ArticleClinical cancer research : an official journal of the American Association for Cancer Research2023
The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 after Progression on Rucaparib.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03140670 (A Phase 2, Open Label Study of Rucaparib in Patients With Advanced Pancreatic Cancer and a Known Deleterious Germline or Somatic BRCA or PALB2 Mutation), which is not on this map. Cited by 13 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Phase 2, Open Label Study of Rucaparib in Patients With Advanced Pancreatic Cancer and a Known Deleterious Germline or Somatic BRCA or PALB2 Mutation
Who cites it
13 citing papers in PubMed, 21 citations in OpenAlex.
- A Phase II Trial of Niraparib in Patients with Advanced Pancreatic Cancer Harboring Pathogenic Variants in ATM, BRCA1, BRCA2, PALB2, and CHEK2.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Trial
- Genomic and Epigenomic ctDNA Profiling in Liquid Biopsies from Heavily Pretreated Patients with DNA Damage Response-Deficient Tumors.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
- Liquid biopsy: a new window on the BRCA genes.ESMO open · 2026Review
- Pancreatic Cancer: Translating Tumor Biology into Actionability.Cancer discovery · 2026Review
- Increasing Use of Germline Genetic Testing in Pancreatic Ductal Adenocarcinoma and Relationship to Clinical Outcome: A Single-Institution Study.JCO precision oncology · 2026Article
- Sequential platinum and PARP Inhibition enhances PD1 immunotherapy efficacy in murine Brca2 mutated pancreatic cancer.Scientific reports · 2026Article
- Sequential ATR and PARP inhibition overcomes acquired DNA damaging agent resistance in pancreatic ductal adenocarcinoma.British journal of cancer · 2025Article
- Prevalence and clinical relavance of germline mutations in Chinese patients with pancreatic cancer.Cell communication and signaling : CCS · 2025Article
- The tandem duplicator phenotype may be a novel targetable subgroup in pancreatic cancer.NPJ precision oncology · 2025Article
- Article
- Familial Pancreatic Cancer Research: Bridging Gaps in Basic Research and Clinical Application.Biomolecules · 2024Review
- PARP Inhibitors in Pancreatic Cancer with Homologous Recombination Repair Gene Mutations: A Single-Institution Experience.Cancers · 2024Article
- Clinical utility of BRCA and ATM mutation status in circulating tumour DNA for treatment selection in advanced pancreatic cancer.British journal of cancer · 2024Article
Corrections and comments
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Authors and funding
14 authors at 2 institutions in 1 country.
Funding
Abstract
purposePARP inhibitors (PARPi) provide an effective maintenance option for patients with BRCA- or PALB2-mutated pancreatic cancer. However, mechanisms of PARPi resistance and optimal post-PARPi therapeutic strategies are poorly characterized. EXPERIMENTAL
designWe collected paired cell-free DNA samples and post-PARPi clinical data on 42 patients with advanced, platinum-sensitive pancreatic cancer who were treated with maintenance rucaparib on NCT03140670, of whom 32 developed progressive disease.
resultsPeripherally detected, acquired BRCA or PALB2 reversion variants were uncommon (5/30; 16.6%) in patients who progressed on rucaparib. Reversions were significantly associated with rapid resistance to PARPi treatment (median PFS, 3.7 vs. 12.5 months; P = 0.001) and poor overall survival (median OS, 6.2 vs. 23.0 months; P < 0.0001). All patients with reversions received rechallenge with platinum-based chemotherapy following PARPi progression and experienced faster progression on this therapy than those without reversion variants (real-world time-to-treatment discontinuation, 2.4 vs. 5.8 months; P = 0.004). Of the patients who progressed on PARPi and received further chemotherapy, the OS from initiation of second-line therapy was significantly lower in those with reversion variants than in those without (5.5 vs. 12.0 months, P = 0.002). Finally, high levels of tumor shedding were independently associated with poor outcomes in patients who received rucaparib.
conclusionsAcquired reversion variants were uncommon but detrimental in a population of patients with advanced BRCA- or PALB2-related pancreatic ductal adenocarcinoma who received maintenance rucaparib. Reversion variants led to rapid progression on PARPi, rapid failure of subsequent platinum-based treatment, and poor OS of patients. The identification of such variants in the blood may have both predictive and prognostic value. See related commentary by Tsang and Gallinger, p. 5005.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.