Management of Ovarian Cancer

Konstantinopoulos, Panagiotis A.; Awtrey, Christopher S.

doi:10.1001/jama.2012.269

Cited by 11 publications

(7 citation statements)

References 96 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Section: Introductionmentioning

confidence: 99%

“…Approximately 75% of EOC patients are diagnosed with advanced disease which is curable only in a minority of the cases resulting in a modest 5-year overall survival rate of 20–30% (2, 3). The standard of care management of EOC consists of primary surgical cytoreduction followed by platinum-based chemotherapy (3, 4). Platinum analogues have been used to treat ovarian cancer since the late 1970s when clinical trials demonstrated that cisplatin was capable of achieving almost double the overall response rates and the number of complete responses compared with non-platinum agents (5, 6).…”

Section: Introductionmentioning

confidence: 99%

“…Since then, platinum agents (initially cisplatin, then carboplatin which is better tolerated but equally effective (7)) have constituted the backbone of chemotherapy used in EOC and have defined the comparison arms for the majority of the clinical trials conducted in this disease. However, despite important advancements in the efficacy of platinum chemotherapy achieved by incorporation of taxanes (8) in the 1990s and by administration of chemotherapy via the intraperitoneal (IP) route (9) in early 2000, the plateau of the survival curve has not changed appreciably (3, 8, 10–12), suggesting that alternative approaches are urgently needed.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer

et al. 2015

View full text Add to dashboard Cite

Approximately 50% of epithelial ovarian cancers (EOCs) exhibit defective DNA repair via homologous recombination (HR) due to genetic and epigenetic alterations of HR pathway genes. Defective HR is an important therapeutic target in EOC as exemplified by the efficacy of platinum analogues in this disease, as well as the advent of poly-ADP ribose polymerase inhibitors which exhibit synthetic lethality when applied to HR deficient cells. Here, we describe the genotypic and phenotypic characteristics of HR deficient EOCs, discuss current and emerging approaches for targeting these tumors, and present challenges associated with these approaches focusing on development and overcoming resistance.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Platinum analogues (cisplatin and carboplatin) are active agents against epithelial ovarian cancer (EOC) and constitute the backbone of first-line chemotherapy used in this disease (1, 2). The enhanced platinum sensitivity of EOC tumors is thought to be related to an underlying defect in homologous repair (HR)–mediated DNA repair, particularly in those tumors with high-grade serous histology.…”

Section: Introductionmentioning

confidence: 99%

A Unique Subset of Epithelial Ovarian Cancers with Platinum Sensitivity and PARP Inhibitor Resistance

et al. 2015

View full text Add to dashboard Cite

Platinum and PARP inhibitor (PARPi) sensitivity commonly coexist in epithelial ovarian cancer (EOC) due to the high prevalence of alterations in the homologous recombination (HR) DNA repair pathway that confer sensitivity to both drugs. In this report, we describe a unique subset of EOC with alterations in another DNA repair pathway, the nucleotide excision repair (NER) pathway, which may exhibit a discordance in sensitivities to these drugs. Specifically, 8% of high-grade serous EOC from The Cancer Genome Atlas dataset exhibited NER alterations, including nonsynonymous or splice site mutations and homozygous deletions of NER genes. Tumors with NER alterations were associated with improved overall survival (OS) and progression-free survival (PFS), compared with patients without NER alterations or BRCA1/2 mutations. Furthermore, patients with tumors with NER alterations had similar OS and PFS as BRCA1/2-mutated patients, suggesting that NER pathway inactivation in EOC conferred enhanced platinum sensitivity, similar to BRCA1/2-mutated tumors. Moreover, two NER mutations (ERCC6-Q524* and ERCC4-A583T), identified in the two most platinum-sensitive tumors, were functionally associated with platinum sensitivity in vitro. Importantly, neither NER alteration affected HR or conferred sensitivity to PARPi or other double-strand break–inducing agents. Overall, our findings reveal a new mechanism of platinum sensitivity in EOC that, unlike defective HR, may lead to a discordance in sensitivity to platinum and PARPi, with potential implications for previously reported and ongoing PARPi trials in this disease.

show abstract

“…Epithelial ovarian cancers (EOCs) are the most lethal gynecologic malignancies 18,19 . The high mortality rate is a result of delayed diagnosis and limited therapeutic options despite the use of new drugs, such as the inhibitors of angiogenesis or DNA repair pathways 20,21 .…”

Section: Introductionmentioning

confidence: 99%

Low centrosome numbers correlate with higher aggressivity in ovarian cancer

Morretton

Herbette

Cosson

et al. 2019

Preprint

View full text Add to dashboard Cite

Centrosome amplification has been described as a common feature of human cancers and it is known to promote tumorigenesis when induced in animals.However, little is known about the real status of centrosome numbers in human cancers and whether numerical alterations are solely associated with poor prognosis. To address this question, we have analyzed a large cohort of human epithelial ovarian cancers (EOCs) from 100 patients using state-of-the-art microscopy to determine the Centrosome-Nucleus Index (CNI) of each tumor. We found that EOCs are highly heterogeneous, with infrequent but strong centrosome amplifications leading to higher CNI than in healthy tissues. Strikingly, while a correlation between CNI and genomic alterations, such as aneuploidy or chromosome rearrangements could not be established, we found that high CNI correlates with increased patient survival and sensitivity to chemotherapy. Using ovarian cancer cellular models to manipulate centrosome numbers and Patient-Derived Xenografts (PDXs), we found that higher CNIs can positively impact the response to chemotherapy and inhibit cell dissemination. Our findings highlight a novel paradigm linking centrosome amplification to the inhibition of tumor progression.

show abstract

Management of Ovarian Cancer

Cited by 11 publications

References 96 publications

Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer

Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer

A Unique Subset of Epithelial Ovarian Cancers with Platinum Sensitivity and PARP Inhibitor Resistance

Low centrosome numbers correlate with higher aggressivity in ovarian cancer

Contact Info

Product

Resources

About