Publications by authors named "Marie Wood"

54 Publications

Lifestyle, behavioral, and dietary risk factors in relation to mammographic breast density in women at high risk for breast cancer.

Cancer Epidemiol Biomarkers Prev 2021 Feb 22. Epub 2021 Feb 22.

University of Vermont Medical Center.

Background: Women at high risk for breast cancer due to genetics or to risk factor profiles are counseled to adopt lifestyle, behavioral, and dietary changes to help reduce their risk. These recommendations are based on studies of women at average risk, so their effectiveness in high-risk women is unclear.

Methods: We evaluated the impact of physical activity, smoking, alcohol consumption, and intake of folate and carotenoids on mammographic breast density-a proxy for breast cancer risk-among 387 high-risk women. Exposures were self-reported on questionnaires. Breast dense area, non-dense area, and percent dense area were measured from screening mammograms with Library for Breast Radiodensity Assessment software. Cross-sectional associations were estimated with multivariable quantile regression models.

Results: After adjusting for age, adiposity, reproductive history, and use of postmenopausal hormones, no breast density measure was associated with physical activity level, smoking status, alcohol consumption, or estimated intake of folate, alpha carotene, beta carotene, lutein/zeaxanthin, and beta cryptoxanthin. Lycopene intake was associated with lower dense area when comparing the highest and lowest intake categories (adjusted difference in median= -14 cm2, 95% CI: -29 to 1.3 cm2). This association may be explained by incomplete adjustment for adiposity.

Conclusions: Recommended lifestyle, behavioral, and dietary changes to mitigate personal risk of breast cancer do not substantially impact mammographic breast density measures.

Impact: Alternative strategies, such as increased uptake of chemoprevention, may better serve risk reduction efforts in women at high risk for breast cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1567DOI Listing
February 2021

Risk for breast cancer and management of unaffected individuals with non-BRCA hereditary breast cancer.

Breast J 2020 08 2;26(8):1528-1534. Epub 2020 Aug 2.

DFCI, Harvard, Boston, Massachusetts, USA.

About 5%-10% of breast cancer is hereditary with BRCA1 and BRCA2 being the most common genes associated with hereditary breast cancer (HBC). Several additional genes have recently been associated with HBC. These genes can be classified as highly or moderately penetrant genes with lifetime risk >30% or 17%-30%, respectively. Highly penetrant genes associated with HBC include TP53, PTEN, CDH1, STK11, and PALB2. While, moderately penetrant genes include CHEK2, ATM, BARD1, BRIP1, NBN, NF1, RAD51D, and MSH6. Breast cancer risk and recommendations for screening and risk-reduction vary by gene. In general, screening breast MRI is recommended for women at >20% lifetime risk, which includes women with mutations in highly penetrant genes and the majority (but not all) moderately penetrant genes. Consideration of chemoprevention is recommended for women with mutations in high and moderately penetrant genes. Risk-reducing mastectomy does reduce the risk of breast cancer to the greatest extent and can be considered for women with highly penetrant genes. However, this procedure is associated with significant morbidities that should be considered, especially given the benefit of using screening breast MRI for high-risk women. BSO is only recommended for women with mutations in genes associate with increased risk for ovarian cancer and not as a breast cancer risk-reducing strategy. As more women undergo testing, additional genes may be identified and risk estimates for current genes and management recommendations may be modified.
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http://dx.doi.org/10.1111/tbj.13969DOI Listing
August 2020

Effect of neuromuscular electrical stimulation on skeletal muscle size and function in patients with breast cancer receiving chemotherapy.

J Appl Physiol (1985) 2020 06 7;128(6):1654-1665. Epub 2020 May 7.

Department of Medicine, University of Vermont, Burlington, Vermont.

Exercise has numerous benefits for patients with cancer, but implementation is challenging because of practical and logistical hurdles. This study examined whether neuromuscular electrical stimulation (NMES) can serve as a surrogate for classic exercise by eliciting an exercise training response in skeletal muscle of women diagnosed with breast cancer undergoing chemotherapy. Patients ( = 22) with histologically confirmed stage I, II, or III breast cancer scheduled to receive neoadjuvant or adjuvant chemotherapy were randomized to 8 wk of bilateral neuromuscular electrical stimulation (NMES; 5 days/wk) to their quadriceps muscles or control. Biopsy of the vastus lateralis was performed at baseline and after 8 wk of intervention to assess muscle fiber size, contractility, and mitochondrial content. Seventeen patients (8 control/9 NMES) completed the trial and were included in analyses. NMES promoted muscle fiber hypertrophy ( < 0.001), particularly in fast-twitch, myosin heavy chain (MHC) IIA fibers ( < 0.05) and tended to induce fiber type shifts in MHC II fibers. The effects of NMES on single-muscle fiber contractility were modest, and it was unable to prevent declines in the function in MHC IIA fibers. NMES did not alter intermyofibrillar mitochondrial content/structure but was associated with reductions in subsarcolemmal mitochondria. Our results demonstrate that NMES induces muscle fiber hypertrophy and fiber type shifts in MHC II fibers but had minimal effects on fiber contractility and promoted reductions in subsarcolemmal mitochondria. Further studies are warranted to evaluate the utility of NMES as an exercise surrogate in cancer patients and other conditions. This is the first study to evaluate whether neuromuscular electrical stimulation (NMES) can be used as an exercise surrogate to improve skeletal muscle fiber size or function in cancer patients receiving treatment. We show that NMES promoted muscle fiber hypertrophy and fiber type shifts but had minimal effects on single-fiber contractility and reduced subsarcolemmal mitochondria.
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http://dx.doi.org/10.1152/japplphysiol.00203.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311687PMC
June 2020

Quantitative Analysis of Oncology Professional Learning Preferences.

