Publications by authors named "B Arun"

314 Publications

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Authors:
Juliette Coignard Michael Lush Jonathan Beesley Tracy A O'Mara Joe Dennis Jonathan P Tyrer Daniel R Barnes Lesley McGuffog Goska Leslie Manjeet K Bolla Muriel A Adank Simona Agata Thomas Ahearn Kristiina Aittomäki Irene L Andrulis Hoda Anton-Culver Volker Arndt Norbert Arnold Kristan J Aronson Banu K Arun Annelie Augustinsson Jacopo Azzollini Daniel Barrowdale Caroline Baynes Heko Becher Marina Bermisheva Leslie Bernstein Katarzyna Białkowska Carl Blomqvist Stig E Bojesen Bernardo Bonanni Ake Borg Hiltrud Brauch Hermann Brenner Barbara Burwinkel Saundra S Buys Trinidad Caldés Maria A Caligo Daniele Campa Brian D Carter Jose E Castelao Jenny Chang-Claude Stephen J Chanock Wendy K Chung Kathleen B M Claes Christine L Clarke J Margriet Collée Don M Conroy Kamila Czene Mary B Daly Peter Devilee Orland Diez Yuan Chun Ding Susan M Domchek Thilo Dörk Isabel Dos-Santos-Silva Alison M Dunning Miriam Dwek Diana M Eccles A Heather Eliassen Christoph Engel Mikael Eriksson D Gareth Evans Peter A Fasching Henrik Flyger Florentia Fostira Eitan Friedman Lin Fritschi Debra Frost Manuela Gago-Dominguez Susan M Gapstur Judy Garber Vanesa Garcia-Barberan Montserrat García-Closas José A García-Sáenz Mia M Gaudet Simon A Gayther Andrea Gehrig Vassilios Georgoulias Graham G Giles Andrew K Godwin Mark S Goldberg David E Goldgar Anna González-Neira Mark H Greene Pascal Guénel Lothar Haeberle Eric Hahnen Christopher A Haiman Niclas Håkansson Per Hall Ute Hamann Patricia A Harrington Steven N Hart Wei He Frans B L Hogervorst Antoinette Hollestelle John L Hopper Darling J Horcasitas Peter J Hulick David J Hunter Evgeny N Imyanitov Agnes Jager Anna Jakubowska Paul A James Uffe Birk Jensen Esther M John Michael E Jones Rudolf Kaaks Pooja Middha Kapoor Beth Y Karlan Renske Keeman Elza Khusnutdinova Johanna I Kiiski Yon-Dschun Ko Veli-Matti Kosma Peter Kraft Allison W Kurian Yael Laitman Diether Lambrechts Loic Le Marchand Jenny Lester Fabienne Lesueur Tricia Lindstrom Adria Lopez-Fernández Jennifer T Loud Craig Luccarini Arto Mannermaa Siranoush Manoukian Sara Margolin John W M Martens Noura Mebirouk Alfons Meindl Austin Miller Roger L Milne Marco Montagna Katherine L Nathanson Susan L Neuhausen Heli Nevanlinna Finn C Nielsen Katie M O'Brien Olufunmilayo I Olopade Janet E Olson Håkan Olsson Ana Osorio Laura Ottini Tjoung-Won Park-Simon Michael T Parsons Inge Sokilde Pedersen Beth Peshkin Paolo Peterlongo Julian Peto Paul D P Pharoah Kelly-Anne Phillips Eric C Polley Bruce Poppe Nadege Presneau Miquel Angel Pujana Kevin Punie Paolo Radice Johanna Rantala Muhammad U Rashid Gad Rennert Hedy S Rennert Mark Robson Atocha Romero Maria Rossing Emmanouil Saloustros Dale P Sandler Regina Santella Maren T Scheuner Marjanka K Schmidt Gunnar Schmidt Christopher Scott Priyanka Sharma Penny Soucy Melissa C Southey John J Spinelli Zoe Steinsnyder Jennifer Stone Dominique Stoppa-Lyonnet Anthony Swerdlow Rulla M Tamimi William J Tapper Jack A Taylor Mary Beth Terry Alex Teulé Darcy L Thull Marc Tischkowitz Amanda E Toland Diana Torres Alison H Trainer Thérèse Truong Nadine Tung Celine M Vachon Ana Vega Joseph Vijai Qin Wang Barbara Wappenschmidt Clarice R Weinberg Jeffrey N Weitzel Camilla Wendt Alicja Wolk Siddhartha Yadav Xiaohong R Yang Drakoulis Yannoukakos Wei Zheng Argyrios Ziogas Kristin K Zorn Sue K Park Mads Thomassen Kenneth Offit Rita K Schmutzler Fergus J Couch Jacques Simard Georgia Chenevix-Trench Douglas F Easton Nadine Andrieu Antonis C Antoniou

Nat Commun 2021 02 17;12(1):1078. Epub 2021 Feb 17.

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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http://dx.doi.org/10.1038/s41467-020-20496-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890067PMC
February 2021

Clinical practice guidelines for BRCA1 and BRCA2 genetic testing.

Eur J Cancer 2021 Feb 10;146:30-47. Epub 2021 Feb 10.

Medical Oncology Department, Hospital Nuestra Señora de Sonsoles, Ávila, Ávila, Spain. Electronic address:

BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices.
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http://dx.doi.org/10.1016/j.ejca.2020.12.023DOI Listing
February 2021

The first BGICC consensus and recommendations for breast cancer awareness, early detection and risk reduction in low- and middle-income countries and the MENA region.

Int J Cancer 2021 Feb 9. Epub 2021 Feb 9.

Clinical Oncology Department, Ain shams University, Cairo, Egypt.

In low-middle income countries (LMICs) and the Middle East and North Africa (MENA) region, there is an unmet need to establish and improve breast cancer (BC) awareness, early diagnosis and risk reduction programs. During the 12th Breast, Gynecological & Immuno-oncology International Cancer Conference - Egypt 2020, 26 experts from 7 countries worldwide voted to establish the first consensus for BC awareness, early detection and risk reduction in LMICs/MENA region. The panel advised that there is an extreme necessity for a well-developed BC data registries and prospective clinical studies that address alternative modalities/modified BC screening programs in areas of limited resources. The most important recommendations of the panel were: (a) BC awareness campaigns should be promoted to public and all adult age groups; (b) early detection programs should combine geographically distributed mammographic facilities with clinical breast examination (CBE); (c) breast awareness should be encouraged; and (d) intensive surveillance and chemoprevention strategies should be fostered for high-risk women. The panel defined some areas for future clinical research, which included the role of CBE and breast self-examination as an alternative to radiological screening in areas of limited resources, the interval and methodology of BC surveillance in women with increased risk of BC and the use of low dose tamoxifen in BC risk reduction. In LMICs/MENA region, BC awareness and early detection campaigns should take into consideration the specific disease criteria and the socioeconomic status of the target population. The statements with no consensus reached should serve as potential catalyst for future clinical research.
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http://dx.doi.org/10.1002/ijc.33506DOI Listing
February 2021

Genetic counselor approaches to BRCA1/2 direct-to-consumer genetic testing results.

J Genet Couns 2021 Feb 6. Epub 2021 Feb 6.

University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.

The National Comprehensive Cancer Network recommends clinical-grade genetic testing to confirm commercial results from direct-to-consumer genetic testing (DTC-GT) companies and third-party interpretation (TPI) services; however, the type of confirmatory testing that genetic counselors (GCs) recommend remains uncharacterized. Therefore, we aimed to describe GCs testing strategies for patients who have already obtained DTC-GT results (23andMe) or TPI data (Promethease) that reported a BRCA1/2 pathogenic variant. We invited GCs specializing in clinical cancer genetics to complete an online survey distributed to members of the National Society of Genetic Counselors. The survey, completed by 80 respondents, contained case scenarios featuring probands with variable personal and family histories of cancer. Our results show that the majority of participating GCs have counseled patients for their health-related commercial test results; 94% have encountered patient DTC-GT reports (3 per year), and 69% have encountered patient TPI data (2 per year). Most participating GCs would recommend confirmatory clinical-grade testing for probands with a positive 23andMe BRCA1/2 result (77/80, 96%). However, there was strong variability between the type of recommended testing. Approximately 20% recommended single-site analysis, 11%-14% recommended the three Ashkenazi Jewish BRCA1/2 founder mutations, 4% recommended BRCA1/2 testing, and 61%-64% recommended multi-gene panel testing. The most commonly recommended panels were split between a breast and gynecological cancer-focused panel and a broad pan-cancer panel. The majority of participants (98%-100%) would also recommend confirmatory testing for patients with positive TPI data for BRCA1/2. Similarly, results were mixed between those who recommended targeted, single-site analysis (10%-15%) compared to a multi-gene panel (72%-83%). These data show that while most GCs were uniform in their practice of recommending confirmatory testing, they are mixed in their approach to the specific type of testing they would select. These results may help inform counseling approaches and consensus for this expanding group of patients.
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http://dx.doi.org/10.1002/jgc4.1380DOI Listing
February 2021

Disclosure of familial implications of pathogenic variants in breast-cancer genes to patients: Opportunity for prompting family communication.

J Community Genet 2021 Jan 22. Epub 2021 Jan 22.

Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Familial communication of pathogenic genetic variants is necessary to maximize the clinical utility of genetic testing and its public health benefits. Insights to family communication considerations may be obtained from existing clinical documentation available in medical records. The goal of this study was to describe and characterize information about family communication of pathogenic variants and cascade genetic testing from genetic counseling summary notes. We completed structured content analysis of 656 summary notes describing pathogenic variants in breast cancer genes, for patients seen at a tertiary cancer center. Patients were 89.5% female, median age of 49 years, 32.6% non-White, and were counseled by 23 unique genetic counselors (GCs) with mean post-certification experience of 3.7 years. Cascade genetic testing was documented in 92.2% of all notes. Specific relatives (i.e., relationship to patient) who would benefit from genetic counseling and cascade testing were referenced in 33.1% of notes. Specific risk messaging was 2.5 times more likely to be present in notes of high- compared to moderate-risk genes (OR=2.53, 95% CI: 1.71-3.80), and when summary notes indicated the presence of a friend or relative (OR=2.29, 95% CI: 1.50-3.48). Summary notes frequently attempted to contextualize the patients' familial relationships by referencing positive family communication patterns (41.6%) or negative communication issues (2.4%) and included various strategies to address barriers to communication and assist relatives with cascade testing. Overall, GCs consistently documented family communication recommendations when pathogenic variants are identified on patients' genetic testing, albeit with heterogeneous use of specific communication prompts.
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http://dx.doi.org/10.1007/s12687-021-00504-9DOI Listing
January 2021

PARP Inhibitors in Triple-Negative Breast Cancer Including Those With BRCA Mutations.

Cancer J 2021 Jan-Feb 01;27(1):67-75

From the Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX.

Abstract: Poly(ADP-ribose) polymerase (PARP) is involved in single-strand DNA break base excision repair. PARP inhibition causes synthetic lethality in breast cancers associated with germline BRCA1 and BRCA2 mutations and is routinely used in clinical practice for metastatic breast cancer. Breast cancers with homologous recombination deficiency or BRCAness, most commonly triple-negative breast cancers, may also benefit. Currently, PARP inhibitor use for triple-negative breast cancer with wild-type BRCA does not have definitive efficacy; however, this is an area of active research. Further clinical and translational data may identify additional patient populations that will benefit from PARP inhibitor therapy.
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http://dx.doi.org/10.1097/PPO.0000000000000499DOI Listing
January 2021

Preparation, Spectroscopic Characterization, Theoretical Investigations, and In Vitro Anticancer Activity of Cd(II), Ni(II), Zn(II), and Cu(II) Complexes of 4(3)-Quinazolinone-Derived Schiff Base.

Molecules 2020 Dec 16;25(24). Epub 2020 Dec 16.

Departament de Química, Universitat de les IllesBalears, 07122 Palma de Mallorca, Spain.

Herein, we report the synthesis and characterization of a new Schiff base ligand 3-[[()-(3-hydroxyphenylmethylidene]amino]methylquinazolin43one (HAMQ) and its Cd(II), Ni(II), Zn(II), and Cu(II) complexes (-). The ligand HAMQ was synthesized by reacting 3-hydroxybenzaldehyde and 3-amino-2-methyl-4(3quinazolinone in a 1:1 molar ratio. The structure of the ligand and its complexes (-) were evaluated using ultraviolet (UV)-visible (Vis) light spectroscopy, H-NMR, Fourier-transform infrared (FT-IR) spectroscopy, MS, elemental analysis, conductance data, and thermogravimetric analysis (TGA). The characterization results suggested that the bidentate ligand, HAMQ, coordinated to the metal center through the lactum oxygen and the azomethine nitrogen. Moreover, all the metal complexes were analyzed using powder X-ray diffraction studies, which revealed that all of them belong to a triclinic crystal system. The research was supplemented by density functional theory (DFT) studies on the IR and UV-Vis spectra, as well as the chemical reactivity of the HAMQ and its four metallic derivatives making use of conceptual density functional theory (CDFT) by means of KID (Koopmans in DFT) methodology. The synthesized complexes displayed significant in vitro anticancer activity against human cancer cell lines (HeLa and HCT-115).
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http://dx.doi.org/10.3390/molecules25245973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766817PMC
December 2020

A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia.

Mol Cell 2020 12;80(6):1013-1024.e6

Department of Experimental Radiation Oncology, the University of Texas, MD Anderson Cancer, Houston, TX 77030, USA; Life Sciences Institute, Zhejiang University, Hangzhou 310058, China. Electronic address:

Impaired DNA crosslink repair leads to Fanconi anemia (FA), characterized by a unique manifestation of bone marrow failure and pancytopenia among diseases caused by DNA damage response defects. As a germline disorder, why the hematopoietic hierarchy is specifically affected is not fully understood. We find that reprogramming transcription during hematopoietic differentiation results in an overload of genotoxic stress, which causes aborted differentiation and depletion of FA mutant progenitor cells. DNA damage onset most likely arises from formaldehyde, an obligate by-product of oxidative protein demethylation during transcription regulation. Our results demonstrate that rapid and extensive transcription reprogramming associated with hematopoietic differentiation poses a major threat to genome stability and cell viability in the absence of the FA pathway. The connection between differentiation and DNA damage accumulation reveals a novel mechanism of genome scarring and is critical to exploring therapies to counteract the aplastic anemia for the treatment of FA patients.
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http://dx.doi.org/10.1016/j.molcel.2020.11.040DOI Listing
December 2020

Perceptions of provider's epistemic authority in response to variant of uncertain significance-related recommendations.

J Genet Couns 2020 Oct 8. Epub 2020 Oct 8.

Department of Behavioral Science, UT MD Anderson Cancer Center, Houston, TX, USA.

Uncertain genetic information such as variants of uncertain significance (VUS) is often encountered by patients in clinical cancer genetic testing. Although healthcare providers facilitate patient's understanding of VUS-associated empirical risk and its medical implications, patients' understanding and perceptions of risk often differ and may be based on subjective evaluations such as their perception of provider's epistemic authority (EA). This study examines the hypothesis that individuals attribute greater EA to genetic counselors (GCs) (compared to gastrointestinal oncologists) and to providers who recommend more active VUS-related recommendations (compared to inactive). In a factorial experiment, 652 adult participants recruited on Amazon Mechanical Turk were block-randomized to read one of 10 different types of VUS-related scenarios in the context of colon cancer (5 recommendation types × 2 provider types). GCs were attributed higher EA than gastrointestinal oncologists (p = <.001). Active recommendations (comprehensive, check back, wrong) were attributed lower EA (M = 3.67, SD = 0.79) compared to the inactive (stand by, disregard) (M = 3.89, SD = 0.67) (p-value = <.001). The wrong recommendation was attributed lowest EA compared to the four correct recommendations (mean difference = -0.34, -0.45, -0.35, and -0.44, respectively; p = .002), which, when dropped from the analysis, showed no difference between the correct active and inactive recommendations (3.78 vs. 3.89, p = .095). The higher EA attributed to GCs is encouraging and possibly explained by increased public awareness of the genetic counseling profession. The lack of difference in EA attributed to various correct, yet incomplete forms of VUS-related recommendation indicates that individuals may be unaware of and thus completely rely on providers for complex medical topics like VUS. Communicating VUS-related uncertainty warrants caution and further research to elucidate best practices and outcomes.
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http://dx.doi.org/10.1002/jgc4.1337DOI Listing
October 2020

Patient characteristics associated with sleep disturbance in breast cancer survivors.

Support Care Cancer 2020 Sep 22. Epub 2020 Sep 22.

Department of Palliative, Rehabilitation, and Integrative Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.

Background: Disturbed sleep is common among breast cancer survivors. Identifying patients at risk for disturbed sleep and its sequelae will aid in improving screening and intervention strategies to improve sleep and cancer-related quality of life (QOL).

Methods: Women with stages I-III breast cancer undergoing neoadjuvant or adjuvant chemotherapy (N = 415) reported subjectively assessed sleep quality (PSQI) and actigraphy-assessed wake after sleep onset (AAS-WASO), total sleep time (AAS-TST), and sleep efficiency (AAS-SE), sociodemographic, and clinical characteristics and completed questionnaires assessing physical and mental health QOL at study entry and 3, 6, 12, and 15 months later.

Results: Being from a racially/ethnically underserved population was associated with poorer sleep in all indices (p's < .04). Lower income was associated with poorer subjective sleep and greater AAS-WASO (p's < .02). BMI was associated with lower AAS-SE (p < .001). Baseline subjective sleep complaints were positively associated with depression, fatigue, and health-related QOL and cancer-related symptoms across follow-up (p's < 0.05). Baseline AAS-WASO was positively associated with anxiety and negatively associated with physical health-related QOL at the 3-month follow-up (p's < .001). Baseline AAS-WASO and AAS-SE were associated with mental health-related QOL at the 6-month follow-up (p's < .05).

Conclusions: In keeping with previous health disparity research, racially/ethnically underserved populations, lower household income, and higher BMI were associated with increased risk for disturbed sleep. Sleep disturbance may have long-term effects on multiple aspects of QOL for women undergoing treatment for breast cancer. Results may inform strategies to identify patients at greatest risk for disturbed sleep and its sequelae.
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http://dx.doi.org/10.1007/s00520-020-05777-3DOI Listing
September 2020

Setting up a lung stereotactic body radiotherapy service in a tertiary center in Eastern India: The process, quality assurance, and early experience.

J Cancer Res Ther 2020 Jul-Sep;16(4):888-899

Department of Radiation Oncology, Tata Medical Center, Kolkata, West Bengal, India.

Context: Stereotactic body radiotherapy (SBRT) is increasingly being used for early-stage lung cancer and lung oligometastases.

Aims: To report our experience of setting up lung SBRT and early clinical outcomes.

Settings And Design: This was a retrospective, interventional, cohort study.

Subjects And Methods: Patients were identified from multidisciplinary tumor board meetings. They underwent four-dimensional computed tomography-based planning. The ROSEL trial protocol, the Radiation Therapy Oncology Group (RTOG) 0236, and the UK-Stereotactic Ablative Body Radiotherapy Consortium guidelines were used for target volume and organs-at-risks (OARs) delineation, dosimetry, and plan quality assessment. Each SBRT plan underwent patient-specific quality assurance (QA). Daily online image guidance using KVCT or MVCT was done to ensure accurate treatment delivery.

