BRCA1 Mutation Carriers Research Articles

Short-term hormone replacement therapy in BRCA mutation carriers and risk of breast cancer: A nationwide study in Korea (1155)

Short-term hormone replacement therapy in BRCA mutation carriers and risk of breast cancer: A nationwide study in Korea (1155)

Identification of an exosomal-derived biomarker signature for early detection of ovarian cancer in BRCA mutation carriers (033)

Identification of an exosomal-derived biomarker signature for early detection of ovarian cancer in BRCA mutation carriers (033)

Bayesian combinatorial MultiStudy factor analysis.

Mutations in the BRCA1 and BRCA2 genes are known to be highly associated with breast cancer. Identifying both shared and unique transcript expression patterns in blood samples from these groups can shed insight into if and how the disease mechanisms differ among individuals by mutation status, but this is challenging in the high-dimensional setting. A recent method, Bayesian Multi-Study Factor Analysis (BMSFA), identifies latent factors common to all studies (or equivalently, groups) and latent factors specific to individual studies. However, BMSFA does not allow for factors shared by more than one but less than all studies. This is critical in our context, as we may expect some but not all signals to be shared by BRCA1-and BRCA2-mutation carriers but not necessarily other high-risk groups. We extend BMSFA by introducing a new method, Tetris, for Bayesian combinatorial multi-study factor analysis, which identifies latent factors that any combination of studies or groups can share. We model the subsets of studies that share latent factors with an Indian Buffet Process, and offer a way to summarize uncertainty in the sharing patterns using credible balls. We test our method with an extensive range of simulations, and showcase its utility not only in dimension reduction but also in covariance estimation. When applied to transcript expression data from high-risk families grouped by mutation status, Tetris reveals the features and pathways characterizing each group and the sharing patterns among them. Finally, we further extend Tetris to discover groupings of samples when group labels are not provided, which can elucidate additional structure in these data.

A transcriptional response to replication stress selectively expands a subset of Brca2-mutant mammary epithelial cells

Germline BRCA2 mutation carriers frequently develop luminal-like breast cancers, but it remains unclear how BRCA2 mutations affect mammary epithelial subpopulations. Here, we report that monoallelic Brca2mut/WT mammary organoids subjected to replication stress activate a transcriptional response that selectively expands Brca2mut/WT luminal cells lacking hormone receptor expression (HR-). While CyTOF analyses reveal comparable epithelial compositions among wildtype and Brca2mut/WT mammary glands, Brca2mut/WT HR- luminal cells exhibit greater organoid formation and preferentially survive and expand under replication stress. ScRNA-seq analysis corroborates the expansion of HR- luminal cells which express elevated transcript levels of Tetraspanin-8 (Tspan8) and Thrsp, plus pathways implicated in replication stress survival including Type I interferon responses. Notably, CRISPR/Cas9-mediated deletion of Tspan8 or Thrsp prevents Brca2mut/WT HR- luminal cell expansion. Our findings indicate that Brca2mut/WT cells activate a transcriptional response after replication stress that preferentially favours outgrowth of HR- luminal cells through the expression of interferon-responsive and mammary alveolar genes.

Contralateral breast cancer risk with radiation therapy in BRCA mutation carriers: what do we tell patients?

Contralateral breast cancer risk with radiation therapy in BRCA mutation carriers: what do we tell patients?

Comparison of Long-Term Oncological Results in Young Women with Breast Cancer between BRCA-Mutation Carriers Versus Non-Carriers: How Tumor and Genetic Risk Factors Influence the Clinical Prognosis.

Breast cancer (BC) is very uncommon in young women (YW) and it is unclear whether a BRCA mutation has prognostic implications. Our aim was to evaluate the characteristics of YW with BC by comparing the long-term oncological results between BRCA-mutation carriers and non-carriers. We retrospectively reviewed all the consecutive YW (aged 18-40 years) diagnosed with BC. Endpoints were disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS). 63 YW with a BRCA mutation were compared with 339 YW without BRCA mutation. BRCA-mutation carriers were younger (60.3% versus 34.8% if age ≤ 35 years, p = 0.001) and presented with more aggressive tumors (66.7% versus 40.7% if G3, p = 0.001; 57.2% versus 12.4% if biological subtype triple-negative, p = 0.001; 73.0% versus 39.2% if Ki67 ≥ 25%, p = 0.001). Non-carriers presented significantly better DFS, DDFS, and OS compared with BRCA-mutation carriers. Neoadjuvant chemotherapy was found to be an independent protective factor for OS in BRCA-mutation carriers. BC is more likely to present at a younger age (≤ 35 years) and with more aggressive characteristics (G3, triple-negative, Ki67 ≥ 25%) in YW with BRCA mutation compared with their non-mutated counterparts. Young BRCA-mutation carriers showed a poorer prognosis in terms of recurrence and survival compared with non-carriers. The implementation of neoadjuvant chemotherapy may improve survival in YW with BC and BRCA mutation.

