The Experts below are selected from a list of 64833 Experts worldwide ranked by ideXlab platform
William M Audeh - One of the best experts on this subject based on the ideXlab platform.
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novel treatment strategies in triple negative breast cancer specific role of poly adenosine diphosphate ribose polymerase inhibition
Pharmacogenomics and Personalized Medicine, 2014Co-Authors: William M AudehAbstract:Inhibitors of the poly(adenosine triphosphate-ribose) polymerase (PARP)-1 enzyme induce synthetic lethality in cancers with ineffective DNA (DNA) repair or homologous repair deficiency, and have shown promising clinical activity in cancers deficient in DNA repair due to germ-line mutation in BRCA1 and BRCA2. The majority of breast cancers arising in carriers of BRCA1 germ-line mutations, as well as half of those in BRCA2 carriers, are classified as triple-negative breast cancer (TNBC). TNBC is a biologically heterogeneous group of breast cancers characterized by the lack of immunohistochemical expression of the ER, PR, or HER2 proteins, and for which the current standard of care in systemic therapy is cytotoxic chemotherapy. Many “sporadic” cases of TNBC appear to have indicators of DNA repair dysfunction similar to those in BRCA-mutation carriers, suggesting the possible utility of PARP inhibitors in a subset of TNBC. Significant genetic heterogeneity has been observed within the TNBC cohort, creating challenges for interpretation of prior clinical trial data, and for the design of future clinical trials. Several PARP inhibitors are currently in clinical development in BRCA-mutated breast cancer. The use of PARP inhibitors in TNBC without BRCA mutation will require biomarkers that identify cancers with homologous repair deficiency in order to select patients likely to respond. Beyond mutations in the BRCA genes, dysfunction in other genes that interact with the homologous repair pathway may offer opportunities to induce synthetic lethality when combined with PARP inhibition.
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oral poly adp ribose polymerase inhibitor olaparib in patients with BRCA1 or brca2 mutations and recurrent ovarian cancer a proof of concept trial
The Lancet, 2010Co-Authors: Andrew Tutt, Jeffrey N Weitzel, Susan M Domchek, Mark E Robson, Judy Garber, William M Audeh, Michael Friedlander, Banu Arun, Niklas Loman, Rita K SchmutzlerAbstract:Summary Background Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA -deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA -deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. Methods Women (aged ≥18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234. Findings Patients had been given a median of three previous chemotherapy regimens (range 1–5 in cohort 1, and 2–4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25–59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11–41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]). Interpretation The results of this study provide positive proof of concept for PARP inhibition in BRCA -deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1 -associated or BRCA2 -associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations. Funding AstraZeneca.
Alan Ashworth - One of the best experts on this subject based on the ideXlab platform.
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making the best of parp inhibitors in ovarian cancer
Nature Reviews Clinical Oncology, 2010Co-Authors: Susana Banerjee, Stan B. Kaye, Alan AshworthAbstract:Inhibitors of poly(ADP-ribose)polymerase (PARP) have shown promise as therapeutic agents for the treatment of ovarian cancers with mutations in BRCA1 or BRCA2. By exploiting the synthetic lethal interaction that exists between PARP inhibition and BRCA mutations, these agents specifically kill cancer cells by targeting their DNA repair system. The authors of this Review describe the importance of BRCA mutations for the efficacy of PARP inhibitors. They also discuss the preclinical and clinical trial results of PARP inhibitors, the challenges related to the use of these agents, and future directions.
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inhibition of poly adp ribose polymerase in tumors from brca mutation carriers
The New England Journal of Medicine, 2009Co-Authors: Peter C C Fong, D S Boss, Timothy A Yap, Andrew Tutt, Marja Merguiroelvink, Peter S Mortimer, Helen Swaisland, Alan Lau, Mark J Oconnor, Alan AshworthAbstract:Background The inhibition of poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects, including those arising in carriers of a BRCA1 or BRCA2 mutation. We conducted a clinical evaluation in humans of olaparib (AZD2281), a novel, potent, orally active PARP inhibitor. Methods This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib. Selection was aimed at having a study population enriched in carriers of a BRCA1 or BRCA2 mutation. Results We enrolled and treated 60 patients; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated cancer but declined to undergo mutational testing. The olaparib dose and schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice...
Andrew Tutt - One of the best experts on this subject based on the ideXlab platform.
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oral poly adp ribose polymerase inhibitor olaparib in patients with BRCA1 or brca2 mutations and recurrent ovarian cancer a proof of concept trial
The Lancet, 2010Co-Authors: Andrew Tutt, Jeffrey N Weitzel, Susan M Domchek, Mark E Robson, Judy Garber, William M Audeh, Michael Friedlander, Banu Arun, Niklas Loman, Rita K SchmutzlerAbstract:Summary Background Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA -deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA -deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. Methods Women (aged ≥18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234. Findings Patients had been given a median of three previous chemotherapy regimens (range 1–5 in cohort 1, and 2–4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25–59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11–41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]). Interpretation The results of this study provide positive proof of concept for PARP inhibition in BRCA -deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1 -associated or BRCA2 -associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations. Funding AstraZeneca.
