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Rowan E Miller, Jonathan A Ledermann
Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors have shown clinical activity in epithelial ovarian cancer, leading both the US Food and Drug Administration (FDA) and the European Medicines Agency to approve olaparib for tumors characterized by BRCA1 and BRCA2 mutations. However, it is becoming increasingly evident that tumors that share molecular features with BRCA-mutant tumors-a concept known as BRCAness-also may exhibit defective homologous recombination DNA repair, and therefore will respond to PARP inhibition...
September 2016: Clinical Advances in Hematology & Oncology: H&O
Anselmo Papa, Davide Caruso, Martina Strudel, Silverio Tomao, Federica Tomao
BACKGROUND: Despite standard treatment for epithelial ovarian cancer (EOC), that involves cytoreductive surgery followed by platinum-based chemotherapy, and initial high response rates to these, up to 80 % of patients experience relapses with a median progression-free survival of 12-18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and Poly(ADP-ribose) polymerase (PARP) inhibitors...
2016: Journal of Translational Medicine
Elena Mogilyansky, Peter Clark, Kevin Quann, Honglei Zhou, Eric Londin, Yi Jing, Isidore Rigoutsos
Breast cancer type 2, early onset susceptibility gene (BRCA2) is a major component of the homologous recombination DNA repair pathway. It acts as a tumor suppressor whose function is often lost in cancers. Patients with specific mutations in the BRCA2 gene often display discrete clinical, histopathological, and molecular features. However, a subset of sporadic cancers has wild type BRCA2 and display defects in the homology-directed repair pathway, which is the hallmark of 'BRCAness.' The mechanisms by which BRCAness arises are not well understood but post-transcriptional regulation of BRCA2 gene expression by microRNAs (miRNAs) may contribute to this phenotype...
2016: Frontiers in Genetics
Esther H Lips, Rashmie Debipersad, Caroline E Scheerman, Lennart Mulder, Gabe S Sonke, Lizet E van der Kolk, Jelle Wesseling, Frans B L Hogervorst, Petra M Nederlof
Purpose As estrogen receptor (ER)-positive breast cancer in BRCA1 mutation carriers arises at an older age with less aggressive tumor characteristics than ER negative BRCA1 mutated breast cancer, it has been suggested that these tumors are 'sporadic' and not BRCA1-driven. With the introduction of targeted treatments specific for tumors with a non-functioning BRCA1 or BRCA2 gene, the question whether the BRCA genes are impaired in the tumor, is highly relevant. Therefore, we performed genomic profiling of BRCA1-mutated ER+ tumors...
September 12, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Gianmaria Miolo, Alessandra Viel, Vincenzo Canzonieri, Tania Baresic, Angela Buonadonna, Davide Adriano Santeufemia, Della Puppa Lara, Giuseppe Corona
We report an interesting clinical case of a patient carrying a specific BRCA2 germline variant affected by bone and hepatic metastases from a high grade uterine stromal sarcoma who obtained a complete metabolic response after only 3 cycles of trabectedin treatment (1.5 mg/m(2) given intravenously over 24 hours every 21 days). Molecular investigations linked this outstanding positive pharmacological response with the loss of heterozygosity (LOH) of the mutated BRCA2 gene. These data support the hypothesis that the response to trabectedin may be positively conditioned by the different DNA repair defects present in the neoplasm and that BRCAness tumor genotype is important in determining the efficacy of trabectedin-based chemotherapy...
October 2, 2016: Cancer Biology & Therapy
Florian Engert, Michal Kovac, Daniel Baumhoer, Michaela Nathrath, Simone Fulda
We recently discovered mutation signatures reminiscent of BRCA deficiency in the vast majority of a set of primary osteosarcomas (OS). In the current study, we therefore investigated the sensitivity of a panel of OS cell lines to the poly(ADP)-ribose polymerase (PARP) inhibitor talazoparib alone and in combination with several chemotherapeutic drugs (i.e. temozolomide (TMZ), SN-38, doxorubicin, cisplatin, methotrexate (MTX), etoposide/carboplatin). Here, we identified an association between homologous recombination (HR) repair deficiency and the response of OS cell lines to talazoparib...
July 20, 2016: Oncotarget
Priyanka Sharma
UNLABELLED: : Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancers and is associated with poor long-term outcomes compared with other breast cancer subtypes. Because of the lack of approved targeted therapy, at present chemotherapy remains the mainstay of treatment for early and advanced disease. TNBC is enriched for germline BRCA mutation, providing a foundation for the use of this as a biomarker to identify patients suitable for treatment with DNA-damaging agents...