JCO Oncol Pract 2020 02 7;16(2):e155-e165. Epub 2020 Jan 7.

Vanderbilt University School of Medicine, Nashville, TN.

Purpose: ASCO is the premier and largest global professional society for oncology care professionals. In 2015, ASCO launched a longitudinal Learning Cohort Pilot Project to catalog and better understand the learning behaviors and preferences of oncology health care providers. A secondary goal was to assess learner preferences and utilization related to ASCO's portfolio of educational resources.

Methods: The Learning Cohort Pilot Project was conducted between November 2015 and August 2016 with 49 ASCO members. Participants were selected via convenience sampling and stratified random sampling to generate a cohort that mirrored the demographic distribution of overall ASCO membership. Participants completed a different ASCO resource-specific feedback activity each month, which measured professional educational needs, sources sought, and preferences for educational resources. Responses were organized by demographic variables in our participant pool to identify trends in provider learning preferences. Fisher's exact test was used to assess the association between participant demographics and practice setting and responses. Holm's procedure was used to adjust for multiple testing.

Results: The Learning Cohort Pilot Project revealed statistically significant relationships between participant demographic variables and learning preferences. Age and practice setting were the demographic variables most consistently associated with the different preferences explored throughout the targeted activities.

Conclusion: The results of this pilot cohort reinforced the hypothesis that oncology care providers have different professional educational needs and preferences that can be potentially anticipated and met with tailored resources. Delivering solutions to meet these needs represents an opportunity for further research and resource development.
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http://dx.doi.org/10.1200/JOP.18.00731DOI Listing
February 2020

Importance of family history and indications for genetic testing.

Breast J 2020 01 22;26(1):100-104. Epub 2019 Dec 22.

MD Anderson Cancer Center, Houston, Texas.

Family history is an important cancer risk assessment tool, and it is easy to use. The family history is integral in identifying an individual's risk for primary cancer and assists in the assessment of risk for a second primary cancer. For oncology providers, the critical family history is defined as including first- and second-degree family history, maternal and paternal history, type of primary cancer, and age at diagnosis and ethnicity. Family history should be taken at diagnosis and updated periodically. Despite the importance of family history to patient care, there are significant barriers to taking a family history. We review the impact of collecting complete family history data with respect to calculation of cancer risk, recommendations for screening, and prevention strategies and referral for genetic testing.
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http://dx.doi.org/10.1111/tbj.13722DOI Listing
January 2020

Cancer Risks Associated With Germline Pathogenic Variants: An International Study of 524 Families.

Authors:
Xin Yang Goska Leslie Alicja Doroszuk Sandra Schneider Jamie Allen Brennan Decker Alison M Dunning James Redman James Scarth Inga Plaskocinska Craig Luccarini Mitul Shah Karen Pooley Leila Dorling Andrew Lee Muriel A Adank Julian Adlard Kristiina Aittomäki Irene L Andrulis Peter Ang Julian Barwell Jonine L Bernstein Kristie Bobolis Åke Borg Carl Blomqvist Kathleen B M Claes Patrick Concannon Adeline Cuggia Julie O Culver Francesca Damiola Antoine de Pauw Orland Diez Jill S Dolinsky Susan M Domchek Christoph Engel D Gareth Evans Florentia Fostira Judy Garber Lisa Golmard Ellen L Goode Stephen B Gruber Eric Hahnen Christopher Hake Tuomas Heikkinen Judith E Hurley Ramunas Janavicius Zdenek Kleibl Petra Kleiblova Irene Konstantopoulou Anders Kvist Holly Laduca Ann S G Lee Fabienne Lesueur Eamonn R Maher Arto Mannermaa Siranoush Manoukian Rachel McFarland Wendy McKinnon Alfons Meindl Kelly Metcalfe Nur Aishah Mohd Taib Jukka Moilanen Katherine L Nathanson Susan Neuhausen Pei Sze Ng Tu Nguyen-Dumont Sarah M Nielsen Florian Obermair Kenneth Offit Olufunmilayo I Olopade Laura Ottini Judith Penkert Katri Pylkäs Paolo Radice Susan J Ramus Vilius Rudaitis Lucy Side Rachel Silva-Smith Valentina Silvestri Anne-Bine Skytte Thomas Slavin Jana Soukupova Carlo Tondini Alison H Trainer Gary Unzeitig Lydia Usha Thomas van Overeem Hansen James Whitworth Marie Wood Cheng Har Yip Sook-Yee Yoon Amal Yussuf George Zogopoulos David Goldgar John L Hopper Georgia Chenevix-Trench Paul Pharoah Sophia H L George Judith Balmaña Claude Houdayer Paul James Zaki El-Haffaf Hans Ehrencrona Marketa Janatova Paolo Peterlongo Heli Nevanlinna Rita Schmutzler Soo-Hwang Teo Mark Robson Tuya Pal Fergus Couch Jeffrey N Weitzel Aaron Elliott Melissa Southey Robert Winqvist Douglas F Easton William D Foulkes Antonis C Antoniou Marc Tischkowitz

J Clin Oncol 2020 03 16;38(7):674-685. Epub 2019 Dec 16.

Department of Medical Genetics, NIHR Cambridge Biomedical Research Centre, and Cancer Research UK Cambridge Centre, University of Cambridge, Cambridge, United Kingdom.

Purpose: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline pathogenic variants (PVs) because these risks have not been extensively characterized.

Methods: We analyzed data from 524 families with PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes.

