BRCA1 Mutation Carriers Research Articles

Contraceptive use and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation

BackgroundBRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations.MethodsA total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure.ResultsEver use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52–0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54–0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12–0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10–1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer.ConclusionsThese findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation.

Cell-type-specific epigenomic variations associated with BRCA1 mutation in pre-cancer human breast tissues.

BRCA1 germline mutation carriers are predisposed to breast cancers. Epigenomic regulations have been known to strongly interact with genetic variations and potentially mediate biochemical cascades involved in tumorigenesis. Due to the cell-type specificity of epigenomic features, profiling of individual cell types is critical for understanding the molecular events in various cellular compartments within complex breast tissue. Here, we produced cell-type-specific profiles of genome-wide histone modifications including H3K27ac and H3K4me3 in basal, luminal progenitor, mature luminal and stromal cells extracted from a small pilot cohort of pre-cancer BRCA1 mutation carriers (BRCA1mut/+) and non-carriers (BRCA1+/+), using a low-input ChIP-seq technology that we developed. We discovered that basal and stromal cells present the most extensive epigenomic differences between mutation carriers (BRCA1mut/+) and non-carriers (BRCA1+/+), while luminal progenitor and mature luminal cells are relatively unchanged with the mutation. Furthermore, the epigenomic changes in basal cells due to BRCA1 mutation appear to facilitate their transformation into luminal progenitor cells. Taken together, epigenomic regulation plays an important role in the case of BRCA1 mutation for shaping the molecular landscape that facilitates tumorigenesis.

CDK5RAP3, a New BRCA2 Partner That Regulates DNA Repair, Is Associated with Breast Cancer Survival.

Simple SummaryBRCA2 is an essential gene for DNA repair by homologous recombination and is often mutated in families at risk of breast and ovarian cancer. In this study we identified CDK5RAP3 tumor suppressor as a new BRCA2-interacting protein. CDK5RAP3 negatively regulates DNA repair of double-strand breaks, providing a new mechanism of DNA damage resistance. Consistently, gene expression data analysis showed CDK5RAP3 overexpression in breast cancer is associated with poorer survival. Finally, we identified common genetic variations in the CDK5RAP3 locus as potentially associated with breast and ovarian cancer risk in a large cohort of BRCA1 and BRCA2 mutation carriers.BRCA2 is essential for homologous recombination DNA repair. BRCA2 mutations lead to genome instability and increased risk of breast and ovarian cancer. Similarly, mutations in BRCA2-interacting proteins are also known to modulate sensitivity to DNA damage agents and are established cancer risk factors. Here we identify the tumor suppressor CDK5RAP3 as a novel BRCA2 helical domain-interacting protein. CDK5RAP3 depletion induced DNA damage resistance, homologous recombination and single-strand annealing upregulation, and reduced spontaneous and DNA damage-induced genomic instability, suggesting that CDK5RAP3 negatively regulates double-strand break repair in the S-phase. Consistent with this cellular phenotype, analysis of transcriptomic data revealed an association between low CDK5RAP3 tumor expression and poor survival of breast cancer patients. Finally, we identified common genetic variations in the CDK5RAP3 locus as potentially associated with breast and ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. Our results uncover CDK5RAP3 as a critical player in DNA repair and breast cancer outcomes.

Analysis of pathogenic variants in BRCA1 and BRCA2 genes using next-generation sequencing in women with triple negative breast cancer from South India.

