the disease completely melted away.”
Overall, 32 percent of patients experienced disease control, in which tumors either stopped growing, got smaller or disappeared. Among patients who had only received one previous chemotherapy regimen, 44 percent experienced disease control.
The fact that patients with less exposure to chemotherapy were more likely to respond to PARP inhibitors indicates that resistance to platinum-based drugs might have lessened patients’ response to PARP inhibitors.
“Platinums also work in the space of DNA repair,” explained Dr. Shroff. “They don’t target PARP, but they work within the same sphere.”
In other words, tumor cells that acquire the tools to resist platinum-based drugs could also have the skills needed to resist PARP inhibitors.
“As we started to think about the 'would have, could have, should haves,' we thought perhaps the way to design the study would be in patients who were platinum-sensitive,” said Dr. Shroff.
Despite the small sample size, investigators concluded that PARP inhibitors such as rucaparib could help the subset of pancreatic cancer patients with BRCA mutations, especially those whose diseases did not worsen when on platinum-based therapy.
“This study paves the way for further studies with PARP inhibitors in patients with advanced pancreatic cancer and alterations in the BRCA pathway,” said Dr. Shroff. “It was one of the landmark studies looking at this therapy in BRCA-mutated pancreatic cancer only.”
Currently, only a few studies are investigating the use of PARP inhibitors to treat pancreatic cancer patients with the BRCA mutation. One study in particular looks at patients with the inherited BRCA mutation, whereas Dr. Shroff’s study enrolled patients with both inherited and acquired BRCA mutations. More studies are needed to determine how helpful PARP inhibitors can be in this subset of pancreatic cancer patients.
Currently, pancreatic cancer is difficult to catch early, as it usually has no symptoms and originates deep in the body where tumors can’t be discovered during a routine physical exam. There is no screening test recommended by the FDA, but genetic testing could someday help more people at high risk of pancreatic cancer.
“We would make it standard practice that anybody with a family history that smelled like BRCA would immediately get testing done,” said Dr. Shroff. “I always counsel my patients to get their family in for testing.”
Patients also need expanded treatment options. Although current research into PARP inhibitors focuses on these drugs when used alone, Dr. Shroff believes they might be better when combined with other treatments. She hopes to design trials to test the efficacy of PARP inhibitors with immunotherapy, drugs that train the body’s immune system to recognize and attack cancer cells.
“Pancreatic cancer is a devastating disease with very poor survival in advanced stages,” said Dr. Shroff. “It is now the third-leading cause of cancer death in the United States. Finding new treatment options is crucial.”
About the University of Arizona Cancer Center
The University of Arizona Cancer Center is the only National Cancer Institute-designated Comprehensive Cancer Center with headquarters in Arizona. The UA Cancer Center is supported by NCI Cancer Center Support Grant No. CA023074. With primary locations at the University of Arizona in Tucson and at Dignity Health St. Joseph’s Hospital and Medical Center in Phoenix, the UA Cancer Center has more than a dozen research and education offices throughout the state, with more than 300 physicians and scientists working together to prevent and cure cancer. For more information: uacc.arizona.edu (Follow us: Facebook | Twitter | YouTube)