The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 after Progression on Rucaparib
©2023 American Association for Cancer Research..
PURPOSE: PARP 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 DESIGN: We 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.
RESULTS: Peripherally 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.
CONCLUSIONS: Acquired 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.
| Errataetall: |
CommentIn: Clin Cancer Res. 2023 Dec 15;29(24):5005-5007. - PMID 37787975 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:29 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 29(2023), 24 vom: 15. Dez., Seite 5207-5216 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Brown, Timothy J [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 16.12.2023 Date Revised 14.03.2024 published: Print ClinicalTrials.gov: NCT03140670 CommentIn: Clin Cancer Res. 2023 Dec 15;29(24):5005-5007. - PMID 37787975 Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-23-1467 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM359865682 |
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| 100 | 1 | |a Brown, Timothy J |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The Clinical Implications of Reversions in Patients with Advanced Pancreatic Cancer and Pathogenic Variants in BRCA1, BRCA2, or PALB2 after Progression on Rucaparib |
| 264 | 1 | |c 2023 | |
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| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 16.12.2023 | ||
| 500 | |a Date Revised 14.03.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT03140670 | ||
| 500 | |a CommentIn: Clin Cancer Res. 2023 Dec 15;29(24):5005-5007. - PMID 37787975 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2023 American Association for Cancer Research. | ||
| 520 | |a PURPOSE: PARP 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 | ||
| 520 | |a EXPERIMENTAL DESIGN: We 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 | ||
| 520 | |a RESULTS: Peripherally 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 | ||
| 520 | |a CONCLUSIONS: Acquired 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
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| 700 | 1 | |a Yablonovitch, Arielle |e verfasserin |4 aut | |
| 700 | 1 | |a Till, Jacob E |e verfasserin |4 aut | |
| 700 | 1 | |a Yen, Jennifer |e verfasserin |4 aut | |
| 700 | 1 | |a Kiedrowski, Lesli A |e verfasserin |4 aut | |
| 700 | 1 | |a Hood, Ryan |e verfasserin |4 aut | |
| 700 | 1 | |a O'Hara, Mark H |e verfasserin |4 aut | |
| 700 | 1 | |a Teitelbaum, Ursina |e verfasserin |4 aut | |
| 700 | 1 | |a Karasic, Thomas B |e verfasserin |4 aut | |
| 700 | 1 | |a Schneider, Charles |e verfasserin |4 aut | |
| 700 | 1 | |a Carpenter, Erica L |e verfasserin |4 aut | |
| 700 | 1 | |a Nathanson, Katherine |e verfasserin |4 aut | |
| 700 | 1 | |a Domchek, Susan M |e verfasserin |4 aut | |
| 700 | 1 | |a Reiss, Kim A |e verfasserin |4 aut | |
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