Results: We found associations between PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; = 6.5 × 10), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; = 4.1 × 10), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; = 8.7 × 10), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; = 2.6 × 10). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( for trend = 2.0 × 10). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer.

Conclusion: These results confirm as a major breast cancer susceptibility gene and establish substantial associations between germline PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of into risk prediction models and optimize the clinical cancer risk management of PV carriers.
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http://dx.doi.org/10.1200/JCO.19.01907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049229PMC
March 2020

Establishing and Evaluating an ASCO Learning Cohort: a Longitudinal Project Assessing the Learning Needs and Behaviors of Oncology Professionals.

J Cancer Educ 2019 Nov 18. Epub 2019 Nov 18.

Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, USA.

Background: In 2013, the American Society of Clinical Oncology (ASCO)'s Continuing Education Committee recommended establishing an interprofessional, longitudinal cohort pilot project. The main goals of the cohort were to gain feedback from oncology providers on how they use resources to address their learning needs and gain insights into the utility of different ASCO educational activities.

Methods: The ASCO Learning Cohort Pilot Project included 49 ASCO members that were representative of the overall Society membership demographics and ran from November 2015 through August 2016. Participants documented monthly learning needs and completed monthly feedback activities focused on specific ASCO educational resources.

Results: The Learning Cohort Pilot Project proved a viable and innovative cohort model for analyzing the learning process for oncology healthcare professionals. The development, operations, and compliance required unique infrastructure to accomplish this project. Relationships between participant demographic variables and learning preferences are reported elsewhere.

Conclusion: The ASCO Learning Cohort Project is a unique educational project that demonstrated feasibility and has met its goals. This paper outlines the processes of establishing a learning cohort, including participant selection, project design, and participant feedback. We evaluate the project model as a means to better understand the learning needs and behaviors of oncology healthcare professionals.
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http://dx.doi.org/10.1007/s13187-019-01649-5DOI Listing
November 2019

Increasing Adherence to Adjuvant Hormone Therapy Among Patients With Breast Cancer: A Smart Phone App-Based Pilot Study.

Cancer Control 2019 Jan-Dec;26(1):1073274819883287

Deceased.

Purpose: This study tested the feasibility and efficacy of using a text-based intervention to increase initiation, decrease discontinuation, and improve adherence as prescribed to adjuvant hormone therapy (AHT) among hyphenate post-menopausal breast cancer survivors.

Methods: The 3-month intervention consisted of daily text message reminders to take medication, coupled with a dynamic (eg, feedback on progress) tailored intervention using weekly interactive surveys delivered by a smartphone app. Five clinic sites within the Alliance for Clinical Trials in Oncology participated. Hormone levels were measured prior to AHT initiation and at study exit.

Results: Of the 39 patients recruited to the pilot study, 27 (69.2%) completed all study requirements (completed both the baseline and the exit surveys, both blood draws, and did not miss more than 2 weekly surveys). Significant improvements were observed pre- to postintervention for self-reported medication adherence ( = .015), mental health functioning ( = .007), and perceived stress ( = .04). Significant decreases in estradiol, estrogen, and estrone hormone levels were observed from baseline to study exit ( < .001), indicating the accuracy of self-reported AHT adherence. Participants (91.9%) and physicians (100%) agreed that participant participation in the intervention was beneficial.

Conclusions: The results of this pilot study established the general feasibility and efficacy of an app-based intervention to support patient AHT adherence. Larger controlled, randomized trials are needed to examine the effectiveness of the app-based intervention in improving AHT and quality of life among breast cancer survivors.
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http://dx.doi.org/10.1177/1073274819883287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862779PMC
May 2020

Quantitative Assessment of Learning Behaviors for Oncology Providers.

J Cancer Educ 2021 Feb;36(1):25-32

Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN, 37232, USA.

How health care providers select topics and activities for learning is key to meeting their needs. The goal of this study was to investigate how oncology providers identify knowledge gaps and choose learning activities. An online focus group within a larger longitudinal study was conducted between November 2015 and August 2016. Participants were chosen by convenience and stratified random sampling of diverse types of oncology providers. Providers were asked monthly to identify learning needs, explain how they identified those needs, and describe the learning activity they chose to meet those needs. Thirty-two oncology providers recorded 201 learning needs via online journal entries (mean 6 entries per person). Needs were associated with practice setting and professional role (p < .05). Colleague recommendation predicted learning needs for advanced practice providers (APPs) (p = .003). Patient cases drove > 50% of identified learning needs across groups. Learning activity preferences were associated with practice setting (p < .05). Choice of learning activity was associated with practice setting, professional role, and geographic location. Colleague recommendation was important for APPs (p = .025). Over 75% of learner responses identify convenience and content quality as important factors in choosing an activity. This study represents a quantitative assessment of learning behaviors for oncology providers and shows that identification of learning needs and activity selection differ by provider demographics. Limitations include small size and underrepresentation of some groups. Our findings should be confirmed with larger samples. Future research should focus on assessment of cohort versus individual needs and learning priorities.
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http://dx.doi.org/10.1007/s13187-019-01593-4DOI Listing
February 2021

Prevention Therapy for Breast Cancer: How Can We Do Better?

Ann Surg Oncol 2019 Jul 23;26(7):1970-1972. Epub 2019 Feb 23.

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

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http://dx.doi.org/10.1245/s10434-019-07243-9DOI Listing
July 2019

Towards a more precise and individualized assessment of breast cancer risk.

Aging (Albany NY) 2019 02;11(4):1305-1316

University of Vermont Cancer Center, The Robert Larner MD College of Medicine, University of Vermont, Burlington, VT 05405, USA.

