Germline testing should now be considered for any patient with pancreatic cancer, and molecular analysis of tumors should be considered in patients with metastatic disease, according to the most recent National Comprehensive Cancer Network (NCCN) guideline (version 1.2019) for the management of pancreatic cancer.
While first-line treatment regimens haven’t changed, the guideline now recommends consideration of adjuvant therapy with modified FOLFIRINOX (leucovorin, 5-fluorouracil, irinotecan, oxaliplatin) for patients who can tolerate it.
The guideline updates were presented by Margaret A. Tempero, MD, Professor of Medicine and Director, University of California San Francisco (UCSF) Pancreas Center, at the 2019 NCCN Annual Conference.
The recommended first-line treatment regimens remain FOLFIRINOX, gemcitabine plus albumin-bound nab-paclitaxel, and gemcitabine and cisplatin for patients with BRCA1/2 and PALB2 mutations.
FOLFIRINOX is a difficult regimen with dominating toxicities of myelosuppression, diarrhea, and neuropathy, said Dr Tempero. Omitting the 5-fluorouracil bolus, reducing the doses of the medications, and chemotherapy holidays after achieving maximum benefit from treatment may be tried to make FOLFIRINOX tolerable. The gemcitabine plus nab-paclitaxel regimen “is a bit easier to manage than FOLFIRINOX but is still not a walk in the park,” she said.
“Pancreatic cancer is associated with a lot of hereditary syndromes,” supporting germline testing, said Dr Tempero. These include familial atypical multiple mole melanoma (p16 gene), familial breast and ovarian cancer (BRCA1/2), Fanconi anemia (PALB2), hereditary pancreatitis (PRSS10), and others.
Familial pancreatic cancer is a phenomenon in which the disease occurs in multiple generations, but genetic mutations are not found when testing is performed using the usual panel of mutations. “That’s because each one of these families probably has its own mutation,” Dr Tempero said. “You could do extensive studies to try and figure out what their pathogenic mutation is, but that’s very labor intensive and isn’t going to help those people right now.”
For such families, screening of first- and second-degree relatives is recommended using either annual endoscopic ultrasound or magnetic resonance cholangiopancreatography.
Germline testing will not uncover most deleterious mutations, however, as evidenced by the Memorial Sloan Kettering IMPACT study, in which 1040 cancer patients underwent germline testing of almost 100 predisposition genes. Some 17% of the pancreatic subset had germline mutations, including several that had not been described previously. However, 42% had no family history of the cancer and would not have met screening recommendations, a finding that has since been validated in other studies. This finding has led to the recommendation to strongly consider germline testing in all patients with pancreatic cancer.
“At UCSF, we have implemented the same program, and we are astounded at what we’re seeing in terms of the number of germline mutations that we would not have recognized had we not started a universal testing program,” she said.
Germline testing not only has implications for family but may also provide “therapeutic direction,” said Dr Tempero. For example, in IMPACT, 52% of patients had mutations in DNA damage repair genes, “suggesting a platinum-containing regimen might be better for them.”
PARP inhibitors are approved by the FDA in patients with ovarian cancer with mutations in DNA damage repair genes, including BRCA1/2. Approvals in other BRCA-related cancers, such as pancreatic cancer, await the results of late-phase clinical trials, she said.
Preliminary data from a randomized phase 2 trial show an 80% response rate to cisplatin plus gemcitabine in cancer patients with germline BRCA/PALB2 mutations. “That’s just amazing to me,” said Dr Tempero. “The fact that I can give a patient with a BRCA mutation a simple, easy-to-tolerate regimen like gemcitabine and cisplatin, and not put them through FOLFIRINOX, is huge.” The second arm of this trial is exploring the addition of veliparib to gemcitabine plus cisplatin.
The POLO trial is examining olaparib as maintenance therapy following platinum therapy in patients with metastatic pancreatic cancer with a germline BRCA mutation, and results are expected to be announced at the 2019 ASCO meeting.
Another part of molecular profiling is assessment of mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) status. Pembrolizumab is now approved across metastatic cancer types for patients with dMMR/MSI-H status.
Only 1% of patients with pancreatic cancer have dMMR/MSI-H disease, but “this is the needle in the haystack you want to find,” Dr Tempero said, noting the response rate is >80% in this subpopulation. “In our mind, it’s worth it to test everybody for MSI-H status and to use pembrolizumab when you can after first-line treatment.”
The NCCN guideline contains a strong recommendation to perform somatic profiling of tumor tissue. Although KRAS is the main driver mutation, several other alterations that can be identified through molecular profiling are clinically relevant in pancreatic cancer.
Whole exome sequencing has found that 48% of patients with pancreatic cancer had a genomic tumor that was theoretically “actionable,” 15% had a therapeutic decision altered by the finding, and 30% had a change in their clinical management. A finding of a TRK fusion confers eligibility for larotrectinib, for example, which was associated with durable responses.
Adjuvant treatment saw few changes in the past 30 years, said Dr Tempero, but in 2018, the results of the PRODIGE 24/CCTG PA.6 trial demonstrated significantly longer overall survival with mFOLFIRINOX compared with gemcitabine (54.4 vs 35.0 months) in patients with pancreatic cancer following resection. “This was a big game changer,” she said.
The rate of grade 3/4 adverse events, however, was much higher in the mFOLFIRINOX arm (75.8% vs 51.5%).
The data from PRODIGE 24/CCTG PA.6 were “enough for us to incorporate this into the NCCN guidelines,” she said. “It is for patients who are fit enough to receive this type of treatment postoperatively.”