September 2016: Oncologist
Stefania Tommasi, Rosamaria Pinto, Katia Danza, Brunella Pilato, Orazio Palumbo, Lucia Micale, Simona De Summa
In recent years, the assessment of biomarkers useful for "precision medicine" has been a hot topic in research. The involvement of microRNAs in the pathogenesis of breast cancer has been highly investigated with the aim of being able to molecularly stratify this highly heterogeneous disease. Our aim was to identify microRNAs targeting DNA repair machinery, through Affymetrix GeneChip miRNA Arrays, in a cohort of BRCA-related and sporadic breast cancers. Moreover, we analyzed microRNA expression taking into account our previous results on the expression of PARP1, because of its importance in targeted therapy...
June 30, 2016: Oncotarget
Mette Hjortkjær, Marianne Waldstrøm, Anders Jakobsen, Hanne Kanstrup, Erik Søgaard-Andersen, Karina Dahl Steffensen
BRCA1/2 mutation status in epithelial ovarian cancer (EOC) presently relies on genetic testing which is resource consuming. Immunohistochemistry is cheap, fairly reproducible, and may identify gene product alterations due to both germline and somatic mutations and other defects along the BRCA gene pathway (BRCAness phenomenon), which is important when treatment with poly (adenosine-diphosphate-ribose) polymerase (PARP) inhibitors is considered. The aim of this study was to investigate immunohistochemical detection of BRCA1 and PARP expression in EOC and their possible prognostic relevance...
June 29, 2016: International Journal of Gynecological Pathology
Laura Spugnesi, Michele Gabriele, Rosa Scarpitta, Mariella Tancredi, Luisa Maresca, Gaetana Gambino, Anita Collavoli, Paolo Aretini, Ilaria Bertolini, Barbara Salvadori, Elisabetta Landucci, Andrea Fontana, Elena Rossetti, Manuela Roncella, Giuseppe Antonio Naccarato, Maria Adelaide Caligo
Triple Negative Breast Cancers (TNBCs) represent about 15-20% of all breast cancer cases and are characterized by a complex molecular heterogeneity. Some TNBCs exhibit clinical and pathological properties similar to BRCA-mutated tumors, without actually bearing a mutation in BRCA genes. This "BRCAness" phenotype may be explained by germline mutations in other genes involved in DNA repair. Although respond to chemotherapy with alkylating agents, they have a high risk of recurrence and progression. Some studies have shown the efficacy of neoadjuvant therapy in TNBC patients with DNA repair defects, but proper biomarkers of DNA repair deficiency are still needed...
June 21, 2016: Genes, Chromosomes & Cancer
Mallika Dhawan, Charles J Ryan, Alan Ashworth
UNLABELLED: : Advances in DNA sequencing technology have created a wealth of information regarding the genomic landscape of prostate cancer. It had been thought that BRCA1 and BRCA2 mutations were associated with only a small fraction of prostate cancer cases. However, recent genomic analysis has revealed that germline or somatic inactivating mutations in BRCA1 or BRCA2, or other genes involved in the homologous recombination (HR) pathway of DNA repair collectively occur in as much as 20%-25% of advanced prostate cancers...
August 2016: Oncologist
Rebecca S Kristeleit, Rowan E Miller, Elise C Kohn
The presence of a BRCA mutation, somatic or germline, is now established as a standard of care for selecting patients with ovarian cancer for treatment with a PARP inhibitor. During the clinical development of the PARP inhibitor class of agents, a subset of women without BRCA mutations were shown to respond to these drugs (termed "BRCAness"). It was hypothesized that other genetic abnormalities causing a homologous recombinant deficiency (HRD) were sensitizing the BRCA wild-type cancers to PARP inhibition. The molecular basis for these other causes of HRD are being defined...
2016: American Society of Clinical Oncology Educational Book
Diana Lim, Joanne Ngeow
The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in treating cancers associated with BRCA1/2 mutations hinges upon the concept of synthetic lethality and exemplifies the principles of precision medicine. Currently, most clinical trials are recruiting patients based on pathological subtypes or have included BRCA mutation analysis (germ line and/or somatic) as part of the selection criteria. Mounting evidence, however, suggests that these drugs may also be efficacious in tumors with defects in other genes involved in the homologous recombination repair pathway...