Many clinically based models are available for breast cancer risk assessment; however, these models are not particularly useful at the individual level, despite being designed with that intent. There is, therefore, a significant need for improved, precise individualized risk assessment. In this Research Perspective, we highlight commonly used clinical risk assessment models and recent scientific advances to individualize risk assessment using precision biomarkers. Genome-wide association studies have identified >100 single nucleotide polymorphisms (SNPs) associated with breast cancer risk, and polygenic risk scores (PRS) have been developed by several groups using this information. The ability of a PRS to improve risk assessment is promising; however, validation in both genetically and ethnically diverse populations is needed. Additionally, novel classes of biomarkers, such as microRNAs, may capture clinically relevant information based on epigenetic regulation of gene expression. Our group has recently identified a circulating-microRNA signature predictive of long-term breast cancer in a prospective cohort of high-risk women. While progress has been made, the importance of accurate risk assessment cannot be understated. Precision risk assessment will identify those women at greatest risk of developing breast cancer, thus avoiding overtreatment of women at average risk and identifying the most appropriate candidates for chemoprevention or surgical prevention.
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http://dx.doi.org/10.18632/aging.101803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402518PMC
February 2019

Development of a predictive miRNA signature for breast cancer risk among high-risk women.

Oncotarget 2017 Dec 28;8(68):112170-112183. Epub 2017 Nov 28.

University of Vermont Cancer Center, The Robert Larner MD College of Medicine, University of Vermont, Burlington, VT, USA.

Significant limitations exist in our ability to predict breast cancer risk at the individual level. Circulating microRNAs (C-miRNAs) have emerged as measurable biomarkers (liquid biopsies) for cancer detection. We evaluated the ability of C-miRNAs to identify women most likely to develop breast cancer by profiling miRNA from serum obtained long before diagnosis. 24 breast cancer cases and controls (matched for risk and age) were identified from women enrolled in the High-Risk Breast Program at the UVM Cancer Center. Isolated RNA from serum was profiled for over 2500 human miRNAs. The miRNA expression data were input into a stepwise linear regression model to discover a multivariable miRNA signature that predicts long-term risk of breast cancer. 25 candidate miRNAs were identified that individually classified cases and controls based on statistical methodologies. A refined 6-miRNA risk-signature was discovered following regression modeling that distinguishes cases and controls (AUC0.896, CI 0.804-0.988) in this cohort. A functional relationship between miRNAs that cluster together when cases are contrasted against controls was suggested and confirmed by pathway analyses. The discovered 6 miRNA risk-signature can discriminate high-risk women who ultimately develop breast cancer from those who remain cancer-free, improving current risk assessment models. Future studies will focus on functional analysis of the miRNAs in this signature and testing in larger cohorts. We propose that the combined signature is highly significant for predicting cancer risk, and worthy of further screening in larger, independent clinical cohorts.
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http://dx.doi.org/10.18632/oncotarget.22750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762501PMC
December 2017

Thorough in silico and in vitro cDNA analysis of 21 putative BRCA1 and BRCA2 splice variants and a complex tandem duplication in BRCA2 allowing the identification of activated cryptic splice donor sites in BRCA2 exon 11.

Hum Mutat 2018 04 22;39(4):515-526. Epub 2018 Jan 22.

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

For 21 putative BRCA1 and BRCA2 splice site variants, the concordance between mRNA analysis and predictions by in silico programs was evaluated. Aberrant splicing was confirmed for 12 alterations. In silico prediction tools were helpful to determine for which variants cDNA analysis is warranted, however, predictions for variants in the Cartegni consensus region but outside the canonical sites, were less reliable. Learning algorithms like Adaboost and Random Forest outperformed the classical tools. Further validations are warranted prior to implementation of these novel tools in clinical settings. Additionally, we report here for the first time activated cryptic donor sites in the large exon 11 of BRCA2 by evaluating the effect at the cDNA level of a novel tandem duplication (5' breakpoint in intron 4; 3' breakpoint in exon 11) and of a variant disrupting the splice donor site of exon 11 (c.6841+1G > C). Additional sites were predicted, but not activated. These sites warrant further research to increase our knowledge on cis and trans acting factors involved in the conservation of correct transcription of this large exon. This may contribute to adequate design of ASOs (antisense oligonucleotides), an emerging therapy to render cancer cells sensitive to PARP inhibitor and platinum therapies.
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http://dx.doi.org/10.1002/humu.23390DOI Listing
April 2018

Randomized Noninferiority Trial of Telephone vs In-Person Genetic Counseling for Hereditary Breast and Ovarian Cancer: A 12-Month Follow-Up.

JNCI Cancer Spectr 2017 Sep 22;1(1):pkx002. Epub 2017 Sep 22.

Georgetown Lombardi Comprehensive Cancer Center (MKI, HS, BNP, RN, MS, TD, GH, KG, CI, MDS) and Jess and Mildred Fisher Center for Hereditary Cancer and Clinical Genomics Research (MKI, HS, BNP, KG, CI, MDS), Georgetown University, Washington, DC; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY (HBV, JH); Department of Psychology, Reykjavik University, Reykjavik, Iceland (HBV); School of Medicine, University of Maryland, Baltimore, MD (RN); National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD (MS); Cancer Genetic Counseling Program, Inova Translational Medicine Institute, Inova Health System, Falls Church, VA (TD); NextGxDx, Inc, Franklin, TN (GH); Familial Cancer Program of the Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT (MW, WM); Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute-Harvard Medical School, Boston, MA (JG, SM); Center for Cancer Risk Assessment, Massachusetts General Hospital Cancer Center, Boston, MA (SM); Carol G. Simon Cancer Center, Atlantic Health Services, Summit, NJ (JH); University of Utah School of Medicine and Huntsman Cancer Institute, Salt Lake City, UT (AYK); Cancer Control and Population Sciences, University of New Mexico Cancer Center, Albuquerque, NM (AYK).

