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Figure.
Breast Cancer Incidence Among BRCA1 Mutation Carriers by HRT Use
Breast Cancer Incidence Among BRCA1 Mutation Carriers by HRT Use

A, Breast cancer incidence among BRCA1 mutation carriers who used any HRT compared with women who did not use HR. B, Breast cancer incidence among BRCA1 mutation carriers who used estrogen-alone HRT compared with women who used combined estrogen plus progesterone HRT. C, Breast cancer incidence among BRCA1 mutation carriers who used estrogen-alone HRT compared with women who used combined estrogen plus progesterone HRT, among women who underwent oophorectomy prior to age 45 years. Abbreviations: E, estrogen; HRT, hormone replacement therapy; PE, progesterone plus estrogen.

Table 1.  
Hormone Replacement Therapy Use After Oophorectomy and Risk of Breast Cancer Among 872 BRCA1 Mutation Carriers and Stratified by Age at Oophorectomy
Hormone Replacement Therapy Use After Oophorectomy and Risk of Breast Cancer Among 872 BRCA1 Mutation Carriers and Stratified by Age at Oophorectomy
Table 2.  
Duration of HRT Use and Risk of Breast Cancer Among 872 BRCA1 Mutation Carriers
Duration of HRT Use and Risk of Breast Cancer Among 872 BRCA1 Mutation Carriers
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Original Investigation
August 2018

Hormone Replacement Therapy After Oophorectomy and Breast Cancer Risk Among BRCA1 Mutation Carriers

Author Affiliations
  • 1Women’s College Research Institute, Women's College Hospital, Toronto, Ontario, Canada
  • 2Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
  • 3International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 4Gynecology Oncology, Cedars Sinai Medical Center, Los Angeles, California
  • 5Beth Israel Deaconess Medical Center, Boston, Massachusetts
  • 6Inherited Cancer Research Group, The Norwegian Radium Hospital, Department for Medical Genetics, Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital; Oslo University Hospital, Oslo, Norway
  • 7Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Toronto, Ontario, Canada
  • 8Department of Preventive Medicine and Public Health, Creighton University School of Medicine, Omaha, Nebraska
  • 9Division of Human Genetics, the Ohio State University Medical Center, Comprehensive Cancer Center, Columbus
  • 10Toronto-Sunnybrook Regional Cancer Center, Toronto, Ontario, Canada
  • 11Department of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
  • 12Program in Cancer Genetics, Department of Oncology and Human Genetics, McGill University, Montréal, Quebec, Canada
JAMA Oncol. 2018;4(8):1059-1065. doi:10.1001/jamaoncol.2018.0211
Key Points

Question  Is there an association between hormone replacement therapy (HRT) use after oophorectomy and risk of breast cancer among women with a BRCA1 mutation.

Findings  Results of this prospective study suggest no association between ever use of any type of HRT after oophorectomy compared with no use and the risk of breast cancer. However, the effects differed for estrogen-alone HRT and combination hormonal therapy.

Meaning  Use of estrogen-alone HRT after oophorectomy does not increase the risk of BRCA1-associated breast cancer; the potential harmful effect of progesterone-containing HRT warrants further study.

Abstract

Importance  Prophylactic bilateral salpingo-oophorectomy is recommended for BRCA1 mutation carriers to prevent ovarian cancer. Whether or not hormone replacement therapy (HRT) initiated after oophorectomy is associated with an increased risk of breast cancer has not been evaluated in a prospective study.

Objective  To determine the association between HRT use and BRCA1-associated breast cancer.

Design, Setting, and Participants  A prospective, longitudinal cohort study of BRCA1 and BRCA2 mutation carriers from 80 participating centers in 17 countries was conducted between 1995 and 2017 with a mean follow-up of 7.6 years. Participants had sought genetic testing for a BRCA1 or BRCA2 mutation because of a personal or family history of breast and/or ovarian cancer. Carriers of BRCA1 mutation with no personal medical history of cancer who underwent bilateral oophorectomy following enrollment were eligible for the cohort study.

Exposures  A follow-up questionnaire was administered every 2 years to obtain detailed information on HRT use. A left-truncated Cox proportional hazard analysis was used to estimate the hazard ratios (HRs) and 95% CIs associated with the initiation of HRT use postoophorectomy.

Main Outcomes and Measures  Incident breast cancer.

