The NCCN Guidelines for pancreatic adenocarcinoma reflect the recent advances in diagnostics and adjuvant therapies which have led to improved outcome. The guideline recommends germline testing for all patients with pancreatic cancer and molecular analysis for those with metastatic disease. The use of modified FOLFIRINOX as adjuvant therapy is also recommended.

Pancreatic cancer constitutes a relatively smaller percentage of all cancers' deaths around the globe; however, it is one of the most fatal types presenting with a five-year relative survival rate of only 8%. Without treatment, the median survival of patients with metastatic disease is only 3 months.

---

Challenges with the Current Treatment strategy of Metastatic Disease

Pancreatic cancer is a challenging disease - there are no early symptoms, tumor metastasizes quickly and exhibits chemo-resistance.

The current first-line treatment regimens for pancreatic cancer include:

• FOLFIRINOX and gemcitabine/albumin-bound nab-paclitaxel
• Gemcitabine/Cisplatin - for patients with BRCA1/2 and PALB2 mutations

As per Dr. Margaret A. Tempero, who presented the NCCN updates, even though FOLFIRINOX produces better response rate, progression-free and overall survival (OS), it is a difficult regimen and is recommended for fit patients; Nab-paclitaxel/gemcitabine regimen is easier to manage than FOLFIRINOX.

---

Recent advances and changes to the NCCN Guidelines

Emerging research has led to better understanding of the molecular basis of pancreatic cancer. The NCCN Guidelines recommends:

• Germline testing in patient diagnosed with pancreatic cancer
• Molecular analysis of tumors in those with metastatic disease
• Modified FOLFIRINOX as adjuvant therapy, in patients who can tolerate it

---

Germline testing can be the game changer

As pancreatic cancer is associated with numerous hereditary syndromes, germline testing can be the game changer. There is also the probability of familial pancreatic cancer; familial pancreatic cancer includes kindreds that contain at least two first degree relatives with pancreatic ductal adenocarcinoma, but they are devoid of the typical genetic mutations. As per Dr. Tempero pathogenic mutation in these families is responsible for this phenomenon. In such cases, annual endoscopic ultrasound or magnetic resonance cholangiopancreatography of first- and second-degree relatives is recommended.

Even though screening by former mentioned techniques is helpful; it will not detect all persons at risk. In the MSK-IMPACT study, germline testing of 1,040 patients with cancer, revealed a high incidence (17%) of mutations in the pancreatic cancer subset. More than half the mutations were found in the DNA repair genes, which suggested that this subset of patients may benefit from platinum-containing regimens. Interestingly, 42% of patients had no family history of the cancer and would not have met the current recommendation for screening. This led to the recommendation of germline testing in all patients with pancreatic cancer.

---

Profiling of Mismatch Repair Deficiency

Patients with mismatch repair deficiency (dMMR) and microsatellite instability–high (MSI-H) generally respond to pembrolizumab. Pembrolizumab is approved for patients with metastatic cancer of any type and dMMR/MSI-H status.

Molecular profiling can help detect dMMR/MSI-H status. Even though dMMR/MSI-H is present in only 1% of patients with pancreatic cancer, study evaluating pembrolizumab, found that 83% of patients with dMMR pancreatic cancer showed a response.

Hence, it is recommended to test the MSI-H status and to use pembrolizumab after first-line treatment.

---

Molecular Subtyping recommended

The NCCN panel strongly recommends somatic profiling of tumor tissue. Molecular profiling can help to detect potentially actionable mutations and can provide vital information that affects treatment.

Whole-exome sequencing can be used to find such genomic lesions. Additional molecular testing would mean obtaining sufficient tissue in the diagnostic tumor sample. Multiple biopsies, fine-needle aspiration biopsies, and core biopsies would be required to ensure that the vital information is gained to offer the appropriate treatments.

---

The advent of effective adjuvant therapy

Pancreatic cell treatment in the adjuvant setting had not changed much in 30 years. The phase III Unicancer GI PRODIGE 24/CCTG PA.6 trial, compared adjuvant modified FOLFIRINOX with single-agent gemcitabine after tumor resection. The trial reported outstanding results, which lead to inclusion of this adjuvant regimen in the NCCN guidelines.

1. Treatment with modified FOLFIRINOX resulted in an OS of 54.4 months compared with 35.0 months with gemcitabine.
2. Median disease-free survival was 21.6 modified (FOLFIRINOX) versus 12.8 months (gemcitabine).

However, toxicity occurred more in the modified FOLFIRINOX arm. Hence this adjuvant regimen is recommended only in patients who are able to tolerate it.

Another adjuvant therapy is being evaluated is the APACT trial. The APACT trial is testing gemcitabine/nab-paclitaxel versus gemcitabine alone. The results of this trial are much anticipated and will be presented at the 2019 ASCO Annual Meeting.

---

PARP inhibitors in DNA damage repair mutations

Trials are testing the efficacy of PARP inhibitors in patients with pancreatic cancer and germline BRCA mutations. A phase II trial is testing veliparib with cisplatin and gemcitabine in the first-line metastatic setting and the phase III POLO trial is testing olaparib as first-line maintenance monotherapy in patients whose disease has not progressed on platinum-based chemotherapy.

Preliminary data from the veliparib trial has demonstrated encouraging results; the trial has shown that with cisplatin/gemcitabine alone, approximately 80% of patients can show a response. Inclusion of PARP inhibitors could lead to improved outcomes and the trial results are much awaited.