Efficacy of Chemotherapy in <i>BRCA1/2</i> Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study

Ang, Joo Ern; Gourley, Charlie; Powell, Charles; High, Hilda; Shapira‐Frommer, Ronnie; Castonguay, Vincent; Grève, Jacques De; Atkinson, Tina; Yap, Timothy A.; Sandhu, Shahneen; Banerjee, Susana; Chen, Lee May; Friedlander, Michael; Kaufman, Bella; Oza, Amit M.; Matulonis, Ursula A.; Barber, Louise J.; Kozarewa, Iwanka; Fenwick, Kerry; Assiotis, Ioannis; Campbell, James; Chen, Lina; Bono, Johann S. de; Gore, Martin; Lord, Christopher J.; Ashworth, Alan; Kaye, Stan B.

doi:10.1158/1078-0432.ccr-13-1262

Cited by 132 publications

(90 citation statements)

References 31 publications

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“…For patients treated post-olaparib with platinum-based chemotherapy, the ORR was 40% (n ¼ 19 of 48 patients; ref. 25). The corresponding ORRs when incorporating CA-125 were 45% and 49%, respectively (25).…”

Section: Discussionmentioning

confidence: 97%

“…25). The corresponding ORRs when incorporating CA-125 were 45% and 49%, respectively (25). The length of the platinum-to-platinum interval with intervening olaparib was associated with an increased likelihood of response (25).…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of the preclinical data, early essayists were concerned that treatment with PARP inhibitors would result in acquisition of secondary BRCA1/2 mutations that would limit the efficacy of subsequent chemotherapy, specifically, platinumbased agents. Ang and colleagues (25) collected data from 89 patients with BRCA-deficient ovarian cancer who had been previously treated with olaparib at daily dosages of 200 mg and higher. The ORR by RECIST to post-olaparib chemotherapy was 36% (n ¼ 24 of 67 patients).…”

Section: Discussionmentioning

confidence: 99%

“…The corresponding ORRs when incorporating CA-125 were 45% and 49%, respectively (25). The length of the platinum-to-platinum interval with intervening olaparib was associated with an increased likelihood of response (25). Tumor was available from 6 cases and subjected to massively parallel sequencing, which demonstrated no evidence of secondary BRCA mutations (25).…”

Section: Discussionmentioning

confidence: 99%

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Development of Olaparib for BRCA-Deficient Recurrent Epithelial Ovarian Cancer

Tewari

Eskander

Monk

2015

Clinical Cancer Research

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The FDA approval of the PARP inhibitor olaparib for fourth-line therapy of germline BRCA1/2-mutated ovarian cancer represents the first registered indication for this class of drugs in any disease. PARP is a family of proteins involved in the repair of single-strand DNA breaks. High-grade serous ovarian carcinomas with BRCA deficiencies may be particularly vulnerable to both direct and indirect effects of PARP inhibition. This phenotype frequently arises as a consequence of defects in the repair of damaged DNA, rendering cancer cells susceptible to DNA-damaging platinum compounds and targeted therapies affecting homologous recombination repair (HRR). When cells already deficient in HRR are exposed to PARP inhibitors, apoptosis occurs by way of synthetic lethality. In this review, we trace the clinical development of olaparib for women with recurrent epithelial ovarian carcinoma harboring germline BRCA mutations, a biomarker for HRR deficiency present in 15% to 20% of cases. Clinical trials highlighted include not only those pivotal studies that have led to regulatory approval in the United States and in Europe, but also those in which olaparib was studied in novel combinations, including chemotherapy and antiangiogenesis agents.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Development of Olaparib for BRCA-Deficient Recurrent Epithelial Ovarian Cancer

Tewari

Eskander

Monk

2015

Clinical Cancer Research

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“…They already tested no less than 89 patients in a retrospective review of patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC) who received chemotherapy following disease progression on olaparib, administered at 200 mg twice daily for 1 month or more (10). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum.…”