Results  A total of 872 BRCA1 mutation carriers with a mean postoophorectomy follow-up period of 7.6 years (range, 0.4-22.1) were included in this study. Mean (SD) age of participants was 43.4 (8.5) years. Among these, 92 (10.6%) incident breast cancers were diagnosed. Overall, HRT use after oophorectomy was not associated with an increased risk of breast cancer. The HR was 0.97 (95% CI, 0.62-1.52; P = .89) for ever use of any type of HRT vs no use; however, the effects of estrogen alone and combination hormonal therapy were different. After 10 years of follow-up, the cumulative incidence of breast cancer among women who used estrogen-alone HRT was 12% compared with 22% among women who used estrogen plus progesterone HRT (absolute difference, 10%; log rank P = .04).

Conclusions and Relevance  These findings suggest that use of estrogen after oophorectomy does not increase the risk of breast cancer among women with a BRCA1 mutation and should reassure BRCA1 mutation carriers considering preventive surgery that HRT is safe. The possible adverse effect of progesterone-containing HRT warrants further study.

Introduction

Hormone replacement therapy (HRT) has been prescribed for women to ameliorate the symptoms of menopause, in particular for the reduction of vasomotor symptoms, and to mitigate other aging-related conditions, including osteoporosis, cardiovascular disease, and cognitive decline.1 In 2002, the Women’s Health Initiative (WHI), a randomized clinical trial of combined estrogen plus progesterone-containing HRT vs placebo, was terminated early owing to findings of an increase in breast cancer incidence (and cardiovascular disease) among postmenopausal women using the combined regimen.2 The estrogen-alone arm of the WHI trial was terminated in 2004 owing to a reported increase in stroke with estrogen-alone therapy (but a reduction in breast cancer risk).3 The relative risk of invasive breast cancer was 1.24 (95% CI, 1.01-1.53; P = .04) for estrogen plus progesterone, but was 0.79 (95% CI, 0.61-1.02; P = .07) for estrogen alone.4 As a result, there has been a marked decline in HRT use globally.5,6

Women with an inherited BRCA1 mutation are at risk of developing breast and ovarian cancer.7 In North America, most of these women will undergo prophylactic bilateral-salpingo oophorectomy to prevent ovarian cancer8; many will experience early surgical menopause and possibly long-term health consequences associated with abrupt ovarian hormonal withdrawal.9 Exogenous hormone use may be prescribed to mitigate adverse effects associated with oophorectomy. Although HRT after surgical menopause is prescribed to BRCA1 mutation carriers without a personal history of breast cancer, the impact on breast cancer risk remains unclear.10-12 In a case-control study of 432 matched pairs, we reported no increase in BRCA1-breast cancer risk with HRT use.12 To our knowledge, there has not been a prospective evaluation of HRT use and breast cancer among women with a BRCA1 mutation. In the current report, we conduct a detailed prospective analysis of HRT use and breast cancer risk following oophorectomy.

Methods
Overview of Study Design

In this prospective analysis, we only included women with a BRCA1 mutation and considered HRT use following oophorectomy. Women with a prior diagnosis of breast cancer or those who underwent oophorectomy prior to study enrollment were excluded from the analysis. Given that we did not have detailed information on fallopian tube removal, oophorectomy in this analysis refers to preventive removal of both ovaries.

Study Population

Eligible study participants included women enrolled in a multicenter, longitudinal study of BRCA1 and BRCA2 mutation carriers from 80 participating centers in 17 countries. All abnormal nucleotide sequences were confirmed by direct sequencing of DNA. Only women with a deleterious BRCA1 mutation were eligible for the current study. The study was approved by the institutional ethics review boards of the respective host institutions and all study participants provided written informed consent. They were not compensated.