The frequency of triple-negative breast cancer (TNBC) incidence varies among different populations suggesting the involvement of genetic components towards TNBC development. Previous studies have reported that BRCA1/2 germline mutations confer a lifetime risk of developing TNBC. However, there is hardly any information regarding the common pathogenic variants (PVs) in BRCA1/2 genes that contribute to TNBC in the Indian population. Hence, we screened for PVs in BRCA1/2 and their association with clinico-pathological features in TNBC patients. The study recruited 59 TNBC patients without hereditary breast and ovarian cancer (HBOC) from South India. The entire BRCA1 and BRCA2 genes were sequenced for the 59 patients using the Illumina HiSeq X Ten sequencer. Among the 59 TNBC genomic DNA samples sequenced, BRCA mutations were identified in 8 patients (13.6%), BRCA1 mutations in 6 patients, and BRCA2 mutations in 2 patients. Among the 6 BRCA1 mutations, three were c.68_69delAG (185delAG) mutation. Remarkably, all the TNBC patients with BRCA mutations exhibited higher-grade tumors (grade 2 or 3). However, among all the BRCA mutation carriers, only one patient with a BRCA2 mutation (p.Glu1879Lys) developed metastasis. Our data advocates that South Indian women with higher grade TNBC tumors and without HBOC could be considered for BRCA mutation screening, thereby enabling enhanced decision-making and preventive therapy.

Evaluation of the indication of BRCA1/2 genetic tests in Iranian women and acceptance rate of risk-reducing surgeries in BRCA mutation carriers.

BackgroundA higher risk for breast and ovarian cancer has been reported in BRCA carriers and prophylactic surgeries are proposed to reduce this risk. This retrospective cohort study has evaluated the indication of BRCA1/2 genetic tests in Iranian women and the rate of women's acceptance of prophylactic surgeries recommended by the surgeon.MethodsMedical records of 147 high‐risk women according to NCCN clinical practice guidelines who referred for BRCA mutations testing were assessed. Individual information, indications for BRCA1/2 genetic testing and their results, physician recommendations, and type of accepted surgery were registered. To evaluate the current status of women an active visit follow‐up every six months was conducted.ResultsThe mean age of women was 43.40 ± 10.94 and the median follow‐up time was 1.92 years. Genetic test results showed 49(33.3%) women were positive for either BRCA1/2 mutations. Although the occurrence of breast cancer younger than 40 was the most common indication for genetic tests (26.5%), positive breast cancer history in first‐degree relatives and two relatives younger than 50 was the most common indications with positive results. The rate of acceptance of prophylactic mastectomy and bilateral salpingo‐oophorectomy was (14.3% and 34.7%) in BRCA mutation carriers.ConclusionIf the onset of breast cancer at a young age (less than 40) will be the only indication for a BRCA analysis, the rate of a positive result (12.8%) is very low. Further studies are warranted to evaluate the age limit for genetic testing in our country. Prophylactic mastectomy acceptance is very low in BRCA1/2 carriers in our centers.

Long term use of oral contraceptives comprising synthetic estrogens induces an excessive breast cancer risk in BRCA mutation carrier women: a meta-analysis

Background: The relationship between oral contraceptive (OC) use and breast cancer risk is highly debated. Recent publications support a slight increase in overall breast cancer risk among OC user women, in particular among the current users. Women with inherited BRCA1 (Breast cancer type 1) or BRCA2 (Breast cancer type 2) gene mutations are at increased risk of breast and ovarian cancers, which is often mistakenly attributed to their elevated endogenous estrogen levels. The aim of presented meta-analysis was to assess the effects of OC use on breast cancer risk in BRCA mutation carrier women with minimal bias. Methods: A systematic search strategy was used to identify relevant studies, Stata (version 15) was used for meta-analysis. Results: Individual datasets from 13 studies totaling 20,202 patients were analyzed. The combined results showed no significant increase in risk of breast cancer in BRCA mutation carriers who had ever used oral contraceptive (HR = 1.09, 95% CI: 0.71–1.69 among BRCA1 mutation carriers and HR = 1.19, 95% CI: 0.73–1.95 among BRCA2 mutation carriers, respectively). However, in correlation with long-term (&gt;5 years) OC users, the breast cancer risk was significantly increased in both BRCA1 mutation carriers (HR = 1.39, 95% CI: 1.19–1.60) and BRCA1 mutation carriers (HR = 1.61, 95% CI: 1.25–1.96). Conclusion: The presented results indicate that in BRCA mutation carriers women who have defective liganded activation of estrogen receptors (ERs), the use of synthetic estrogens means an additive factor for ER deregulation further increasing the risk for breast cancer. Long term OC use in BRCA mutation carriers results in a significantly increased risk for breast cancer by exhausting the compensatory genome defending process.