Statistical Analysis Used: Microsoft Excel 2010 was used for data analysis.

Results: Fifteen patients were treated to one or more lung tumors. One patient received helical tomotherapy in view of bilateral lung oligometastases at similar axial levels. All the remaining patients received volumetric modulated arc therapy (VMAT)-based treatment. The prescription dose varied from 40 to 60 Gy in 5-8 fractions with alternate-day treatment. The mean and median lung V20 was 5.24% and 5.16%, respectively (range, 1.66%-9.10%). The mean and median conformity indexes were 1.02 and 1.06, respectively (range, 0.70-1.18). After a median follow-up of 17 months, the locoregional control rate was 93.3%.

Conclusions: SBRT was implemented using careful evaluation of OAR dose constraints, dosimetric accuracy and plan quality, patient-specific QA, and online image guidance for accurate treatment delivery. It was safe and effective for early-stage nonsmall cell lung cancer and lung metastases. Prospective data were collected to audit our outcomes.
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http://dx.doi.org/10.4103/jcrt.JCRT_427_18DOI Listing
November 2020

Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet Oncol 2020 10 27;21(10):1269-1282. Epub 2020 Aug 27.

The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: BRCA1 or BRCA2-mutated breast cancers are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents owing to deficiency in homologous recombination repair of DNA damage. In this trial, we compared veliparib versus placebo in combination with carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel were discontinued before progression, in patients with HER2-negative advanced breast cancer and a germline BRCA1 or BRCA2 mutation.

Methods: BROCADE3 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 147 hospitals in 36 countries. Eligible patients (aged ≥18 years) had deleterious germline BRCA1 or BRCA2 mutation-associated, histologically or cytologically confirmed advanced HER2-negative breast cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received up to two previous lines of chemotherapy for metastatic disease. Patients were randomly assigned (2:1) by interactive response technology by means of permuted blocks within strata (block size of 3 or 6) to carboplatin (area under the concentration curve 6 mg/mL per min intravenously) on day 1 and paclitaxel (80 mg/m intravenously) on days 1, 8, and 15 of 21-day cycles combined with either veliparib (120 mg orally twice daily, on days -2 to 5) or matching placebo. If patients discontinued carboplatin and paclitaxel before progression, they could continue veliparib or placebo at an intensified dose (300 mg twice daily continuously, escalating to 400 mg twice daily if tolerated) until disease progression. Patients in the control group could receive open-label veliparib monotherapy after disease progression. Randomisation was stratified by previous platinum use, history of CNS metastases, and oestrogen and progesterone receptor status. The primary endpoint was investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy analyses were done by intention to treat, which included all randomly assigned patients with a centrally confirmed BRCA mutation, and safety analyses included all patients who received at least one dose of velilparib or placebo. This study is ongoing and is registered with ClinicalTrials.gov, NCT02163694.

Findings: Between July 30, 2014, and Jan 17, 2018, 2202 patients were screened, of whom 513 eligible patients were enrolled and randomly assigned. In the intention-to-treat population (n=509), 337 patients were assigned to receive veliparib plus carboplatin-paclitaxel (veliparib group) and 172 were assigned to receive placebo plus carboplatin-paclitaxel (control group). Median follow-up at data cutoff (April 5, 2019) was 35·7 months (IQR 24·9-43·6) in the veliparib group and 35·5 months (23·1-45·9) in the control group. Median progression-free survival was 14·5 months (95% CI 12·5-17·7) in the veliparib group versus 12·6 months (10·6-14·4) in the control group (hazard ratio 0·71 [95% CI 0·57-0·88], p=0·0016). The most common grade 3 or worse adverse events were neutropenia (272 [81%] of 336 patients in the veliparib group vs 143 [84%] of 171 patients in the control group), anaemia (142 [42%] vs 68 [40%]), and thrombocytopenia (134 [40%] vs 48 [28%]). Serious adverse events occurred in 115 (34%) patients in the veliparib group versus 49 (29%) patients in the control group. There were no study drug-related deaths.

Interpretation: The addition of veliparib to a highly active platinum doublet, with continuation as monotherapy if the doublet were discontinued, resulted in significant and durable improvement in progression-free survival in patients with germline BRCA mutation-associated advanced breast cancer. These data indicate the utility of combining platinum and PARP inhibitors in this patient population.

Funding: AbbVie.
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http://dx.doi.org/10.1016/S1470-2045(20)30447-2DOI Listing
October 2020

Impact of a Genetic Evaluation Initiative to Increase Access to Genetic Services for Adolescent and Young Adults at a Tertiary Cancer Hospital.

J Adolesc Young Adult Oncol 2020 Aug 19. Epub 2020 Aug 19.

Department of Pediatrics, and University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Adolescents and young adults (AYAs) with cancer are at increased risk for inherited cancer predisposition syndromes. Genetic counseling (GC) is important for accurate risk assessment, diagnosis, and management of inherited cancers. Numerous barriers prevent AYA access to genetic services. This study describes outcomes of a genetic evaluation initiative (GEI) regarding utilization of genetic services among AYAs. To improve AYA access to GC, the AYA program at UT MD Anderson Cancer Center implemented GEI, a process for identifying and referring eligible patients for GC. We collected retrospective electronic medical record data between July 12, 2018 and July 12, 2019 to capture AYA's clinical characteristics, genetic referral, scheduled appointments, counseling, testing, and results. In total, 516 AYAs were referred to the AYA clinic during the study period with a median age of first cancer diagnosis of 17 years. One hundred sixty-six AYAs were identified who would benefit from genetic evaluation, 57 (34.3%) of whom had previously undergone counseling. One hundred nine patients were recommended for referral to GC, and 64.2% (70/109) were referred by the AYA team. To date, 58.6% (41/70) met with a genetic counselor and 75.6% (31/41) completed genetic testing, which yielded 1 pathogenic, 2 uncertain, and 29 benign results. The GEI resulted in a 72.0% relative increase in the rate of GC utilization and represents a novel approach to increasing AYA patient access to cancer genetic services in this population.
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http://dx.doi.org/10.1089/jayao.2020.0066DOI Listing
August 2020

Contralateral Risk-Reducing Mastectomy in Breast Cancer Patients Who Undergo Multigene Panel Testing.

Ann Surg Oncol 2020 Nov 27;27(12):4613-4621. Epub 2020 Jul 27.

Department of Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: An increasing number of breast cancer patients are undergoing expanded genetic testing and are being identified as germline mutation carriers. We sought to determine rates of contralateral risk-reducing mastectomy (CRRM) in patients with various germline mutations.

Patients And Methods: All women ≥ 18 years of age with unilateral breast cancer who underwent multigene panel testing between January 1, 2014 and August 1, 2019 at our academic institution were identified. Demographic, tumor, and treatment variables were identified from the medical record. Multivariable analyses were performed to compare factors associated with performance of CRRM.

Results: We identified 1613 patients, of whom 28.1% had a pathogenic variant and 40.1% had variants of uncertain significance (VUS). Overall, 420 patients (26.0%) underwent a CRRM. On multivariable analysis, factors associated with CRRM included age < 50 years (OR 3.8, 95% CI 3.0, 5.0), race (OR 0.5, 95% CI 0.3, 0.7 and OR 0.4, 95% CI 0.2, 0.7 for Black and Asian women, respectively, versus White women), and the presence of any germline mutation or VUS (OR 13.2, 95% CI 8.7, 20.2 for BRCA1/2; OR 3.9, 95% CI 2.7, 5.8 for non-BRCA germline mutation; and OR 1.8, 95% CI 1.3, 2.6 for VUS).

Conclusions: In breast cancer patients who undergo multigene panel testing, a sizeable number of women with pathogenic non-BRCA germline findings are opting for CRRM. Given that the risk of contralateral breast cancer in women with most pathogenic mutations other than BRCA1/2 remains poorly characterized, these data have implications for risk counseling and for ascertaining the true risks of contralateral breast cancer in this population.
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http://dx.doi.org/10.1245/s10434-020-08889-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554051PMC
November 2020

Clinical implications of breast cancer tumor genomic testing.

Breast J 2020 08 22;26(8):1565-1571. Epub 2020 Jul 22.

Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.

One of the important applications of genetic testing is genetic testing of the tumor to identify non-inherited somatic mutations. The advent of high-throughput genomic and proteomic techniques has enabled characterization of genomic alterations and accelerated development of novel matching therapies for cancer. Consequently, mutational status has increasingly defined treatment selection for patients with solid tumors. The effectiveness of targeted therapy depends on matching with the right target; targets that are differentially expressed in tumor cells and provide growth and survival advantage. Currently, multiple targeted therapies have been approved by the Food and Drug Administration (FDA) for treatment of solid tumors including breast, lung, and melanoma, while many others are being evaluated in clinical trials. In addition to identifying actionable genomic alterations of interest, tumor genome sequencing also has the potential to detect germline mutations that has clinical implications for both the patient and their family. While targeted therapies have transformed our approach to cancer care in solid tumor patients within the past decade, lack of sustained responses and emergence of acquired resistance limit their clinical activity. In this article, we discuss tumor genome sequencing in breast cancers and their clinical implication.
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http://dx.doi.org/10.1111/tbj.13966DOI Listing
August 2020

