Germline Testing Emphasized in NCCN Guidelines on Pancreatic Cancer

Margaret A. Tempero, MD

In recent years, pancreatic has passed breast cancer as the third leading cause of cancer death in the United States, and by 2030 it could be the leading cause, Margaret Tempero, MD, of the University of California San Francisco Helen Diller Family Comprehensive Cancer Center, said at the 2019 NCCN Annual Conference.¹

Many things about pancreatic cancer have not changed—it still lacks early symptoms and remains remarkably resistant to chemotherapy—but as Tempero shared at the NCCN meeting researchers are becoming savvier at pinpointing who is at risk. Her talk covered 3 areas that she said are important new additions to the NCCN guidelines:

• Germline testing should be considered for all pancreatic cancer patients.
• Molecular analysis of tumors should be considered for patients with metastatic disease.
• A new adjuvant therapy option increased survival in a recent study.

The foundation for treatment of metastatic pancreatic cancer is FOLFIRINOX (fluorouracil, leucovorin, irinotecan, and oxaliplatin), which Tempero said marked an advance nearly 10 years ago, but “It’s tough to take, and it’s tough for us to give.”

Clinicians have learned to make FOLFIRINOX tolerable—with strategies such as reduced doses of chemotherapy holidays. For some patients, gemcitabine plus nab-paclitaxel is an option. But the latest waves of progress have come by identifying familial syndromes, the associated genes, and the relative risk of pancreatic cancer, including the genes BRCA1/2, PALB2, and p16.

Tempero said work at Memorial Sloan Kettering Cancer Center offered germline testing (MSK IMPACT) to families for 76 to 88 cancer predisposition genes, along with genetic counseling.² More than 10,000 people received tumor DNA sequencing, and 1040 were referred for germline analysis; 176 (16.9%) had genes associated with pancreatic cancer (only 42% of these would have been detected based on existing clinical guidelines).

Tempero said her own institution is doing germline testing. “We are astounded at what we are seeing,” she said. Most of the mutations are BRCA, but not always.

“Why does it matter? It matters a lot,” she said. ” It might give you therapeutic direction,” including whether a patient would be a candidate for a PARP inhibitor.

Molecular Profiling

And, the knowledge matters to families. She said she doesn’t recommend screening for pancreatic cancer just based on a BRCA mutation, but if a family member with this mutation develops pancreatic cancer, then screening would be recommended.Tempero reviewed research presented in 2018 at the ASCO annual meeting from The Cancer Genome Atlas Project, which identified clinically relevant alterations in pancreatic cancer. The analysis of 150 specimens found 42% with 1 clinically relevant alteration, 25% with 2 or more alterations, and germline alterations in 8% of patients. The project paired alterations with 11 different therapies.

Tempero acknowledged that molecular profiling will not yield results for every patient, but when it does the results could be dramatic. “This is the needle in the haystack you want to find,” she said. One key going forward will be to take a different approach to collecting biopsy samples, so there is enough tissue for testing. “It’s going to change the way we do business,” Tempero said.

Treatments are starting to emerge for some of the molecular targets being identified. In February 2019, AstraZeneca and Merck (MSD), the codevelopers of olaparib (Lynparza), announced that findings from the phase III POLO trial showed that frontline maintenance therapy with the PARP inhibitor significantly reduced the risk of disease progression or death versus placebo in patients with germline BRCA-mutated metastatic adenocarcinoma of the pancreas. The companies plan to report the specific data from the trial at a future medical meeting.

Adjuvant Therapy

Pembrolizumab (Keytruda) was approved in 2017 for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options. The pivotal data that led to the approval included 6 patients with dMMR pancreatic cancers. Among this group 83% (n = 5) achieved a response to pembrolizumab.Tempero said over a 30-year period of trying adjuvant therapy, “We haven’t been able to move the bar very much.” But in 2017, data from the ESPAC-4 trial showed that the combination of gemcitabine and capecitabine produced a median overall survival (OS) of 28 months, an increase of 5 months over previous results in resected pancreatic cancer.³

The study randomized patients with resected pancreatic cancer to gemcitabine alone (n = 366) or in combination with capecitabine (n = 364). The median OS was 28.0 months with the combination versus 25.5 months with gemcitabine alone (HR, 0.82; 95% CI 0.68-0.98 ; P =.032).

Results subsequently presented at the 2018 ASCO Annual Meeting represented a milestone breakthrough in the adjuvant setting for pancreatic cancer. Findings from the PRODIGE 24/CCTG PA.6 study showed that the median OS was 54.4 months with modified FOLFIRINOX (mFOLFIRINOX) versus 35.0 months with gemcitabine.⁴ This translated to a 36% reduction in the risk of death (HR, 0.64; 95% CI, 0.48-0.86; P = .003).

After a median follow-up of 33.6 months, the median disease-free survival (DFS) was 21.6 months for the mFOLFIRINOX arm compared with 12.8 months in the gemcitabine group (HR, 0.58; 95% CI, 0.46-0.73; P <.001). The 3-year DFS rates were 39.7% versus 21.4%, respectively.

There was also a recent setback in the adjuvant setting, with Celgene announcing that the adjuvant combination of nab-paclitaxel (Abraxane) and gemcitabine was not found to improve DFS compared with gemcitabine alone, as confirmed by independent radiological review, in patients with resected pancreatic cancer, according to topline findings of the phase III APACT trial. There was, however, an improvement in OS with the combination versus gemcitabine alone, reaching nominal statistical significance. Full findings will be presented at an upcoming medical meeting, according to Celgene.

References

1. Tempero MA. NCCN Guidelines Updates: Treatment of Pancreatic Cancer. Presented at: 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.
2. Mandelker D, Zhang L, Kemel Y, et al. Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. JAMA. 2017;318(9):825-835. doi: 10.1001/jama.2017.11137.
3. Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389(10073):1011-1024. doi: 10.1016/S0140-6736(16)32409-6.
4. Conroy T, Hammel P, Hebbar M, et al; CCTG and the UNICANCER-GI/PRODIDGE Group. Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. Presented at: 2018 ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract LBA4001. meetinglibrary.asco.org/record/159164/abstract.

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