Pancreatic Cancer: BRCA Targeted Therapy and Beyond
Abstract
:Simple Summary
Abstract
1. Introduction
2. BRCA and DNA Damage Repair Pathways
2.1. Prevalence of BRCA and HRD in Pancreatic Cancer
2.2. BRCAness Phenotype
3. Treatment of BRCA and HRD-Mutated Pancreatic Cancer
3.1. Platinum-Based Chemotherapy
3.2. Poly-ADP Ribose Polymerase Inhibitors
3.3. Resistance to PARP Inhibition
4. Combination Treatment Strategies
4.1. PARP Inhibition and Chemotherapy
4.2. PARPi and Immune Checkpoint Inhibitors
4.3. PARPi and Anti-Angiogenic Agents
4.4. PARPi and Other Agents
4.5. Immune Checkpoint Blockade in BRCA and HRD Pancreatic Cancer
4.6. Targeting DNA Replication Stress
4.7. Other Promising Strategies in BRCA and HRD
5. Conclusions and Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Test | Description |
---|---|
Telomeric Allelic Imbalance (TAI) [28] | Allelic imbalance at the telomere of the chromosome is due to the propensity for inappropriate end joining in HRD, identified by single nucleotide polymorphism (SNP) genotyping. |
Large Scale Transitions (LST) [29] | Chromosomal breaks larger than 10 Mb, which arise in HRD cells secondary to erroneous recombination between segments of the chromosome, are identified by single nucleotide polymorphism (SNP) genotyping. |
Loss of Heterozygosity (LOH) [30] | Uniparental disomy is owing to inaccurate repair of sister chromatids during S/G2 phase, resulting in the loss of entire genes and the surrounding chromosomal region, as identified by single nucleotide polymorphism (SNP) genotyping. |
Genomic Instability Score eg by Myriad Genetics MyChoice Assay | TAI + LST + LOH |
Signature 3 (Sig 3) [35] | A single base substitution mutational pattern, associated with microhomology and large deletions, was identified by whole exome sequencing. |
HRDetect [36] | A weighted model incorporating a weighted score of base substitution/rearrangement signatures, microhomology-mediated deletions, and an HRD score based on genomic scars identified by whole exome sequencing. |
NCT Identifier | Phase | Target Population | Experimental Arm | Control Arm | Primary Outcome | Other Key Findings |
---|---|---|---|---|---|---|
NCT02184195(POLO) | 3 | Metastatic PDAC, gBRCA1/2 mutated, with platinum sensitivity | Olaparib | Placebo | PFS 7.4 mo (experimental arm) vs. 3.8 mo (control arm) | PFS 2 16.9 mo (experimental arm) vs. 9.3 mo (placebo arm). Quality of life scores equivalent. OS 19.0 mo (olaparib) vs. 19.2 months (placebo) |
NCT03140670 | 2 | Metastatic PDAC, s/g BRCA1/2 or PALB2 mutated, with platinum sensitivity | Rucaparib | N/A | PFS6 59.5% | mPFS 13.1 mo mOS 23.5 mo ORR 41.7% |
NCT02042378 (RUCAPANC) | 2 | Metastatic or advanced PDAC, s/g BRCA mutation, 1–2 lines of previous treatment | Rucaparib | N/A | RR 15.8% (1 CR, 2 PR) | DCR 31.6% Terminated early due to insufficient response rate |
NCT02184195 | 2 | Metastatic or locally advanced PDAC, previously treated, with gBRCA1/2 or gPALB2 mutations | Cisplatin, gemcitabine (Arm B) plus veliparib (Arm A) | Cisplatin, gemcitabine (Arm B) | RR 74.1% for Arm A, 65.2% for Arm B | DCR 100% for Arm A, 78.3% for Arm B. mPFS 10.1 mo for Arm A, 9.7mo for Arm B. mOS 15.5 mo for Arm A, 16.4 mo for Arm B |
NCT03404960 | 2 | Locally advanced or metastatic PDAC with platinum sensitivity, in the platinum-sensitive, maintenance setting | Niraparib plus nivolumab and niraparib plus ipilimumab | N/A | 6m PFS 20.6% in niraparib + nivo arm versus 59.6% in the niraparib + ipi arm | mOS 10.2 mo in niraparib + nivo, 38 mo for niraparib + ipi Higher grade 3 toxicity with niraparib + ipilimumab |
NCT02184195 | 2 | Metastatic or locally advanced PDAC, gBRCA1/2 or gPALB2, 1–2 lines of previous treatment | Veliparib 300mg twice daily or veliparib 400mg twice daily | N/A | ORR 0% | mPFS 1.7 mo OS 3.1 mo |
