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Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment
Wungki Park1,2,3,4, Jiapeng Chen1,5,6, Joanne F Chou1,7
1Memorial Sloan Kettering Cancer Center, New York, New York.
Purpose:
Genomic methods can identify homologous recombination deficiency (HRD). Rigorous evaluation of their outcome association to DNA damage response-targeted therapies like platinum in pancreatic ductal adenocarcinoma (PDAC) is essential in maximizing therapeutic outcome.
Experimental Design:
We evaluated progression-free survival (PFS) and overall survival (OS) of patients with advanced-stage PDAC, who had both germline- and somatic-targeted gene sequencing. Homologous recombination gene mutations (HRm) were evaluated: BRCA1, BRCA2, PALB2, ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1 HRm status was grouped as: (i) germline versus somatic; (ii) core (BRCAs and PALB2) versus non-core (other HRm); and (iii) monoallelic versus biallelic. Genomic instability was compared using large-scale state transition, signature 3, and tumor mutation burden.
Results:
Among 262 patients, 50 (19%) had HRD (15% germline and 4% somatic). Both groups were analyzed together due to lack of difference in their genomic instability and outcome. Median [95% confidence interval (CI)] follow-up was 21.9 (1.4-57.0) months. Median OS and PFS were 15.5 (14.6-19) and 7 (6.1-8.1) months, respectively. Patients with HRD had 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. Multivariate analysis showed HRD patients had improved OS regardless of their first-line treatment, but most had platinum exposure during their course. Biallelic HRm (11%) and core HRm (12%) had higher genomic instability, which translated to improved PFS on first-line platinum (1L-platinum) versus 1L-non-platinum.
Conclusions:
Pathogenic HRm identifies HRD in patients with PDAC with the best outcome when treated with 1L-platinum. Biallelic HRm and core HRm further enriched benefit from 1L-platinum from HRD.
Insights
Homologous recombination deficiency (HRD) in pancreatic cancer patients significantly improves outcomes with platinum-based chemotherapy. Specific mutations, like biallelic or core homologous recombination mutations, further enhance this benefit, guiding targeted therapy selection.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a challenging disease with limited treatment options.
- Genomic methods can identify homologous recombination deficiency (HRD), a state associated with DNA repair pathway defects.
- Evaluating the association between HRD and DNA damage response-targeted therapies, such as platinum agents, is crucial for optimizing treatment outcomes in PDAC.
Purpose of the Study:
- To evaluate the association between homologous recombination deficiency (HRD) and treatment outcomes (progression-free survival [PFS] and overall survival [OS]) in patients with advanced-stage pancreatic ductal adenocarcinoma (PDAC).
- To investigate the impact of different types of homologous recombination mutations (HRm) on therapeutic response to platinum-based therapies.
Main Methods:
- Germline and somatic targeted gene sequencing were performed on advanced-stage PDAC patients.
- Homologous recombination genes (BRCA1, BRCA2, PALB2, ATM, etc.) were analyzed for mutations (HRm).
- HRm status was categorized (germline vs. somatic, core vs. non-core, monoallelic vs. biallelic), and genomic instability was assessed.
Main Results:
- Of 262 patients, 19% had HRD (15% germline, 4% somatic).
- Patients with HRD showed improved PFS with first-line platinum therapy compared to those without HRD (HR, 0.44; P < 0.01), but not with non-platinum agents.
- Biallelic HRm and core HRm were associated with higher genomic instability and improved PFS with first-line platinum therapy.
Conclusions:
- Pathogenic HRm identifies patients with PDAC who benefit most from first-line platinum therapy.
- Biallelic and core HRm further enrich the benefit of first-line platinum therapy in HRD-positive PDAC patients.
- Genomic evaluation for HRD can guide personalized treatment strategies in pancreatic cancer.
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