BRCA Mutations in Prostate Cancer: Assessment, Implications and Treatment Considerations

Shah, Sidrah; Rachmat, Rachelle; Enyioma, Synthia; Ghose, Aruni; Revythis, Antonios; Boussios, Stergios

doi:10.3390/ijms222312628

Cited by 59 publications

(63 citation statements)

References 160 publications

(253 reference statements)

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“…Six primary pathways of DNA repair have been identified, which are variably used to address double-stranded DNA break damage (DSB) and SSB from a variety of mechanisms of injury [ 25 ]. HR and nonhomologous end joining (NHEJ) are the two major pathways responsible for repairing DNA DSB, whereas the primary mechanisms for resolving DNA SSB are base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and the translesional synthesis [ 26 ].…”

Section: Dna Damage Repair Pathwaysmentioning

confidence: 99%

“…HR occurs in the S and G2 phases of the cell cycle, as it requires a template of a sister chromatid and repairs the DNA damage error-free. NHEJ is faster than HR and occurs throughout the cell cycle, but especially in the G1 phase; nevertheless, it is prone to error [ 26 ]. Meiotic recombination 11-Like (MRE11) is a nuclease that leads to the degradation of replication fork protection in the absence of BRCA proteins.…”

Section: Dna Damage Repair Pathwaysmentioning

confidence: 99%

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Recent Insights into PARP and Immuno-Checkpoint Inhibitors in Epithelial Ovarian Cancer

Revythis

Limbu

Mikropoulos

et al. 2022

IJERPH

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Ovarian cancer is one of the most common gynecologic cancers and has the highest mortality rate of any other cancer of the female reproductive system. Epithelial ovarian cancer (EOC) accounts for approximately 90% of all ovarian malignancies. The standard therapeutic strategy includes cytoreductive surgery accompanied by pre- or postoperative platinum-based chemotherapy. Nevertheless, up to 80% of the patients relapse within the following 12–18 months from the completion of the treatment and then receive first-line chemotherapy depending on platinum sensitivity. Mutations in BRCA1/2 genes are the most significant molecular aberrations in EOC and serve as prognostic and predictive biomarkers. Poly ADP-ribose polymerase (PARP) inhibitors exploit defects in the DNA repair pathway through synthetic lethality. They have also been shown to trap PARP1 and PARP2 on DNA, leading to PARP-DNA complexes. Olaparib, rucaparib, and niraparib have all obtained Food and Drug Administration (FDA) and/or the European Medicine Agency (EMA) approval for the treatment of EOC in different settings. Immune checkpoint inhibitors (ICI) have improved the survival of several cancers and are under evaluation in EOC. However, despite the success of immunotherapy in other malignancies, the use of antibodies inhibiting the immune checkpoint programmed cell death (PD-1) or its ligand (PD-L1) obtained modest results in EOC so far, with median response rates of up to 10%. As such, ICI have not yet been approved for the treatment of EOC. We herein provided a comprehensive insight into the most recent progress in synthetic lethality PARP inhibitors, along with the mechanisms of resistance. We also summarised data regarding the role of immune checkpoint inhibitors, the use of vaccination therapy, and adoptive immunotherapy in treating epithelial ovarian cancer.

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Section: Dna Damage Repair Pathwaysmentioning

confidence: 99%

Section: Dna Damage Repair Pathwaysmentioning

confidence: 99%

Recent Insights into PARP and Immuno-Checkpoint Inhibitors in Epithelial Ovarian Cancer

Revythis

Limbu

Mikropoulos

et al. 2022

IJERPH

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“…They are particularly effective in BRCA1/2 mutations with increased survival outcomes. Olaparib is used in this subset of patients after a progression on novel hormonal agents, e.g., enzalutamide or abiraterone, whilst rucaparib is considered in combination with androgen receptor-guided therapy and paclitaxel-based chemotherapy [55]. Moreover, PARP inhibitor monotherapy induces an objective anti-tumour activity in patients with PALB2, BRIP1, or FANCA aberrations.…”

Section: Molecular Landscapementioning

confidence: 99%

Epithelial Ovarian Cancer: Providing Evidence of Predisposition Genes

Shah

Cheung

Kutka

et al. 2022

IJERPH

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Epithelial ovarian cancer (EOC) is one of the cancers most influenced by hereditary factors. A fourth to a fifth of unselected EOC patients carry pathogenic variants (PVs) in a number of genes, the majority of which encode for proteins involved in DNA mismatch repair (MMR) pathways. PVs in BRCA1 and BRCA2 genes are responsible for a substantial fraction of hereditary EOC. In addition, PV genes involved in the MMR pathway account for 10–15% of hereditary EOC. The identification of women with homologous recombination (HR)-deficient EOCs has significant clinical implications, concerning chemotherapy regimen planning and development as well as the use of targeted therapies such as poly(ADP-ribose) polymerase (PARP) inhibitors. With several genes involved, the complexity of genetic testing increases. In this context, next-generation sequencing (NGS) allows testing for multiple genes simultaneously with a rapid turnaround time. In this review, we discuss the EOC risk assessment in the era of NGS.

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“…Therefore, germline and somatic mutation testing in men with PCa could guide treatment options [ 111 ]. Thus, since the approval of PARPi in PCa treatment, PCa guidelines recommend germline testing of mutations in DNA repair genes [ 112 ].…”

Section: Mutation Testing: Whom When and Howmentioning

confidence: 99%

PARP Inhibitors: A New Horizon for Patients with Prostate Cancer

et al. 2022

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The introduction of PARP inhibitors (PARPi) in prostate cancer is a milestone and provides a pathway to hope in fighting this disease. It is the first time that drugs, based on the concept of synthetic lethality, have been approved for prostate cancer. In addition, it is also the first time that genetic mutation tests have been included in the therapeutic algorithm of this disease, representing a significant step forward for precision and personalized treatment of prostate cancer. The objectives of this review are: (1) understanding the mechanism of action of PARPi in monotherapy and combinations; (2) gaining insights on patient selection for PARPi; (3) exposing the pivotal studies that have allowed its approval, and; (4) offering an overview of the ongoing trials. Nevertheless, many unsolved questions remain, such as the number of patients who could potentially benefit from PARPi, whether to use PARPi in monotherapy or in combination, and when is the best time to use them in advanced or localized disease. To answer these and other questions, many clinical trials are underway. Some of them have recently demonstrated promising results that may favor the introduction of new combinations in metastatic castration-resistant prostate cancer.

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BRCA Mutations in Prostate Cancer: Assessment, Implications and Treatment Considerations

Cited by 59 publications

References 160 publications

Recent Insights into PARP and Immuno-Checkpoint Inhibitors in Epithelial Ovarian Cancer

Recent Insights into PARP and Immuno-Checkpoint Inhibitors in Epithelial Ovarian Cancer

Epithelial Ovarian Cancer: Providing Evidence of Predisposition Genes

PARP Inhibitors: A New Horizon for Patients with Prostate Cancer

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