Exposure Data

Each participant completed a baseline questionnaire at the time of a clinic appointment or at their home. Follow-up questionnaires were completed every 2 years thereafter. These were either mailed to the participant to complete and return, or were administered over the phone by a genetic counsellor or research assistant. The baseline and follow-up questionnaires requested detailed information on history of cancer and reproductive and medical histories. Detailed information regarding HRT use was collected in the baseline and follow-up questionnaires. Specifically, women were asked if they had ever taken HRT (ie, estrogen, progesterone) for menopausal symptoms. Women who had used HRT were asked to provide: the brand name of the HRT, starting year, ending year, length of time used (years), and the method of administration (eg, pills, skin patches, vaginal suppositories). They were also asked if they were still taking HRT (yes/no) and the name and dose of the hormone. Similar information was queried in the follow-up questionnaires, which also included a question on dose (mg per day). We classified women according to HRT use (ever/never), duration of HRT use (years), and type of HRT (estrogen alone, estrogen plus progesterone, progesterone alone, other). Women who did not indicate the formulation were coded as other HRT users. Use of HRT was updated at each follow-up questionnaire cycle, and analyzed as a time-varying exposure. Only HRT use following oophorectomy was considered in the final analysis. For cumulative duration, we created 2 (independent) variables for total years of estrogen exposure and for total years of progesterone exposure by summing the total years of use reported in the entire follow-up period following oophorectomy.

Women were asked if their periods had stopped (yes/no) and (for those women who answered yes) the age at which their periods stopped completely and the reason (ie, natural menopause, hysterectomy, uterus and ovaries removed, oophorectomy, medication/chemotherapy, other).

Identification of Breast Cancer Cases

The primary end point was invasive breast cancer. On each follow-up questionnaire, we asked whether a breast cancer had been diagnosed, and if so, the date of diagnosis. We obtained written consent from all the women reporting a diagnosis (or their next of kin) to review pathology records.

Exclusions

For the current study, 13 087 BRCA1 mutation carriers were identified. Participants were not eligible for inclusion if they had a previous diagnosis of any cancer (n = 8216), did not have an oophorectomy during the follow-up period (n = 1818), did not complete at least 1 follow-up questionnaire (n = 1216), had an oophorectomy prior to completion of the baseline questionnaire (n = 394), were missing information on prophylactic mastectomy (n = 148), or had a bilateral mastectomy at baseline or prior to an oophorectomy (n = 356) (eFigure in the Supplement). Among the 939 eligible women, women were excluded if they were missing information on HRT use (n = 51) or on other relevant information (ie, date of death, date of birth) (n = 16). After these exclusions, a total of 872 participants with a BRCA1 mutation were available for the analysis.

Statistical Analysis

Participants were followed from the date of oophorectomy until either the date of a breast cancer diagnosis, date of prophylactic mastectomy, date of death, or date of completion of their last follow-up questionnaire. Cumulative breast cancer incidence by HRT use was estimated using Kaplan-Meier survival analysis. We performed a left-truncated survival analysis to account for the time elapsed between the date of baseline questionnaire and date of oophorectomy. We used Cox proportional hazards regression to estimate the hazard ratio (HR) and 95% CIs (CI) of breast cancer associated with each HRT exposure using days of follow-up as the time variable. The multivariable model adjusted for age at baseline (≤39, 40-49, ≥50 years), parity (0, 1, 2, 3, ≥4), period started age (≤12, 13, ≥14 years), first-degree relative with breast cancer (yes/no), oral contraceptive use (ever/never), country of residence (Poland, Canada, United States, other), and HRT used at baseline (ever/never). Participants who carried both a BRCA1 and BRCA2 mutation were categorized as BRCA1 mutation carriers (n = 9). We modeled duration of use continuously for either estrogen-containing or progesterone-containing HRT to estimate the HRs and 95% CIs associated with each year of use.

All analyses were conducted using the SAS statistical software package (version 9.4, SAS Institute). All P values were 2-sided and were considered statistically significant if P ≤ .05.

Results

A total of 872 BRCA1 mutation carriers were included in the study. All of these women had a preventive bilateral oophorectomy in the follow-up period. None of the women had developed breast cancer prior to oophorectomy. eTable 1 in the Supplement is a summary of the baseline characteristics of 377 (43%) women who used HRT after oophorectomy and 495 (57%) women who did not use HRT after oophorectomy. Women who used HRT were on average younger at the time of completion of the baseline questionnaire (40.3 vs 45.8 years; absolute difference, 5.5 years; P < .001) and younger at the time of prophylactic oophorectomy (43.0 vs 48.4 years; absolute difference, 5.5 years; P < .001) compared with women who never used HRT. Participants who were HRT users were more likely to have a medical history of oral contraceptive use (65% vs 56%; P = .007), have a lower mean parity (1.8 vs 2.1; absolute difference, 0.3 months; P = .001), and were less likely to have a family history of breast cancer (46% vs 59%; absolute difference, 13%; P < .001) than nonusers.