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

Authors:
Daniel R Barnes Matti A Rookus Lesley McGuffog Goska Leslie Thea M Mooij Joe Dennis Nasim Mavaddat Julian Adlard Munaza Ahmed Kristiina Aittomäki Nadine Andrieu Irene L Andrulis Norbert Arnold Banu K Arun Jacopo Azzollini Judith Balmaña Rosa B Barkardottir Daniel Barrowdale Javier Benitez Pascaline Berthet Katarzyna Białkowska Amie M Blanco Marinus J Blok Bernardo Bonanni Susanne E Boonen Åke Borg Aniko Bozsik Angela R Bradbury Paul Brennan Carole Brewer Joan Brunet Saundra S Buys Trinidad Caldés Maria A Caligo Ian Campbell Lise Lotte Christensen Wendy K Chung Kathleen B M Claes Chrystelle Colas Marie-Agnès Collonge-Rame Jackie Cook Mary B Daly Rosemarie Davidson Miguel de la Hoya Robin de Putter Capucine Delnatte Peter Devilee Orland Diez Yuan Chun Ding Susan M Domchek Cecilia M Dorfling Martine Dumont Ros Eeles Bent Ejlertsen Christoph Engel D Gareth Evans Laurence Faivre Lenka Foretova Florentia Fostira Michael Friedlander Eitan Friedman Debra Frost Patricia A Ganz Judy Garber Andrea Gehrig Anne-Marie Gerdes Paul Gesta Sophie Giraud Gord Glendon Andrew K Godwin David E Goldgar Anna González-Neira Mark H Greene Daphne Gschwantler-Kaulich Eric Hahnen Ute Hamann Helen Hanson Julia Hentschel Frans B L Hogervorst Maartje J Hooning Judit Horvath Chunling Hu Peter J Hulick Evgeny N Imyanitov Claudine Isaacs Louise Izatt Angel Izquierdo Anna Jakubowska Paul A James Ramunas Janavicius Esther M John Vijai Joseph Beth Y Karlan Karin Kast Marco Koudijs Torben A Kruse Ava Kwong Yael Laitman Christine Lasset Conxi Lazaro Jenny Lester Fabienne Lesueur Annelie Liljegren Jennifer T Loud Jan Lubiński Phuong L Mai Siranoush Manoukian Véronique Mari Noura Mebirouk Hanne E J Meijers-Heijboer Alfons Meindl Arjen R Mensenkamp Austin Miller Marco Montagna Emmanuelle Mouret-Fourme Semanti Mukherjee Anna Marie Mulligan Katherine L Nathanson Susan L Neuhausen Heli Nevanlinna Dieter Niederacher Finn Cilius Nielsen Liene Nikitina-Zake Catherine Noguès Edith Olah Olufunmilayo I Olopade Kai-Ren Ong Aoife O'Shaughnessy-Kirwan Ana Osorio Claus-Eric Ott Laura Papi Sue K Park Michael T Parsons Inge Sokilde Pedersen Bernard Peissel Ana Peixoto Paolo Peterlongo Georg Pfeiler Kelly-Anne Phillips Karolina Prajzendanc Miquel Angel Pujana Paolo Radice Juliane Ramser Susan J Ramus Johanna Rantala Gad Rennert Harvey A Risch Mark Robson Karina Rønlund Ritu Salani Hélène Schuster Leigha Senter Payal D Shah Priyanka Sharma Lucy E Side Christian F Singer Thomas P Slavin Penny Soucy Melissa C Southey Amanda B Spurdle Doris Steinemann Zoe Steinsnyder Dominique Stoppa-Lyonnet Christian Sutter Yen Yen Tan Manuel R Teixeira Soo Hwang Teo Darcy L Thull Marc Tischkowitz Silvia Tognazzo Amanda E Toland Alison H Trainer Nadine Tung Klaartje van Engelen Elizabeth J van Rensburg Ana Vega Jeroen Vierstraete Gabriel Wagner Lisa Walker Shan Wang-Gohrke Barbara Wappenschmidt Jeffrey N Weitzel Siddhartha Yadav Xin Yang Drakoulis Yannoukakos Dario Zimbalatti Kenneth Offit Mads Thomassen Fergus J Couch Rita K Schmutzler Jacques Simard Douglas F Easton Georgia Chenevix-Trench Antonis C Antoniou

Genet Med 2020 Oct 15;22(10):1653-1666. Epub 2020 Jul 15.

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.

Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.

Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10) carriers. The associations in the prospective cohort were similar.

Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
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http://dx.doi.org/10.1038/s41436-020-0862-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521995PMC
October 2020

Should abbreviated breast MRI be compliant with American College of Radiology requirements for MRI accreditation?

Magn Reson Imaging 2020 10 2;72:87-94. Epub 2020 Jul 2.

Department of Diagnostic Radiology, UT Southwestern Medical Center, 2201 Inwood Rd, Dallas, TX 75390-8585, United States of America. Electronic address:

Objective: To evaluate non-inferiority and diagnostic performance of an American College of Radiology compliant abbreviated MRI protocol (AB-MRI) compared with standard-of-care breast MRI (SOC-BMRI) in patients with increased breast cancer risk.

Material And Methods: Women with increased lifetime breast cancer risk by American Cancer Society guidelines underwent breast MRI at a single institution between October 2015 and February 2018. AB-MRI was acquired at 3.0 T with T2-weighted extended fast spin echo triple-echo Dixon and pre- and post-contrast 3D dual-echo fast spoiled gradient echo two-point Dixon sequences with an 8-channel breast coil 1-7 days after SOC-BMRI. Three readers independently reviewed AB-MRI and assigned BI-RADS categories for maximum intensity projection images (AB1), dynamic contrast-enhanced (DCE) images (AB2), and DCE and non-contrast T2 and fat-only images (AB3). These scores were compared to those from SOC-BMRI.

Results: Cancer yield was 14 per 1000 (women-years) in 73 women aged 26-75 years (mean 53.5 years). AB-MRI acquisition times (mean 9.63 min) and table times (mean 15.07 min) were significantly shorter than those of SOC-BMRI (means 19.46 and 36.3 min, respectively) (p < .001). Accuracy, sensitivity, specificity, and positive and negative predictive values were identical for AB3 and SOC-BMRI (93%, 100%, 93%, 16.7%, and 100%, respectively). AB-MRI with AB1 and AB2 had significantly lower specificity (AB1 = 73.6%, AB2 = 77.8%), positive predictive values (AB1 = 5%, AB2 = 5.9%), and accuracy (AB1 = 74%, AB2 = 78%) than those of SOC-BMRI (p = .002 for AB1, p = .01 for AB2).

Conclusion: AB-MRI was acquired significantly faster than SOC-BMRI and its diagnostic performance was non-inferior. Inclusion of T2 and fat-only images was necessary to achieve non-inferiority by multireader evaluation.
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http://dx.doi.org/10.1016/j.mri.2020.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454030PMC
October 2020

Biomarker Modulation Study of Celecoxib for Chemoprevention in Women at Increased Risk for Breast Cancer: A Phase II Pilot Study.

Cancer Prev Res (Phila) 2020 09 8;13(9):795-802. Epub 2020 Jun 8.

Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

In preclinical studies, celecoxib has been associated with reduced risk of breast cancer. In this study, the aim was to assess the biomodulatory effect of celecoxib on blood and benign breast tissue biomarkers in women at increased risk for breast cancer. Women at increased risk for breast cancer [5-year Gail risk score of >1.67%, history of atypical hyperplasia, lobular carcinoma , or previous estrogen receptor (ER)-negative breast cancer] were treated with celecoxib at 400 mg orally twice daily for 6 months. Participants underwent random periareolar fine needle aspiration and blood draw at baseline and at 6 months for analysis of biomarkers: serum levels of insulin-like growth factor 1 (IGF-1), IGF-binding protein 1 (IGFBP-1), and IGFBP-3; tissue expression of Ki-67 and ER; as well as cytology. Forty-nine patients were eligible for analysis. Median IGFBP-1 levels increased significantly from 6.05 ng/mL at baseline to 6.93 ng/mL at 6 months ( = 0.04), and median IGFBP-3 levels decreased significantly from 3,593 ng/mL to 3,420 ng/mL ( = 0.01). We also detected favorable changes in cytology of 52% of tested sites after 6 months of celecoxib therapy. No changes in tissue Ki-67 and ER expression levels were observed. No grade 3 or 4 toxicity was recorded. Celecoxib was well tolerated and induced favorable changes in serum biomarkers as well as cytology in this pilot phase II trial. A phase IIb placebo-controlled study with celecoxib could be considered for women at increased risk for breast cancer.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0095DOI Listing
September 2020

Clinical outcome and toxicity from taxanes in breast cancer patients with BRCA1 and BRCA2 pathogenic germline mutations.

Breast J 2020 08 4;26(8):1572-1582. Epub 2020 Jun 4.

Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

Germline variations in genes coding for proteins involved in the oxidative stress and DNA repair greatly influence drug response and toxicity. Because BRCA1 and BRCA2 proteins play a role in DNA damage repair, we postulated that taxane-related toxicity is potentially higher and clinical outcome in different in patients with BRCA pathogenic variants (PV). Seven hundred nineteen women who underwent BRCA genetic testing and were treated with taxane-containing chemotherapy for early-stage breast cancer between 1997 and 2018 were included in the study. Patients with BRCA variants of uncertain significance were excluded. The Kaplan-Meier product-limit method was used to estimate recurrence-free survival (RFS) and overall survival (OS) rates. Logistic regression models were used to assess the association between chemotherapy toxicity and factors of interest. Cox regression models were used to assess the association between RFS and OS and factors of interest. Ninety-four (13%) and 54 (7%) patients had BRCA1 and BRCA2-PVs, respectively. While anemia (P = .0025) and leukopenia (P = .001) were more frequently seen in BRCA noncarriers, there was no difference in regards to peripheral neuropathy or other toxicities between the groups. Increasing doses of taxane were associated with increased risk of neutropenia, stomatitis, nausea, vomiting, acne/rash, and peripheral neuropathy across all groups. In a multivariate logistic regression model, BRCA2 status remained as an independent significant predictor for decreased hematologic toxicity (HR: 0.36; 95% CI: 0.20-0.67; P = .001) and increased gastrointestinal toxicity (HR: 1.93; 95% CI: 1.02-3.67; P = .04). Being overweight, obese and African-American race were significant predictors for peripheral neuropathy (P = .04; P = .03; P = .06, respectively). Total taxane dose received did not have any impact on survival outcomes. Our study demonstrates that taxane-containing chemotherapy regimens do not increase risk of peripheral neuropathy or hematologic toxicity in patients with BRCA PVs. The mechanisms for this finding need to be further investigated as it may provide an opportunity to combine taxanes with other agents, such as platinum salts or PARP inhibitors, with less anticipated toxicity.
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http://dx.doi.org/10.1111/tbj.13922DOI Listing
August 2020

Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.

