PARP Inhibitors in Pancreatic Cancer: From Phase I to Plenary Session

Patel, Rajvi; Fein, Daniel; Ramirez, Carolina Bernabe; Do, Kevin; Saif, Muhammad Wasif

doi:10.17140/poj-3-e011

Cited by 14 publications

(14 citation statements)

References 16 publications

(16 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PC remains one of the most lethal solid malignancies. The identification of damaging mutations in DDR system genes, including ATM , in 17–25% of this type of cancer and the recent suggestion that PARP inhibitors could have therapeutic potential in cancers with loss or mutation of ATM are opening up the possibility of new therapies, such as platinum and more recently PARP inhibitors, also in ATM -mutated patients with PC [ 83 , 84 , 85 ].…”

Section: Discussionmentioning

confidence: 99%

Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers

Germani

Petrucci

Marchis

et al. 2020

JCM

View full text Add to dashboard Cite

The 5–10% of breast/ovarian cancers (BC and OC) are inherited, and germline pathogenic (P) variants in DNA damage repair (DDR) genes BRCA1 and BRCA2 explain only 10–20% of these cases. Currently, new DDR genes have been related to BC/OC and to pancreatic (PC) cancers, but the prevalence of P variants remains to be explored. The purpose of this study was to investigate the spectrum and the prevalence of pathogenic variants in DDR pathway genes other than BRCA1/2 and to correlate the genotype with the clinical phenotype. A cohort of 113 non-BRCA patients was analyzed by next-generation sequencing using a multigene panel of the 25 DDR pathways genes related to BC, OC, and PC. We found 43 unique variants in 18 of 25 analyzed genes, 14 classified as P/likely pathogenic (LP) and 28 as variants of uncertain significance (VUS). Deleterious variants were identified in 14% of index cases, whereas a VUS was identified in 20% of the probands. We observed a high incidence of deleterious variants in the CHEK2 gene, and a new pathogenic variant was detected in the RECQL gene. These results supported the clinical utility of multigene panel to increase the detection of P/LP carriers and to identify new actionable pathogenic gene variants useful for preventive and therapeutic approaches.

show abstract

Section: Discussionmentioning

confidence: 99%

Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers

Germani

Petrucci

Marchis

et al. 2020

JCM

View full text Add to dashboard Cite

show abstract

“…Monoclonal antibody inhibitors include cetuximab, panitumumab and nimotuzumab (Ref. 30). Cetuximab combined with irinotecan has been widely used in the treatment of metastatic rectal cancer with irinotecan failure (Ref.…”

Section: Egfr Inhibitorsmentioning

confidence: 99%

Opportunities and challenges in targeted therapy and immunotherapy for pancreatic cancer

Cao

Song

et al. 2021

Expert Rev. Mol. Med.

View full text Add to dashboard Cite

Pancreatic cancer is one of the most malignant tumours with a poor prognosis. In recent years, the incidence of pancreatic cancer is on the rise. Traditional chemotherapy and radiotherapy for pancreatic cancer have been improved, first-line and second-line palliative treatments have been developed, and adjuvant treatments have also been used in clinical. However, the 5-year survival rate is still less than 10% and new treatment methods such as targeted therapy and immunotherapy need to be investigated. In the past decades, many clinical trials of targeted therapies and immunotherapies for pancreatic cancer were launched and some of them showed an ideal prospect in a subgroup of pancreatic cancer patients. The experience of both success and failure of these clinical trials will be helpful to improve these therapies in the future. Therefore, the current research progress and challenges of selected targeted therapies and immunotherapies for pancreatic cancer are reviewed.

show abstract

“…[21][22][23][24][25][26] Studies of olaparib in cancers driven by other DNA HR repair deficiencies beyond BRCA mutations have also been approved. 27,28 We hypothesized that patients with mesothelioma carrying germline or somatic BAP1 mutations or other DNA repair genes deficiencies may clinically benefit from olaparib monotherapy. To address this hypothesis, we enrolled patients with mesothelioma on a nonrandomized open-label, single-arm, phase 2 clinical trial to receive the PARP inhibitor olaparib at 300 mg twice daily until progression or intolerable toxicity.…”

Section: Introductionmentioning

confidence: 99%

Phase 2 Study of Olaparib in Malignant Mesothelioma and Correlation of Efficacy With Germline or Somatic Mutations in BAP1 Gene

Ghafoor

Mian

Wagner

et al. 2021

JTO Clinical and Research Reports

View full text Add to dashboard Cite

Introduction: PARP inhibition may enhance antitumor responses in BAP1-associated mesothelioma by inducing synthetic lethality.Methods: A single-center, nonrandomized, phase 2 trial was conducted, in which patients with refractory mesothelioma were given olaparib 300 mg twice daily in a 21-day cycle until disease progression or intolerable toxicity. The primary objective was to determine the objective response rate on the basis of somatic or germline mutation status of DNA repair genes. The secondary objectives were to assess safety and tolerability and to determine progression-free survival (PFS) and overall survival (OS). Whole-exome sequencing was performed on blood and tumor.Results: A total of 23 previously treated patients with pleural and peritoneal mesothelioma were enrolled and treated (germline BAP1, n ¼ 4; germline MRE11A, n ¼ 1; somatic BAP1, n ¼ 8 mutations). There was one (4%) partial response, 18 (78%) with stable disease at 6 weeks, and four (17%) with progressive disease. The median overall PFS and OS were 3.6 months (95% confidence interval [CI]: 2.7-4.2 mo) and 8.7 months (95% CI: 4.7 mo-not estimable), respectively. The median PFS of germline BAP1 mutants (n ¼ 4) was 2.3 months (95% CI: 1.3-3.6 mo) versus 4.1 months (95% CI: 2.7-5.5 mo) for wild-type (n ¼ 19; p ¼ 0.019). The median OS was 4.6 months (95% CI: 3.1-4.9 mo) for germline BAP1 mutation versus 9.6 months (95% CI: 5.5 mo-not estimable) in no germline mutation (p ¼ 0.0040). Olaparib was safe with no new safety concerns.Conclusions: Olaparib has limited activity in previously treated mesothelioma including patients with BAP1 mutations. Germline BAP1 mutations were associated with decreased PFS and OS.

show abstract

PARP Inhibitors in Pancreatic Cancer: From Phase I to Plenary Session

Cited by 14 publications

References 16 publications

Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers

Beyond BRCA1 and BRCA2: Deleterious Variants in DNA Repair Pathway Genes in Italian Families with Breast/Ovarian and Pancreatic Cancers

Opportunities and challenges in targeted therapy and immunotherapy for pancreatic cancer

Phase 2 Study of Olaparib in Malignant Mesothelioma and Correlation of Efficacy With Germline or Somatic Mutations in BAP1 Gene

Contact Info

Product

Resources

About