Background: Telephone delivery of genetic counseling is an alternative to in-person genetic counseling because it may extend the reach of genetic counseling. Previous reports have established the noninferiority of telephone counseling on short-term psychosocial and decision-making outcomes. Here we examine the long-term impact of telephone counseling (TC) vs in-person counseling (usual care [UC]).

Methods: We recruited high-risk women for a noninferiority trial comparing TC with UC. Of 1057 potentially eligible women, 669 were randomly assigned to TC (n = 335) or UC (n = 334), and 512 completed the 12-month follow-up. Primary outcomes were patient-reported satisfaction with genetic testing decision, distress, and quality of life. Secondary outcomes were uptake of cancer risk management strategies.

Results: TC was noninferior to UC on all primary outcomes. Satisfaction with decision (0.13, lower bound of 97.5% confidence interval [CI] = -0.34) did not cross its one-point noninferiority limit, cancer-specific distress (-2.10, upper bound of 97.5% CI = -0.07) did not cross its four-point noninferiority limit, and genetic testing distress (-0.27, upper bound of 97.5% CI = 1.46), physical function (0.44, lower bound of 97.5% CI = -0.91) and mental function (-0.04, lower bound of 97.5% CI = -1.44) did not cross their 2.5-point noninferiority limit. Bivariate analyses showed no differences in risk-reducing mastectomy or oophorectomy across groups; however, when combined, TC had significantly more risk-reducing surgeries than UC (17.8% vs 10.5%; = 4.43, .04).

Conclusions: Findings support telephone delivery of genetic counseling to extend the accessibility of this service without long-term adverse outcomes.
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http://dx.doi.org/10.1093/jncics/pkx002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6611491PMC
September 2017

Adjuvant Capecitabine for Breast Cancer.

N Engl J Med 2017 08;377(8):790-1

University of Vermont Medical Center, Burlington, VT

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http://dx.doi.org/10.1056/NEJMc1708487DOI Listing
August 2017

Multi-institutional Evaluation of Women at High Risk of Developing Breast Cancer.

Clin Breast Cancer 2017 10 14;17(6):427-432. Epub 2017 Apr 14.

Department of Surgery, New York University Langone Medical Center, New York, NY.

Introduction: We performed the present study to better understand the practices and preferences of women with an elevated risk of breast cancer by merging the registries from 2 separate institutions and comparing the clinical characteristics and outcomes.

Materials And Methods: The data from women enrolled in institutional review board-approved registries from 2003 to 2015 at the New York University Langone Medical Center and University of Vermont Medical Center were evaluated. We compared patient characteristics, risk factors, uptake of prevention methods, and cancer rates between the 2 registries.

Results: A total of 1035 women were included in the present analysis. We found a 99% concordance of variables collected between the 2 registries. Significant differences were found in age, risk characteristics, uptake of prevention methods, and cancer rates between the 2 registries. The uptake of chemoprevention was low (8% for all women), with greater uptake among women with atypia found on biopsy examination (66%) than among those with a strong family history or BRCA mutations. Women with BRCA mutations accounted for 76% of those undergoing risk-reducing surgery. Of the 1035 women, 43 (4%) developed breast cancer. Of these, 86% were diagnosed with American Joint Committee on Cancer stage 0 or 1 disease, 95% with tumors < 2 cm, and 70% with poor to moderately differentiated pathologic features. Only 1 of the women who developed breast cancer had been undergoing chemoprevention, and none had undergone previous prophylactic surgery.

Conclusion: We found a high degree of concordance between registries, suggesting no barriers exist to multi-institutional collaboration. Overall, a low uptake of prevention opportunities was found in this high-risk population. Women developing breast cancer had predominantly low-stage but higher grade disease, which might suggest a benefit to participation in surveillance (or high-risk) programs.
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http://dx.doi.org/10.1016/j.clbc.2017.04.005DOI Listing
October 2017

Placing negative multi-gene panel results into clinical context.

Fam Cancer 2017 10;16(4):595

University of Vermont, Burlington, VT, USA.

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http://dx.doi.org/10.1007/s10689-017-9974-0DOI Listing
October 2017

Aspirin use is associated with lower mammographic density in a large screening cohort.

Breast Cancer Res Treat 2017 04 4;162(3):419-425. Epub 2017 Feb 4.

Department of Radiology, Perelman School of MedicineUniversity of Pennsylvania, Philadelphia, PA, USA.

Background: Observational and biologic studies suggest that aspirin is a promising prevention therapy for breast cancer. However, clinical trials to date have not corroborated this evidence, potentially due to study design. We evaluated the effect of aspirin on mammographic density (MD), an established modifiable risk factor for breast cancer.

Methods: Electronic medical records from the University of Pennsylvania were evaluated for women who underwent screening mammography, saw their primary care provider, and had a confirmed list of medications during 2012-2013. Logistic regression was performed to test for associations between clinically recorded MD and aspirin use, after adjusting for age, body mass index (BMI), and ethnicity.

Results: We identified 26,000 eligible women. Mean age was 57.3, mean BMI was 28.9 kg/m, 41% were African American, and 19.7% reported current aspirin use. Aspirin users were significantly older and had higher BMI. There was an independent, inverse association between aspirin use and MD (P  < 0.001). Women with extremely dense breasts were less likely to be aspirin users than women with scattered fibroglandular density (OR 0.73; 95% CI 0.57-0.93). This association was stronger for younger women (P = 0.0002) and for African Americans (P = 0.011). The likelihood of having dense breasts decreased with aspirin dose (P  = 0.007), suggesting a dose response.

