Breast Cancer Research

Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction

Los olvidados: Non-BRCA variants associated with Hereditary breast cancer in Mexican population

Abstract Background Hereditary predisposition to breast and ovarian cancer syndrome (HBOC) is a pathological condition with increased cancer risk, including breast (BC), ovarian cancer (OC), and others. HBOC pathogenesis is caused mainly by germline pathogenic variants (GPV) in BRCA1 and BRCA2 genes. However, other relevant genes are related to this syndrome diagnosis, prognosis, and treatment, including TP53 , PALB2 , CHEK2 , ATM , etc. This study aimed to identify the prevalence of non- BRCA genes in HBOC patients of Northeast Mexico. Methods This multicentric study included 1285 patients with HBOC diagnosis from four oncologic centers in northeast Mexico from 2016 to 2023. Genomic and clinical data were analyzed based on multi-gene panel results and electronic records of the medical geneticist consultation. For the data analysis of qualitative and quantitative variants, JASP statistical software (version 0.18.1) was used, taking p < 0.05 as a significant result. Results We found that 32.7% of the patients had at least one GPV in non- BRCA genes. The five most frequent non- BRCA genes were CHEK2 , PALB2 , MUTYH , CDKN2A , and ATM . Among the group of non- BRCA genes, six are involved in the homologous repair pathway (HR), and three are related to DNA damage repair (DDR) pathways. In analyzing GPVs in molecular pathways, both have similar frequencies with no statistical difference for BC. Conclusion Multi-gene testing implementation improves the detection of often overlooked genes related to HBOC pathogenesis and treatment. Non- BRCA GPVs in Northern Mexico correspond to one-third of the HBOC cases, including HR and DDR pathways genes that would be misdiagnosed if not tested. HR patient carriers are potential targets of iPARP therapies. The optimal approach to cancer treatment for non- BRCA mutation carriers warrants further investigation to develop newer therapies.

Prediction of menstrual recovery patterns in premenopausal women with breast cancer taking tamoxifen after chemotherapy: an ASTRRA Substudy

Safety and efficacy of topical testosterone in breast cancer patients receiving ovarian suppression and aromatase inhibitor therapy

Abstract Background Premenopausal, high-risk, hormone receptor-positive breast cancer patients are often treated with ovarian suppression in combination with aromatase inhibitors (AI). This combination has important adverse effects, particularly in sexual function, such as vaginal dryness and loss of libido. There is no effective therapy for reduced sexual function in this setting. Our study aimed to determine the efficacy and safety, particularly regarding sexual function, of a low-dose, topical testosterone gel administration. Methods This is a pilot, single-center study, designed to evaluate the efficacy of topical testosterone gel (3 mg/day) in improving sexual function in 29 premenopausal patients on ovarian suppression in combination with an AI. The primary safety endpoint was to assess serum estradiol elevation. The primary efficacy endpoint was sexual function improvement, assessed by the Female Sexual Function Index questionnaire. Results We report the results on 29 patients. Twenty-two patients (75%) completed the 3-month treatment, and seven discontinued treatment before completion, mostly due to logistical difficulties related to the COVID-19 pandemic. All patients maintained the value of baseline mass spectrometry assay for estradiol of less than 2.7 pg/mL during the undertaken measurements. We observed a significant improvement in Female Sexual Function Index measures over the visits, with an increase from a mean of 11.7 at baseline to 19.1 in the third month ( p  < 0.001), with the greatest improvement observed between the second and third months. Conclusions Our findings suggest that topical testosterone seems to be safe and may be effective in improving sexual function in patients on ovarian suppression and AI. Trial registration The project was submitted and approved through the hospital’s SGPP platform in 11/26/2019 (Project No. SGPP 393819) and CAAE (Research Ethics Committee) (CAAE No 25609719.5.0000.007).

Functional characterization of BRCA1 variants of unknown significance using homologous recombination repair assays