Q and A: A New Standard of Care for Germline BRCA1 and/or BRCA2 Mutation Carriers With Early-Stage Breast Cancer.

Q and A: A New Standard of Care for Germline BRCA1 and/or BRCA2 Mutation Carriers With Early-Stage Breast Cancer.

Differences in age at diagnosis of ovarian cancer for each BRCA mutation type in Japan: optimal timing to carry out risk-reducing salpingo-oophorectomy.

ObjectiveBRCA1 and BRCA2 mutation carriers are recommended to undergo risk-reducing salpingo-oophorectomy (RRSO) by age 40 and 45, respectively. However, the carriers have a different way of thinking about their life plan. We aimed to investigate the distribution of age at diagnosis of ovarian cancer (OC) patients to examine the optimal timing of RRSO in the carriers.MethodsWe examined a correlation between age at diagnosis of OC and common mutation types in 3,517 probands that received BRCA genetic testing. Among them, germline BRCA1 mutation (gBRCA1m), germline BRCA2 mutation (gBRCA2m) and germline BRCA wild-type (gBRCAwt) were found in 185, 42 and 241 OC patients, respectively.ResultsThe average age at diagnosis of OC in gBRCA1m and gBRCA2m was 51.3 and 58.3 years, respectively, and the difference from gBRCAwt (53.8 years) was significant. The gBRCA2m carriers did not develop OC under the age of 40. The average age was 50.1 years for L63X and 52.8 years for Q934X in BRCA1, and 55.1 years for R2318X and 61.1 years for STOP1861 in BRCA2. The age at diagnosis in L63X or R2318X carriers was relatively younger than other BRCA1 or BRCA2 carriers, however their differences were not significant. With L63X and R2318X carriers, 89.4% (42/47) and 100% (7/7) of women were able to prevent the development of OC, respectively, when RRSO was performed at age 40.ConclusionThere appears to be no difference in the age at diagnosis of OC depending on the type of BRCA common mutation. Further analysis would be needed.

A prospective multicentric study of risk-reducing salpingo-oophorectomy in BRCA mutation patients.

Background and aim of the work:BRCA1/2 are tumour-suppressor genes involved in DNA homologous recombination and ovarian cancer development. The study evaluated the risk of tumor cancer in women presenting the BRCA mutations.Methods:Risk-reducing surgery (RRS) was performed in 100 patients carrying BRCA1 (aged between 30-73 years, median age was 51 years) and BRCA 2 mutation (aged between 36-70 years, median age was 53 years). Fifty-eight patients had previous history of breast cancer.Results:Between the 100 patients, 82 women underwent risk-reducing salpingo-oophorectomy (RRSO) through a laparoscopic minimally invasive approach, 7 (7%) underwent laparoscopic RRSO and contextual hysterectomy, 1 woman (1%) underwent RRSO through a laparotomic approach and 10 women (10%) laparotomic RRSO and hysterectomy. During 5 (5%) laparoscopic RRSO, prophylactic bilateral mastectomy was also performed. Early and late complication occurred in 3 patients (3%). Two patients (2%) were found to have occult Serous Tubal Intraepithelial Carcinoma (STIC) and three patients (3%) occult cancer.Conclusions:RRSO is safe and feasible in BRCA mutation carriers. The procedure is effective for genetic prevention of ovarian cancer. (www.actabiomedica.it)

Hereditary Risk Assessment for BRCA Breast and/or Ovarian Cancer

Germline BRCA1 and BRCA2 (BRCA1/2) mutations are most frequently associated with hereditary breast/ovarian cancer. The study of genetic discriminators and dysregulated pathways involved in hereditary breast/ovarian syndromes has been key in the development of molecular diagnostic strategies, targeted therapies (such as PARP inhibitors), and prevention approaches. The recent development and implementation of next generation sequencing technologies has improved patient selection processes to offer such prevention and surveillance strategies. This review summarizes current knowledge on management and follow-up of BRCA mutation patients and carriers, and also reviews current research lines on the subject that could help improve future management of BRCA germline mutant patients.