Conclusions: We demonstrate an independent association between aspirin use and lower MD in a large, diverse screening cohort. This association was stronger for younger and African American women: two groups at greater risk for ER- breast cancer. These results contribute to the importance of investigating aspirin for breast cancer prevention.
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http://dx.doi.org/10.1007/s10549-017-4127-6DOI Listing
April 2017

Platelet phenotype changes associated with breast cancer and its treatment.

Platelets 2016 Nov 2;27(7):703-711. Epub 2016 May 2.

e University of North Carolina Lineberger Comprehensive Cancer Center , Chapel Hill , NC , USA.

Platelets and their granular contents influence both angiogenesis and breast cancer progression. This study was performed to assess the effect of breast cancer and its treatment on platelet biology and the response to inhibition of the platelet P2Y12 receptor. Receptor-specific platelet activation and inhibition was studied for three platelet-associated proteins important in cancer angiogenesis and progression, vascular endothelial growth factor (VEGF), thrombospondin1 (TSP1), and transforming growth factor beta 1 (TGF-β1). Twenty-four women with active breast cancer and 10 healthy controls not receiving antiplatelet therapy participated in the study. Ex vivo activation of platelets in whole blood was accomplished using PAR1AP, PAR4AP, convulxin, and ADP. Platelet inhibition was accomplished using the P2Y12 receptor antagonist cangrelor (the in vitro equivalent of clopidogrel). VEGF, TSP1, and TGF-β1 were measured using standard ELISA. Platelet activation by ADP, PAR1, PAR4, and collagen receptors increased VEGF, TSP1, and TGF-β1 secretion in patients with breast cancer. Agonist-induced release of VEGF was greater in cancer patients as compared to healthy controls (p = 0.02 for ADP, p < 0.001 for PAR1AP, PAR4AP, and convulxin) despite a decrease in the efficiency of VEGF secretion in patients with breast cancer. These differences were not observed for TSP1 and TGF-β1 secretion. P2Y12 receptor inhibition decreased VEGF, TSP1, and TGF-β1 secretion. In patients with cancer, cangrelor inhibited TSP1 release to a greater extent than VEGF and TGF-β1 release. In patients with breast cancer, the magnitude of platelet inhibition achieved by cangrelor was greater than that achieved with healthy controls for all agonists and platelet proteins studied. While platelets are known to influence progression of breast cancer, our results show that breast cancer and its treatment influence the platelet phenotype by increasing the secretion of pro-angiogenic proteins following platelet activation, modulating the efficiency of platelet protein release as well as increasing the response to antiplatelet therapy.
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http://dx.doi.org/10.3109/09537104.2016.1171302DOI Listing
November 2016

Contribution of extended family history in assessment of risk for breast and colon cancer.

BMC Fam Pract 2016 09 1;17(1):126. Epub 2016 Sep 1.

University of Vermont Medical Center, 111 Colchester Ave, Burlington, VT, 05401, USA.

Background: Family history is important for identifying candidates for high risk cancer screening and referral for genetic counseling. We sought to determine the percentage of individuals who would be eligible for high risk cancer screening or genetic referral and testing if family history includes an extended (vs limited) family history.

Methods: Family histories were obtained from 626 women at UVMMC associated mammography centers from 2001 to 2002. ACS guidelines were used to determine eligibility for high risk breast or colon cancer screening. Eligibility for referral for genetic counseling for hereditary breast and colon cancer was determined using the Referral Screening Tool and Amsterdam II screening criteria, respectively. All family histories were assessed for eligibility by a limited history (first degree relatives only) and extended history (first and second degree relatives).

Results: Four hundred ninety-nine histories were eligible for review. 18/282 (3.6 %) and 62/123 (12 %) individuals met criteria for high risk breast and colon cancer screening, respectively. 13/18 (72 %) in the high risk breast cancer screening group and 12/62 (19 %) in the high risk colon cancer screening group met criteria based upon an extended family history. 9/282 (1.8 %) and 31/123 (6.2 %) individuals met criteria for genetic counseling referral and testing for breast and colon cancer, respectively. 2/9 (22 %) of individuals in the genetic breast cancer screening group and 21/31 (68 %) individuals in the genetic colon cancer screening group met criteria based upon extended family history.

Conclusions: This is one of the first studies to suggest that first degree family history alone is not adequate for identification of candidates for high risk screening and referral for genetic counseling for hereditary breast and colon cancer syndromes. A larger population is needed to further validate this data.
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http://dx.doi.org/10.1186/s12875-016-0521-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5007707PMC
September 2016

Multi-gene panel testing for hereditary cancer susceptibility in a rural Familial Cancer Program.

Fam Cancer 2017 01;16(1):159-166

Department of Medicine and University of Vermont Cancer Center, University of Vermont College of Medicine, 89 Beaumont Ave, Given E214, Burlington, VT, 05405, USA.

