215 Updated clinical and preliminary correlative results of ARIEL2, a Phase 2 study to identify ovarian cancer patients likely to respond to rucaparib

Swisher, E.; Brenton, James D.; Kaufmann, S.; Oza, Amit M.; Coleman, R.L.; O’Malley, D.; Konecny, Gottfried E.; Ma, Lin; Visscher, DW; Hendrickson, Andrea Wahner; Lin, Kathleen; Raponi, Mitch; Mann, Elaina; Giordano, Heidi; Maloney, Lara; Rolfe, Lindsey; McNeish, Iain A.

doi:10.1016/s0959-8049(14)70341-7

Cited by 8 publications

(3 citation statements)

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“…Of note, genomic LOH was recently shown to correlate well with response to the PARPi rucaparib in a phase 2 clinical trial in EOC (ARIEL2). Specifically, among the women without the BRCA 1/2 mutations, those with high genomic LOH had an overall response rate of between 32–40%, while those without LOH had an overall response rate of just 8% (59). …”

Section: Biomarkers Of Hr Deficiencymentioning

confidence: 99%

Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer

et al. 2015

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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.

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Section: Biomarkers Of Hr Deficiencymentioning

confidence: 99%

Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer

et al. 2015

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“…The HRD test developed by Clovis has been associated with sensitivity to the PARP inhibitor rucaparib, even in the absence of BRCA mutation. 26 An ongoing phase II trial (RUBY) is testing whether rucaparib could present antitumor activity in patients with BRCA1/2 wild-type who present a high HRD. Beyond HRD and BRCA, assessing other DNA repair genes or pathways could allow expanding the array of patients who could be eligible for synthetic lethality strategies.…”

Section: Key Pointsmentioning

confidence: 99%

Precision Medicine for Metastatic Breast Cancer

Deluche

Onesti

Varga

2015

American Society of Clinical Oncology Educational Book

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OVERVIEWGenomic studies have shown that large numbers of candidate targets are observed in breast cancer. Nevertheless, only a few of them are validated as relevant targets in clinical studies. Estrogen receptor (ER) and HER2 expressions could be associated with a level I evidence. Beyond ER and HER2, BRCA and PIK3CA mutations (when targeted with alpha-specific PI3K inhibitors) could be considered as promising targets in breast cancer since they have been associated with objective responses in phase I/II trials. In addition to these four molecular alterations, several others have shown promising results in preclinical studies and are being investigated in clinical trials. These genomic alterations include AKT1, ERBB2, and ESR1 mutations. These considerations highlight the lack of evidence for using multiplex technologies to individualize therapy in metastatic breast cancer. Sequencing multiple genes to treat metastatic breast cancer is very promising but should be done in the context of clinical trials, either to enrich phase I/II trials in patients with genomic alterations or to show medical usefulness of new biotechnologies like next-generation sequencing (NGS). Although most current approaches of precision medicine are aiming at targeting drivers, additional applications could be developed in the future. This includes the identification of DNA repair deficiencies, mechanisms of immune suppression, and identification of minority lethal subclones. Finally, one of the very promising applications of genomics for metastatic breast cancer is the identification of pathway activation or defects at the individual level. For example, gene expression and single nucleotide polymorphisms (SNP) signatures are being developed to detect kinase (such as mammalian target of rapamycin [mTOR]/CDK4) activations or DNA repair deficiencies.

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“…What if we find a variant of unknown significance? PARP inhibitors are predicted to be effective in ovarian cancers with other non‐ BRCA1 / 2 homologous recombination deficiencies or “BRCAness,” but studies remain ongoing, and these drugs are not yet approved for therapeutic use in this setting.…”

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confidence: 99%

The more you look, the more you will find

Walsh

2015

Cancer

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In the current issue of Cancer, Sakamoto et al 1 report on the prevalence of deleterious BRCA1 and BRCA2 germline mutations in an otherwise unselected population of Japanese women with ovarian, fallopian tube, and primary peritoneal cancer. Using a comprehensive next-generation sequencing protocol, this study that found 12 of 95 patients (approximately 13%) carried a deleterious mutation in BRCA1 (5.3%) or BRCA2 (7.4%). This is higher than the rates of approximately 5% to 6% reported by prior Japanese studies. 2,3 This rate also equals those described in Western countries, where 13% to 15% of ovarian cancer patients have been found to harbor a BRCA1/2 mutation. [4][5][6] This study challenges the previously held notion that germline BRCA1/2 mutations are less prevalent in ovarian cancer patients from Asian countries such as Japan.These findings support the concept that the more you look, the more you will find. The 2 prior Japanese studies reporting a lower prevalence of mutations used more limited sequencing approaches.2,3 One study limited its sequencing strategy to the BRCA1 gene only, whereas the other study used an even more restricted approach and sequenced only exon 11 of the BRCA1 gene. In contrast, the current study by Sakamoto et al 1 used a next-generation sequencing protocol to comprehensively analyze the full exons as well as the exon-intron boundaries of the BRCA1 and BRCA2 genes. The current study also used multiplex ligation-dependent probe amplification, a method for detecting large genomic rearrangements, and found a deleterious multiple exon deletion in BRCA2 for 1 patient. Table 1 in this study demonstrates the heterogeneity of the mutations detected, with the 12 different mutations represented by 5 frameshift mutations, 5 nonsense mutations, a missense mutation resulting in a splicing defect, and a genomic rearrangement. The mutations were not clustered in any particular locations but rather were found scattered throughout the 2 genes. This diversity is in line with the fact that more than 1600 and 1800 different mutations have been reported in BRCA1 and BRCA2, respectively, 7 and it supports a more comprehensive approach to mutation detection. The more you look, the more you will find.This study also addresses the important question of whether or not there are clinical characteristics with which we should triage our genetic testing strategies, such as the age of ovarian cancer onset or a family history of cancer. Although BRCA1/2 mutation carriers tend to have a particular ovarian cancer phenotype, there are data to support an unselected and more comprehensive screening approach. Although BRCA1 carriers have an age of ovarian cancer onset that is decades earlier than that of their sporadic counterparts, this is offset by the later age of onset of BRCA2 carriers, which mirrors that of sporadic ovarian cancer development.8 BRCA1/2 carriers may have a family history that is suggestive of a genetic syndrome, but carriers are not infrequently found among those individuals lacking suspicious pedi...

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215 Updated clinical and preliminary correlative results of ARIEL2, a Phase 2 study to identify ovarian cancer patients likely to respond to rucaparib

Cited by 8 publications

References 0 publications

Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer

Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer

Precision Medicine for Metastatic Breast Cancer

The more you look, the more you will find

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