June 2016: Endocrine-related Cancer
Giampaolo Bianchini, Justin M Balko, Ingrid A Mayer, Melinda E Sanders, Luca Gianni
Chemotherapy is the primary established systemic treatment for patients with triple-negative breast cancer (TNBC) in both the early and advanced-stages of the disease. The lack of targeted therapies and the poor prognosis of patients with TNBC have fostered a major effort to discover actionable molecular targets to treat patients with these tumours. Massively parallel sequencing and other 'omics' technologies have revealed an unexpected level of heterogeneity of TNBCs and have led to the identification of potentially actionable molecular features in some TNBCs, such as germline BRCA1/2 mutations or 'BRCAness', the presence of the androgen receptor, and several rare genomic alterations...
May 17, 2016: Nature Reviews. Clinical Oncology
T Ishikawa, K Narui, M Tanabe, K Kida, M S Oba, A Yamada, Y Ichikawa, I Endo
AIM: Triple negative breast cancer (TNBC) is a heterogeneous disease and is associated with the cancer stem cell (CSC), basal-like, and BRCA1 function deficient (BRCAness) subtypes. We examined these 3 subtypes in TNBC and compared their chemosensitivity against anthracycline or taxane with a special attention to BRCAness. METHODS: Sixty-six TNBC cases were obtained from a randomized phase II trial comparing TCx6 (TC6) with FEC-Docetaxel (FEC-D) as neoadjuvant chemotherapy...
July 2016: European Journal of Surgical Oncology
Min Zhang, Guoyan Liu, Fengxia Xue, Robert Edwards, Anil K Sood, Wei Zhang, Da Yang
OBJECTIVE: To identify novel prognostic and therapeutic markers for PARP inhibitors in BRCA wild type ovarian cancer (OvCa). METHODS: BRCAness status was defined by analyzing whole-exome deep sequencing data from 220 BRCAwt OvCa cases in TCGA. Thirty-three DNA-repair genes were screened in an integrated manner for BRCA-independent mechanism of BRCAness using multiple-dimensional genomic data. Publicly available databases and siRNA knock-down were used for external validation and evaluation of drug response in OvCa cell lines...
April 2016: Gynecologic Oncology
Carolina Alvarez, Andrés Aravena, Teresa Tapia, Ester Rozenblum, Luisa Solís, Alejandro Corvalán, Mauricio Camus, Manuel Alvarez, David Munroe, Alejandro Maass, Pilar Carvallo
BACKGROUND: Array CGH analysis of breast tumors has contributed to the identification of different genomic profiles in these tumors. Loss of DNA repair by BRCA1 functional deficiency in breast cancer has been proposed as a relevant contribution to breast cancer progression for tumors with no germline mutation. Identifying the genomic alterations taking place in BRCA1 not expressing tumors will lead us to a better understanding of the cellular functions affected in this heterogeneous disease...
2016: BMC Cancer
Sanghee Hong, Pauline Funchain, Abdo Haddad, Joseph Crowe, Nancy Dalpiaz, Jame Abraham
No abstract text is available yet for this article.
March 2016: Journal of Oncology Practice
Niamh E Buckley, Paula Haddock, Ricardo De Matos Simoes, Eileen Parkes, Gareth Irwin, Frank Emmert-Streib, Stephen McQuaid, Richard Kennedy, Paul Mullan
Triple negative (TNBCs) and the closely related Basal-like (BLBCs) breast cancers are a loosely defined collection of cancers with poor clinical outcomes. Both show strong similarities with BRCA1-mutant breast cancers and BRCA1 dysfunction, or 'BRCAness', is observed in a large proportion of sporadic BLBCs. BRCA1 expression and function has been shown in vitro to modulate responses to radiation and chemotherapy. Exploitation of this knowledge in the treatment of BRCA1-mutant patients has had varying degrees of success...
April 12, 2016: Oncotarget
Renaud Sabatier, Elise Lavit, Jessica Moretta, Eric Lambaudie, Tetsuro Noguchi, François Eisinger, Elisabeth Cherau, Magali Provansal, Doriane Livon, Laetitia Rabayrol, Cornel Popovici, Emmanuelle Charaffe-Jauffret, Hagay Sobol, Patrice Viens
Ovarian neoplasms secondary to germline BRCA mutations had been described to have a more favourable survival. There is only few data concerning the prognosis of non mutated patients presenting clinical features evocative of BRCA alterations. We retrospectively collected data from patients treated in our institution for an invasive ovarian carcinoma between 1995 and 2011. Patients considered at high risk of BRCA mutation were tested for BRCA1/2 germline mutations. We described clinical, pathological and therapeutic features and compared prognosis of BRCA mutation carriers and non-mutated patients...
October 2016: Familial Cancer
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