Patients with metastatic pancreatic cancer who had germline or somatic mutations in DNA repair genes had better clinical outcomes after platinum-based chemotherapy compared to patients without these mutations, according to results from a study published by Park et al in Clinical Cancer Research.
Metastatic pancreatic cancer is associated with a challenging prognosis, with a relative 5-year survival rate of 2.9%. The current standard of care for metastatic pancreatic cancer includes platinum-based chemotherapy. “Unfortunately, there are no validated biomarkers to predict which patients might benefit from standard treatment,” said senior study author Eileen O’Reilly, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, in a statement.
Eileen O’Reilly, MD
Approximately 5% to 9% of patients with pancreatic cancer have germline or somatic mutations in the BRCA1, BRCA2, and/or PALB2 genes, according to Dr. O’Reilly. The proteins encoded by these genes are involved in a form of DNA repair known as homologous recombination. Results from recent clinical trials showed that patients with germline mutations in BRCA1, BRCA2, and/or PALB2 had clinical responses to platinum-based chemotherapy or treatment with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib.
“These studies demonstrate that germline mutations in BRCA1, BRCA2, or PALB2 are valuable biomarkers to predict response to treatment,” said lead study author Wungki Park, MD, a medical oncologist at Memorial Sloan Kettering. “This led us to ask whether the benefit was limited to germline mutations only, or whether somatic mutations in these genes or mutations in other [homologous recombination] genes are also associated with responses to platinum-based chemotherapy.”
Methods
In this study, the research team analyzed the association between mutations in homologous recombination genes and clinical outcome. The study included 262 patients with metastatic pancreatic cancer who underwent both germline and somatic sequencing using the MSK-IMPACT sequencing test.
The researchers analyzed 17 homologous recombination genes included in both the somatic and germline panels of the MSK-IMPACT gene set. Analysis of sequencing data allowed the researchers to determine whether mutations were germline or somatic, in core homologous recombination genes (BRCA1, BRCA2, or PALB2) or in noncore homologous recombination genes (such as ATM, CHEK2, BAP1, RAD51, FANCA, and nine others), and in one or both copies of each gene.
Mutation Analysis and Survival Data
Out of 262 patients, 50 patients had mutations in homologous recombination genes; 40 patients had germline mutations and 10 had somatic mutations. Thirty-one patients had mutations in core genes, while 19 patients had mutations in noncore genes. Twenty-nine patients had mutations in both copies of a gene, and 21 patients had mutations in only one gene copy.
The median overall survival for the entire cohort of 262 patients was 15.5 months. Overall survival was similar between patients with germline mutations and those with somatic mutations. Thus, these subgroups were combined in the ensuing analyses.
The authors found that for the 35 patients who were treated with first-line platinum-based chemotherapy, those with mutations in homologous recombination genes had greater overall survival compared with those without mutations in these genes (25.1 months vs 15.3 months), suggesting that mutations in homologous recombination genes may be associated with enhanced overall survival. Furthermore, patients with homologous recombination mutations had a 44% lower risk of disease progression than patients without these mutations after first-line treatment with platinum-based chemotherapy. The lower risk of disease progression was observed regardless of whether the mutations were in core or noncore homologous recombination genes.
Among patients with mutations in homologous recombination genes, those who were treated with platinum-based chemotherapy had higher progression-free survival rates than those who received nonplatinum treatment (12.6 months vs 4.4 months). For patients with mutations in both gene copies, those who were treated with platinum-based chemotherapy had greater progression-free survival than those treated with other therapies (13.3 months vs 3.8 months). This association was not observed for patients with mutations in only one gene copy, suggesting that platinum-based chemotherapy may provide a greater clinical benefit in patients with mutations in both copies of homologous recombination genes.
“Our data support the use of platinum-based chemotherapy as first-line treatment for patients with defects in various [homologous recombination] genes. The results underscore the importance of genetic testing in newly diagnosed patients to help refine treatment decisions.”— Eileen O’Reilly, MD
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“Our data support the use of platinum-based chemotherapy as first-line treatment for patients with defects in various [homologous recombination] genes,” said Dr. O’Reilly. “The results underscore the importance of genetic testing in newly diagnosed patients to help refine treatment decisions.”
“[Homologous recombination] deficiency defined by pathogenic mutation of core [homologous recombination] genes and loss of both copies of either core or noncore [homologous recombination] genes confers the greatest platinum sensitivity,” said Dr. Park. “Patients with these deficiencies represent the optimal subgroup for therapies that target DNA repair pathways, such as platinum-based chemotherapy.” He noted that these deficiencies could also be predictive of response to other targeted developmental therapeutics in DNA repair pathways, to other PARP inhibitors, and to immunotherapy, although additional research with these agents will be needed.
“Identifying factors associated with treatment response may also help us understand why some patients’ tumors do not respond to treatment and why some that respond ultimately develop resistance,” added Dr. Park.
A limitation of the study is that the analysis was performed on a highly selected group of patients and therefore may not represent all patients with pancreatic cancer. “While the data are very compelling, we need to validate the results prospectively in wider and larger datasets,” noted Dr. O’Reilly.
Additional challenges included low sample purity, limited tissue availability, and other technical limitations.
Disclosure: The study was supported by Memorial Sloan Kettering Cancer Center, the National Institutes of Health, the Parker Institute for Cancer Immunotherapy, David M. Rubenstein Center for Pancreatic Cancer Research, Bonnie Reiss Family Foundation, Breast Cancer Research Foundation, and the Sarah Jenkins Fund. For full disclosures of the study authors, visit clincancerres.aacrjournals.org.