Persistent EGFR/K-RAS/SIAH pathway activation drives chemo-resistance and early tumor relapse in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It disproportionately affects BRCA mutation carriers and young women, especially African American (AA) women. Chemoresistant TNBC is a heterogeneous and molecularly unstable disease that challenges our ability to apply personalized therapies. With the approval of immune checkpoint blockade (ICB) for TNBC, the addition of pembrolizumab to systemic chemotherapy has become standard of care (SOC) in neoadjuvant systemic therapy (NST) for high-risk early-stage TNBC. Pembrolizumab plus chemotherapy significantly increased the pathologic complete response (pCR) and improved event-free survival in TNBC. However, clinical uncertainties remain because similarly treated TNBC partial responders with comparable tumor responses to neoadjuvant therapy often experience disparate clinical outcomes. Current methods fall short in accurately predicting which high-risk patients will develop chemo-resistance and tumor relapse. Therefore, novel treatment strategies and innovative new research initiatives are needed. We propose that the EGFR-K-RAS-SIAH pathway activation is a major tumor driver in chemoresistant TNBC. Persistent high expression of SIAH in residual tumors following NACT/NST reflects that the EGFR/K-RAS pathway remains activated (ON), indicating an ineffective response to treatment. These chemoresistant tumor clones persist in expressing SIAH (SIAHHigh/ON) and are linked to early tumor relapse and poorer prognosis. Conversely, the loss of SIAH expression (SIAHLow/OFF) in residual tumors post-NACT/NST reflects EGFR/K-RAS pathway inactivation (OFF), indicating effective therapy and chemo-sensitive tumor cells. SIAHLow/OFF signal is linked to tumor remission and better prognosis post-NACT/NST. Therefore, SIAH is well-positioned to become a novel tumor-specific, therapy-responsive, and prognostic biomarker. Potentially, this new biomarker (SIAHHigh/ON) could be used to quantify therapy response, predict chemo-resistance, and identify those patients at the highest risk for tumor relapse and poor survival in TNBC.

Oral contraceptives and risk of breast cancer and ovarian cancer in women with a BRCA1 or BRCA2 mutation: a meta-analysis of observational studies.

It remains inconclusive whether the use of oral contraceptives (OCs) alters the risks of breast or ovarian cancer in women with a breast cancer susceptibility gene 1 (BRCA1) or breast cancer susceptibility gene 2 (BRCA2) mutation. We investigated the association between OC use and the risks of breast or ovarian cancer in this group by using a meta-analysis. PubMed and EMBASE were searched using keywords until February 2021 to identify relevant studies that evaluated the association between OC ever use and the risks of breast or ovarian cancer in women with a BRCA1 or BRCA2 mutation. Twelve studies for breast cancer and eight studies for ovarian cancer were identified. In the random-effects meta-analysis, the ever use of OCs was significantly associated with an increased risk of breast cancer [odds ratio (OR), relative risk (RR) or hazard ratio (HR) = 1.24; 95% confidence interval (CI) 1.08-1.41] and a decreased risk of ovarian cancer (OR/RR/HR = 0.53, 95% CI 0.41-0.67). Consistent findings were observed when BRCA1 and BRCA2 mutation carriers were analyzed separately. The increased risk of breast cancer was observed only in the long-term (>5 years) users of OCs, while the decreased risk of ovarian cancer was observed regardless of the duration of OC use. The current study suggests that the ever use of OCs in BRCA mutation carriers is significantly associated with an increased risk of breast cancer and a decreased risk of ovarian cancer. Therefore, the use of OCs as chemoprevention of ovarian cancer should be cautious in BRCA mutation carriers.

