Optimizing Treatment for Patients with Metastatic Pancreatic Cancer, DNA Repair Defects

May 24, 2020
Hannah Slater
Hannah Slater

Researchers found that patients with metastatic pancreatic cancer who had germline or somatic mutations in DNA repair genes had better clinical outcomes after platinum-based chemotherapy.

A study published in Clinical Cancer Research found that patients with metastatic pancreatic cancer who had germline or somatic mutations in DNA repair genes had superior clinical outcomes after platinum-based chemotherapy, as compared to patients without these mutations.1

Moreover, biallelic mutation of homologous recombination (HR) genes showed the best association with this genomic characteristic, independent of germline versus somatic origin. Given these findings, researchers indicated that determining the homologous recombination deficiency (HRD) status is ideally needed at the time of diagnosis to optimize survival and refine treatment selection for this patient population.

“Our data support the use of platinum-based chemotherapy as first-line treatment for patients with defects in various HR genes,” senior author Eileen O’Reilly, MD, medical oncologist at Memorial Sloan Kettering Cancer Center (MSKCC), said in a press release.2 “The results underscore the importance of genetic testing in newly diagnosed patients to help refine treatment decisions.” 

The primary objective of the study was to determine the biological and clinical significance of HRD determined by several genomic methods in canonical BRCA germline mutations and other putative HR gene mutations in pancreatic cancer. 

Using a large prospectively maintained database, researchers systemically assessed these methods and their associated clinical outcomes. Specifically, researchers analyzed 17 HR 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 HR genes (BRCA1, BRCA2, or PALB2) or in noncore HR genes (such as ATM, CHEK2, BAP1, RAD51, FANCA, and 9 others), and in one or both copies of each gene.

Of 262 patients with metastatic pancreatic cancer who underwent both germline and somatic sequencing using the MSK-IMPACT sequencing test, 50 (19%) had HRD (15% germline and 4% somatic). Notably, 31 patients had mutations in core genes, while 19 patients had mutations in noncore genes. Additionally, 29 patients had mutations in both copies of a gene, and 21 patients had mutations in only 1 gene copy. Due to the lack of difference in their genomic instability and outcome, both groups were evaluated together.

Median follow-up was 21.9 (95% CI, 1.4-57.0) months. Median overall survival (OS) and progression-free survival (PFS) were 15.5 (95% CI, 14.6-19) and 7 (95% CI, 6.1-8.1) months, respectively.

Patients with HRD were found to have improved PFS compared with no HRD when treated with first-line (1L) platinum (HR, 0.44; 95% CI, 0.29-0.67; P < 0.01), but not with 1L-non-platinum. Even further, multivariate analysis showed patients with HRD had improved OS, regardless of their first-line treatment; however, most had platinum exposure during their course.

Importantly, biallelic HR gene mutations (11%) and core HR gene mutations (12%) had higher genomic instability, which translated to improved PFS on 1L-platinum versus 1L-non-platinum.

“HR deficiency defined by pathogenic mutation of core HR genes and loss of both copies of either core or noncore HR genes confers the greatest platinum sensitivity,” lead author Wungki Park, MD, medical oncologist at MSKCC, said in a press release. “Patients with these deficiencies represent the optimal subgroup for therapies that target DNA repair pathways, such as platinum-based chemotherapy.”

Park also noted that these deficiencies could potentially be predictive of response to other targeted developmental therapeutics in DNA repair pathways, to other PARP inhibitors, and to immunotherapy, though further research will be necessary. 

“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,” Park concluded.

References:

1. Park W, Chen J, Chou JF, et al. Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection. Clinical Cancer Research. doi:10.1158/1078-0432.CCR-20-0418.

2. Patients with Metastatic Pancreatic Cancer and DNA Repair Defects May Have Improved Survival after Platinum-based Chemotherapy [news release]. Published May 22, 2020. Accessed May 22, 2020.