SUMMARY: The American Cancer Society estimates that for 2019, about 56,770 people will be diagnosed with pancreatic cancer and about 45,750 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made, and outcomes for patients with advanced pancreatic cancer has been dismal, with a 5-year survival rate for metastatic pancreatic cancer of approximately 2%. Pancreatic cancer has surpassed breast cancer as the third leading cause of cancer death in the United States and is on track to surpass colorectal cancer, to move to the second leading cause of cancer related deaths in the United States around 2020.
At the 2019 NCCN Annual Conference, three important pancreatic cancer guideline updates were discussed. They included germline testing, molecular analysis of tumors and a new adjuvant chemotherapy option for pancreatic adenocarcinoma.
Germline Testing
Germline testing should be considered for all patients with pancreatic cancer and is especially recommended for those with a personal history of cancer, family history or clinical suspicion of a family history of pancreatic cancer. Approximately 10% of pancreatic cancer cases have a familial component. When hereditary cancer syndrome is suspected in patients with pancreatic cancer, genetic counseling should be considered.
1) Lynch Syndrome (Hereditary Nonpolyposis Colorectal Carcinoma – HNPCC) is a Autosomal Dominant disorder caused by germline mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 or PMS2 and most often predisposes to colorectal cancer. Patients with Lynch Syndrome also have a 9-11 fold increase in the risk for pancreatic cancer. Consider testing for MSI and/or MMR for patients with locally advanced or metastatic pancreatic adenocarcinoma.
2) BRCA1/2 mutations have been detected in 4-7% of patients with pancreatic cancer, with a 2-6 fold increase in risk, associated with these mutations. These patients tend to be younger. Among pancreatic cancer patients with Ashkenazi Jewish ancestry, the prevalence of BRCA1/2 mutations is 6-19%, with mutations more common for BRCA2.
3) Mutations in Fanconi Anemia/BRCA pathway genes including PALB, FANCC and FANCG have also been identified as increasing pancreatic cancer risk.
4) Germline mutations in ATM gene has been identified in approximately 4% of individuals with familial pancreatic cancer.
5) Germline mutations in STK11 gene resulting in Peutz-Jeghers syndrome (associated with GI polyps) increases the risk of developing pancreatic cancer 132 fold. In approximately 5% of pancreatic cancers, somatic mutations in STK11 has been noted.
6) Similar to non-hereditary forms of pancreatitis, familial pancreatitis is also associated with increased risk of pancreatic cancer. Those with familial pancreatitis have been noted to have mutations in the PRSS1, SPINK1 and CFTR genes, increasing the risk of developing pancreatic cancer by 26-87 fold.
7) Familial malignant melanoma syndrome, also known as melanoma–pancreatic cancer syndrome or Familial Atypical Multiple Mole Melanoma (FAMMM) syndrome, is associated with a 20-47 fold increased risk of pancreatic cancer. This has been attributed to germline mutation of CDKN2A gene.
Molecular Profiling
Molecular analysis of tumors should be considered for patients with metastatic disease, for treatment guidance
1) In the phase III POLO trial, patients with germline BRCA-mutated metastatic adenocarcinoma of the pancreas, benefited with PARP inhibitor, LYNPARZA® (Olaparib), which when given as frontline maintenance therapy, significantly reduced the risk of disease progression or death, when compared to placebo.
2) Patients with unresectable or metastatic MSI-High or MMR deficient (dMMR) solid tumors who had progressed on prior therapies, have significant responses with KEYTRUDA® (Pembrolizumab), and has been approved by the FDA for this indication.
3) For those patients with PALB2 mutation, Gemcitabine along with Cisplatin is a treatment option.
4) The presence of P16 alterations in resected tumors of patients with pancreatic adenocarcinoma is associated with a worse prognosis and may therefore benefit from adjuvant chemotherapy.
Adjuvant mFOLFIRINOX
In a large phase III multicenter, randomized clinical trial, adjuvant mFOLFIRINOX significantly improved Disease Free Survival, Metastasis Free Survival and Overall Survival, compared to Gemcitabine, after pancreatic cancer resection. The median OS was nearly 20 months longer with a mFOLFIRINOX regimen than with Gemcitabine (54.4 months versus 35 months), representing a 34% reduction in the risk of death with mFOLFIRINOX.
NCCN Guidelines Updates: Tempero MA. Treatment of Pancreatic Cancer. Presented at: 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.
