Poly(ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in <i>BRCA</i> Carrier Ovarian Cancer Correlating With Platinum-Free Interval

Fong, Peter; Yap, Timothy A.; Boss, David S.; Carden, Craig P.; Mergui-Roelvink, Marja; Gourley, Charlie; Grève, Jacques De; Lubiński, Jan; Shanley, Susan; Messiou, Christina; A’Hern, Roger; Tutt, Andrew; Ashworth, Alan; Stone, Joseph; Carmichael, James; Schellens, Jan H.M.; Bono, Johann S. de; Kaye, Stan B.

doi:10.1200/jco.2009.26.9589

Cited by 880 publications

(648 citation statements)

References 26 publications

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“…This subgroup may be amenable to specific therapeutic strategies such as inhibitors of the PARP enzyme. 32,[81][82][83]130,131 Consistent with this hypothesis, results of PARP inhibitor phase I and phase II clinical trials that have included patients with BRCA-deficient tumors have been encouraging [132][133][134] and sustained responses in patients with BRCA1/2-deficient breast or ovarian metastatic cancers have been observed. Furthermore, preliminary results of a phase II clinical trial revealed that addition of BSI-201, a PARP inhibitor, to gemcitabine/carboplatin chemotherapy led to a significantly increased clinical benefit and longer progression-free survival.…”

Section: Clinical Behavior Of Basal-like and Triple-negative Breast Cmentioning

confidence: 76%

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

et al. 2011

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Breast cancer is a heterogeneous disease encompassing a variety of entities with distinct morphological features and clinical behaviors. Although morphology is often associated with the pattern of molecular aberrations in breast cancers, it is also clear that tumors of the same histological type show remarkably different clinical behavior. This is particularly true for 'basal-like cancer', which is an entity defined using gene expression analysis. The purpose of this article was to review the current state of knowledge of basal-like breast cancers, to discuss the relationship between basal-like and triple-negative breast cancers, and to clarify practical implications of these diagnoses for pathologists and oncologists.

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Section: Clinical Behavior Of Basal-like and Triple-negative Breast Cmentioning

confidence: 76%

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

et al. 2011

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“…In the absence of HR, as occurs when BRCA mutations are present, these DSBs are repaired by error-prone forms of DSB, such as non-homologous en-joining potentially resulting in accumulation of gene aberrations and loss of cell viability. 106,107 Significant efficacy has been established for PARP inhibitors in BRCA-mutated breast and ovarian tumours, [108][109][110] although the evidence for PCa is still limited. Clinical trials are currently ongoing to assess the role of PARP inhibitors in PCa BRCA-related, as well as in sporadic tumours.…”

Section: Discussionmentioning

confidence: 99%

“…101,[108][109][110] The aggressive phenotype and poor prognosis associated with PCa in patients with germline BRCA mutations is very likely to be associated with a different cancer biology from BRCA wild-type PCa. The identification of these differential molecular characteristics could be essential in tailoring treatment for this population, but it may also be of great importance for the management of some sporadic PCa cases which may have similar clinical characteristics and aggressive behaviour.…”

Section: Discussionmentioning

confidence: 99%

The role of BRCA1 and BRCA2 in prostate cancer

Castro¹,

Eeles²

2012

Asian J Androl

135

105

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One of the strongest risk factors for prostate cancer is a family history of the disease. Germline mutations in the breast cancer predisposition gene 2 (BRCA2) are the genetic events known to date that confer the highest risk of prostate cancer (8.6-fold in men f65 years). Although the role of BRCA2 and BRCA1 in prostate tumorigenesis remains unrevealed, deleterious mutations in both genes have been associated with more aggressive disease and poor clinical outcomes. The increasing incidence of prostate cancer worldwide supports the need for new methods to predict outcome and identify patients with potentially lethal forms of the disease. As we present here, BRCA germline mutations, mainly in the BRCA2 gene, are one of those predictive factors. We will also discuss the implications of these mutations in the management of prostate cancer and hypothesize on the potential for the development of strategies for sporadic cases with similar characteristics.

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“…Several studies have confirmed anti-tumour effects in human breast and ovarian cancers in patients carrying BRCA1 or BRCA2 germline mutations. [249][250][251][252][253][254] Of note, although ovarian cancer patients treated for high-grade epithelial cancers not harbouring BRCA1/2 germline mutations responded to PARP inhibition with Olaparib with a response rate similar to that of BRCA1/2 mutation carriers, no response to Olaparib monotherapy was recorded among patients treated for triple-negative breast cancer harbouring wild-type BRCA1/2. 253 BRCA1/2 somatic and germline mutations are observed more frequently in ovarian (420%) as compared with breast cancers; 255 yet, the finding of a high response rate to PARP inhibitors in high-grade ovarian cancers suggests alternative mechanisms of HRR inactivation may operate in addition.…”

Section: Homologous Recombination Repairmentioning

confidence: 99%

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

Lønning

Knappskog

2013

Oncogene

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Although new agents are implemented to cancer therapy, we lack fundamental understandings of the mechanisms of chemoresistance, the main obstacle to cure in cancer. Here we review clinical evidence linking molecular defects to drug resistance across different tumour forms and discuss contemporary experimental evidence exploring these mechanisms. Although evidence, in general, is sparse and fragmentary, merging knowledge links drug resistance, and also sensitivity, to defects in functional pathways having a key role in cell growth arrest or death and DNA repair. As these pathways may act in concert, there is a need to explore multiple mechanisms in parallel. Taking advantage of massive parallel sequencing and other novel high-throughput technologies and base research on biological hypotheses, we now have the possibility to characterize functional defects related to these key pathways and to design a new generation of studies identifying the mechanisms controlling resistance to different treatment regimens in different tumour forms.

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Poly(ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer Correlating With Platinum-Free Interval

Abstract: Olaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.

Cited by 880 publications

References 26 publications

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

Basal-like and triple-negative breast cancers: a critical review with an emphasis on the implications for pathologists and oncologists

The role of BRCA1 and BRCA2 in prostate cancer

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

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