There were 92 incident invasive breast cancers diagnosed in the follow-up period. The annual breast cancer risk was 1.4%. Among the 92 women who developed breast cancer, a mean of 4.5 (range, 1-19) years elapsed between the date of oophorectomy and the date of breast cancer. The proportion of women diagnosed with breast cancer in the follow-up period was similar for women who used HRT and for women who never used HRT after oophorectomy (10.3% vs 10.7%; absolute difference, 0.4%; P = .86).

Among the 377 women who used HRT after oophorectomy, the mean duration of HRT use was 3.9 (range, 0.5-19) years. Among the HRT users, 259 (69%) used estrogen alone, 66 (18%) used estrogen plus progesterone, 40 (11%) used progesterone alone, and 80 (21%) used another formulation (eTable 2 in the Supplement). There was no significant difference in the 10-year actuarial risk of breast cancer comparing women who used any HRT regimen and women who did not use HRT (log rank P = .72) (Figure, A). In contrast, the 10-year actuarial risk of breast cancer was significantly lower for women who used estrogen alone compared with women who used estrogen plus progesterone (12% vs 22%; absolute difference, 10%; log rank P = .04) (Figure, B). This effect was stronger for women who had an oophorectomy prior to age 45 years (9% vs 24%; log rank P = .009) (Figure, C).

Table 1 summarizes the univariate and multivariable HRs and 95% CIs for breast cancer associated with HRT use after oophorectomy. Among all women, there was no significant relationship between ever use of any HRT and the risk of breast cancer compared with women who never used HRT after oophorectomy (multivariable HR, 0.97; 95% CI, 0.62-1.52). The multivariable HRs and 95% CIs for use of estrogen alone was 0.73 (95% CI, 0.41-1.32), 1.31 (95% CI, 0.66-2.57) for estrogen plus progesterone, and 1.29 (95% CI, 0.63-2.67) for other. We also stratified our analysis by age at oophorectomy (Table 1). Among women who underwent oophorectomy prior to age 45, the HR for use of estrogen-alone HRT was 0.47 (95% CI, 0.20-1.15) and for estrogen plus progesterone HRT was 1.64 (95% CI, 0.68-3.98). The corresponding risk estimates for women who underwent oophorectomy at or after age 45 were 1.18 (95% CI, 0.53-2.64) for estrogen-alone HRT and 0.96 (95% CI, 0.28-3.33) for estrogen plus progesterone HRT.

The associations between duration of HRT use after oophorectomy and breast cancer risk is summarized in Table 2. For each year of estrogen-containing HRT use, there was a significant 8% reduction in breast cancer risk (HR, 0.92; 95% CI, 0.83-1.01; P = .07). In contrast, the HR for each year of progesterone-containing HRT use was 1.08 (95% CI, 0.92-1.27) but this was not statistically significant (P = .34). For women who underwent an oophorectomy prior to age 45, each year of estrogen-containing HRT use was associated with a significant 18% reduction in breast cancer risk (95% CI, 0.69-0.97), whereas each year of progesterone-containing HRT was associated with a nonsignificant 14% increase in risk (95% CI, 0.90-1.46). There was no association between HRT use and breast cancer among women who underwent oophorectomy after age 45 (eTable 3 in the Supplement).

Discussion

In this prospective analysis of 872 BRCA1 mutation carriers, we observed that use of any HRT following oophorectomy was not associated with an increased risk of developing breast cancer. However, we found a possible protective effect for women who used estrogen-containing HRT alone. Each year of estrogen use was associated with an 8% reduction in breast cancer risk (HR, 0.92; 95% CI, 0.83-1.01), whereas each year of progesterone use was associated with a (nonsignificant) 8% increased risk (HR,1.08; 95% CI, 0.92-1.27). The actuarial 10-year risks were 12% for estrogen-only HRT and 22% for estrogen plus progesterone for all participants combined and were 9% vs 24% for participants who had an oophorectomy prior to age 45. These associations were stronger for women who underwent oophorectomy prior to age 45 years (Figure, C). The current study represents the first prospective evaluation of HRT use and breast cancer risk among women with a BRCA1 mutation. Previously in a matched case-control study (a subset of which were also included in the current study), we reported no significant relationship between HRT use and breast cancer risk among BRCA1 mutation carriers (odds ratio [OR] for ever vs never use, 0.80; 95% CI, 0.55-1.16; P = .24).12

