BRCA Status Could Inform Pancreatic Cancer Management

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The development of BRCA-targeted therapies might offer the best opportunities to bring pancreatic cancer into the precision-oncology era.
The development of BRCA-targeted therapies might offer the best opportunities to bring pancreatic cancer into the precision-oncology era.

According to the National Cancer Institute (NCI), an estimated 55,440 Americans will be diagnosed with pancreatic cancer in 2018 and 44,330 will die of the disease.1

Rachna Shroff, MD, section chief of gastrointestinal medical oncology at the University of Arizona Cancer Center in Tucson, has likened systemic chemotherapy to a “wrecking-ball” approach to managing pancreatic cancer.

Dr Shroff is among the small but growing cadre of researchers who hope to develop targeted treatments for these patients. But that will be a challenge, because pancreatic cancer harbors few well-known, targetable gene variants.

BRCA-positive disease is the best-established molecular subtype. These mutations can impair cells' ability to repair DNA and to suppress tumorigenesis.

At least 9% — and perhaps as many as 15% — of patients with pancreatic cancer have germline or somatic BRCA1/2 mutations, Dr Shroff said.

A few other candidate treatment-relevant gene variants in pancreatic cancer have also been identified in preclinical research, but these are not as well understood.2 Recent preclinical experiments have suggested that pancreatic tumor overexpression of the chemokine ligand CXCL1 can inhibit antitumor CD8+ immune T-cell infiltration, for example.3

“As we are sequencing tumors more and more, and doing deeper dives into DNA, RNA, and the immune microenvironment, I think we're learning that there are probably a number of types of 'molecular subtypes' of pancreatic cancer,” Dr Shroff explained. “But I don't think we have many that have yet been truly categorized, systematically, that well.”

In contrast, BRCA1/2 mutation-positive pancreatic cancers have been recognized for several years now.

“We [now] have a better sense of how they behave, how they present, how they act — and so, [we understand] how we can approach them in terms of therapy," Dr Shroff noted.

"We know that there appears to be exquisite platinum sensitivity in BRCA-positive cancers; we're seeing that in breast, ovarian, [and] pancreatic cancer,” she explained. “That being said, I think most providers agree that not all platinums are created equal. A lot of the data from the initial work come from cisplatin.”

Dr Shroff was lead author of a small, 19-patient clinical cohort study of rucaparib poly (ADP-ribose) polymerase (PARP)-inhibition monotherapy for BRCA-positive pancreatic cancer; 16 participants had germline BRCA1/2 mutations and 3 had somatic mutations.4

Unfortunately, recruitment of patients into the study had to be halted because of low tumor response rates. Only 2 patients achieved a partial response (PR) and only 1 patient experienced a complete response (CR), for an overall response rate (ORR) of 16%. Treatment-emergent adverse events included nausea (63%) and anemia (47%; grade ≥ 3, 31.6%).

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