Section: Resistancementioning

confidence: 99%

PARP inhibitors and more

Bose¹,

Basu²

2015

J Turkish German Gynecol Assoc

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Review 107 IntroductionThe history of polyadenosine diphosphate (ADP) ribose polymerase (PARP) invention is fascinating. Japanese did equally well when a French group (1) discovered in an experiment of kidney cortical nuclei that more phosphate is absorbed from nicotine adenine dinucleotide (NAD). This gives rise to branched poly's of ADP ribose, which not only could anchor on the single stand defects of DNA but could also bring the other players of single strand repair to the field. X-ray repair cross-complementing protein 1 (XRCC1) and other proteins are such players. The initiation of repair is a little confusing activity of the protein enzyme PARPs, which has its 17 types working mainly through types 1 and 2. Inflammation, chemical, and radiation injury are the least known about that activity. They have the onus to manage about ten thousand single strand breaks (SSB's) of a mixed etiology per day. In the presence of inhibitors, PARP cannot prevent stand breaks, instead SSB's pile up at fork to cause double strand breaks (DSB). This DSB is historically managed by breast cancer (BRCA) 1 in female breasts and in male breasts, particularly with tumor suppressor twin BRCA 2. They repair DSB, but being mutated congregates huge load of unrepaired DSB causing "synthetic lethality" of cancer cell. (2-4). These inhibitors will even be tried now in related tumors with BRCAness (5). BRCAness is a behavior of certain tumors, such as some non BRCA ovarian cancer and triple negative breast cancer. "BRCAness" traits in some sporadic cancers are similar to either BRCA1-or BRCA2-mutation carriers. They have 396 well appearances reciprocating those of BRCA negatives.In the pharmaceutical industry, the invention of PARP inhibitor (PARPi) and eventual availability in the market of first molecule of its kind, such as olaparib, becomes possible only after very stringent clinical trial. Then, there will be a question of resistance, which could be as high as more than seventy percent in refractory group (6). We will take a look at the progress of the subject in following few paragraphs. th , 2014 after an expedited review process over the same trial on the basis of second interim analysis. On the other hand, a diagnostic company announced approval from the U.S. FDA on the same day for their BRACAnalysis CDx diagnostic kit to be used as the only companion diagnostic in conjunction with olaparib. BRACAnalysis CDx is this company's first FDA-approved companion diagnostic for use with a novel PARP inhibitor. It is a highly accurate molecular companion diagnostic test that identifies deleterious or suspected deleterious mutations in BRCA1 and BRCA2 genes using DNA obtained from a blood sample. Olaparib was approved for a similar indication in the European Union just only a day earlier than done by USF-DA after a recommendation for approval obtained in October from the European Medicines Agency. Breast cancer, which is associated with lesser percentage of such mutation (10% against 15%), is reasonably in the pipeline as a trial of this ca...

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Homologous recombination deficiency score is an independent prognostic factor in esophageal squamous cell carcinoma

Wang,

Ding,

Tao

et al. 2024

The Journal of Pathology CR

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Homologous recombination deficiency (HRD) represents an impairment in the homologous recombination repair (HRR) pathway, crucial for repairing DNA double‐strand breaks and contributing to genomic instability in cancer. The HRD score may be a more reliable biomarker than HRR‐related gene mutations for identifying patients sensitive to poly(ADP‐ribose) polymerase inhibitors. Despite its relevance in various cancers, the HRD score remains underexplored in esophageal squamous cell carcinoma (ESCC). We retrospectively analyzed HRD scores in 96 ESCC patients, examining correlations with clinical characteristics and survival outcomes, and validated our findings using the TCGA dataset. Genomic sequencing utilized a custom superHRD next‐generation sequencing panel, and HRD scores were calculated from 54,000 single‐nucleotide polymorphisms using Kruskal–Wallis rank‐sum tests and two cut‐off points for analysis. Higher HRD scores correlated with advanced tumor stages, recurrence, and mutations in TP53 and ABCB1, while APC mutations were linked to lower HRD scores. Patients with high HRD scores had significantly shorter disease‐free survival (p = 0.013) and a trend toward shorter overall survival (OS) (p = 0.005), particularly those not receiving adjuvant therapy. Conversely, HRD‐high patients undergoing adjuvant therapy showed a trend toward longer OS (p = 0.015). Multivariate analysis identified HRD as an independent prognostic factor (hazard ratio = 2.814 for recurrence, p = 0.015). Validation with the TCGA dataset supported these findings. This study highlights the associations between HRD scores, clinical characteristics, and genomic mutations in ESCC, suggesting HRD as a potential prognostic biomarker. HRD assessment may aid in patient stratification and personalized treatment strategies, warranting further investigation to validate the therapeutic implications of HRD scores in ESCC.

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Efficacy of Chemotherapy in BRCA1/2 Mutation Carrier Ovarian Cancer in the Setting of PARP Inhibitor Resistance: A Multi-Institutional Study

Cited by 132 publications

References 31 publications

Development of Olaparib for BRCA-Deficient Recurrent Epithelial Ovarian Cancer

Development of Olaparib for BRCA-Deficient Recurrent Epithelial Ovarian Cancer

PARP inhibitors and more

Homologous recombination deficiency score is an independent prognostic factor in esophageal squamous cell carcinoma

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