Short-term Impact of Hormone Replacement Therapy on Risk of Breast Cancer in BRCA Mutation Carriers: A Nationwide Study in South Korea.

BRCA1/2 mutations are well-known risk factors for breast and ovarian cancers in women. Risk-reducing salpingo-oophorectomy (RRSO) is the standard treatment for preventing ovarian cancer with BRCA mutations. Postmenopausal syndrome (symptoms after RRSO can be alleviated by hormone replacement therapy (HRT); however, the use of HRT in carriers of BRCA mutations has been controversial because of the concern that HRT increases the risk of breast cancer. This study aimed to evaluate the effects of HRT in BRCA mutation carriers who underwent RRSO. A total of 151 carriers, who underwent RRSO between 2013 and 2020 after the diagnosis of BRCA1 or BRCA2 mutations were selected and followed up for a median of 3.03 years. Patients were divided into two groups: those who received HRT after RRSO (n=33) and those who did not (n=118). We compared the incidence of breast cancer over time between these two groups. There was no significant difference in the incidence of breast cancer between women who received HRT and those who did not (p=0.229). Multivariate logistic regression analysis, adjusted for age and parity revealed no significant difference in the risk of breast cancer between these two groups (hazard ratio, 0.312; 95% confidence interval, 0.039 to 2.480; p=0.278). In this study, we found no relationship between post-RRSO HRT and breast cancer in the population with BRCA mutations. Therefore, healthcare providers may consider the alleviation of symptoms of postmenopausal syndrome through HRT in patients who underwent RRSO.

Satisfaction and Well-Being After Contralateral Prophylactic Mastectomy Among BRCA Mutation Carriers and Noncarriers: A Longitudinal Analysis of BREAST-Q Domains.

Contralateral prophylactic mastectomy (CPM) is recommended for BRCA mutation carriers; its use in noncarriers relies on patient choice. We characterized differences in satisfaction and well-being after CPM between BRCA carriers and noncarriers. BREAST-Q data were obtained before and after CPM with immediate reconstruction performed at a single institution from 2016 to 2022. Associations between BRCA status and satisfaction with breasts, psychosocial well-being, and sexual well-being were assessed, with adjustment for preoperative scores and relevant confounders. In total, 149 BRCA carriers and 842 noncarriers were included. Response rates varied over time (preoperative, 56%; 6 months, 78%; 1 year, 51%; 2 years, 52%; 3 years, 59%). BRCA carriers were younger (p < 0.001), with a higher rate of neoadjuvant chemotherapy (p < 0.001). More noncarriers had HR+/HER2- tumors (p < 0.001) and underwent endocrine therapy (p < 0.001). Baseline satisfaction with breasts was higher among BRCA carriers (median [interquartile range] score, 70 [53-82] vs. 58 [48-70]; p = 0.006); psychosocial (p = 0.20) and sexual (p = 0.14) well-being were not significantly different between groups. BRCA carriers had a greater decrease in satisfaction with breasts (p = 0.04) and psychological well-being (p = 0.05) from baseline to 6 months; decrease in sexual well-being (p = 0.38) was not significantly different between groups. On univariate and multivariable analyses, BRCA status was not associated with satisfaction with breasts, sexual well-being, or psychosocial well-being. Satisfaction and well-being were similar between BRCA carriers and noncarriers treated with CPM. Relative to noncarriers, BRCA carriers experienced a greater decline in satisfaction with breasts and psychological well-being at 6 months after CPM.

Expression of Concern: Barańska, A.; Kanadys, W. Oral Contraceptive Use and Breast Cancer Risk for BRCA1 and BRCA2 Mutation Carriers: Systematic Review and Meta-Analysis of Case-Control Studies. Cancers 2022, 14, 4774.

