458 DNA repair deficiencies in ovarian cancer: Genomic analysis of high grade serous ovarian tumors from the NOVA study

Timms, Kirsten M.; Neff, Christopher; Abkevich, Victor; Jones, Joshua T.; Kolquist, Kathryn A.; Mirza, M.Azim; Lanchbury, Jerry S.; Mikule, Keith; Agarwal, Sandeep K.; Hartman, Anne‐Renee; Gutin, Alexander; Wilcoxen, Keith

doi:10.1016/s0959-8049(16)30292-1

Cited by 2 publications

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“…109 Patients who met the cutoff score in the nongermline BRCA1/2-mutated cohort also had a significant improvement in PFS compared with placebo (median, 12.9 months vs 3.8 months; P<.0001). 109 A positive HRD score, or meeting the cutoff for HRD, also has been shown to predict pathologic response to neoadjuvant chemotherapy in patients with triple-negative and BRCA1/2mutated breast cancer. 110 Preclinical studies currently are underway to validate the accuracy of these tools to predict HRD and PARPi sensitivity in patients with PCa and bladder UC.…”

Section: Future Directionsmentioning

confidence: 89%

“…Using the Myriad HRD test, Timms et al analyzed samples from the NOVA study, a phase 3 trial of niraparib in patients with platinum‐sensitive ovarian cancer who either had a germline BRCA1/2 mutation or responded to their most recent platinum‐based chemotherapeutic regimen. All patients in the germline BRCA1/2 mutation cohort met the cutoff score for HRD, as did 55% of patients in the nongermline BRCA1/2‐ mutated cohort . Patients who met the cutoff score in the nongermline BRCA1/2‐ mutated cohort also had a significant improvement in PFS compared with placebo (median, 12.9 months vs 3.8 months; P <.0001) .…”

Section: Future Directionsmentioning

confidence: 92%

“…All patients in the germline BRCA1/2 mutation cohort met the cutoff score for HRD, as did 55% of patients in the nongermline BRCA1/2‐ mutated cohort . Patients who met the cutoff score in the nongermline BRCA1/2‐ mutated cohort also had a significant improvement in PFS compared with placebo (median, 12.9 months vs 3.8 months; P <.0001) . A positive HRD score, or meeting the cutoff for HRD, also has been shown to predict pathologic response to neoadjuvant chemotherapy in patients with triple‐negative and BRCA1/2 ‐mutated breast cancer .…”

Section: Future Directionsmentioning

confidence: 94%

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The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies

Rimar

Tran

Matulewicz

et al. 2017

Cancer

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As cells age and are exposed to genotoxic stress, preservation of the genomic code requires multiple DNA repair pathways to remove single or double- strand breaks. Loss of function somatic genomic aberrations or germline deficiency in genes involved in DNA repair can result in acute cell death or following a latency period cellular transformation. Therapeutic exploitation of DNA repair by inhibition of poly (adenosine diphosphate [ADP]) ribose polymerases (PARP), a family of enzymes involved in the repair of single-strand and in some cases double-strand breaks, has become a novel cancer treatment. While the application of PARP inhibitors (PARPis) was initially focused on tumors with BRCA1 or BRCA2 deficiency, our current knowledge has extended synthetic susceptibilities of PARPi to deficiencies in proteins and pathways involved in DNA damage repair (DDR) in particular those that repair double-strand breaks using homologous recombination (HR). There is an increasing appreciation that genitourinary (GU) malignancies, including bladder, and especially prostate cancers, contain subsets of patients with germline and somatic alterations in HR genes that may reflect increased response to PARPis. In this review, we describe the mechanisms and rationale of PARPi use in GU cancers, summarize previously reported pre-clinical and clinical trials, and identify ongoing trials to determine how PARPis and strategies targeted at HR repair can be applied for widespread application in GU cancers.

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Section: Future Directionsmentioning

confidence: 89%

Section: Future Directionsmentioning

confidence: 92%

Section: Future Directionsmentioning

confidence: 94%

See 1 more Smart Citation

The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies

Rimar

Tran

Matulewicz

et al. 2017

Cancer

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PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions

2016

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Poly(ADP-ribose) polymerase (PARP) inhibitors cause targeted tumour cell death in homologous recombination (HR)-deficient cancers, including BRCA-mutated tumours, by exploiting synthetic lethality. PARP inhibitors are being evaluated in late-stage clinical trials of ovarian cancer (OC). Recently, olaparib was the first PARP inhibitor approved in the European Union and United States for the treatment of advanced BRCA-mutated OC. This paper reviews the role of BRCA mutations for tumorigenesis and PARP inhibitor sensitivity, and summarises the clinical development of PARP inhibitors for the treatment of patients diagnosed with OC. Among the five key PARP inhibitors currently in clinical development, olaparib has undergone the most extensive clinical investigation. PARP inhibitors have demonstrated durable antitumour activity in BRCA-mutated advanced OC as a single agent in the treatment and maintenance setting, particularly in platinum-sensitive disease. PARP inhibitors are well tolerated; however, further careful assessment of moderate and late-onset toxicity is mandatory in the maintenance and adjuvant setting, respectively. PARP inhibitors are also being evaluated in combination with chemotherapeutic and novel targeted agents to potentiate antitumour activities. Current research is extending the use of PARP inhibitors beyond BRCA mutations to other sensitising molecular defects that result in HR-deficient cancer, and is defining an HR-deficiency signature. Trials are underway to determine whether such a signature will predict sensitivity to PARP inhibitors in women with sporadic OC.

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458 DNA repair deficiencies in ovarian cancer: Genomic analysis of high grade serous ovarian tumors from the NOVA study

Cited by 2 publications

References 0 publications

The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies

The emerging role of homologous recombination repair and PARP inhibitors in genitourinary malignancies

PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions

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