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inhibition of poly adp ribose polymerase in tumors from brca mutation carriers
The New England Journal of Medicine, 2009Co-Authors: Peter C C Fong, D S Boss, Timothy A Yap, Andrew Tutt, Marja Merguiroelvink, Peter S Mortimer, Helen Swaisland, Alan Lau, Mark J Oconnor, Alan AshworthAbstract:Background The inhibition of poly(adenosine diphosphate [ADP]–ribose) polymerase (PARP) is a potential synthetic lethal therapeutic strategy for the treatment of cancers with specific DNA-repair defects, including those arising in carriers of a BRCA1 or BRCA2 mutation. We conducted a clinical evaluation in humans of olaparib (AZD2281), a novel, potent, orally active PARP inhibitor. Methods This was a phase 1 trial that included the analysis of pharmacokinetic and pharmacodynamic characteristics of olaparib. Selection was aimed at having a study population enriched in carriers of a BRCA1 or BRCA2 mutation. Results We enrolled and treated 60 patients; 22 were carriers of a BRCA1 or BRCA2 mutation and 1 had a strong family history of BRCA-associated cancer but declined to undergo mutational testing. The olaparib dose and schedule were increased from 10 mg daily for 2 of every 3 weeks to 600 mg twice daily continuously. Reversible dose-limiting toxicity was seen in one of eight patients receiving 400 mg twice...
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deficiency in the repair of dna damage by homologous recombination and sensitivity to poly adp ribose polymerase inhibition
Cancer Research, 2006Co-Authors: Nuala Mccabe, Andrew Tutt, Mark J Oconnor, Nicholas C Turner, Christopher J Lord, Katarzyna Kluzek, Aneta Bialkowska, Sally Swift, Sabrina Giavara, Malgorzata Z ZdzienickaAbstract:Deficiency in either of the breast cancer susceptibility proteins BRCA1 or BRCA2 induces profound cellular sensitivity to the inhibition of poly(ADP-ribose) polymerase (PARP) activity. We hypothesized that the critical role of BRCA1 and BRCA2 in the repair of double-strand breaks by homologous recombination (HR) was the underlying reason for this sensitivity. Here, we examine the effects of deficiency of several proteins involved in HR on sensitivity to PARP inhibition. We show that deficiency of RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CHK1, CHK2, FANCD2, FANCA, or FANCC induces such sensitivity. This suggests that BRCA-deficient cells are, at least in part, sensitive to PARP inhibition because of HR deficiency. These results indicate that PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutation-associated tumors but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway or displaying properties of 'BRCAness.'
Rosette Lidereau - One of the best experts on this subject based on the ideXlab platform.
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description and analysis of genetic variants in french hereditary breast and ovarian cancer families recorded in the umd BRCA1 brca2 databases
Nucleic Acids Research, 2012Co-Authors: Sandrine Caputo, Louisa Benboudjema, Olga Sinilnikova, Etienne Rouleau, Christophe Beroud, Rosette LidereauAbstract:BRCA1 and BRCA2 are the two main genes responsible for predisposition to breast and ovarian cancers, as a result of protein-inactivating monoallelic mutations. It remains to be established whether many of the variants identified in these two genes, so-called unclassified/unknown variants (UVs), contribute to the disease phenotype or are simply neutral variants (or polymorphisms). Given the clinical importance of establishing their status, a nationwide effort to annotate these UVs was launched by laboratories belonging to the French GGC consortium (Groupe Genetique et Cancer), leading to the creation of the UMD-BRCA1/BRCA2 databases (http://www.umd.be/BRCA1/ and http://www.umd.be/BRCA2/). These databases have been endorsed by the French National Cancer Institute (INCa) and are designed to collect all variants detected in France, whether causal, neutral or UV. They differ from other BRCA databases in that they contain co-occurrence data for all variants. Using these data, the GGC French consortium has been able to classify certain UVs also contained in other databases. In this article, we report some novel UVs not contained in the BIC database and explore their impact in cancer predisposition based on a structural approach.
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Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases
Nucleic Acids Research, 2012Co-Authors: Sandrine Caputo, Louisa Benboudjema, Olga Sinilnikova, Etienne Rouleau, Christophe Beroud, Rosette Lidereau, French Brca Ggc ConsortiumAbstract:BRCA1 and BRCA2 are the two main genes responsible for predisposition to breast and ovarian cancers, as a result of protein-inactivating monoallelic mutations. It remains to be established whether many of the variants identified in these two genes, so-called unclassified/unknown variants (UVs), contribute to the disease phenotype or are simply neutral variants (or polymorphisms). Given the clinical importance of establishing their status, a nationwide effort to annotate these UVs was launched by laboratories belonging to the French GGC consortium (Groupe Génétique et Cancer), leading to the creation of the UMD-BRCA1/BRCA2 databases (http://www.umd.be/BRCA1/ and http://www.umd.be/BRCA2/). These databases have been endorsed by the French National Cancer Institute (INCa) and are designed to collect all variants detected in France, whether causal, neutral or UV. They differ from other BRCA databases in that they contain co-occurrence data for all variants. Using these data, the GGC French consortium has been able to classify certain UVs also contained in other databases. In this article, we report some novel UVs not contained in the BIC database and explore their impact in cancer predisposition based on a structural approach.