The Cancers Editorial Office is issuing this expression of concern to alert readers to concerns regarding the findings of the published manuscript [...].

Tamoxifen and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation.

Chemoprevention with a selective estrogen receptor modulator (tamoxifen or raloxifene) is a non-surgical option offered to high-risk women to reduce the risk of breast cancer. The evidence for tamoxifen benefit is based on trials conducted among predominantly postmenopausal women from the general population and on studies of contralateral breast cancer in women with a pathogenic variant (mutation hereafter) in BRCA1 or BRCA2. Tamoxifen has not been assessed as a primary prevention agent in women with an inherited BRCA mutation. We conducted a prospective analysis of tamoxifen chemoprevention and the risk of breast cancer in women with a BRCA1 or BRCA2 mutation. Data on tamoxifen (and raloxifene) use was collected by questionnaire and updated biennially. Information on incident cancers was collected by self-report and was confirmed by medical record review. In a matched analysis, we estimated the hazard ratio (HR) and 95% confidence intervals (CI) for developing a first primary breast cancer associated with tamoxifen or raloxifene use, using Cox proportional hazards analysis. There were 4578 unaffected women in the cohort, of whom 137 reported tamoxifen use (3%), 83 reported raloxifene use (2%) and 12 used both drugs (0.3%). Women who used tamoxifen or raloxifene were matched 1:3 with women who used neither drug on year of birth, country of residence, year of study entry and gene (BRCA1 or BRCA2). We generated 202 matched pairs. After a mean follow-up of 6.8years, there were 22 incident breast cancers diagnosed among tamoxifen/raloxifene users (10.9% of users) and 71 cases diagnosed among non-users (14.3% of non-users; HR = 0.64; 95% CI 0.40-1.03; P = 0.07). Chemoprevention may be an effective risk-reduction option for BRCA mutation carriers, but further studies with longer follow-up are necessary.

CA125 Levels in BRCA mutation carriers – a retrospective single center cohort study

BackgroundOvarian cancer screening in BRCA1/2 mutation carriers utilizes assessment of carbohydrate antigen 125 (CA125) and transvaginal ultrasound (TVU), despite low sensitivity and specificity. We evaluated the association between CA125 levels, BRCA1/2 mutation status and menopausal status to provide more information on clinical conditions that may influence CA125 levels.MethodsWe retrospectively analyzed repeated measurements of CA125 levels and clinical data of 466 women at high risk for ovarian cancer. CA125 levels were compared between women with and without deleterious mutations in BRCA1/2. Pearson's correlation was used to determine the association between age and CA125 serum level. Differences in CA125 levels were assessed with the Mann–Whitney U test. The effect of BRCA1/2 mutation status and menopausal status on the change in CA125 levels was determined by Two-factor analysis of variance (ANOVA).ResultsThe CA125 serum levels of premenopausal women (median, 13.8 kU/mL; range, 9.4 – 19.5 kU/mL) were significantly higher than in postmenopausal women (median, 10.4 kU/mL; range, 7.7 – 14.0 kU/mL; p < .001). There was no significant difference in the CA125 levels of BRCA mutation carriers and non-mutation carriers across all age groups (p = .612). When investigating the combined effect of BRCA1/2 mutation and menopausal status, variance analysis revealed a significant interaction between BRCA1/2 mutation status and menopausal status on CA125 levels (p < .001). There was a significant difference between the CA125 levels of premenopausal and postmenopausal women, with a large effect in BRCA mutation carriers (p < .001, d = 1.05), whereas in non-mutation carriers there was only a small effect (p < .001, d = 0.32).ConclusionOur findings suggest that hereditary mutations in BRCA1/2 affect the decline of CA125 levels with increasing age. To prove a definite effect of this mutation on the CA125 level, prospective trials need to be conducted to define new cut-off levels of CA 125 in mutation carriers and optimize ovarian cancer screening.

Implant-Based Breast Reconstruction after Risk-Reducing Mastectomy in BRCA Mutation Carriers: A Single-Center Retrospective Study.