NCT0129673 | 1 | Unresectable PDAC, not confined to those with BRCA or HRD mutations | Olaparib, cisplatin, irinotecan, and mitomycin | N/A | ORR 23% Grade 3 AEs in 89% 11% pts developed MDS 1 pt with gBRCA2 had durable response for >4 years |
NCT Identifier | Phase | Target Population | Experimental Arm | Control Arm | Primary Outcome | Anticipated Completion |
---|---|---|---|---|---|---|
NCT02677038 | 2 | Metastatic PDAC with s/gHRD gene mutations (except BRCA1/2) or a family history suggestive of a HRD mutation. | Olaparib | N/A | ORR | November 2022 |
NCT04858334 (APOLLO) | 2 | Surgically removed PDAC, post-adjuvant chemo(radiotherapy), and a g/sBRCA1/2 or PALB2 mutation. | Olaparib | N/A | RFS relapse free survival | November 2024 |
NCT04666740 (POLAR) | 2 | Metastatic PDAC with core or non-core HRD mutations or platinum sensitivity. | Olaparib plus pembrolizumab | N/A | PFS | January 2024 |
NCT04548752 | 2 | Metastatic PDAC with gBRCA1/2 mutations. | Olaparib plus pembrolizumab | Olaparib | PFS | March 2025 |
NCT04171700 (LODESTAR) | 2 | Metastatic solid tumors, including PDA with mutations in BRCA1/2, PALB2, RAD51C, RAD51D, BARD1, FANCA, NBN, RAD51, or RAD51B. | Rucaparib | N/A | ORR | March 2023 |
NCT03553004 (NIRAPANC) | 2 | Locally advanced or metastatic PDAC with g/sHRD mutations. | Niraparib | N/A | ORR | February 2025 |
NCT03601923 | 2 | Locally advanced or metastatic PDAC with g/sBRCA1/2, PALB2, CHEK2, and ATM mutations. | Niraparib | N/A | PFS | February 2025 |
NCT04493060 | 2 | Metastatic PDAC with a BRCA1/2 or PALB2 mutation. | Niraparib plus dostarlimab | N/A | DCR12 | September 2022 |
NCT04673448 | 1 | Metastatic solid tumors, including PDAC with a g/sBRCA1/2 mutation. | Niraparib plus TSR-042 | N/A | PFS | March 2026 |
NCT03601923 | 2 | Previously treated PDAC with g/sHRD mutations. | Niraparib plus small field palliative radiation | N/A | PFS | February 2025 |
NCT04005690 | 1 | Locally advanced or metastatic PDAC. | Arm 1: cobimetinib Arm 2: olaparib | N/A | Feasibility of obtaining tumor tissue pre and post treatment | February 2025 |
NCT04550494 | 2 | Locally advanced or metastatic solid tumors, including PDAC with g/s DDR gene alterations. | Talazoparib | N/A | PD | August 2022 |
NCT04348045 MAZEPPA) | 2 | Metastatic PDAC and known somatic profile—stratified by BRCAness and KRAS mutation status. | Pts with BRCAness (somatic profile): olaparib (Arm A) Pts without BRCAness and with KRAS mutation are randomized to durvalumab + selumetinib (Arm B) or FOLFIRI (Arm C) | N/A | PFS | December 2024 |
NCT03337087 | 1/2 | Metastatic PDAC (colorectal, gastroesophageal, and biliary cancer) and for the phase 2 component, BRCA1/2, PALB2, or HRD, untreated in the metastatic setting. | Liposomal irinotecan, fluorouracil, calcium leucovorin, and rucaparib | N/A | DLT rate (Phase 1) ORR (Phase 1b) Best response (Phase 2) | Not recruiting |
NCT02194829 | 1 | Metastatic or unresectable PDAC with alterations in DDR genes, previously untreated. | Novobiocin | N/A | MTD RP2D | Anticipated to open in 2023 |
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© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
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Keane, F.; O’Connor, C.A.; Park, W.; Seufferlein, T.; O’Reilly, E.M. Pancreatic Cancer: BRCA Targeted Therapy and Beyond. Cancers 2023, 15, 2955. https://doi.org/10.3390/cancers15112955
Keane F, O’Connor CA, Park W, Seufferlein T, O’Reilly EM. Pancreatic Cancer: BRCA Targeted Therapy and Beyond. Cancers. 2023; 15(11):2955. https://doi.org/10.3390/cancers15112955
Chicago/Turabian StyleKeane, Fergus, Catherine A. O’Connor, Wungki Park, Thomas Seufferlein, and Eileen M. O’Reilly. 2023. "Pancreatic Cancer: BRCA Targeted Therapy and Beyond" Cancers 15, no. 11: 2955. https://doi.org/10.3390/cancers15112955
APA StyleKeane, F., O’Connor, C. A., Park, W., Seufferlein, T., & O’Reilly, E. M. (2023). Pancreatic Cancer: BRCA Targeted Therapy and Beyond. Cancers, 15(11), 2955. https://doi.org/10.3390/cancers15112955