Authors:
Haoyu Zhang Thomas U Ahearn Julie Lecarpentier Daniel Barnes Jonathan Beesley Guanghao Qi Xia Jiang Tracy A O'Mara Ni Zhao Manjeet K Bolla Alison M Dunning Joe Dennis Qin Wang Zumuruda Abu Ful Kristiina Aittomäki Irene L Andrulis Hoda Anton-Culver Volker Arndt Kristan J Aronson Banu K Arun Paul L Auer Jacopo Azzollini Daniel Barrowdale Heiko Becher Matthias W Beckmann Sabine Behrens Javier Benitez Marina Bermisheva Katarzyna Bialkowska Ana Blanco Carl Blomqvist Natalia V Bogdanova Stig E Bojesen Bernardo Bonanni Davide Bondavalli Ake Borg Hiltrud Brauch Hermann Brenner Ignacio Briceno Annegien Broeks Sara Y Brucker Thomas Brüning Barbara Burwinkel Saundra S Buys Helen Byers Trinidad Caldés Maria A Caligo Mariarosaria Calvello Daniele Campa Jose E Castelao Jenny Chang-Claude Stephen J Chanock Melissa Christiaens Hans Christiansen Wendy K Chung Kathleen B M Claes Christine L Clarke Sten Cornelissen Fergus J Couch Angela Cox Simon S Cross Kamila Czene Mary B Daly Peter Devilee Orland Diez Susan M Domchek Thilo Dörk Miriam Dwek Diana M Eccles Arif B Ekici D Gareth Evans Peter A Fasching Jonine Figueroa Lenka Foretova Florentia Fostira Eitan Friedman Debra Frost Manuela Gago-Dominguez Susan M Gapstur Judy Garber José A García-Sáenz Mia M Gaudet Simon A Gayther Graham G Giles Andrew K Godwin Mark S Goldberg David E Goldgar Anna González-Neira Mark H Greene Jacek Gronwald Pascal Guénel Lothar Häberle Eric Hahnen Christopher A Haiman Christopher R Hake Per Hall Ute Hamann Elaine F Harkness Bernadette A M Heemskerk-Gerritsen Peter Hillemanns Frans B L Hogervorst Bernd Holleczek Antoinette Hollestelle Maartje J Hooning Robert N Hoover John L Hopper Anthony Howell Hanna Huebner Peter J Hulick Evgeny N Imyanitov Claudine Isaacs Louise Izatt Agnes Jager Milena Jakimovska Anna Jakubowska Paul James Ramunas Janavicius Wolfgang Janni Esther M John Michael E Jones Audrey Jung Rudolf Kaaks Pooja Middha Kapoor Beth Y Karlan Renske Keeman Sofia Khan Elza Khusnutdinova Cari M Kitahara Yon-Dschun Ko Irene Konstantopoulou Linetta B Koppert Stella Koutros Vessela N Kristensen Anne-Vibeke Laenkholm Diether Lambrechts Susanna C Larsson Pierre Laurent-Puig Conxi Lazaro Emilija Lazarova Flavio Lejbkowicz Goska Leslie Fabienne Lesueur Annika Lindblom Jolanta Lissowska Wing-Yee Lo Jennifer T Loud Jan Lubinski Alicja Lukomska Robert J MacInnis Arto Mannermaa Mehdi Manoochehri Siranoush Manoukian Sara Margolin Maria Elena Martinez Laura Matricardi Lesley McGuffog Catriona McLean Noura Mebirouk Alfons Meindl Usha Menon Austin Miller Elvira Mingazheva Marco Montagna Anna Marie Mulligan Claire Mulot Taru A Muranen Katherine L Nathanson Susan L Neuhausen Heli Nevanlinna Patrick Neven William G Newman Finn C Nielsen Liene Nikitina-Zake Jesse Nodora Kenneth Offit Edith Olah Olufunmilayo I Olopade Håkan Olsson Nick Orr Laura Papi Janos Papp Tjoung-Won Park-Simon Michael T Parsons Bernard Peissel Ana Peixoto Beth Peshkin Paolo Peterlongo Julian Peto Kelly-Anne Phillips Marion Piedmonte Dijana Plaseska-Karanfilska Karolina Prajzendanc Ross Prentice Darya Prokofyeva Brigitte Rack Paolo Radice Susan J Ramus Johanna Rantala Muhammad U Rashid Gad Rennert Hedy S Rennert Harvey A Risch Atocha Romero Matti A Rookus Matthias Rübner Thomas Rüdiger Emmanouil Saloustros Sarah Sampson Dale P Sandler Elinor J Sawyer Maren T Scheuner Rita K Schmutzler Andreas Schneeweiss Minouk J Schoemaker Ben Schöttker Peter Schürmann Leigha Senter Priyanka Sharma Mark E Sherman Xiao-Ou Shu Christian F Singer Snezhana Smichkoska Penny Soucy Melissa C Southey John J Spinelli Jennifer Stone Dominique Stoppa-Lyonnet Anthony J Swerdlow Csilla I Szabo Rulla M Tamimi William J Tapper Jack A Taylor Manuel R Teixeira MaryBeth Terry Mads Thomassen Darcy L Thull Marc Tischkowitz Amanda E Toland Rob A E M Tollenaar Ian Tomlinson Diana Torres Melissa A Troester Thérèse Truong Nadine Tung Michael Untch Celine M Vachon Ans M W van den Ouweland Lizet E van der Kolk Elke M van Veen Elizabeth J vanRensburg Ana Vega Barbara Wappenschmidt Clarice R Weinberg Jeffrey N Weitzel Hans Wildiers Robert Winqvist Alicja Wolk Xiaohong R Yang Drakoulis Yannoukakos Wei Zheng Kristin K Zorn Roger L Milne Peter Kraft Jacques Simard Paul D P Pharoah Kyriaki Michailidou Antonis C Antoniou Marjanka K Schmidt Georgia Chenevix-Trench Douglas F Easton Nilanjan Chatterjee Montserrat García-Closas

Nat Genet 2020 06 18;52(6):572-581. Epub 2020 May 18.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA.

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
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http://dx.doi.org/10.1038/s41588-020-0609-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808397PMC
June 2020

Feasibility and efficacy of a weight gain prevention intervention for breast cancer patients receiving neoadjuvant chemotherapy: a randomized controlled pilot study.

Support Care Cancer 2020 Dec 5;28(12):5821-5832. Epub 2020 Apr 5.

Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Purpose: Weight gain is common among breast cancer patients and may contribute to poorer treatment outcomes. Most programs target breast cancer survivors after the completion of therapy and focus on weight reduction. This study examined the feasibility and preliminary efficacy of an intervention designed to prevent primary weight gain among women receiving neoadjuvant chemotherapy for breast cancer.

Methods: Thirty-eight newly diagnosed stage II or III breast cancer patients were randomized to the BALANCE intervention or usual care within 3 weeks of starting neoadjuvant chemotherapy. The intervention used a size acceptance-based approach and encouraged home-based resistance and moderate-intensity aerobic exercise as well as a low energy-dense diet to prevent weight gain. Assessments were conducted at baseline, mid-chemotherapy (3 months), and post-chemotherapy (6 months). Intervention feasibility, acceptability, and preliminary effects on anthropometric, quality of life, and circulating biomarker measures were evaluated.

Results: Intervention participant retention (100%) and in-person session attendance (80%) were high during the intervention period, although attendance dropped to 43% for telephone-delivered sessions. The majority of participants reported being satisfied with the intervention during chemotherapy (88%). Participants in the intervention group had greater reductions in waist circumference (p = .03) and greater improvements in self-reported vitality scores (p = .03) than the control group at the end of chemotherapy. Significant effects on biomarkers were not observed.

Conclusions: A size acceptance weight management program is feasible during neoadjuvant chemotherapy among breast cancer patients and may have beneficial effects on waist circumference and patient vitality.

Trial Registration: This study was registered as a clinical trial at www.clinicaltrials.gov (NCT00533338).
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http://dx.doi.org/10.1007/s00520-020-05411-2DOI Listing
December 2020

Prospective Evaluation of Universal Testing for Women With Triple-Negative Breast Cancer.

JNCI Cancer Spectr 2020 Apr 20;4(2):pkaa002. Epub 2020 Jan 20.

Breast and Ovarian Cancers Moon Shots Program, The University of Texas MD Anderson Cancer Center, 1155 Pressler Street, Houston, TX, USA.

Background: Limited published literature exists on women with triple-negative breast cancer (TNBC) diagnosed over the age of 60 years with breast cancer gene () pathogenic variants. Our study determined whether the rate of pathogenic variants in a prospective cohort of TNBC patients outside the definition of current clinical genetic testing (GT) guidelines warrants a change in recommendations.

Methods: A prospective study of 395 women with TNBC underwent genetic counseling and 380 (96.2%) underwent clinical GT regardless of age of diagnosis beginning January 2014 to October 2015 at The University of Texas MD Anderson Cancer Center, Houston. TNBC patients older than 60 years who did not meet clinical GT guidelines had comprehensive sequencing and large rearrangement GT as part of the research protocol.

Results: Fifty-one of 380 (13.4%) women with TNBC who underwent clinical GT were positive. Of the 86 patients diagnosed at age over 60 years and underwent GT, only two (2.3%) were positive for . These two patients would have met clinical testing criteria due to family or ancestral history.