Women with BRCA gene mutations have a higher lifetime risk of developing breast cancer. Furthermore, cancer is usually diagnosed at a younger age compared to the wild-type counterpart. Strategies for risk management include intensive surveillance or risk-reducing mastectomy. The latter provides a significant reduction of the risk of developing breast cancer, simultaneously ensuring a natural breast appearance due to the preservation of the skin envelope and the nipple-areola complex. Implant-based breast reconstruction is the most common technique after risk-reducing surgery and can be achieved with either a submuscular or a prepectoral approach, in one or multiple stages. This study analyzes the outcomes of the different reconstructive techniques through a retrospective review on 46 breasts of a consecutive, single-center case series. Data analysis was carried out with EpiInfo version 7.2. Results of this study show no significant differences in postoperative complications between two-stage tissue expander/implant reconstruction and direct-to-implant (DTI) reconstruction, with DTI having superior aesthetic outcomes, especially in the prepectoral subgroup. In our experience, the DTI prepectoral approach has proven to be a safe and less time-consuming alternative to the submuscular two-stage technique, providing a pleasant reconstructed breast and overcoming the drawbacks of subpectoral implant placement.

'Earlier than Early' Detection of Breast Cancer in Israeli BRCA Mutation Carriers Applying AI-Based Analysis to Consecutive MRI Scans.

Female BRCA1/BRCA2 (=BRCA) pathogenic variants (PVs) carriers are at a substantially higher risk for developing breast cancer (BC) compared with the average risk population. Detection of BC at an early stage significantly improves prognosis. To facilitate early BC detection, a surveillance scheme is offered to BRCA PV carriers from age 25-30 years that includes annual MRI based breast imaging. Indeed, adherence to the recommended scheme has been shown to be associated with earlier disease stages at BC diagnosis, more in-situ pathology, smaller tumors, and less axillary involvement. While MRI is the most sensitive modality for BC detection in BRCA PV carriers, there are a significant number of overlooked or misinterpreted radiological lesions (mostly enhancing foci), leading to a delayed BC diagnosis at a more advanced stage. In this study we developed an artificial intelligence (AI)-network, aimed at a more accurate classification of enhancing foci, in MRIs of BRCA PV carriers, thus reducing false-negative interpretations. Retrospectively identified foci in prior MRIs that were either diagnosed as BC or benign/normal in a subsequent MRI were manually segmented and served as input for a convolutional network architecture. The model was successful in classification of 65% of the cancerous foci, most of them triple-negative BC. If validated, applying this scheme routinely may facilitate 'earlier than early' BC diagnosis in BRCA PV carriers.

Clinical predictors of survival in advanced epithelial ovarian cancer: Can we foresee the long-term survivors and develop a personalized treatment approach?

e17605 Background: While women with recurrent disease have a poor prognosis, a subset of women are long term survivors (LTS). We aimed to characterize the demographic and clinical characteristics associated with long and short-term survival of patients with advanced epithelial OC (EOC). Methods: We conducted a retrospective descriptive analysis of 822 patients diagnosed with advanced EOC (FIGO stage III/IV) and treated at a single institution, between 2002-2020. Characteristics of short-term survivors (STS), women who survived less than 2 years, were compared to LTS, patients who lived beyond 7 and 10 years from diagnosis. Descriptive statistics of the clinical, oncologic, and treatment parameters were performed using t-test, chi-square. We assessed the contribution of age and stage, BRCA carrier status, interval or primary debulking, optimal debulking, platinum sensitivity, and treatment scheduling upon oncological outcomes. Results: Among 822 patients with advanced EOC, 112 women (13.6%) died withing 24 months from diagnosis, while 139 (16.9%), and 64 (7.8%) survived beyond 7 and 10 years, respectively. Histology, CA125 level at diagnosis, and interval or primary debulking approach, were not significant among the STS and LTS. LTS were younger at diagnosis, (median age of 57, and 56.5 among women who lived &gt; 7 and 10 years, respectively vs. 70 in STS, p &lt; 0.0001). The majority of LTS were diagnosed with stage III disease, (95%, and 97%, &gt; 7 and &gt; 10 years, respectively vs. 67% of STS), in contrast to a greater proportion of STS diagnosed with stage IV (33.0% of STS vs. 5.0%, 3.1% of LTS &gt; 7 and &gt; 10 years, respectively, p &lt; 0.0001). BRCA mutation status was the strongest prognostic factor for LTS ( &gt; 7 and 10 years, OR = 17.8, 21.2 respectively, p &lt; 0.001). Almost half of LTS who were carriers of a deleterious BRCA mutation, (47.3%, 46.2% of LTS &gt; 7 and 10 years, respectively, p &lt; 0.0001), whereas most STS were not carriers of BRCA mutations (89.8%). LTS were predominantly platinum sensitive (99.3%, 98.4% &gt; 7 and &gt; 10 year, vs. 21.6% of STS, P &lt; 0.0001). Optimal cytoreductive surgery was performed in a smaller number of STS compared to the LTS (41.9% of STS vs. 83.5% and 88.7% of LTS &gt; 7 and 10 years, respectively, p &lt; 0.0001). A greater proportion of LTS received weekly treatment scheduling of paclitaxel and carboplatin compared to STS (50.8% and 49.2% of LTS &gt; 7 and 10 years, respectively vs. 31.6% of STS, p &lt; 0.01). Conclusions: The long and short-term survivors of advanced EOC may be identified early in the clinical assessment, based on distinct patient characteristics associated with survivorship, which are critical in developing a personalized treatment approach. Our work demonstrated that LTS are a distinct group of women diagnosed at a younger age, lower stage, optimally debulked, platinum sensitive disease, and BRCA mutation carriers.

