PARP inhibitors in ovarian cancer: evidence for maintenance and treatment strategies

AbstractMutations in BRCA1 and BRCA2 high penetrance genes account for most hereditary breast and ovarian cancer, although other new high-moderate penetrance genes included in multigene panels have increased the genetic diagnosis of hereditary breast and ovarian cancer families by 50%. Multigene cancer panels provide new challenges related to increased frequency of variants of uncertain significance, new gene-specific cancer risk assessments, and clinical recommendations for carriers of mutations of new genes. Although clinical criteria for genetic testing continue to be largely based on personal and family history with around a 10% detection rate, broader criteria are being applied with a lower threshold for detecting mutations when there are therapeutic implications for patients with breast or ovarian cancer. In this regard, new models of genetic counselling and testing are being implemented following the registration of PARP inhibitors for individuals who display BRCA mutations. Massive sequencing techniques in tumor tissue is also driving a paradigm shift in genetic testing and potential identification of germline mutations. In this paper, we review the current clinical criteria for genetic testing, as well as surveillance recommendations in healthy carriers, risk reduction surgical options, and new treatment strategies in breast cancer gene-mutated carriers.

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Use of First-Line PARP Inhibitors in Ovarian Cancer

healthbook TIMES Oncology Hematology ◽

10.36000/hbt.oh.2019.02.006 ◽

2019 ◽

pp. 26-29

Author(s):

Ursula Hasler-Strub

Keyword(s):

Ovarian Cancer ◽

Treatment Strategies ◽

Advanced Ovarian Cancer ◽

Standard Of Care ◽

Parp Inhibitors ◽

Phase Iii ◽

Line Treatment ◽

Front Line ◽

First Line ◽

Platinum Based Chemotherapy

Platinum-based chemotherapy regimens are the mainstay of advanced ovarian cancer treatment. However, up to 85% of the patients experience recurrence under these settings. To fill this gap, novel front-line treatment strategies have been established, leading to unprecedented clinical benefits. For example, first-line bevacizumab, an anti-angiogenic agent, plus chemotherapy followed by bevacizumab maintenance, has emerged as a new standard of care for newly diagnosed high risk ovarian cancer patients. This was based on the results of the phase III GOG 0218 and ICON-7 trials. More recently, poly(ADP)-ribose polymerase (PARP) inhibitors, including niraparib, olaparib and veliparib, have offered a new treatment option as part of the front-line treatment in ovarian cancer. Here we provide an overview of three recent studies that may lead to a paradigm shift in the first-line treatment for advanced ovarian cancer.

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Tumour Versus Germline BRCA Testing in Ovarian Cancer: A Single-Site Institution Experience in the United Kingdom

Diagnostics ◽

10.3390/diagnostics11030547 ◽

2021 ◽

Vol 11 (3) ◽

pp. 547

Author(s):

Iolia Akaev ◽

Siavash Rahimi ◽

Olubukola Onifade ◽

Francis John Edward Gardner ◽

David Castells-Rufas ◽

...

Keyword(s):

Ovarian Cancer ◽

Unknown Origin ◽

Parp Inhibitors ◽

Serous Carcinoma ◽

High Grade ◽

Brca1 And Brca2 ◽

Brca Mutations ◽

Epithelial Cancers ◽

Pathogenic Variants ◽

Pathogenic Mutations

The aim of this audit was to evaluate the usefulness and serviceability of testing for pathogenic mutations in BRCA1 or BRCA2 (BRCA1/2) genes in ovarian cancer (OC) patients. One hundred and thirty-five patients with more common histological sub-types of OC were retrospectively identified between 2011 and 2019. The fail rate of the molecular analysis was 7.4% (10/135). One hundred and twenty-five records were evaluated: 99 (79.2%) patients had wild-type BRCA (both somatic and germline); tumour BRCA1/2 (tBRCA1/2) pathogenic mutations were found in 20 (16%) patients with distribution between BRCA1 and BRCA2 being 40% and 60%, respectively; 13 (10.4%) patients with pathogenic variants had germline mutations; and tBRCA1/2 with variant of unknown significance (VUS), in the absence of pathogenic BRCA1 or BRCA2 variants, was detected in 6 (4.8%) patients. Our data show that expanding the molecular service to the routine first-tumour testing for patients with OC will potentially increase the detection rate of BRCA mutations, thereby providing early benefits of PARP inhibitors therapy. The tumour testing service should continue to be offered to newly diagnosed patients with high-grade epithelial cancers, including high-grade serous carcinoma, but also with carcinosarcomas and poorly-differentiated metastatic adenocarcinomas of unknown origin.

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Differences in PARP Inhibitors for the Treatment of Ovarian Cancer: Mechanisms of Action, Pharmacology, Safety, and Efficacy

International Journal of Molecular Sciences ◽

10.3390/ijms22084203 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4203

Author(s):

Giorgio Valabrega ◽

Giulia Scotto ◽

Valentina Tuninetti ◽

Arianna Pani ◽

Francesco Scaglione

Keyword(s):

Ovarian Cancer ◽

Signal Transduction ◽

Dna Damage ◽

Chemical Structure ◽

Parp Inhibitors ◽

Mechanisms Of Action ◽

Point Of View ◽

Safety And Efficacy ◽

Damage Repair ◽

Pharmacokinetic Properties

Poly(ADP-ribose) polymerases (PARP) are proteins responsible for DNA damage detection and signal transduction. PARP inhibitors (PARPi) are able to interact with the binding site for PARP cofactor (NAD+) and trapping PARP on the DNA. In this way, they inhibit single-strand DNA damage repair. These drugs have been approved in recent years for the treatment of ovarian cancer. Although they share some similarities, from the point of view of the chemical structure and pharmacodynamic, pharmacokinetic properties, these drugs also have some substantial differences. These differences may underlie the different safety profiles and activity of PARPi.

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