Effects of chemotherapy on contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers: A nationwide cohort study

AimBRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers. Patients and methodsBRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression. ResultsWe included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1–8.6] and 16.7% [95%CI: 10.8–23.7] in BRCA1 and 4.8% [95%CI: 2.7–7.8] and 16.0% [95%CI: 9.3–24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29–0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29–1.39). In BRCA1, risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17–0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17–0.68 and HR: 0.22, 95%CI: 0.08–0.62, respectively). ConclusionRisk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers.

Breast cancer risk in BRCA mutation carriers after diagnosis of epithelial ovarian cancer is lower than in carriers without ovarian cancer

ObjectiveEvaluate the incidence and characteristics of breast cancers (BC) diagnosed following an epithelial ovarian cancer (EOC) diagnosis in women with pathogenic BRCA mutations. MethodsRetrospective cohort study of all women in an integrated healthcare system with BRCA mutations diagnosed with EOC from 1/1/1997–12/31/2018. Primary outcome was rate of subsequent BC diagnosis. Secondary outcomes included risk factors associated with development of BC, median time to detection following EOC, and method of detection. ResultsThere were 284 women with BRCA-associated EOC identified. Fifty-two women had risk-reducing mastectomy and were excluded. Of the 232 eligible women with a median follow-up of 5.6 years, 33 (14%) women were diagnosed with BC following EOC: 27 (11%) new cases and 6 (3%) recurrences. Twelve (36%) cases of BC were detected on screening mammogram, 4 (12%) on screening MRI, and 9 (27%) on work-up after presenting with a palpable lump. Twenty-nine (87%) were early stage (0-II) disease. Median interval from EOC to BC diagnosis was 80 months (IQR 32, 134) for new and 63 months (IQR 21, 94) for recurrent BCs. There was one death from breast cancer while 12 women died of ovarian cancer. ConclusionsMost BC following BRCA-associated EOC is early stage and not associated with mortality. Given BC rate similar to general population and median diagnosis at 6.6 years following ovarian cancer, increased BC screening may not be warranted in the early years after EOC diagnosis.

Inference of tissue relative proportions of the breast epithelial cell types luminal progenitor, basal, and luminal mature

Single-cell analysis has revolutionised genomic science in recent years. However, due to cost and other practical considerations, single-cell analyses are impossible for studies based on medium or large patient cohorts. For example, a single-cell analysis usually costs thousands of euros for one tissue sample from one volunteer, meaning that typical studies using single-cell analyses are based on very few individuals. While single-cell genomic data can be used to examine the phenotype of individual cells, cell-type deconvolution methods are required to track the quantities of these cells in bulk-tissue genomic data. Hormone receptor negative breast cancers are highly aggressive, and are thought to originate from a subtype of epithelial cells called the luminal progenitor. In this paper, we show how to quantify the number of luminal progenitor cells as well as other epithelial subtypes in breast tissue samples using DNA and RNA based measurements. We find elevated levels of cells which resemble these hormone receptor negative luminal progenitor cells in breast tumour biopsies of hormone receptor negative cancers, as well as in healthy breast tissue samples from BRCA1 (FANCS) mutation carriers. We also find that breast tumours from carriers of heterozygous mutations in non-BRCA Fanconi Anaemia pathway genes are much more likely to be hormone receptor negative. These findings have implications for understanding hormone receptor negative breast cancers, and for breast cancer screening in carriers of heterozygous mutations of Fanconi Anaemia pathway genes.

