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JOURNAL ARTICLE
Tokiwa Motonari, Yuki Yoshino, Moe Haruta, Shino Endo, Shota Sasaki, Minoru Miyashita, Hiroshi Tada, Gou Watanabe, Toshiro Kaneko, Takanori Ishida, Natsuko Chiba
Homologous recombination (HR) repairs DNA damage including DNA double-stranded breaks and alterations in HR-related genes results in HR deficiency. Germline alteration of HR-related genes, such as BRCA1 and BRCA2, causes hereditary breast and ovarian cancer (HBOC). Cancer cells with HR deficiency are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents. Thus, accurately evaluating HR activity is useful for diagnosing HBOC and predicting the therapeutic effects of anti-cancer agents...
April 8, 2024: Scientific Reports
#2
JOURNAL ARTICLE
Jean E Abraham, Karen Pinilla, Alimu Dayimu, Louise Grybowicz, Nikolaos Demiris, Caron Harvey, Lynsey M Drewett, Rebecca Lucey, Alexander Fulton, Anne N Roberts, Joanna R Worley, Anita Chhabra, Wendi Qian, Anne-Laure Vallier, Richard M Hardy, Steve Chan, Tamas Hickish, Devashish Tripathi, Ramachandran Venkitaraman, Mojca Persic, Shahzeena Aslam, Daniel Glassman, Sanjay Raj, Annabel Borley, Jeremy P Braybrooke, Stephanie Sutherland, Emma Staples, Lucy C Scott, Mark Davies, Cheryl A Palmer, Margaret Moody, Mark J Churn, Jacqueline C Newby, Mukesh B Mukesh, Amitabha Chakrabarti, Rebecca R Roylance, Philip C Schouten, Nicola C Levitt, Karen McAdam, Anne C Armstrong, Ellen R Copson, Emma McMurtry, Marc Tischkowitz, Elena Provenzano, Helena M Earl
PARTNER is a prospective, phase II-III, randomised controlled clinical trial, which recruited patients with Triple Negative Breast Cancer (TNBC)1,2 , who were gBRCA wild type (gBRCAwt)3 . Patients (n=559) were randomised on a 1:1 basis to neoadjuvant carboplatin with paclitaxel +/- olaparib 150mg twice daily, days 3 to 14, for 4 cycles (gap schedule olaparib, research arm) followed by 3 cycles of anthracycline chemotherapy before surgery. The primary endpoint was pathological complete response (pCR)4 , and secondary endpoints included event-free survival (EFS), and overall survival (OS)5 ...
April 8, 2024: Nature
#3
JOURNAL ARTICLE
Esin Orhan, Carolina Velazquez, Imene Tabet, Lise Fenou, Geneviève Rodier, Béatrice Orsetti, William Jacot, Claude Sardet, Charles Theillet
One in three Triple Negative Breast Cancer (TNBC) is Homologous Recombination Deficient (HRD) and susceptible to respond to PARP inhibitor (PARPi), however, resistance resulting from functional HR restoration is frequent. Thus, pharmacologic approaches that induce HRD are of interest. We investigated the effectiveness of CDK-inhibition to induce HRD and increase PARPi sensitivity of TNBC cell lines and PDX models. Two CDK-inhibitors (CDKi), the broad range dinaciclib and the CDK12-specific SR-4835, strongly reduced the expression of key HR genes and impaired HR functionality, as illustrated by BRCA1 and RAD51 nuclear foci obliteration...
April 3, 2024: Cancer Letters
#4
Xia-Bo Shen, Jia-Yi Wu, Jia-Ying Li, Xi-Ying Shao, Xiao-Jia Wang
KEY CLINICAL MESSAGE: In a patient with metastatic breast cancer, an acquired BRCA mutation in the BRCA gene was detected, resulting in benefits from olaparib treatment. This underscores the importance of ongoing genetic phenotype testing after paclitaxel chemotherapy. ABSTRACT: Triple-negative breast cancer (TNBC) is associated with a poor prognosis and elevated mortality risk. BRCA mutations are commonly regarded as prevalent mutations in TNBC patients, strongly associated with congenital familial heredity...
April 2024: Clinical Case Reports
#5
JOURNAL ARTICLE
Yongsheng Huang, Yuntan Qiu, Linxiaoxiao Ding, Shuwei Ren, Yuanling Jiang, Jiahuan Luo, Jinghua Huang, Xinke Yin, Sha Fu, Jianli Zhao, Kaishun Hu, Jianwei Liao
Breast cancers involving mutations in homologous recombination (HR) genes, most commonly BRCA1 and BRCA2 (BRCA1/2), respond well to PARP inhibitors and platinum-based chemotherapy. However, except for these specific HR genes, it is not clear which other mutations contribute to homologous recombination defects (HRD). Here, we performed next-generation sequencing of tumor tissues and matched blood samples from 119 breast cancer patients using the OncoScreen Plus panel. Genomic mutation characteristics and HRD scores were analyzed...