Pathologic complete response after neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers.

544 Background: Distinct pathological characteristics and mutational signatures in BRCA-associated breast cancers may result in differential response to chemotherapy but understanding of treatment response after neoadjuvant chemotherapy (NAC) is limited. We describe a single-institutional experience to compare rates of pathologic complete response (pCR) after NAC in BRCA carriers (g BRCA1/2) and noncarriers. Methods: From 11/2013 to 01/2022, 1426 consecutive women with clinical stage I-III breast cancer were treated with NAC followed by surgery. Baseline disease characteristics were compared between g BRCA1/2 and noncarriers using two-sample non-parametric tests. Conditional logistic regression was used to evaluate the association between BRCA status and pCR (i.e., ypT0/is pN0) adjusting for variables selected using backward elimination. Results: 92 (6.5%) and 73 (5.1%) had deleterious mutations in BRCA1 and BRCA2, respectively. Compared to noncarriers, g BRCA1/2 were younger (p&lt;0.001) with clinical T1 (p=0.002) and triple negative disease (TN) (57% vs 25% noncarriers, p&lt;0.001). Almost all patients received doxorubicin/cyclophosphamide/paclitaxel therapy (93%) with g BRCA1/2 more likely to receive carboplatin (p&lt;0.001). pCR rate was 42% of g BRCA1, 21% of g BRCA2, and 26% of noncarriers (p=0.001). Among clinically node positive (cN+) patients, nodal pCR was higher in g BRCA1/2 compared to noncarriers (53/96 (55%) vs 371/856 (43%), p=0.012). This difference was seen in ER+/HER2- (36% gBRCA1/2 vs 20% noncarriers; p=0.027) and TN subtypes (79% g BRCA1/2 vs 45% noncarriers; p&lt;0.001). Poorly differentiated tumors (p&lt;0.001), cN+ (p=0.010), lower cT stage (p=0.028), ductal histology (p&lt;0.001), TN and HER2+ receptor status (p&lt;0.001), absence of lymphovascular invasion (p&lt;0.001), carboplatin receipt (p=0.041), and BRCA1 status (p=0.001) were also associated with pCR on univariate analysis. After adjusting for differentiation and molecular subtype, BRCA1 status remained independently associated with pCR. Conclusions: g BRCA1 undergoing NAC have higher pCR rates relative to g BRCA2 and patients with sporadic disease. Across breast cancer subtypes, g BRCA1/2 more frequently converted to pN0. Defining biological mechanism for these findings would allow customization of treatment based on germline genetics. [Table: see text]

