Personalizing Medicine With Germline and Somatic Sequencing in Advanced Pancreatic Cancer: Current Treatments and Novel Opportunities

Abstract

Performing germline and somatic sequencing in locally advanced and metastatic pancreatic cancer can identify potentially targetable genomic aberrations that impact current standard treatment options or eligibility for biomarker-targeted clinical trials. Testing for deleterious germline mutations in BRCA1/2 impacts patient selection for platinum-based chemotherapy regimens and selection of patients who are candidates to receive maintenance therapy with olaparib. Additional germline mutations also similarly introduce potential vulnerabilities to the cancers that arise and may be targeted by clinical trials. Somatic mutation testing also provides opportunities for optimal selection of patients for biomarker-driven clinical trials. Although KRAS mutations are found in 90% to 93% of pancreatic cancers, there are increasing opportunities for therapies against particular mutant KRAS isoforms, especially with the advent of KRAS G12C–specific small molecule inhibitors, and KRAS targeting trials will increasingly require identification of the specific KRAS mutation present. There are also a range of tumor site–agnostic molecular features, such as microsatellite instability and NTRK fusions that, although rarely found in pancreatic cancers, impact selection of patients who have the potential for dramatic benefit with immune checkpoint inhibitors such as pembrolizumab or TRK inhibitors such as larotrectinib or entrectinib, respectively, and thus motivate broader somatic mutation and fusion testing for patients with locally advanced and metastatic pancreatic cancers. Multiple other rare actionable aberrations, particularly gene fusions in the 8% to 10% of KRAS wild-type pancreatic cancers, are also known, and enrollment in basket trials for these rare patient cohorts is highly encouraged.

Clinical Response to Seribantumab, an Anti–Human Epidermal Growth Factor Receptor-3 Immunoglobulin 2 Monoclonal Antibody, in a Patient With Metastatic Pancreatic Ductal Adenocarcinoma Harboring an NRG1 Fusion

“…[42][43][44] Although only 7%-10% of pancreatic cancers are KRAS wt, this is more common in patients younger than 50 years. 36 This case study provides rationale for further evaluation of HER3-directed therapies such as seribantumab in these patient subsets, with the added advantage of less toxicities compared with standard therapies. 2,11,19,20 Several studies are underway to assess the efficacy of HER3targeting therapies in tumors harboring NRG1 fusions.…”

“…This case report demonstrates proof of clinical activity of seribantumab in a patient with a treatment-refractory, metastatic KRAS wt PDAC harboring an ATP1B1-NRG1 fusion. 1 , 33 , 36 The patient was treated with seribantumab under the SAS program following the dosing schema used in the CRESTONE study. When the study was amended to evaluate a weekly dosing regimen, the patient transitioned to the new dosing frequency, which may have contributed to continued clinical benefit.…”

Therapeutic advances in metastatic pancreatic cancer: a focus on targeted therapies

“…The KRYSTAL-2 trial of adagrasib explores the role of the SHP2 inhibitor TNO155 (NCT04330664). Multiple additional promising G12C inhibitors are currently in clinical development as well, including JNJ-74699157 (NCT04006301), GDC-6036 (NCT04449874), and JDQ443 (NCT04699188) 99 in PDAC patients. Whether the depth and duration of response will be comparable to that obtained in lung cancer (up to 40% response rate) remains to be determined.…”

Current Systemic Treatments for the Hereditary Cancer Syndromes: Drug Development in Light of Genomic Defects

“…While many of these errors are somatic, some reflect underlying germline mutations in DNA damage-repair mechanisms. Up to 9% of patients with pancreatic ductal adenocarcinoma harbor a gBRCA mutation, 61 which causes homologous recombination defects and synthetic lethality with PARPi. 62 The POLO trial sought to establish the first targeted therapy in gBRCA-mutant pancreatic ductal adenocarcinoma.…”