March 2024: Journal of Pathology. Clinical Research
#6
JOURNAL ARTICLE
M L Frevert, D Dannehl, L Jansen, S Hermann, H Schäffler, S Huwer, W Janni, I Juhasz-Böss, A D Hartkopf, F-A Taran
BACKGROUND: Following the positive iDFS and OS results of the phase III clinical trials monarchE, NATALEE and OlympiA, new oral anticancer agents (the CDK4/6 inhibitors abemaciclib, ribociclib as well as the PARP inhibitor olaparib) have recently been introduced into the treatment of high-risk early breast cancer (eBC). However, only few male patients were included in these trials (0.4%, 0.6% and 0.3%, respectively). The objective of this real-world analysis was to determine the proportion of male patients with eBC fulfilling the clinical high-risk criteria of above-mentioned trials...
March 12, 2024: Archives of Gynecology and Obstetrics
#7
Takumi Motohashi, Kazutoshi Isobe, Takahiro Yoshizawa, Yusuke Usui, Hiroshige Shimizu, Muneyuki Sekiya, Shion Miyoshi, Yasuhiko Nakamura, Naohisa Urabe, Susumu Sakamoto, Sakae Homma, Sota Sadamoto, Naobumi Tochigi, Kazuma Kishi
A 66-year-old woman was found to have abnormal shadows on a chest radiograph at a previous hospital 4 years ago, which led to a diagnosis of lung adenocarcinoma, cT2aN1M1b stage IVA. First-line treatment included carboplatin and paclitaxel plus thoracic radiotherapy and stereotactic radiation therapy for brain metastases. The patient later underwent second-line pemetrexed treatment, followed by third-line nivolumab, fourth-line docetaxel and bevacizumab, fifth-line tegafur-gimeracil-oteracil, and sixth-line gemcitabine...
March 2024: Respirology Case Reports
#8
JOURNAL ARTICLE
Zheng Zhang, Yuxin Liu, Yaolin Xu, Zijin Xu, Jinbin Jia, Yun Jin, Wenquan Wang, Liang Liu
Poly ADP-ribose polymerase (PARP) inhibitor monotherapies are selectively effective in patients with pancreatic, breast, prostate, and ovarian cancers with BRCA1 mutations. Cancer patients with more frequent wild-type BRCA show poor responses to PARP inhibitors. Moreover, patients who are initially sensitive to these inhibitors eventually respond poorly to drugs. In the present study, we discover that abrogation of Kruppel-like factor 5 (KLF5) significantly inhibits homologous recombination, which is the main mechanism for DNA double-stranded repair...
March 4, 2024: Acta Biochimica et Biophysica Sinica
#9
JOURNAL ARTICLE
Yiduo Hu, Azeet Narayan, Yunshan Xu, Julia Wolfe, Dennis Vu, Thi Trinh, Chaitanya Kantak, S Percy Ivy, Joseph Paul Eder, Yanhong Deng, Patricia LoRusso, Joseph W Kim, Abhijit A Patel
PURPOSE: Cell-free circulating tumor DNA (ctDNA) has shown its potential as a quantitative biomarker for longitudinal monitoring of response to anticancer therapies. However, ctDNA dynamics have not been studied in patients with heavily pretreated, advanced solid tumors, for whom therapeutic responses can be weak. We investigated whether changes in ctDNA could predict clinical outcomes in such a cohort treated with combined poly(ADP-ribose) polymerase/vascular endothelial growth factor receptor inhibitor therapy...
February 2024: JCO Precision Oncology
#10
JOURNAL ARTICLE
Takashi Furusawa, Renzo Cavero, Yue Liu, Haojian Li, Xia Xu, Thorkell Andresson, William Reinhold, Olivia White, Myriem Boufraqech, Thomas J Meyer, Oliver Hartmann, Markus E Diefenbacher, Yves Pommier, Urbain Weyemi
Homologous recombination (HR) and poly ADP-ribosylation are partially redundant pathways for the repair of DNA damage in normal and cancer cells. In cell lines that are deficient in HR, inhibition of poly (ADP-ribose) polymerase (poly (ADP-ribose) polymerase [PARP]1/2) is a proven target with several PARP inhibitors (PARPis) currently in clinical use. Resistance to PARPi often develops, usually involving genetic alterations in DNA repair signaling cascades, but also metabolic rewiring particularly in HR-proficient cells...