This study explores our Familial Cancer Program's experience implementing multi-gene panel testing in a largely rural patient population. We conducted a retrospective review of patients undergoing panel testing between May 2011 and August 2015. Our goal was to evaluate factors that might be predictors of identifying variants (pathogenic or uncertain significance) and to assess clinical management changes due to testing. We utilized a structured family history tool to determine the significance of patient's family histories with respect to identification of genetic variants. A total of 227 patients underwent panel testing at our center and 67 patients (29.5 %) had variants identified, with 8 (3.5 %) having multiple variants. Overall, 44 patients (19.4 %) had a variant of uncertain significance (VUS) and 28 patients (12.3 %) had a pathogenic variant detected, with 10 (4.4 %) having pathogenic variants in highly penetrant genes. We found no statistical difference in patient familial and personal cancer history, age, rural status, Ashkenazi Jewish ancestry, insurance coverage and prior single-gene testing among those with pathogenic, VUS and negative panel testing results. There were no predictors of pathogenic variants on regression analysis. Panel testing changed cancer screening and management guidelines from that expected based on family history alone in 13.2 % of patients. Ultimately, cancer panel testing does yield critical information not identified by traditional single gene testing but maximal utility through a broad range of personal and family histories requires improved interpretation of variants.
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http://dx.doi.org/10.1007/s10689-016-9913-5DOI Listing
January 2017

Effect of Vitamin D Supplementation on Breast Cancer Biomarkers: CALGB 70806 (Alliance) Study Design and Baseline Data.

Am J Hematol Oncol 2016 Jul;12(7):4-9

Division of Hematology and Oncology, Department of Medicine, University of Vermont, Burlington VT.

One in eight women will develop breast cancer over their lifetime with 230,000 women diagnosed in 2015. For this reason, breast cancer prevention efforts are essential. Vitamin D, with anticancer properties, may have a role in prevention of some cancers, including breast cancer. This report discusses the rationale, study protocol, and baseline data for a clinical trial of vitamin D and its effects on breast cancer biomarkers. This study was a randomized controlled trial designed to evaluate the effect of a fixed dose of vitamin D on specfic breast cancer biomarkers. Study participants were randomized to take either vitamin D or placebo for a period of 1 year. All participants had mammograms and blood drawn for serum biomarkers. A subset of participants underwent random periareolar fine needle aspiration to draw tissue for biomarkers. From January 2011 to December 2013, 300 premenopausal women, aged 59 or younger, were recruited from 41 institutions across the United States. A total of 102 women underwent random periareolar fine needle aspiration. The last subject completed the trial in January 2015. Baseline vitamin D levels for all participants ranged from 4-72 ng/mL, with 62% of participants being vitamin D deficient at enrollment (≥30 ng/mL or ≥75 nmo-l/L). The mean body mass index was 27.0 kg/m (range 15.1-53.6 kg/m). 14% and 11.7% of participants were Hispanic or African American, respectively. Accrual and enrollment of participants is feasible for this type of multi-center prevention trial, and it can readily be carried out in a cooperative group setting.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656380PMC
July 2016

Family history matters.

Authors:
Marie E Wood

Cancer 2016 09 3;122(17):2618-20. Epub 2016 Jun 3.

Department of Medicine, University of Vermont, Burlington, Vermont.

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http://dx.doi.org/10.1002/cncr.30078DOI Listing
September 2016

The Effect of Atorvastatin on Breast Cancer Biomarkers in High-Risk Women.

Cancer Prev Res (Phila) 2016 05 23;9(5):379-84. Epub 2016 Feb 23.

Department of Medicine, University of Vermont, Burlington, Vermont.

Statins have the potential to reduce breast cancer incidence and recurrence as shown in both epidemiologic and laboratory studies. The purpose of this study was to evaluate the effect of a lipophilic statin, atorvastatin, on breast cancer biomarkers of risk [mammographic density (MD) and insulin growth factor 1 (IGF-1)] in high-risk premenopausal women.Premenopausal women at increased risk for breast cancer received either 40 mg of atorvastatin or placebo for 1 year. Biomarker assessment was performed prior to initiation and at completion of study medication. MD was determined using both Breast Imaging Reporting and Data System and the visual analogue scale. Serum IGF-1 was determined by ELISA assay at the end of the study.Sixty-three women were enrolled between December 2005 and May 2010. Sixteen (25%) women withdrew. The mean age of participants was 43 (range, 35-50), 100% were white, and the average body mass index (BMI) was 26.4. The statin group demonstrated a significant decrease in cholesterol and low-density lipoprotein (LDL), suggesting compliance with study medication. After accounting for BMI, there was no difference in change in MD between groups. There was a significant increase in serum IGF-1 in the statin group.In this multi-institutional randomized prospective clinical trial of premenopausal women at increased risk for breast cancer, we did not see an effect of atorvastatin on MD. Further investigation of statins may be warranted; however, design of prior trials and potential mechanism of action of the agent need to be considered in the design of future trials. Cancer Prev Res; 9(5); 379-84. ©2016 AACR.
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http://dx.doi.org/10.1158/1940-6207.CAPR-15-0300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965880PMC
May 2016

Patient Perceptions of Telephone vs. In-Person BRCA1/BRCA2 Genetic Counseling.

J Genet Couns 2016 06 12;25(3):472-82. Epub 2015 Oct 12.

Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.

Telephone genetic counseling (TC) for hereditary breast/ovarian cancer risk has been associated with positive outcomes in high risk women. However, little is known about how patients perceive TC. As part of a randomized trial of TC versus usual care (UC; in-person genetic counseling), we compared high risk women's perceptions of: (1) overall satisfaction with genetic counseling; (2) convenience; (3) attentiveness during the session; (4) counselor effectiveness in providing support; and (5) counselor ability to recognize emotional responses during the session. Among the 554 participants (TC, N = 272; UC, N = 282), delivery mode was not associated with self-reported satisfaction. However, TC participants found counseling significantly more convenient than UC participants (OR = 4.78, 95 % CI = 3.32, 6.89) while also perceiving lower levels of support (OR = 0.56, 95 % CI = 0.40-0.80) and emotional recognition (OR = 0.53, 95 % CI = 0.37-0.76). In exploratory analyses, we found that non-Hispanic white participants reported higher counselor support in UC than in TC (69.4 % vs. 52.8 %; OR = 3.06, 95 % CI = 1.39-6.74), while minority women perceived less support in UC vs. TC (58.3 % vs. 38.7 %; OR = 0.80, 95 % CI = 0.39-1.65). We discuss potential research and practice implications of these findings which may further improve the effectiveness and utilization of TC.
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http://dx.doi.org/10.1007/s10897-015-9897-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4829475PMC
June 2016

Comparison of false positive rates for screening breast magnetic resonance imaging (MRI) in high risk women performed on stacked versus alternating schedules.