Claudine Isaacs - One of the best experts on this subject based on the ideXlab platform.
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Poly(ADP-Ribose) Inhibition: Exploring a New Approach to Breast Cancer Prevention in BRCA1/2 Mutation Carriers
Current Breast Cancer Reports, 2011Co-Authors: Karen L Smith, Claudine IsaacsAbstract:Carriers of deleterious BRCA1 and BRCA2 mutations face an elevated risk of developing breast cancer. This risk warrants consideration of prevention interventions. Currently, the only proven prevention intervention for BRCA mutation carriers is risk-reducing surgery. Inhibitors of poly(ADP-ribose) polymerase (PARP) are a new class of drugs that appear to be effective in treating BRCA mutation–associated cancers and triple-negative breast cancers. PARP inhibitors may offer a new approach to breast cancer prevention in BRCA mutation carriers. This article reviews current breast cancer prevention interventions for BRCA mutation carriers and discusses the rationale for investigating new chemoprevention agents in this population. The mechanism of action of PARP inhibitors and the rationale for studying them in BRCA mutation carriers is reviewed. Published clinical trials regarding PARP inhibitors and ongoing research regarding PARP inhibitors and breast cancer prevention are reviewed.
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risk reducing salpingo oophorectomy for the prevention of BRCA1 and brca2 associated breast and gynecologic cancer a multicenter prospective study
Journal of Clinical Oncology, 2008Co-Authors: Noah D Kauff, Claudine Isaacs, Henry T. Lynch, Susan M Domchek, Tara M Friebel, Mark E Robson, Judy Garber, Gareth D Evans, Rosalind A Eeles, Susan L NeuhausenAbstract:Purpose Risk-reducing salpingo-oophorectomy (RRSO) has been widely adopted as a key component of breast and gynecologic cancer risk-reduction for women with BRCA1 and BRCA2 mutations. Despite 17% to 39% of all BRCA mutation carriers having a mutation in BRCA2, no prospective study to date has evaluated the efficacy of RRSO for the prevention of breast and BRCAassociated gynecologic (ovarian, fallopian tube or primary peritoneal) cancer when BRCA2 mutation carriers are analyzed separately from BRCA1 mutation carriers.
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Management Updates for Women with a BRCA1 or BRCA2 Mutation
Molecular Diagnosis & Therapy, 2007Co-Authors: Rachel Nusbaum, Claudine IsaacsAbstract:In most cases of families with breast and ovarian cancer, the pattern of cancers in the family can be attributed to mutations in the BRCA1 and BRCA2 genes. Genetic testing for these cancer susceptibility genes typically takes place in the context of comprehensive genetic counseling. Strategies have been developed for the medical management of women at high risk of developing breast cancer, including options for screening and prophylactic surgery. BRCA1 and BRCA2 carriers are recommended to undergo prophylactic bilateral salpingo-oophorectomy by age 35–40 years or when childbearing is complete. This surgery significantly reduces the risk of ovarian cancer and also reduces the risk of breast cancer when performed in premenopausal mutation carriers. For breast cancer management, BRCA1 and BRCA2 carriers are offered the options of increased surveillance, with or without chemoprevention, or prophylactic surgery. Currently, BRCA carrier status is not used as an independent prognostic factor regarding systemic treatment options.
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screening mammography and risk of breast cancer in BRCA1 and brca2 mutation carriers a case control study
Lancet Oncology, 2006Co-Authors: Steven A Narod, Charmaine Kimsing, Claudine Isaacs, Jan Lubinski, Henry T. Lynch, Parviz Ghadirian, William D Foulkes, Barry P Rosen, Pal Moller, Susan M DomcheckAbstract:Summary Background Screening mammography is associated with a small dose of radiation to the breast, and women with increased genetic risk might be particularly sensitive to the DNA-damaging effects of ionising radiation. We aimed to assess whether exposure to ionising radiation through mammography screening was associated with risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Methods We identified 1600 cases of breast cancer and 1600 controls without breast cancer who were matched for BRCA mutation, date of birth (within 1 year), and country of residence from an international registry of BRCA1 and BRCA2 mutation carriers. We used a questionnaire to inquire about whether participants had ever had screening mammography, and, if so, the age at which they first had the procedure. Results We found no association between ever having screening mammography and risk of breast cancer (odds ratio [OR] 1·03 [95% CI 0·85–1·25], adjusted for parity, oral-contraceptive use, ethnic origin, and bilateral oophorectomy). The association was much the same for BRCA1 mutation carriers and BRCA2 mutation carriers (1·04 [0·84–1·29] vs 1·06 [0·67–1·66], respectively, adjusted for parity, oral-contraceptive use, ethnic origin, and bilateral oophorectomy). Interpretation These findings do not lend support to the idea that exposure to ionising radiation through routine screening mammography contributes substantially to the burden of breast cancer in BRCA1 and BRCA2 mutation carriers. Prospective studies are needed to confirm the results of this initial report, and, where possible, these studies should assess a more appropriate endpoint of total exposure.