Maintenance Olaparib for Germline
            <i>BRCA</i>
            -Mutated Metastatic Pancreatic Cancer

Golan, Talia; Hammel, Pascal; Reni, Michele; Cutsem, Éric Van; Macarulla, Teresa; Hall, Michael J.; Park, Joon Oh; Hochhauser, Daniel; Arnold, Dirk; Oh, Do Youn; Reinacher‐Schick, Anke; Tortora, Giampaolo; Algül, Hana; O’Reilly, Eileen M.; McGuinness, David; Cui, Karen; Schlienger, Katia; Locker, Gershon Y.; Kindler, Hedy L.

doi:10.1056/nejmoa1903387

Cited by 1,781 publications

(1,532 citation statements)

References 22 publications

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“…This was as effective as Cisplatin monotherapy, or combination treatment using Cisplatin and Olaparib suggesting that in appropriately selected patients, PARP inhibitor monotherapy can potentially induce clinically relevant responses similar to platinum. This provides potential therapeutic options for patients with poor performance status, or after intolerance or acquired resistance to platinum has developed 30 . Predicting platinum response is more complex than using point mutations in DDR genes and the COSMIC BRCA mutational signature alone.…”

Section: Potential Clinical Utility Of the Replication Stress Signaturementioning

confidence: 99%

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Dreyer

Upstill-Goddard

Paulus-Hock³

et al. 2019

Preprint

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Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting the DNA damage response (DDR) and replication stress. We show that patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum and PARP inhibitor therapy in vitro and in vivo. We generated a novel signature of replication stress with potential clinical utility in predicting response to ATR and WEE1 inhibitor treatment. Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy.

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Section: Potential Clinical Utility Of the Replication Stress Signaturementioning

confidence: 99%

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Dreyer

Upstill-Goddard

Paulus-Hock³

et al. 2019

Preprint

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“…Perhaps one of the best examples of this approach is the development of poly-ADP ribose polymerase (PARP) inhibitors to target tumours with defects in DNA damage response (DDR) genes 1 . PARP inhibitors were first shown to target breast cancer cells with depletion of the breast and ovarian cancer susceptibility proteins BRCA1 and BRCA2 2,3 and are now FDA-approved for use in BRCA-deficient ovarian cancer 4 with clinical trials showing potential in BRCA-deficient breast, prostate and pancreatic cancers [5][6][7][8][9][10][11][12] . BRCA1 and 2 play important roles in the detection and repair of DNA double strand breaks (DSBs) through the Homologous Recombination (HR) repair pathway 13 , leading to the idea that cells with deficiency in DSB repair pathways may be sensitive to PARP inhibitors.…”

Section: Introductionmentioning

confidence: 99%

ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738

Jette

Radhamani

et al. 2020

Preprint

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AbstractBackgroundThe ataxia telangiectasia mutated (ATM) protein kinase is mutated in several human cancers, presenting potential opportunities for targeted cancer therapy. We previously reported that the poly-ADP ribose polymerase (PARP) inhibitor olaparib induced transient G2 arrest but not cell death in ATM-deficient A549 lung cancer cells, while the combination of olaparib with the ATM-, Rad3-related (ATR) inhibitor VE-821 induced cell death. Here, we show that the clinically relevant ATR inhibitor, AZD6738, sensitizes ATM-deficient A549 lung, prostate and pancreatic cancer cells to olaparib.MethodsATM was depleted from A549 lung cancer cells, PC-3 prostate cancer cells and Panc 10.05 pancreatic cancer cells, and the effects of olaparib alone and in combination with AZD6738 were determined.ResultsThe combination of olaparib plus AZD6738 induced cell death in ATM-deficient lung, prostate and pancreatic cancer cells with little effect on their ATM-proficient counterparts.ConclusionsLung, prostate and pancreatic patients whose tumours exhibit loss or inactivation of ATM may benefit from combination of a PARP inhibitor plus an ATR inhibitor.

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“…HRD targeted therapy with PARPi is mostly restricted to breast and ovarian cancer 5 , although its use for treating pancreatic cancer was recently approved by the FDA (US Food and Drug Administration) 37 .…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer landscape of homologous recombination deficiency

Nguyen

Martens

Hoeck

et al. 2020

Preprint

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Homologous recombination deficiency (HRD) results in impaired double strand break repair and is a frequent driver of tumorigenesis. Here, we used a machine learning approach to develop a sensitive pan-cancer Classifier of HOmologous Recombination Deficiency (CHORD). CHORD employs genomewide genomic footprints of somatic mutations characteristic for HRD and that discriminates BRCA1and BRCA2-subtypes. Analysis of a metastatic pan-cancer cohort of 3,504 patients revealed HRD to occur at a frequency of 6% with highest rates for ovarian cancer (30%), comparable frequencies for breast, pancreatic and prostate cancer (12-13%) and incidental cases in other cancer types. Ovarian and breast cancer were equally driven by BRCA1-and BRCA2-type HRD, whereas for prostate, pancreatic and urinary tract cancers BRCA2-type HRD was predominant. Biallelic inactivation of BRCA1, BRCA2, RAD51C and PALB2 were found as the most common genetic causes of HRD (60% of all CHORD-HRD cases), with RAD51C and PALB2 inactivation resulting in BRCA2-type HRD. Loss of heterozygosity (LOH) was found to be the main inactivating mechanism in ovarian, breast and pancreatic cancer, whereas for prostate cancer deep deletions (primarily of BRCA2) are also a major cause. From the remaining 40% of CHORD-HRD patients, 35% had a monoallelic mutation in one of the HRD associated genes, suggesting that the second allele could be inactivated by epigenetic or regulatory mechanisms. For only 5% of CHORD-HRD patients, no mutations were identified that could explain the HRD phenotype. Taken together, our results demonstrate that broad genomics-based HRD testing is valuable for cancer diagnostics and could be used for patient stratification towards treatment with e.g. poly ADP-ribose polymerase inhibitors (PARPi).

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Maintenance Olaparib for Germline BRCA -Mutated Metastatic Pancreatic Cancer

Cited by 1,781 publications

References 22 publications

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

ATM-deficient lung, prostate and pancreatic cancer cells are acutely sensitive to the combination of olaparib and the ATR inhibitor AZD6738

Pan-cancer landscape of homologous recombination deficiency

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