Springerplus 2015 13;4:77. Epub 2015 Feb 13.

Department of Medicine, University of Vermont, Burlington, VT USA.

Purpose: Breast MRI added to mammography increases screening sensitivity for high-risk women but false-positive (FP) rates are higher and the optimal screening schedule for coordination with mammography is unclear. We compare rates of FP MRI when studies were performed on two different schedules.

Patients And Methods: High-risk women at the University of Vermont who had at least 1 MRI and 1 mammogram performed within one year between 2004-2012 were eligible for inclusion in this study. Screening was considered stacked if both studies were performed within 90 days and alternating if studies were 4-8 months apart. False positive was defined in one of three ways.

Results: 137 women had screening which met inclusion criteria and 371 MRIs were reviewed. The FP rates were similar for the two schedules when considering BI-RAD 4, 5, 0 or biopsy as a positive test. FP rates were significantly higher for the stacked schedule (18.2 vs. 10.2%, p = 0.026) when considering BI-RADS 3-4-5-0 as positive test, due to the elevated rate of BI-RADS 3 assessments among stacked exams.

Conclusion: False positive rates differ based on the type of exam (baseline or subsequent) and definition of positive but do not differ based on imaging schedule (stacked or alternating); suggesting that women and their providers may choose the imaging schedule they prefer. This is significant as a randomized clinical trial comparing the two schedules is not likely to be performed, given the high cost and large number of women needed for such a study.
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http://dx.doi.org/10.1186/s40064-015-0793-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340856PMC
March 2015

Ductal carcinoma in situ: a brief review of treatment variation and impacts on patients and society.

Crit Rev Eukaryot Gene Expr 2014 ;24(4):281-6

Department of Surgery, College of Medicine, Vermont Cancer Center, University of Vermont, Burlington, Vermont.

Nearly 20% of all breast cancer cases are ductal carcinoma in situ (DCIS), with over 60,000 cases diagnosed each year. Many of these cases would never cause clinical symptoms or threaten the life of the woman; however, it is currently impossible to distinguish which lesions will progress to invasive disease from those that will not. DCIS is generally associated with an excellent prognosis regardless of the treatment pathway, but there is variation in treatment aggressiveness that seems to exceed the medical uncertainty associated with DCIS management. Therefore, it would seem that a significant proportion of women with DCIS receive more extensive treatment than is needed. This overtreatment of DCIS is a growing concern among the breast cancer community and has implications for both the patient (via adverse treatment-related effects, as well as out-of-pocket costs) and society (via economic costs and the public health and environmental harm resulting from health care delivery). This article discusses DCIS treatment pathways and their implications for patients and society and calls for further research to examine the factors that are leading to such wide variation in treatment decisions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372113PMC
http://dx.doi.org/10.1615/critreveukaryotgeneexpr.2014011495DOI Listing
June 2015

Disparities in uptake of BRCA1/2 genetic testing in a randomized trial of telephone counseling.

Genet Med 2015 Jun 18;17(6):467-75. Epub 2014 Sep 18.

Department of Oncology, Cancer Prevention and Control Program and Fisher Center for Familial Cancer Research, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.

Purpose: As genetic counseling and testing become more fully integrated into clinical care, alternative delivery models are increasingly prominent. This study examines predictors of genetic testing for hereditary breast/ovarian cancer among high-risk women in a randomized trial of in-person versus telephone-based genetic counseling.

Methods: Methods include multivariable logistic regression and interaction analyses.

Results: Of the 669 participants, 600 completed counseling and 523 received test results. As previously reported, participants randomized to telephone counseling were significantly less likely to be tested. In intention-to-treat analyses, completion of counseling and testing was associated with: race/ethnicity (odds ratio (OR) = 1.96, 95% confidence interval (CI): 1.20-3.20), perceived stress (OR = 0.89, 95% CI: 0.81-0.98), knowledge (OR = 1.12, 95% CI: 1.02-1.23), and randomization group (OR = 1.48, 95% CI: 1.01-2.16). Further, race/ethnicity moderated the association between randomization group and testing; minority women receiving telephone counseling were least likely to complete testing.

Conclusion: Evidence for logistical and communication-based explanations for this interaction is presented. The overall increased access made possible with telephone genetic counseling should be considered in light of the possibility that this may also lead to lower rates of testing among high-risk minority women. Additional care should be taken to assess and address potential barriers when services are delivered by telephone.Genet Med 17 6, 467-475.
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http://dx.doi.org/10.1038/gim.2014.125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4364924PMC
June 2015

Reply to A.S. Sie et al, K. Hemminki et al, and J. Larsen Haidle.

J Clin Oncol 2014 Oct 2;32(29):3346-7. Epub 2014 Sep 2.

Avon Comprehensive Breast Evaluation Center, Mass General Hospital, Boston, MA.

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http://dx.doi.org/10.1200/JCO.2014.56.8535DOI Listing
October 2014