Our findings are consistent with large prospective studies of noncarriers, as well as randomized clinical trials.2,13-16 The authors of the WHI reported an increased risk of developing breast cancer among postmenopausal women in the estrogen plus progesterone arm of the trial (HR, 1.24; 95% CI, 1.01-1.53), and a reduction in risk among women in the estrogen-only group (HR, 0.79; 95% CI, 0.61-1.02),4 similar to the effects we observed in the current study. Combined formulations are typically prescribed for women with an intact uterus whereas estrogen alone is indicated for those who have had a hysterectomy. The relationship between HRT use and breast cancer risk among women in the general population is complex.1,4,16 Greater risks have been reported with current use, increasing duration of use, time since menopause, and for estrogen receptor (ER)-positive disease.13,15,17-20 Recent publications have reported a reduction in mortality, improved quality of life, and small absolute risks with respect to breast cancer or other adverse events among HRT users.16,21 Importantly, a timing or window hypothesis supports that the benefits of HRT for young women at menopause outweigh any small risks associated with HRT.1 Nevertheless, rates of HRT use in the general population remain low.

Among BRCA1 and BRCA2 mutation carriers without a personal medical history of breast cancer, we have previously shown that HRT use after prophylactic oophorectomy will reduce vasomotor symptoms, improve quality of life, and reduce all-cause mortality.22,23 We have also reported an increased risk of endometrial cancer associated with use of progesterone-containing HRT among BRCA1 mutation carriers.24 The potential adverse effect of progesterone-containing HRT on breast cancer are in line with the emerging role of the progesterone/receptor activator of nuclear factor κB (RANK)-signaling pathway in BRCA1 breast cancer development.25,26 Collectively, our findings suggest that use of estrogen-alone HRT following surgical menopause will not impact BRCA1 breast cancer risk whereas women undergoing preventive oophorectomy (particularly women undergoing oophorectomy prior to age 45) should consider removal of the uterus to avoid the use of progesterone-containing HRT, although total abdominal hysterectomy with oophorectomy is associated with an increased risk of surgical complications and can impact quality of life.27 We had insufficient power to analyze the risk of breast cancer with HRT use among BRCA2 mutation carriers. Nonetheless, given that women with a BRCA2 mutation have a propensity to developing hormone receptor-positive disease, it is plausible that the risk profile with HRT use will be similar to what we observed for BRCA1 mutation carriers especially given studies conducted among women in the general population have shown more pronounced for ER- and PR-positive cancers than for hormone receptor-negative cancers.19,20

In this cohort of women at high-risk for disease, 572 (66%) were aged 50 years or younger at the time of oophorectomy. Among this group of predominantly premenopausal women, 292 (51%) initiated HRT after oophorectomy whereas among women who were postmenopausal (or close to age at natural menopause) at the time of surgery, only 85 (29%) initiated HRT use. In Norway, Johansen et al,28 reported that only 52% of women who underwent risk-reducing salpingo-oophorectomy prior to natural menopause initiated HRT use. Manson and Kaunitz are of the opinion that since the publication of the WHI trials, there has been a lack of training in menopause treatment among primary care and gynecology residents and that women are unnecessarily being denied the use of HRT to treat menopausal symptoms.21 The WHI studies were conducted among women mostly in their 60s (with no women younger than 50 years), and thus, these findings cannot be directly extrapolated to BRCA1 mutation carriers.

A few groups have published studies on the impact of early surgical menopause on various aspects of health among women in the general population. Parker et al,29 showed that bilateral oophorectomy (vs ovarian conservation) was associated with a significant increased risk of cardiovascular disease and of all-cause mortality in 30 000 women enrolled in the Nurses’ Health Study who underwent hysterectomy for benign disease. This group later showed that the effect of oophorectomy on mortality was stronger among women who had surgery prior to age 50 and did not use HRT.30 Studies by Rocca et al,31-35 have demonstrated that oophorectomy preceding the onset of natural menopause is associated with long-term consequences including an increased risk of cognitive impairment, cardiovascular disease, and a host of chronic conditions. Importantly, there is evidence to suggest that these symptoms may be mitigated by HRT.30,36