Editors' Selections from Relevant Scientific Publications

Highlights from the Literature| June 01 2023 Editors' Selections from Relevant Scientific Publications Author & Article Information Online ISSN: 1940-6215 Print ISSN: 1940-6207 ©2023 American Association for Cancer Research2023American Association for Cancer Research Cancer Prev Res (Phila) (2023) 16 (6): 303. https://doi.org/10.1158/1940-6207.CAPR-16-6-HFL Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Article Versions Icon Versions Version of Record June 1 2023 Citation Editors' Selections from Relevant Scientific Publications. Cancer Prev Res (Phila) 1 June 2023; 16 (6): 303. https://doi.org/10.1158/1940-6207.CAPR-16-6-HFL Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest Search Advanced Search Obese adipose tissue in the mammary gland (by Arendt et al. via Cancer Research Bhardwaj et al. investigated whether high body mass index (BMI) increases breast cancer risks for women carrying BRCA 1 or BRCA2 mutations. They examined noncancerous breast tissue from 69 such women and found that BMI and biomarkers of metabolic dysfunction were positively correlated with DNA damage in epithelia. RNA sequencing data revealed that obesity altered breast adipose microenvironment and activated estrogen biosynthesis. Blocking signaling pathways mediated by either estrogen or obesity-associated factors leptin or insulin, reduced DNA damage. Additionally, a high-fat diet increased DNA damage and mammary tumors in Brca1+/−mice. These results provide mechanistic insight linking obesity and breast cancer in BRCA mutation carriers, and suggest that reducing risk may involve maintaining a lower body weight, addressing metabolic problems and targeting estrogen. Bhardwaj P, … Brown KA. Sci Transl Med. 2023 Feb 22;15(684):eade1857.... You do not currently have access to this content.

Healthcare utilization among individuals diagnosed with hereditary breast-ovarian cancer syndrome through a universal germline genetic testing program.

10604 Background: Most individuals with Hereditary Breast-Ovarian Cancer Syndrome (HBOC) are unaware of their risk. Criteria-based testing will not close this gap as it fails to identify ~50% of mutation carriers. Universal germline testing (GT) in oncology stands to identify more mutation carriers and advance cancer control. However, the clinical utility of universal germline testing is unknown. Methods: The City of Hope INSPIRE study offers all consented patients GT for cancer susceptibility (155 genes) and actionable disorders (59 genes). We used an informatics approach to evaluate healthcare utilization for patients found to have BRCA1/ BRCA2 mutations. We queried codified data in our electronic data warehouse before and after GT (post testing interval: 1-29 months). We binned care as possibly related/ not related to HBOC based on NCCN guidelines. Results: Of 10,814 patients who had GT, 217 (2%) had a pathogenic/ likely pathogenic mutation in either BRCA1 or BRCA 2. The demographic distribution of mutation carriers was: white (n = 162, 75%), Asian (n = 28, 13%), Hispanic (n = 65, 30%); female (n = 184, 85%); the mean age was 54 yrs. Eighty-four percent (n = 182) had cancer, including 64% with cancers associated with HBOC (breast 40%, ovarian 13%, pancreatic 3%, 5% prostate, and 0.5% melanoma) and 18% with cancers that are not associated with HBOC. Eighty-three percent of patients had procedures, imaging, and/or therapy potentially related to the BRCA mutation. Eighty-six percent of cancer patients had potentially related care. As expected, use of breast MRI, mammography, MRCP, mastectomy, and bilateral salpingo-oophorectomy (BSO) occurred both before and after testing, with most utilization occurring prior to GT and likely related to cancer staging and treatment. The exception was MRCP which occurred more often following GT (0.6% before vs 1.2% after). Fifty-one (28%) cancer patients received PARP inhibitors. In the unaffected cohort, 67% of patients received possibly related care. Use of mammography was higher prior to GT (7% vs 2%). Consistent with the fact that some unaffected patients were likely known mutation carriers prior to consent, mastectomy was higher prior to GT (5% vs 0%) and BSO was equivalent before and after GT (1.8%). Use of breast MRI (9% vs 15%), MRCP (1.8% vs 3%) and transvaginal US (5% vs 7%) were all higher after GT. Conclusions: We found high levels of relevant healthcare utilization for BRCA mutation carriers in the context of universal GT. However, this initial informatics approach is limited because key information on prior GT and motivations for surgery (e.g., therapeutic vs prophylactic mastectomy) are not adequately captured in codified data. Codified EHR queries will need to be augmented by text mining and/or manual chart review to fully capture care and assess the clinical utility of system-wide genetic care delivery interventions.

Vitamin D and Calcium Supplement Use and High-Risk Breast Cancer: A Case-Control Study among BRCA1 and BRCA2 Mutation Carriers.