February 27, 2024: Molecular Carcinogenesis
#11
JOURNAL ARTICLE
Robert J Cavanagh, Patrícia F Monteiro, Cara Moloney, Alessandra Travanut, Fatemeh Mehradnia, Vincenzo Taresco, Ruman Rahman, Stewart G Martin, Anna M Grabowska, Marianne B Ashford, Cameron Alexander
Combinations of the topoisomerase II inhibitor doxorubicin and the poly (ADP-ribose) polymerase inhibitor olaparib offer potential drug-drug synergy for the treatment of triple negative breast cancers (TNBC). In this study we performed in vitro screening of combinations of these drugs, administered directly or encapsulated within polymer nanoparticles, in both 2D and in 3D spheroid models of breast cancer. A variety of assays were used to evaluate drug potency, and calculations of combination index (CI) values indicated that synergistic effects of drug combinations occurred in a molar-ratio dependent manner...
February 26, 2024: Biomaterials Science
#12
REVIEW
Ilana Schlam, Joshua Dower, Filipa Lynce
PURPOSE OF REVIEW: To summarize the treatment strategies for patients with human epidermal growth factor receptor 2 (HER2)-positive disease and triple-negative breast cancer (TNBC) who have residual disease after preoperative systemic therapy. RECENT FINDINGS: There has been a shift towards neoadjuvant systemic therapy for selected patients with HER2-positive and TNBC. Assessing the tumor's response to therapy provides prognostic information and allows individualization of the postoperative treatment for these patients based on the tumor response to neoadjuvant therapy...
February 23, 2024: Current Oncology Reports
#13
JOURNAL ARTICLE
Anish Gomatam, Bhakti Umesh Hirlekar, Krishan Dev Singh, Upadhyayula Suryanarayana Murty, Vaibhav A Dixit
The poly (ADP-ribose) polymerase-1 (PARP-1) enzyme is an important target in the treatment of breast cancer. Currently, treatment options include the drugs Olaparib, Niraparib, Rucaparib, and Talazoparib; however, these drugs can cause severe side effects including hematological toxicity and cardiotoxicity. Although in silico models for the prediction of PARP-1 activity have been developed, the drawbacks of these models include low specificity, a narrow applicability domain, and a lack of interpretability. To address these issues, a comprehensive machine learning (ML)-based quantitative structure-activity relationship (QSAR) approach for the informed prediction of PARP-1 activity is presented...
February 20, 2024: Molecular Diversity
#14
JOURNAL ARTICLE
Jinghong Chen, Mengpei Zhang, Kemin Li, Yuanqiong Duan, Jing Zeng, Qingli Li, Danqing Wang, Liang Song, Qintong Li, Rutie Yin
PURPOSE: This study evaluated the efficacy and safety in a real-world population of epithelial ovarian cancer (EOC) treated with poly (ADP-ribose) polymerase inhibitor (PARPi) as first-line maintenance therapy in the largest gynecologic oncology center in Western China. METHODS: This study included patients newly diagnosed EOC who received PARPi as first-line maintenance therapy in West China Second University Hospital from August 1, 2018 to September 31, 2022. The primary endpoints were progression-free survival (PFS) and safety evaluated by Common Terminology Criteria for Adverse Events Version 5...
2024: Frontiers in Oncology
#15
JOURNAL ARTICLE
Molecular Basis of XRN2-Deficient Cancer Cell Sensitivity to Poly(ADP-ribose) Polymerase Inhibition.
Talysa Viera, Quinn Abfalterer, Alyssa Neal, Richard Trujillo, Praveen L Patidar
R-loops (RNA-DNA hybrids with displaced single-stranded DNA) have emerged as a potent source of DNA damage and genomic instability. The termination of defective RNA polymerase II (RNAPII) is one of the major sources of R-loop formation. 5'-3'-exoribonuclease 2 (XRN2) promotes genome-wide efficient RNAPII termination, and XRN2-deficient cells exhibit increased DNA damage emanating from elevated R-loops. Recently, we showed that DNA damage instigated by XRN2 depletion in human fibroblast cells resulted in enhanced poly(ADP-ribose) polymerase 1 (PARP1) activity...
January 30, 2024: Cancers
#16
JOURNAL ARTICLE
Hirofumi Terakawa, Chihiro Kawata, Yuki Kurokawa, Yuka Ooe, Ryosuke Mohri, Miki Hirata, Hideki Moriyama, Jun Kinoshita, Hiroko Kawashima, Noriyuki Inaki
The patient is a 51-year-old female with comorbidity of schizophrenia. At the age of 41, she underwent surgery for bilateral breast cancer. Both sides were of the Luminal type, with Stage ⅢC on the right and Stage 0 on the left. She started to receive adjuvant chemotherapy but it was interrupted according to her wish. Approximately 3 years ago, she developed carcinomatous pleuritis, multiple liver metastases, and bone metastases. Despite receiving chemotherapy, her condition worsened. A BRACAnalysis revealed pathogenic variants in BRCA2...
