Updated NCCN Guideline Strongly Recommends Germline Testing for All Patients with Pancreatic Cancer

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 updated National Comprehensive Cancer Network (NCCN) guideline for pancreatic cancer presented at the 2019 NCCN Conference.

Although first-line treatment regimens haven’t changed, the updated guideline recommends considering adjuvant therapy with the modified FOLFIRINOX (leucovorin, 5-fluorouracil [5-FU], irinotecan, and oxaliplatin) for patients who can tolerate it, according to Margaret A. Tempero, MD, MS, Director, UCSF Pancreas Center, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, who presented the updated guideline.

The recommended first-line treatment regimens remain either ­FOLFIRINOX, gemcitabine plus nab-paclitaxel, or gemcitabine and cisplatin for patients with BRCA1/ BRCA2 (BRCA1/2) and PALB2 mutations. FOLFIRINOX is a difficult regimen, with dominating toxicities of myelosuppression, diarrhea, and neuropathy, Dr Tempero said. Omitting the 5-FU bolus, reducing the drug doses, 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.

Germline Testing Strongly Recommended

“Pancreatic cancer is associated with a lot of hereditary syndromes,” supporting germline testing, said Dr Tempero. These syndromes 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 syndrome that occurs in multiple generations, but genetic mutations are not found when testing for the usual panel of mutations.

“That’s because each one of these families probably has its own mutation,” she 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 annual endoscopic ­ultrasound or magnetic resonance cholangiopancreatography.

Germline testing will not uncover most deleterious mutations, however, as evidenced by the Memorial Sloan Kettering IMPACT clinical trial, in which 1040 patients with cancer had germline testing for almost 100 predisposition genes. Some 17% of the subset of patients with pancreatic cancer had germline mutations, including several that had not been described previously. But 42% of these patients had no family history of pancreatic cancer and would not have met recent screening recommendations, which has since been validated in other studies. This finding has led to the new 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,” Dr Tempero said.

Germline testing has implications for the family but may also provide “therapeutic direction,” she said. For example, in the IMPACT study, 52% of patients had mutations in DNA damage repair genes, “suggesting a platinum-containing regimen might be better for them,” Dr Tempero added.

Poly (ADP-ribose) polymerase (PARP) inhibitors are approved by the FDA for patients with ovarian cancer and mutations in DNA damage repair genes, including BRCA1/2. Approvals for other BRCA-related cancers, such as pancreatic cancer, await the results of late-phase clinical trials, Dr Tempero said.

Preliminary data from a randomized phase 2 clinical trial show an 80% ­response rate to cisplatin plus gemci­tabine in patients with pancreatic cancer and 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,” she added. The second arm of this study is exploring the addition of the investigational PARP inhibitor veliparib to gemcitabine plus cisplatin.

The POLO clinical trial is examining the PARP inhibitor olaparib (Lynparza) as maintenance therapy after platinum therapy in patients with metastatic pancreatic cancer with a germline BRCA mutation, and results are expected to be announced at the 2019 American Society of Clinical Oncology annual meeting.

Molecular Profiling for dMMR/MSI-H

The updated NCCN guideline also has a strong recommendation for somatic profiling of tumor tissue in patients with pancreatic cancer. Molecular profiling also includes assessment of tumors for mismatch repair deficiency (dMMR) and microsatellite instability-high (MSI-H) status. Pembrolizumab (Keytruda) is now approved for all metastatic solid tumor types for patients with MSI-H/dMMR status.

Only 1% of patients with pancreatic cancer have dMMR or 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.”

Although KRAS is a common driver mutation, other alterations that can be identified through molecular profiling are clinically relevant in pancreatic cancer.

Whole-exome sequencing has shown 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 the recently approved larotrectinib (Vitrakvi), for example, which has been associated with durable responses.

Adjuvant Treatment

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 clinical trial demonstrated significantly longer overall survival with the modified FOLFIRINOX compared with gemcita­bine (54.4 months vs 35.0 months) in patients with pancreatic cancer after resection. “This was a big game changer,” she said.

The rate of grade 3 or 4 adverse events, however, was much higher in the modified FOLFIRINOX 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,” Dr Tempero said. “It is for patients who are fit enough to receive this type of treatment postoperatively.”

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