Limitations

This study had several limitations including the use of self-administered questionnaires to collect information on lifetime HRT use and breast cancer diagnoses. Despite this, prior studies have previously shown good agreement between self-reported HRT use and physician records.37 Self-report of breast cancer has been shown to be accurate.38 There is evidence to suggest that route, regimen or dose of HRT may differentially impact breast cancer risk; however, we did not take this into account in the current analysis. Also, the impact of intrauterine devices as HRT was not evaluated. Our main comparison of ever vs never HRT use was not significant (HR, 0.97; 95% CI, 0.62-1.52). With 377 ever exposed and 495 never unexposed women, we had a power of 81% to detect an HR of 1.7 or greater at a P value of .05, and thus, we cannot rule out a small effect. Finally, our analysis was limited to women who underwent preventive oophorectomy and we did not evaluate the relationship between HRT and breast cancer risk in women with intact ovaries. Notwithstanding these limitations, strengths of the current study included the large number of ascertained BRCA1 mutation carriers, the relatively long follow-up period, and the detailed information on exposures and covariates.

Conclusions

Women with an inherited mutation in BRCA1 face a high lifetime risk of developing ovarian cancer, estimated at 44%.7 Bilateral salpingo-oophorectomy remains the most effective prevention option to reduce the risk of ovarian cancer and has also been shown to reduce all-cause mortality.22,39 It is estimated that 65% of BRCA1 mutation carriers will undergo oophorectomy prior to natural menopause. Our findings indicate the BRCA1 mutation carriers should not avoid risk-reducing surgery because of the fear associated with estrogen-alone HRT use. The potential harmful effect of progesterone-containing HRT is of interest, especially given the evidence implicating the progesterone/RANK pathway in the etiology of BRCA1 breast cancer.25,26 However, future studies are necessary to confirm our findings. It is of interest to evaluate impact of oophorectomy on other outcomes (including bone, heart, and brain health) and whether HRT may mitigate any adverse events.

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Article Information

Corresponding Author: Steven A. Narod, MD, Women’s College Research Institute, Women’s College Hospital, 76 Grenville St, 6th Flr, Toronto, ON, M5S 1B2, Canada (steven.narod@wchospital.ca).

Accepted for Publication: January 18, 2018.

Correction: This article was corrected on May 10, 2018, to correct an error in the label and caption for the Figure, panel A.

Published Online: April 19, 2018. doi:10.1001/jamaoncol.2018.0211

Author Contributions: Dr Narod had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Kotsopoulos, Moller, Eisen, Narod.

Acquisition, analysis, or interpretation of data: Kotsopoulos, Gronwald, Karlan, Huzarski, Tung, Armel, Lynch, Senter, Singer, Foulkes, Jacobson, Sun, Lubinski, Narod.

Drafting of the manuscript: Kotsopoulos, Huzarski, Singer, Narod.

Critical revision of the manuscript for important intellectual content: Kotsopoulos, Gronwald, Karlan, Tung, Moller, Armel, Lynch, Senter, Eisen, Singer, Foulkes, Jacobson, Sun, Lubinski, Narod.

Statistical analysis: Kotsopoulos, Huzarski, Moller, Sun.

Obtained funding: Singer.

Administrative, technical, or material support: Kotsopoulos, Gronwald, Karlan, Armel, Lynch, Senter, Singer, Foulkes, Jacobson, Lubinski.

Study supervision: Kotsopoulos, Gronwald, Singer, Jacobson, Narod.

Conflict of Interest Disclosures: None reported.

Funding/Support: Dr Kotsopoulos is the recipient of a Cancer Care Ontario Research Chair in Population Studies and a Canadian Cancer Society Career Development Award in Prevention. Dr Narod is the recipient of a Tier I Canada Research Chair. This study was supported by a Canadian Cancer Society Research Institute grant (703058). This work was supported by revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Health and Human Services. Funding was also received from the Liz’s Legacy fund through Kicks for a Cure. Dr Lynch’s work is partially funded through the Charles F. and Mary C. Heider Chair in Cancer Research, which he holds at Creighton University.