December 2023: Gan to Kagaku Ryoho. Cancer & Chemotherapy
#17
JOURNAL ARTICLE
Patricia A Ganz, Hanna Bandos, Tanja Španić, Sue Friedman, Volkmar Müller, Sherko Kuemmel, Suzette Delaloge, Etienne Brain, Masakazu Toi, Hideko Yamauchi, Eduardo-M de Dueñas, Anne Armstrong, Seock-Ah Im, Chuan-Gui Song, Hong Zheng, Tomasz Sarosiek, Priyanka Sharma, Cuizhi Geng, Peifen Fu, Kerstin Rhiem, Heike Frauchiger-Heuer, Pauline Wimberger, Daphné t'Kint de Roodenbeke, Ning Liao, Annabel Goodwin, Camille Chakiba-Brugère, Michael Friedlander, Keun Seok Lee, Sylvie Giacchetti, Toshimi Takano, Fernando Henao-Carrasco, Shamsuddin Virani, Frances Valdes-Albini, Susan M Domchek, Charles Bane, Edward C McCarron, Monica Mita, Giovanna Rossi, Priya Rastogi, Anitra Fielding, Richard D Gelber, Elsemieke D Scheepers, David Cameron, Judy Garber, Charles E Geyer, Andrew N J Tutt
PURPOSE: The OlympiA randomized phase III trial compared 1 year of olaparib (OL) or placebo (PL) as adjuvant therapy in patients with germline BRCA1/2 , high-risk human epidermal growth factor receptor 2-negative early breast cancer after completing (neo)adjuvant chemotherapy ([N]ACT), surgery, and radiotherapy. The patient-reported outcome primary hypothesis was that OL-treated patients may experience greater fatigue during treatment. METHODS: Data were collected before random assignment, and at 6, 12, 18, and 24 months...
February 1, 2024: Journal of Clinical Oncology
#18
JOURNAL ARTICLE
Haruko Takuwa, Shoko Sasaki, Takahiro Yamada, Megumi Takeuchi
We herein describe our experience with patients who had been diagnosed with BRCA1/2 pathogenic variants and metastatic breast cancer. Three patients who experienced postoperative recurrences had received chemotherapy before recurrence, while an additional patient with stage Ⅳ disease at diagnosis required chemotherapy before olaparib administration. Prior anthracycline and/or taxane-based therapies needed prior to administration of poly(adenosine diphosphate ribose) polymerase inhibitors might still be controversial in terms of patient benefits...
December 2023: Gan to Kagaku Ryoho. Cancer & Chemotherapy
#19
JOURNAL ARTICLE
Tira J Tan, Sarah Sammons, Young-Hyuck Im, Lilin She, Kelly Mundy, Robert Bigelow, Tiffany A Traina, Carey Anders, Joe Yeong, Ezequiel Renzulli, Sung-Bae Kim, Rebecca Dent
BACKGROUND: We explored the efficacy of PARP inhibition with or without programmed death ligand-1 (PD-L1) blockade as chemotherapy-free maintenance therapy for advanced triple-negative breast cancer (aTNBC) sensitive to platinum-based chemotherapy. PATIENTS AND METHODS: In the phase II non-comparative DORA trial (NCT03167619), patients with ongoing stable disease (SD) or complete/partial response (CR/PR) from first- or second-line platinum-based chemotherapy for TNBC (≤10% estrogen/progesterone receptor expression) were randomized 1:1 to receive olaparib 300 mg twice daily with or without durvalumab 1500 mg on day 1 every 4 weeks...
January 18, 2024: Clinical Cancer Research
#20
JOURNAL ARTICLE
Saptarshi Sinha, Subarno Paul, Sushree Subhadra Acharya, Chinmay Das, Somya Ranjan Dash, Subhasmita Bhal, Rajalaxmi Pradhan, Biswajit Das, Chanakya Nath Kundu
Recently, we reported that a combination of a natural, bioactive compound Resveratrol (RES) and a PARP inhibitor Olaparib (OLA) deregulated the homologous recombination (HR) pathway, and enhanced apoptosis in BRCA1-wild-type, HR-proficient breast cancer cells. Upon DNA damage, chromatin relaxation takes place, which allows the DNA repair proteins to access the DNA lesion. But whether chromatin remodeling has any role in RES + OLA-mediated HR inhibition is not known. By using in vitro and ex vivo model systems of breast cancer, we have investigated whether RES + OLA inhibits chromatin relaxation and thereby blocks the HR pathway...
January 6, 2024: Medical Oncology
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