Conclusions: Our study does not support universal testing for TNBC patients diagnosed older than 60 years as their only risk factor for a pathogenic variant. Both of the positive patients older than 60 years identified would have met current National Comprehensive Cancer Network criteria for testing. Therefore, our study demonstrates that the National Comprehensive Cancer Network guidelines provide sufficient criteria for identifying pathogenic variants in women with TNBC at 60 years or younger.
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http://dx.doi.org/10.1093/jncics/pkaa002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083268PMC
April 2020

Diet, weight management, physical activity and Ovarian & Breast Cancer Risk in women with pathogenic Germline gene variants: systematic review.

Hered Cancer Clin Pract 2020 7;18. Epub 2020 Mar 7.

1Department of Behavioral Science, The University of Texas MD Anderson Cancer Center, P.O. Box 301439, Unit 1330, Houston, TX 77030-1439 USA.

Introduction: Women with pathogenic germline gene variants in and/or are at increased risk of developing ovarian and breast cancer. While surgical and pharmacological approaches are effective for risk-reduction, it is unknown whether lifestyle approaches such as healthful dietary habits, weight management, and physical activity may also contribute to risk-reduction. We conducted a systematic review of evidence related to dietary habits, weight status/change, and physical activity on ovarian and breast cancer risk among women with pathogenic variants.

Methods: We searched Medline, EMBASE, CENTRAL, PubMed, and clinicaltrials.gov up to October 3, 2019. We identified 2775 records and included 21.

Results: There is limited evidence related to these factors and ovarian cancer risk. For breast cancer risk, evidence suggests higher diet quality, adulthood weight-loss of ≥10 pounds, and activity during adolescence and young-adulthood may be linked with decreased risk. Higher meat intake and higher daily energy intake may be linked with increased risk.

Conclusions: There is not enough evidence to suggest tailored recommendations for dietary habits or weight management among women with pathogenic variants compared to the general population for ovarian and breast cancer risk-reduction, and physical activity recommendations should remain the same.
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http://dx.doi.org/10.1186/s13053-020-0137-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060535PMC
March 2020

Transcriptome-wide association study of breast cancer risk by estrogen-receptor status.

Authors:
Helian Feng Alexander Gusev Bogdan Pasaniuc Lang Wu Jirong Long Zomoroda Abu-Full Kristiina Aittomäki Irene L Andrulis Hoda Anton-Culver Antonis C Antoniou Adalgeir Arason Volker Arndt Kristan J Aronson Banu K Arun Ella Asseryanis Paul L Auer Jacopo Azzollini Judith Balmaña Rosa B Barkardottir Daniel R Barnes Daniel Barrowdale Matthias W Beckmann Sabine Behrens Javier Benitez Marina Bermisheva Katarzyna Białkowska Ana Blanco Carl Blomqvist Bram Boeckx Natalia V Bogdanova Stig E Bojesen Manjeet K Bolla Bernardo Bonanni Ake Borg Hiltrud Brauch Hermann Brenner Ignacio Briceno Annegien Broeks Thomas Brüning Barbara Burwinkel Qiuyin Cai Trinidad Caldés Maria A Caligo Ian Campbell Sander Canisius Daniele Campa Brian D Carter Jonathan Carter Jose E Castelao Jenny Chang-Claude Stephen J Chanock Hans Christiansen Wendy K Chung Kathleen B M Claes Christine L Clarke Fergus J Couch Angela Cox Simon S Cross Cezary Cybulski Kamila Czene Mary B Daly Miguel de la Hoya Kim De Leeneer Joe Dennis Peter Devilee Orland Diez Susan M Domchek Thilo Dörk Isabel Dos-Santos-Silva Alison M Dunning Miriam Dwek Diana M Eccles Bent Ejlertsen Carolina Ellberg Christoph Engel Mikael Eriksson Peter A Fasching Olivia Fletcher Henrik Flyger Florentia Fostira Eitan Friedman Lin Fritschi Debra Frost Marike Gabrielson Patricia A Ganz Susan M Gapstur Judy Garber Montserrat García-Closas José A García-Sáenz Mia M Gaudet Graham G Giles Gord Glendon Andrew K Godwin Mark S Goldberg David E Goldgar Anna González-Neira Mark H Greene Jacek Gronwald Pascal Guénel Christopher A Haiman Per Hall Ute Hamann Christopher Hake Wei He Jane Heyworth Frans B L Hogervorst Antoinette Hollestelle Maartje J Hooning Robert N Hoover John L Hopper Guanmengqian Huang Peter J Hulick Keith Humphreys Evgeny N Imyanitov Claudine Isaacs Milena Jakimovska Anna Jakubowska Paul James Ramunas Janavicius Rachel C Jankowitz Esther M John Nichola Johnson Vijai Joseph Audrey Jung Beth Y Karlan Elza Khusnutdinova Johanna I Kiiski Irene Konstantopoulou Vessela N Kristensen Yael Laitman Diether Lambrechts Conxi Lazaro Dominique Leroux Goska Leslie Jenny Lester Fabienne Lesueur Noralane Lindor Sara Lindström Wing-Yee Lo Jennifer T Loud Jan Lubiński Enes Makalic Arto Mannermaa Mehdi Manoochehri Siranoush Manoukian Sara Margolin John W M Martens Maria E Martinez Laura Matricardi Tabea Maurer Dimitrios Mavroudis Lesley McGuffog Alfons Meindl Usha Menon Kyriaki Michailidou Pooja M Kapoor Austin Miller Marco Montagna Fernando Moreno Lidia Moserle Anna M Mulligan Taru A Muranen Katherine L Nathanson Susan L Neuhausen Heli Nevanlinna Ines Nevelsteen Finn C Nielsen Liene Nikitina-Zake Kenneth Offit Edith Olah Olufunmilayo I Olopade Håkan Olsson Ana Osorio Janos Papp Tjoung-Won Park-Simon Michael T Parsons Inge S Pedersen Ana Peixoto Paolo Peterlongo Julian Peto Paul D P Pharoah Kelly-Anne Phillips Dijana Plaseska-Karanfilska Bruce Poppe Nisha Pradhan Karolina Prajzendanc Nadege Presneau Kevin Punie Katri Pylkäs Paolo Radice Johanna Rantala Muhammad Usman Rashid Gad Rennert Harvey A Risch Mark Robson Atocha Romero Emmanouil Saloustros Dale P Sandler Catarina Santos Elinor J Sawyer Marjanka K Schmidt Daniel F Schmidt Rita K Schmutzler Minouk J Schoemaker Rodney J Scott Priyanka Sharma Xiao-Ou Shu Jacques Simard Christian F Singer Anne-Bine Skytte Penny Soucy Melissa C Southey John J Spinelli Amanda B Spurdle Jennifer Stone Anthony J Swerdlow William J Tapper Jack A Taylor Manuel R Teixeira Mary Beth Terry Alex Teulé Mads Thomassen Kathrin Thöne Darcy L Thull Marc Tischkowitz Amanda E Toland Rob A E M Tollenaar Diana Torres Thérèse Truong Nadine Tung Celine M Vachon Christi J van Asperen Ans M W van den Ouweland Elizabeth J van Rensburg Ana Vega Alessandra Viel Paula Vieiro-Balo Qin Wang Barbara Wappenschmidt Clarice R Weinberg Jeffrey N Weitzel Camilla Wendt Robert Winqvist Xiaohong R Yang Drakoulis Yannoukakos Argyrios Ziogas Roger L Milne Douglas F Easton Georgia Chenevix-Trench Wei Zheng Peter Kraft Xia Jiang

Genet Epidemiol 2020 07 1;44(5):442-468. Epub 2020 Mar 1.

Program in Genetic Epidemiology and Statistical Genetics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

Previous transcriptome-wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome-wide association studies (GWAS), but analyses of breast cancer subtype-specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta-analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER-). We further compared associations with ER+ and ER- subtypes, using a case-only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER- breast cancer. We further identified 30 TWAS-significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast-cancer gene in three of six regions harboring multiple TWAS-significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER- breast cancer.
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http://dx.doi.org/10.1002/gepi.22288DOI Listing
July 2020

TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline Carriers With HER2-Negative Breast Cancer (the INFORM trial).

J Clin Oncol 2020 05 25;38(14):1539-1548. Epub 2020 Feb 25.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: Platinum compounds have activity in triple-negative breast cancer (TNBC) in germline mutation carriers ( carriers). Limited data exist for estrogen receptor (ER)-positive (+) breast cancer among carriers. INFORM is a randomized, multicenter, phase II trial comparing pathologic complete response (pCR) rates (ypT0/is, N0) after neoadjuvant single-agent cisplatin (CDDP) versus doxorubicin-cyclophosphamide (AC) in carriers with stage I-III human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Secondary objectives included residual cancer burden scores (RCB) of 0 or 1 (combined) and toxicity. The goal was to determine whether pCR was ≥ 20% higher with CDDP than AC.

Patients And Methods: carriers with cT1-3 (≥ 1.5 cm), cN0-3 HER2-negative breast cancer were randomly assigned to preoperative CDDP (75 mg/m every 3 weeks × 4 doses) or AC (doxorubicin 60 mg/m; cyclophosphamide 600 mg/m every 2-3 weeks × 4 doses) followed by surgery. Pathologic responses were confirmed by central review.

Results: A total of 118 patients were randomly assigned; 117 were included in outcome analyses. Mean age was 42 years (range, 24-73 years); 69% were +, 30% were +, and 2% had both mutations. Clinical stage was I for 19%, II for 63%, and III for 18%; 45% had nodal involvement at baseline. Seventy percent had TNBC. Clinical and tumor characteristics were well matched between treatment arms. The pCR rate was 18% with CDDP and 26% with AC, yielding a risk ratio (RR) of 0.70 (90% CI, 0.39 to 1.2). The risk of RCB 0 or 1 (RCB 0/1) was 33% with CDDP and 46% with AC (RR, 0.73; 90% CI, 0.50 to 1.1). Both regimens were generally well tolerated without unexpected toxicities.