The role of vitamin D and calcium use in the development of breast cancer among women in the general population is not clear. Furthermore, whether vitamin D and calcium supplement use are associated with breast cancer in high-risk populations has not been evaluated. Thus, we evaluated the association between vitamin D and/or calcium supplement use and breast cancer among women with a pathogenic variant (mutation) in BRCA1 or BRCA2. BRCA mutation carriers enrolled in a longitudinal study were invited to complete a supplemental questionnaire on lifetime supplement use. Cases included women with a prevalent diagnosis of invasive breast cancer, and controls had no history of breast cancer. Vitamin D and calcium use were categorized as never/ever use, and as tertiles of supplement intake (total average daily supplement use). Unconditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CIs) of breast cancer. This study included 134 breast cancer cases and 276 controls. Women who used vitamin D-containing supplements had 46% lower odds of having breast cancer compared to those who never used supplements (OR 0.54; 95% CI 0.31, 0.91; p = 0.02). Increasing vitamin D and calcium supplement intake was inversely associated with the odds of having breast cancer (p-trend = 0.04). Findings were suggestively stronger among BRCA1 mutation carriers; however, analyses were limited by small strata. These findings suggest a potential inverse association between vitamin D and calcium supplementation and BRCA breast cancer. Additional studies are warranted to confirm these findings and accurately inform clinical care guidelines.

Barriers to hormone therapy following prophylactic bilateral salpingo-oophorectomy in BRCA1/2 mutation carriers.

This study aimed to identify barriers to hormone therapy (HT) use among women with BRCA1/2 mutations after prophylactic bilateral salpingo-oophorectomy (BSO). A cross-sectional, electronic survey was conducted of BRCA1/2 mutation carriers at Women and Infants Hospital, Yale Medical Center, Hartford Healthcare, and Maine Medical Center. This study was a subanalysis of a subset of female BRCA1/2 mutation carriers who had undergone a prophylactic BSO. Data were analyzed using the Fisher's exact test or t test. We performed a subanalysis of 60 BRCA mutation carriers who underwent a prophylactic BSO. Only 24 women (40%) reported ever using HT. HT use was higher in women who underwent their prophylactic BSO at age younger than 45 years (51% vs. 25%, P = 0.06). Among all women who had a prophylactic BSO, the majority (73%) reported that a provider talked to them about using HT. Two thirds reported having seen contradictory information in the media about long-term consequences of HT. Seventy percent listed their provider as the primary influence in their decision to start HT. The most common reasons for not starting HT included it not being recommended by their physician (46%) and that it was not necessary (37%). BRCA mutation carriers frequently undergo prophylactic BSO at young ages, and less than half report using HT. This study highlights barriers to HT use, such as patient fears and physician discouragement, and identifies potential areas to improve educational efforts.

Incidence of Cancer and Role of Sentinel Lymph Node Biopsy in BRCA Mutation Carriers Undergoing Prophylactic Mastectomies.

Breast surveillance in patients with BRCA mutations include mammography (MMG) and MRI. Patients may elect to undergo risk-reducing bilateral prophylactic mastectomies (BPM). Sentinel lymph node biopsies (SLNB) are frequently performed and associated with increased morbidity. This study sought to determine the correlation between preoperative imaging and the final pathology and evaluate the role of SLNB in these high-risk patients. A prospective database identified BRCA patients who underwent BPM between 2006 and 2022. Imaging, pathology, and operative reports were reviewed. 170 patients with BRCA 1/2 mutations were identified. 162 (95.3%) had imaging within one year of BPM. Of these, 28 (17.3%) patients had a MMG/ultrasound, 53 (32.7%) had an MRI, and 81 (50%) had both; 21/162 (13.0%) patients had abnormal imaging. Bilateral SLNB were performed in 31 (18.2%) patients, of which 7 had abnormal imaging; unilateral SLNB were performed in 4 (2.4%) patients, of which 3 had abnormal imaging. 11/170 (6.4%) patients had a malignancy and only one (9%) of these patients had imaging abnormalities. 1/170 (0.6%) patient had an invasive carcinoma requiring an axillary lymph node dissection (ALND), and 10/170 (5.9%) patients had ductal carcinoma in situ (DCIS). 25/170 (14.7%) had ADH/ALH. Only 7/170 (4.1%) patients had imaging abnormalities and abnormal pathology. All SLNB and ALND performed demonstrated no metastatic disease. There is a high rate of discordance between preoperative imaging prior to surgery in BRCA patients undergoing prophylactic mastectomies and final pathology. This study does not support routine SLNB at the time of BPM.