Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation
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...This cohort study provides clinically actionable information that could impact treatment decisions for these affected individuals....
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"Olaparib Monotherapy in Patients Wi..." refers background in this paper
...Jaspers JE, Kersbergen A, Boon U, et al: Loss of 53BP1 causes PARP inhibitor resistance in Brca1mutated mouse mammary tumors....
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...Germline status of BRCA1/2 in individuals with cancer defines a target population for whom PARP inhibitors seem beneficial....
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...© 2014 by American Society of Clinical Oncology INTRODUCTION Poly (ADP-ribose) polymerase (PARP) inhibitors have been studied as potential cancer therapeutics in breast and ovarian cancers....
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...Patients were excluded for the following: receipt of prior PARP inhibitors; prior malignancy, active or treated within 5 years, with the exception of a second suspected BRCA-related malignancy, treated in situ cervical carcinoma, stage I endometrial cancer, or nonmelanoma skin cancer; receipt of systemic chemotherapy or radiotherapy within 2 weeks of study (stable doses of bisphosphonates for bone metastases and luteinizing hormone-releasing hormone in patients with prostate cancer were permitted); use of potent inhibitors of CYP4503A4 (CYP3A4); persistent therapy-related toxicities (grade 2 according to Common Terminology Criteria for Adverse Events); major surgery 2 weeks before study; symptomatic uncontrolled brain metastases; and other medical conditions suggesting poor medical risk....
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...Mechanisms of PARP resistance in BRCA1/2-associated tumors have been proposed, including genetic reversion of truncating mutations in BRCA1 or BRCA2, stabilization of mutant protein, loss of 53BP1, and presence of hypomorphic BRCA1 or BRCA2 function (such as that postulated with BRCA1 C61G mutation).19-21 Many of these proposed mechanisms may be important to platinum resistance as well, and therefore, there has been concern that platinum-resistant tumors would not respond to PARP inhibition....
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