Conclusion: pCR or RCB 0/1 is not significantly higher with CDDP than with AC in carriers with stage I-III HER2-negative breast cancer for both TNBC and ER+/HER2-negative disease.
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http://dx.doi.org/10.1200/JCO.19.03292DOI Listing
May 2020

Imaging Features of Triple Negative Breast Cancer and the Effect of BRCA Mutations.

Curr Probl Diagn Radiol 2020 Jan 8. Epub 2020 Jan 8.

Department of Diagnostic Radiology, University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Objective: The purpose of this study is to review the mammographic and the ultrasound features of triple negative breast cancer (TNBC) patients and to investigate the potential effect of BRCA mutations on the imaging features of these patients.

Methods: One hundred and seven patients with TNBC were enrolled in a retrospective study following IRB approval and approval of waiver of informed consent. BRCA mutations were assessed using genetic testing. Imaging features on mammography and ultrasound (US) as well as pathology and clinical information were retrospectively reviewed and characterized according to the BI-RADS lexicon (fifth edition). The relationships between BRCA mutations and the imaging findings were examined.

Results: TNBC commonly presented as an irregular mass with obscured margins on mammography and as an irregular hypoechoic mass with microlobulated or angular margins on US. Approximately two thirds of TNBC cases had a parallel orientation and approximately one third had posterior enhancement, features often associated with benign masses. There was no statistically significant difference in the mammographic and the US features of BRCA positive and BRCA negative triple negative tumors.

Conclusion: TNBC may have a parallel orientation and posterior enhancement, which are features often seen with benign masses. BRCA mutations do not affect the imaging features of triple negative breast tumors.
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http://dx.doi.org/10.1067/j.cpradiol.2020.01.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340565PMC
January 2020

Multigene panel testing results in patients with multiple breast cancer primaries.

Breast J 2020 07 30;26(7):1337-1342. Epub 2020 Jan 30.

Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Currently, the NCCN guidelines recommend testing of BRCA1 and BRCA2 for females with multiple breast primaries, if her first diagnosis was ≤50 years old. With the increase in uptake of multigene panels, testing for genes outside of BRCA1 and BRCA2 has become more prevalent. This study looked at a single institution's cohort of women with multiple primary breast cancers that underwent panel testing to determine the rates of pathogenic mutations in non-BRCA genes. The genetic testing results for each individual were reviewed, along with patient characteristics. Descriptive analysis and two-tailed Z tests were used to analyze the data. Out of 85 eligible women, 33 (38.8%) tested positive for a pathogenic mutation in a cancer predisposition gene: 9 BRCA1, 5 BRCA2, 5 ATM, 1 BARD1, 4 CHEK2, 1 MSH2, 1 MSH6, 2 PALB2, 1 PMS2, 1 PTEN and 3 TP53. Overall, 17.6% tested positive for a non-BRCA breast cancer predisposition gene. There was no difference in the age of first or second breast cancer diagnosis in comparison with genetic testing outcomes. This study found a high positive rate for all individuals with multiple breast cancers, regardless of age, for both BRCA1 and BRCA2 and non-BRCA genes. Future studies should investigate whether individuals with multiple breast cancer primaries that do not meet BRCA1 and BRCA2 testing criteria should undergo genetic testing, regardless of the age of diagnosis.
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http://dx.doi.org/10.1111/tbj.13762DOI Listing
July 2020

Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.

Authors:
Laura Fachal Hugues Aschard Jonathan Beesley Daniel R Barnes Jamie Allen Siddhartha Kar Karen A Pooley Joe Dennis Kyriaki Michailidou Constance Turman Penny Soucy Audrey Lemaçon Michael Lush Jonathan P Tyrer Maya Ghoussaini Mahdi Moradi Marjaneh Xia Jiang Simona Agata Kristiina Aittomäki M Rosario Alonso Irene L Andrulis Hoda Anton-Culver Natalia N Antonenkova Adalgeir Arason Volker Arndt Kristan J Aronson Banu K Arun Bernd Auber Paul L Auer Jacopo Azzollini Judith Balmaña Rosa B Barkardottir Daniel Barrowdale Alicia Beeghly-Fadiel Javier Benitez Marina Bermisheva Katarzyna Białkowska Amie M Blanco Carl Blomqvist William Blot Natalia V Bogdanova Stig E Bojesen Manjeet K Bolla Bernardo Bonanni Ake Borg Kristin Bosse Hiltrud Brauch Hermann Brenner Ignacio Briceno Ian W Brock Angela Brooks-Wilson Thomas Brüning Barbara Burwinkel Saundra S Buys Qiuyin Cai Trinidad Caldés Maria A Caligo Nicola J Camp Ian Campbell Federico Canzian Jason S Carroll Brian D Carter Jose E Castelao Jocelyne Chiquette Hans Christiansen Wendy K Chung Kathleen B M Claes Christine L Clarke J Margriet Collée Sten Cornelissen Fergus J Couch Angela Cox Simon S Cross Cezary Cybulski Kamila Czene Mary B Daly Miguel de la Hoya Peter Devilee Orland Diez Yuan Chun Ding Gillian S Dite Susan M Domchek Thilo Dörk Isabel Dos-Santos-Silva Arnaud Droit Stéphane Dubois Martine Dumont Mercedes Duran Lorraine Durcan Miriam Dwek Diana M Eccles Christoph Engel Mikael Eriksson D Gareth Evans Peter A Fasching Olivia Fletcher Giuseppe Floris Henrik Flyger Lenka Foretova William D Foulkes Eitan Friedman Lin Fritschi Debra Frost Marike Gabrielson Manuela Gago-Dominguez Gaetana Gambino Patricia A Ganz Susan M Gapstur Judy Garber José A García-Sáenz Mia M Gaudet Vassilios Georgoulias Graham G Giles Gord Glendon Andrew K Godwin Mark S Goldberg David E Goldgar Anna González-Neira Maria Grazia Tibiletti Mark H Greene Mervi Grip Jacek Gronwald Anne Grundy Pascal Guénel Eric Hahnen Christopher A Haiman Niclas Håkansson Per Hall Ute Hamann Patricia A Harrington Jaana M Hartikainen Mikael Hartman Wei He Catherine S Healey Bernadette A M Heemskerk-Gerritsen Jane Heyworth Peter Hillemanns Frans B L Hogervorst Antoinette Hollestelle Maartje J Hooning John L Hopper Anthony Howell Guanmengqian Huang Peter J Hulick Evgeny N Imyanitov Claudine Isaacs Motoki Iwasaki Agnes Jager Milena Jakimovska Anna Jakubowska Paul A James Ramunas Janavicius Rachel C Jankowitz Esther M John Nichola Johnson Michael E Jones Arja Jukkola-Vuorinen Audrey Jung Rudolf Kaaks Daehee Kang Pooja Middha Kapoor Beth Y Karlan Renske Keeman Michael J Kerin Elza Khusnutdinova Johanna I Kiiski Judy Kirk Cari M Kitahara Yon-Dschun Ko Irene Konstantopoulou Veli-Matti Kosma Stella Koutros Katerina Kubelka-Sabit Ava Kwong Kyriacos Kyriacou Yael Laitman Diether Lambrechts Eunjung Lee Goska Leslie Jenny Lester Fabienne Lesueur Annika Lindblom Wing-Yee Lo Jirong Long Artitaya Lophatananon Jennifer T Loud Jan Lubiński Robert J MacInnis Tom Maishman Enes Makalic Arto Mannermaa Mehdi Manoochehri Siranoush Manoukian Sara Margolin Maria Elena Martinez Keitaro Matsuo Tabea Maurer Dimitrios Mavroudis Rebecca Mayes Lesley McGuffog Catriona McLean Noura Mebirouk Alfons Meindl Austin Miller Nicola Miller Marco Montagna Fernando Moreno Kenneth Muir Anna Marie Mulligan Victor M Muñoz-Garzon Taru A Muranen Steven A Narod Rami Nassir Katherine L Nathanson Susan L Neuhausen Heli Nevanlinna Patrick Neven Finn C Nielsen Liene Nikitina-Zake Aaron Norman Kenneth Offit Edith Olah Olufunmilayo I Olopade Håkan Olsson Nick Orr Ana Osorio V Shane Pankratz Janos Papp Sue K Park Tjoung-Won Park-Simon Michael T Parsons James Paul Inge Sokilde Pedersen Bernard Peissel Beth Peshkin Paolo Peterlongo Julian Peto Dijana Plaseska-Karanfilska Karolina Prajzendanc Ross Prentice Nadege Presneau Darya Prokofyeva Miquel Angel Pujana Katri Pylkäs Paolo Radice Susan J Ramus Johanna Rantala Rohini Rau-Murthy Gad Rennert Harvey A Risch Mark Robson Atocha Romero Maria Rossing Emmanouil Saloustros Estela Sánchez-Herrero Dale P Sandler Marta Santamariña Christobel Saunders Elinor J Sawyer Maren T Scheuner Daniel F Schmidt Rita K Schmutzler Andreas Schneeweiss Minouk J Schoemaker Ben Schöttker Peter Schürmann Christopher Scott Rodney J Scott Leigha Senter Caroline M Seynaeve Mitul Shah Priyanka Sharma Chen-Yang Shen Xiao-Ou Shu Christian F Singer Thomas P Slavin Snezhana Smichkoska Melissa C Southey John J Spinelli Amanda B Spurdle Jennifer Stone Dominique Stoppa-Lyonnet Christian Sutter Anthony J Swerdlow Rulla M Tamimi Yen Yen Tan William J Tapper Jack A Taylor Manuel R Teixeira Maria Tengström Soo Hwang Teo Mary Beth Terry Alex Teulé Mads Thomassen Darcy L Thull Marc Tischkowitz Amanda E Toland Rob A E M Tollenaar Ian Tomlinson Diana Torres Gabriela Torres-Mejía Melissa A Troester Thérèse Truong Nadine Tung Maria Tzardi Hans-Ulrich Ulmer Celine M Vachon Christi J van Asperen Lizet E van der Kolk Elizabeth J van Rensburg Ana Vega Alessandra Viel Joseph Vijai Maartje J Vogel Qin Wang Barbara Wappenschmidt Clarice R Weinberg Jeffrey N Weitzel Camilla Wendt Hans Wildiers Robert Winqvist Alicja Wolk Anna H Wu Drakoulis Yannoukakos Yan Zhang Wei Zheng David Hunter Paul D P Pharoah Jenny Chang-Claude Montserrat García-Closas Marjanka K Schmidt Roger L Milne Vessela N Kristensen Juliet D French Stacey L Edwards Antonis C Antoniou Georgia Chenevix-Trench Jacques Simard Douglas F Easton Peter Kraft Alison M Dunning

Nat Genet 2020 01 7;52(1):56-73. Epub 2020 Jan 7.

Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.
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http://dx.doi.org/10.1038/s41588-019-0537-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974400PMC
January 2020

Helical Radiotherapy in Early Laryngeal Cancers Could Lead to Excess Local Recurrence: Lessons From a Phase II Prospective Study.

Clin Oncol (R Coll Radiol) 2020 02 5;32(2):e67-e75. Epub 2019 Nov 5.

Department of Radiology, Tata Medical Center, Kolkata, India.

Aims: A prospective study was conducted to investigate the feasibility and efficacy of carotid-sparing intensity-modulated radiotherapy (CSIMRT) in early glottic cancers (EGC).

Materials And Methods: Eighteen patients underwent CSIMRT using helical tomotherapy to a dose of 55 Gy/20 fractions/4 weeks. Carotid intimal thickness (CIT) at prespecified carotid levels was measured using B-mode ultrasound at 6, 18 and 36 months. Serial changes in CIT were also measured in a control prospective cohort of 18 patients with head and neck cancers receiving bilateral neck nodal radiation over the same time period (54-60 Gy/30 fraction/6 weeks). The outcomes of 18 patients undergoing CSIMRT were compared against a retrospective consecutive cohort of 41 patients with EGC to confirm comparable local control.

Results: No significant CIT differences were identified between patients undergoing CSIMRT versus the control group. However, four patients in the CSIMRT group had a local recurrence between 8 and 39 months. In all patients the epicentre of the recurrence was noted at the anterior part of the larynx. The 5-year local recurrence-free survival was 75.1% (95% confidence interval 56.6-99.7%). By contrast, in the group of EGC patients treated without carotid sparing, local recurrence was noted only in a single patient (patient treated with helical tomotherapy) and the 5-year local recurrence-free survival was 97.1% (95% confidence interval 91.8-100%) (Log-rank P = 0.01).

Conclusion: We failed to show the safety of CSIMRT using helical tomotherapy in this population of EGC patients. Use of CSIMRT also did not translate into a substantial reduction in CIT until 36 months. Use of CSIMRT using rotational arc techniques such as helical tomotherapy may be associated with a greater risk of local recurrence due to intrafractional motion interplay effects.
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http://dx.doi.org/10.1016/j.clon.2019.09.048DOI Listing
February 2020

The :p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Authors:
Gisella Figlioli Massimo Bogliolo Irene Catucci Laura Caleca Sandra Viz Lasheras Roser Pujol Johanna I Kiiski Taru A Muranen Daniel R Barnes Joe Dennis Kyriaki Michailidou Manjeet K Bolla Goska Leslie Cora M Aalfs Muriel A Adank Julian Adlard Simona Agata Karen Cadoo Bjarni A Agnarsson Thomas Ahearn Kristiina Aittomäki Christine B Ambrosone Lesley Andrews Hoda Anton-Culver Natalia N Antonenkova Volker Arndt Norbert Arnold Kristan J Aronson Banu K Arun Ella Asseryanis Bernd Auber Päivi Auvinen Jacopo Azzollini Judith Balmaña Rosa B Barkardottir Daniel Barrowdale Julian Barwell Laura E Beane Freeman Charles Joly Beauparlant Matthias W Beckmann Sabine Behrens Javier Benitez Raanan Berger Marina Bermisheva Amie M Blanco Carl Blomqvist Natalia V Bogdanova Anders Bojesen Stig E Bojesen Bernardo Bonanni Ake Borg Angela F Brady Hiltrud Brauch Hermann Brenner Thomas Brüning Barbara Burwinkel Saundra S Buys Trinidad Caldés Almuth Caliebe Maria A Caligo Daniele Campa Ian G Campbell Federico Canzian Jose E Castelao Jenny Chang-Claude Stephen J Chanock Kathleen B M Claes Christine L Clarke Anita Collavoli Thomas A Conner David G Cox Cezary Cybulski Kamila Czene Mary B Daly Miguel de la Hoya Peter Devilee Orland Diez Yuan Chun Ding Gillian S Dite Nina Ditsch Susan M Domchek Cecilia M Dorfling Isabel Dos-Santos-Silva Katarzyna Durda Miriam Dwek Diana M Eccles Arif B Ekici A Heather Eliassen Carolina Ellberg Mikael Eriksson D Gareth Evans Peter A Fasching Jonine Figueroa Henrik Flyger William D Foulkes Tara M Friebel Eitan Friedman Marike Gabrielson Pragna Gaddam Manuela Gago-Dominguez Chi Gao Susan M Gapstur Judy Garber Montserrat García-Closas José A García-Sáenz Mia M Gaudet Simon A Gayther Graham G Giles Gord Glendon Andrew K Godwin Mark S Goldberg David E Goldgar Pascal Guénel Angelica M Gutierrez-Barrera Lothar Haeberle Christopher A Haiman Niclas Håkansson Per Hall Ute Hamann Patricia A Harrington Alexander Hein Jane Heyworth Peter Hillemanns Antoinette Hollestelle John L Hopper H Dean Hosgood Anthony Howell Chunling Hu Peter J Hulick David J Hunter Evgeny N Imyanitov Claudine Isaacs Milena Jakimovska Anna Jakubowska Paul James Ramunas Janavicius Wolfgang Janni Esther M John Michael E Jones Audrey Jung Rudolf Kaaks Beth Y Karlan Elza Khusnutdinova Cari M Kitahara Irene Konstantopoulou Stella Koutros Peter Kraft Diether Lambrechts Conxi Lazaro Loic Le Marchand Jenny Lester Fabienne Lesueur Jenna Lilyquist Jennifer T Loud Karen H Lu Robert N Luben Jan Lubinski Arto Mannermaa Mehdi Manoochehri Siranoush Manoukian Sara Margolin John W M Martens Tabea Maurer Dimitrios Mavroudis Noura Mebirouk Alfons Meindl Usha Menon Austin Miller Marco Montagna Katherine L Nathanson Susan L Neuhausen William G Newman Tu Nguyen-Dumont Finn Cilius Nielsen Sarah Nielsen Liene Nikitina-Zake Kenneth Offit Edith Olah Olufunmilayo I Olopade Andrew F Olshan Janet E Olson Håkan Olsson Ana Osorio Laura Ottini Bernard Peissel Ana Peixoto Julian Peto Dijana Plaseska-Karanfilska Timea Pocza Nadege Presneau Miquel Angel Pujana Kevin Punie Brigitte Rack Johanna Rantala Muhammad U Rashid Rohini Rau-Murthy Gad Rennert Flavio Lejbkowicz Valerie Rhenius Atocha Romero Matti A Rookus Eric A Ross Maria Rossing Vilius Rudaitis Matthias Ruebner Emmanouil Saloustros Kristin Sanden Marta Santamariña Maren T Scheuner Rita K Schmutzler Michael Schneider Christopher Scott Leigha Senter Mitul Shah Priyanka Sharma Xiao-Ou Shu Jacques Simard Christian F Singer Christof Sohn Penny Soucy Melissa C Southey John J Spinelli Linda Steele Dominique Stoppa-Lyonnet William J Tapper Manuel R Teixeira Mary Beth Terry Mads Thomassen Jennifer Thompson Darcy L Thull Marc Tischkowitz Rob A E M Tollenaar Diana Torres Melissa A Troester Thérèse Truong Nadine Tung Michael Untch Celine M Vachon Elizabeth J van Rensburg Elke M van Veen Ana Vega Alessandra Viel Barbara Wappenschmidt Jeffrey N Weitzel Camilla Wendt Greet Wieme Alicja Wolk Xiaohong R Yang Wei Zheng Argyrios Ziogas Kristin K Zorn Alison M Dunning Michael Lush Qin Wang Lesley McGuffog Michael T Parsons Paul D P Pharoah Florentia Fostira Amanda E Toland Irene L Andrulis Susan J Ramus Anthony J Swerdlow Mark H Greene Wendy K Chung Roger L Milne Georgia Chenevix-Trench Thilo Dörk Marjanka K Schmidt Douglas F Easton Paolo Radice Eric Hahnen Antonis C Antoniou Fergus J Couch Heli Nevanlinna Jordi Surrallés Paolo Peterlongo

NPJ Breast Cancer 2019 1;5:38. Epub 2019 Nov 1.

IFOM - the FIRC Institute for Molecular Oncology, Genome Diagnostics Program, Milan, Italy.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes , , , , and are associated with breast cancer risk. , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of or . These three variants were also studied functionally by measuring survival and chromosome fragility in patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44,  = 0.034 and OR = 3.79;  = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for :p.Arg658* and found that also :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96;  = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat -associated tumors.
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http://dx.doi.org/10.1038/s41523-019-0127-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825205PMC
November 2019