Increased Incidence of Visceral Metastases in Scottish Patients With BRCA1/2-Defective Ovarian Cancer: An Extension of the Ovarian BRCAness Phenotype

Gourley, Charlie; Michie, Caroline O.; Roxburgh, Patricia; Yap, Timothy A.; Harden, Sharon; Paul, Jim; Ragupathy, Kalpana; Todd, R; Petty, Russell; Reed, Nick; Hayward, Richard L; Mitchell, Paul; Rye, Tzyvia; Schellens, Jan H.M.; Lubiński, Jan; Carmichael, James; Kaye, Stan B.; Mackean, Melanie; Ferguson, Michelle

doi:10.1200/jco.2009.25.1082

Cited by 84 publications

(55 citation statements)

References 24 publications

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“…Moreover, patients in this series could only access olaparib through clinical trials mainly (83%) involving resistant/partially sensitive disease, that is, patients with anticipated shorter OS. The median OS from initial diagnosis of 66.3 months for our patients lies within the range previously reported in observational studies of BRCA1/2-mutated patients with EOC before PARPi became available (29,30) and randomized trials will be required to properly assess the impact of olaparib on OS in BRCA1/2 mutation-associated EOC patients. In this context, a recently reported subgroup analysis of OS in the olaparib maintenance trial does suggest an OS benefit (HR of 0.74) for patients positive for germline and/or somatic BRCA1/2 mutations which was not evident in the overall population (HR of 0.88; ref 12,31).…”

Section: Discussionmentioning

confidence: 55%

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

Ang

Gourley

Powell

et al. 2013

Clinical Cancer Research

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131

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Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at !200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing.Results: Data were collected from 89 patients who received a median of 3 (range 1-11) lines of preolaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13-21] and 34 weeks (95% CI, 26-42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15-29) and OS of 45 weeks (95% CI, 15-75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0-0.375)].Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development

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Section: Discussionmentioning

confidence: 55%

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

Ang

Gourley

Powell

et al. 2013

Clinical Cancer Research

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131

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“…A recent meta-analysis of gene expression analyses has described a combination of biological markers that identified patients with suboptimal debulking [22]. Moreover, patients with BRCA1/2 mutation had a significantly higher risk of developing visceral metastases than matched controls without BRCA1/2 mutations [23]. Further work is warranted to clarify, whether tumor biology would help to identify those subgroups not suitable for upfront debulking surgery or even any surgery at all.…”

Section: Discussionmentioning

confidence: 97%

Pattern of and reason for postoperative residual disease in patients with advanced ovarian cancer following upfront radical debulking surgery

Heitz

Harter

Alesina

et al. 2016

Gynecologic Oncology

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“…Notably, HR-deficient cancers have a different phenotype and are often more sensitive to crosslinking agents including cisplatin than their HR-proficient counterparts (Bryant et al, 2005;Farmer et al, 2005;Ratnam and Low, 2007). For instance, BRCA1/2-deficient ovarian cancers metastasize to viscera more frequently than sporadic epithelial ovarian cancers (which most often remain confined to the peritoneum), yet are generally more responsive to platinum compounds and associated with better prognosis (Ben David et al, 2002;Chetrit et al, 2008;Gourley et al, 2010). Moreover, it has been shown that cisplatin resistance can develop in initially cisplatinsensitive tumors because of secondary mutations that compensate for BRCA1/2 deficiency and re-establish HR (Edwards et al, 2008;Sakai et al, 2008).…”

Section: Mlh1mentioning

confidence: 99%

Molecular mechanisms of cisplatin resistance

et al. 2011

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Platinum-based drugs, and in particular cis-diamminedichloroplatinum(II) (best known as cisplatin), are employed for the treatment of a wide array of solid malignancies, including testicular, ovarian, head and neck, colorectal, bladder and lung cancers. Cisplatin exerts anticancer effects via multiple mechanisms, yet its most prominent (and best understood) mode of action involves the generation of DNA lesions followed by the activation of the DNA damage response and the induction of mitochondrial apoptosis. Despite a consistent rate of initial responses, cisplatin treatment often results in the development of chemoresistance, leading to therapeutic failure. An intense research has been conducted during the past 30 years and several mechanisms that account for the cisplatin-resistant phenotype of tumor cells have been described. Here, we provide a systematic discussion of these mechanism by classifying them in alterations (1) that involve steps preceding the binding of cisplatin to DNA (pre-target resistance), (2) that directly relate to DNAcisplatin adducts (on-target resistance), (3) concerning the lethal signaling pathway(s) elicited by cisplatin-mediated DNA damage (post-target resistance) and (4) affecting molecular circuitries that do not present obvious links with cisplatin-elicited signals (off-target resistance). As in some clinical settings cisplatin constitutes the major therapeutic option, the development of chemosensitization strategies constitute a goal with important clinical implications.

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Increased Incidence of Visceral Metastases in Scottish Patients With BRCA1/2-Defective Ovarian Cancer: An Extension of the Ovarian BRCAness Phenotype

Cited by 84 publications

References 24 publications

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

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

Pattern of and reason for postoperative residual disease in patients with advanced ovarian cancer following upfront radical debulking surgery

Molecular mechanisms of cisplatin resistance

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