Role of the Funder/Sponsor: The Canadian Cancer Society Research Institute, the Creighton University by the Nebraska Department of Health and Human Services, and Kicks for a Cure had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

The Hereditary Breast Cancer Clinical Study Group: Tuya Pal, MD (Vanderbilt University Medical Center); Georgia Wiesner, MD (Vanderbilt University Medical Center); Charis Eng, MD (Genomic Medicine Institute and Center for Personalized Genetic Healthcare); Susan L. Neuhausen, PhD (Department of Population Sciences, Beckman Research Institute of City of Hope); Peter Ainsworth, MD (London Health Sciences Centre); Louise Bordeleau, MD (McMaster University); Eitan Friedman, MD (Chaim Sheba Medical Center); Wendy Meschino, MD (North York General Hospital); Carrie Snyder, MSc (Creighton University School of Medicine); Kelly Metcalfe, PhD (Women’s College Research Institute); Aletta Poll, MSc (Women’s College Research Institute); Nicole Gojska, MSc (Women’s College Research Institute); Ellen Warner, MD (Odette Cancer Research, Sunnybrook Research Institute); Barry Rosen, MD (Department of Obstetrics and Gynecology, Princess Margaret Cancer Centre); Rochelle Demsky, MSc (Princess Margaret Cancer Center); Jeffrey N. Weitzel, MD (City of Hope Medical Center, Duarte); Karen Panabaker, MSc (London Health Sciences Center); Melanie Taylor, MD (BC Cancer Agency); Fergus Couch, MD (Mayo Clinic College of Medicine); Siranoush Manoukian, MD (Medical Genetics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori); Barbara Pasini, MD (Universita di Torino); Mary B. Daly, MD (Fox Chase Cancer Center); Linda Steele, MD (Beckman Research Institute of City of Hope); Howard Saal, MD (Children's Hospital Medical Center); Taya Fallen, MD (Cancer Genetics Program, Northwestern Medical Faculty Foundation); Marie Wood, MD (Vermont Cancer Center, The University of Vermont); Wendy McKinnon, MSc (Vermont Cancer Center, The University of Vermont); Edmond Lemire, MD (Royal University Hospital, University of Sasketchewan); Albert E. Chudley, MD (Children's Hospital, The University of Manitoba); Kim Serfas, MSc (Hereditary Breast Health Clinic, Health Sciences Centre Winnipeg); Kevin Sweet, MSc (Ohio State University Wexner Medical Center); Seema Panchal, MSc (Mount Sinai Hospital); Christine Elser, MD (Cancer Clinical Research Unit Princess Margaret Cancer Centre); Ophira Ginsburg, MD (Department of Population Health, NYU School of Medicine); Stephanie Hurst, MSc (Lakeridge Health Oshawa); Carey A. Cullinane, MD (Long Beach Memorial Medical Center); Robert E. Reilly, MD (St. Mary Medical Center); Joanne L. Blum, MD (Texas Oncology-Baylor Charles A. Sammons Cancer Center); Theodora Ross, MD (University of Texas Southwestern Medical Center); Caitlin Mauer, MSc (University of Texas Southwestern Medical Center); Ava Kwong, MD (The University of Hong Kong); Cezary Cybulski, MD (Pomeranian Medical University); Jeanna McCuaig, MSc (Department of Gynecologic Oncology, Princess Margaret Cancer Center); Daniel Rayson, MD (Queen Elizabeth II Health Sciences Center and Dalhousie University); and Claudine Isaacs, MD (Georgetown University Medical Center and Georgetown-Lombardi Comprehensive Cancer Center).

Disclaimer: The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the State of Nebraska or the Nebraska Department of Health and Human Services.

Additional Contributions: We thank the study staff, students, and volunteers including Shana Kim, MSc; Farah Shoukat, MBBS; Ellen MacDougall, MSc; Zoella Pasta, MD; Nida Mian, BSc; Jennifer Ng, BSc; Sarah Chin, BSc; Hamida Begum, MD; Harmeet Chaudhary, MD; Asrafi Azmi, MD; Shahana Nargis, MD; Clotilde Ngwa, MD; Mai Abdelhadi, MD; Saiveena Penikalapati, BSc; Laavanya Somasundaram, BSc; and Hannah Horvath, BSc, who helped with the data collection and data entry. Hamida Begum, MD; Harmeet Chaudhary, MD; Asrafi Azmi, MD; Shahana Nargis, MD; Mai Abdelhadi, MD; and Saiveena Penikalapati, BSc; were not compensated, all others were compensated for their contributions.

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