Breast cancer surveillance following ovarian cancer in BRCA mutation carriers

ObjectivesBRCA 1 or 2 mutation carriers have increased risk of developing breast cancer (BC) and serous epithelial ovarian cancer (EOC). The incidence of BC over time after EOC is unknown. Optimal BC surveillance for BRCA mutation carriers following EOC has not been defined. MethodsA multi-institutional retrospective chart review was performed. Patients with BRCA -associated EOC diagnosed between 1996 and 2016 were followed for an average of 80 months. Women with previous bilateral mastectomy were excluded; women with prior BC and an intact breast were included. Descriptive statistics, Chi Square, and univariate survival analysis were performed. Results184 patients with BRCA -associated EOC were identified. Eighteen (10%) were diagnosed with BC a median of 48 months following EOC. Two (1%) with prior BC developed contralateral BC and 16 (9%) developed primary BC. The majority of BC (55%) was diagnosed 3 years following EOC. The 3-, 5- and 10-year incidence of BC was 5.6%, 9.5% and 33.3%. Annual mammography was performed in 43% and MRI in 34%. Twenty-eight (15%) women underwent risk-reducing mastectomy (RRM). There was no statistically significant difference in BC screening between women with, and without, a prior BC. BC was most commonly detected on mammogram. Three (17%) women had occult BC at the time of RRM. Nine (50%) had DCIS, and 8 (44%) had stage I/II BC. Median 5- and 10-year survival was 68% and 43% and was comparable between groups. ConclusionsTen percent of women developed BC after EOC. The incidence of BC following EOC in BRCA carriers increases over time, and surveillance is recommended given their enhanced survival of EOC. Timely genetic testing for women with EOC is imperative to better triage BC screening resources and treatment.

Comparing breast cancer imaging characteristics of CHEK2 with BRCA1 and BRCA2 gene mutation carriers

PurposeBreast cancer gene (BRCA) 1 and 2 mutations are frequently studied gene mutations (GM); the incidence of checkpoint kinase 2 (CHEK2) is increasing.We describe the imaging features of breast cancer (BC) in CHEK2 mutations, compared to BRCA 1 and 2 using mammography, ultrasound (US) and magnetic resonance imaging (MRI). MethodInclusion criteria were primary BC in GM carriers, treated in the same hospital. Age at diagnosis, histology, hormone receptor and human epidermal growth factor receptor 2 (HER2) status were retrieved. Mammography descriptors were mass, asymmetry and suspicious microcalcifications. The enhancement pattern (MRI), shape and border, architectural distortion, the presence of a hyperechoic rim and cystic complex structure (US) were documented. Analyses were performed using SAS software (version 9.4). Fishers' exact test was used to test associations between two categorical variables. ResultsIn 191 women, 233 malignant lesions were diagnosed (78 in BRCA1, 109 in BRCA2, 46 in CHEK2). In CHEK2 carriers, mammographically, suspicious microcalcifications (54%) were more prevalent (BRCA2 (48%) and BRCA1 carriers (33%)) (p-value = 0.057) compared to mass lesions (35%). On US, lesions were most frequently ill-defined (86%) (p = 0.579) and irregular (94.5%) (p = 0.098) compared to BRCA2 (77% and 80% resp.) and BRCA1 carriers (71% and 72% resp.). On MRI, mass lesions showed a type 3 curve in CHEK2 (67%) compared to BRCA1 (36%) and BRCA2 (50%) (p = 0.056). ConclusionsMalignant radiological characteristics of breast cancer, more specifically suspicious microcalcifications, were more frequently seen in CHEK2 and BRCA2 compared to BRCA1 mutation carriers (without a significant difference) indicating the importance of mammography in follow-up of CHEK2 carriers.

Cost–utility analysis of risk-reducing strategies to prevent breast and ovarian cancer in BRCA-mutation carriers in Switzerland

ObjectiveWe aimed to identify the most cost-effective of all prophylactic measures available in Switzerland for women not yet affected by breast and ovarian cancer who tested positive for a BRCA1/2 mutation.MethodsProphylactic bilateral mastectomy (PBM), salpingo-oophorectomy (PBSO), combined PBM&PBSO and chemoprevention (CP) initiated at age 40 years were compared with intensified surveillance (IS). A Markov model with a life-long time horizon was developed from the perspective of the Swiss healthcare system using mainly literature-derived data to evaluate costs, quality-adjusted life years (QALYs) and survival. Costs and QALYs were discounted by 3% per year. Robustness of the results was tested with deterministic and probabilistic sensitivity analyses.ResultsAll prophylactic measures were found to be cost-saving with an increase in QALYs and life years (LYs) compared to IS. PBM&PBSO were found to be most cost-effective and dominated all other strategies in women with a BRCA1 or BRCA2 mutation. Lifetime costs averaged to 141,293 EUR and 14.5 QALYs per woman with a BRCA1 mutation under IS, versus 76,639 EUR and 19.2 QALYs for PBM&PBSO. Corresponding results for IS per woman with a BRCA2 mutation were 102,245 EUR and 15.5 QALYs, versus 60,770 EUR and 19.9 QALYs for PBM&PBSO. The results were found to be robust in sensitivity analysis; no change in the dominant strategy for either BRCA-mutation was observed.ConclusionAll more invasive strategies were found to increase life expectancy and quality of life of women with a BRCA1 or BRCA2 mutation and were cost-saving for the Swiss healthcare system compared to IS.

Matched cohort study of germline BRCA mutation carriers with triple negative breast cancer in brightness

In the BrighTNess trial, carboplatin added to neoadjuvant chemotherapy (NAC) was associated with increased pathologic complete response (pCR) rates in patients with stage II/III triple-negative breast cancer (TNBC). In this matched cohort study, cases with a germline BRCA1/2 mutation (gBRCA; n = 75) were matched 1:2 with non-gBRCA controls (n = 150) by treatment arm, lymph node status, and age to evaluate pCR rates and association of benefit from platinum/PARP inhibitors with validated RNA expression-based immune, proliferation, and genomic instability scores among gBRCA with the addition of carboplatin ± veliparib to NAC. Among the well-matched cohorts, odds of pCR were not higher in gBRCA cancers who received standard NAC with carboplatin (OR 0.24, 95% CI [0.04-1.24], p = 0.09) or with carboplatin/veliparib (OR 0.44, 95% CI [0.10-1.84], p = 0.26) compared to non-gBRCA cancers. Higher PAM50 proliferation, GeparSixto immune, and CIN70 genomic instability scores were each associated with higher pCR rate in the overall cohort, but not specifically in gBRCA cases. In this study, gBRCA carriers did not have higher odds of pCR than non-gBRCA controls when carboplatin ± veliparib was added to NAC, and showed no significant differences in molecular, immune, chromosomal instability, or proliferation gene expression metrics.

Creating Breast and Gynecologic Cancer Guidelines for Transgender Patients With BRCA Mutations.

More than 1.5 million individuals in the United States identify as transgender. Transgender individuals have lower rates of health care utilization and higher rates of health care discrimination than cisgender patients. With a growing interest in providing comprehensive and compassionate care to the transgender community, there has been a concurrent increase in research on transgender health. However, lack of long-term data limits understanding the effects of hormone therapy on cancer risk factors in this population. This is particularly relevant for patients with hormonally mediated cancers and those at elevated risk from hereditary breast and ovarian cancer syndromes. Few cancer-screening and management guidelines currently exist for this population. Specific practices guided by the nuances of gender identity and gender-affirming care are essential to improve clinical management and to avoid further alienating a population that is already marginalized from the health care system. This commentary summarizes screening, management, and surveillance strategies devised for cisgender patients to offer corresponding recommendations tailored for transgender BRCA mutation carriers. In doing so, it highlights critical unanswered questions pertaining to the care of these patients. To address these questions, we must prioritize this population and adopt more inclusive frameworks in medicine and research.