Inherited mutations in BRCA1 are among the primary causes of hereditary breast and ovarian cancer (HBOC). Genetic testing has identified numerous pathogenic and benign mutations in BRCA1, but also thousands of variants of uncertain significance (VUS) with unclear functional consequences. Accurate cancer risk prediction for carriers of these VUS requires functional assays to assess their pathogenicity. In this study, we analyzed 16 BRCA1 VUS detected at the Hereditary Cancer Genetic Counseling Laboratory in Salamanca, Spain, with the goal of providing additional data to guide their reclassification. Since homologous recombination (HR) is the primary tumor-suppressive function of BRCA1, we employed two complementary HR repair assays to evaluate HR efficiency. The first, an already established assay, uses a HeLa-DR cell line harboring an HR reporter cassette and involves silencing endogenous BRCA1 followed by complementation with the VUS under study. The second, developed in this work, is also based in complementation assays that restore the green fluorescence protein (GFP) gene, and employs a breast cancer cell line with a similar HR reporter system (HCC1937-HR) that lacks BRCA1 expression, allowing direct complementation. Both assays consistently identified five VUS (p.V11G, p.H888Y, p.G1201S, p.Q1395R, and p.F1734L) as pathogenic due to significantly reduced HR efficiency, whereas the remaining 11 VUS were benign in terms of HR function. Notably, two pathogenic variants (p.H888Y, p.G1201S) were located outside the known functional domains of BRCA1. The five HR-deficient variants were further evaluated for their sensitivity to ionizing radiation, which confirmed the deleterious impact on DNA repair for variants p.V11G, p.H888Y, p.G1201S and p.F1734L. Sensitivity to the PARP inhibitor olaparib revealed hypersensitivity only in cells expressing p.V11G and p.F1734L, suggesting variant-specific mechanistic effects with potential therapeutic relevance. In conclusion, recombination-based functional assays complemented with sensitivity assays are effective tools for assessing the pathogenicity of BRCA1 VUS and can provide valuable information to support clinical decision-making. We propose that these assays can be completed within a timeframe compatible with clinical needs, offering critical insights for genetic counseling and personalized treatment strategies.

Characterization of ESR1 alterations in patients with breast and gynecologic cancers

Abstract Background ESR1 alterations present a common mechanism of resistance to endocrine therapy (ET) in hormonally driven tumors. The clinical significance of these alterations continues to evolve with newly approved targeted therapies and a range of ongoing investigational trials. Methods A retrospective study of 2574 breast cancer (BC) and 1110 gynecologic cancer samples that underwent whole exome and whole transcriptome profiling was conducted to assess the distribution of ESR1 and associated co-alterations in local (primary breast or regional lymph node) versus metastatic BC samples and in the major BC subtypes. Prior treatment history was unknown. Results ESR1 alterations were present in 6.2% (n = 159/2574) of BC samples and 3.4% (n = 38/1110) of gynecologic cancer samples. In HR + /HER2- BC, ESR1 alterations overall and ESR1 missense mutations were more frequent in samples from metastatic compared to local/regional sites (overall: n = 86/321 (26.8%) and n = 53/1427 (3.7%), respectively ( P  < 0.001); missense: n = 72/321 (22.4%) and n = 20/1427 (1.4%), respectively ( P  < 0.001)). Whole transcriptome sequencing detected ESR1 fusion genes in 2.1% (n = 55/2574) of BC samples and in 1.9% (n = 21/1110) of gynecologic cancer samples, and CCDC170 was the most common fusion partner in both cancer types. In HR + /HER2- BC, ESR1 fusions were more common in metastatic samples compared to local/regional (n = 17/321 (5.3%) and n = 29/1427 (2.0%), respectively; P  < 0.001). Evaluation of 21 therapeutically actionable biomarkers identified co-alterations enriched in ESR1 -altered HR + /HER2- BC, including FGF3/4/19 and CCND1 amplifications. No significant co-alterations were found in gynecologic cancer samples. Conclusions ESR1 alterations were most frequent in HR + /HER2- BC samples and missense mutations were more frequent in metastatic samples, consistent with their role in ET resistance and disease progression. ESR1 alterations co-occurred with therapeutically relevant alterations in other genes that may help inform clinical decision-making. Gynecologic tumors harbored ESR1 alterations that have prognostic and potentially therapeutic relevance.

Plasma metabolomics profiles and breast cancer risk

Distribution of age at natural menopause, age at menarche, menstrual cycle length, height and BMI in BRCA1 and BRCA2 pathogenic variant carriers and non-carriers: results from EMBRACE

Abstract Background Carriers of germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes are at higher risk of developing breast and ovarian cancer than the general population. It is unclear if these PVs influence other breast or ovarian cancer risk factors, including age at menopause (ANM), age at menarche (AAM), menstrual cycle length, BMI or height. There is a biological rationale for associations between BRCA1 and BRCA2 PVs and reproductive traits, for example involving DNA damage and repair mechanisms. The evidence for or against such associations is limited. Methods We used data on 3,046 BRCA1 and 3,264 BRCA2 PV carriers, and 2,857 non-carrier female relatives of PV carriers from the Epidemiological Study of Familial Breast Cancer (EMBRACE). Associations between ANM and PV carrier status was evaluated using linear regression models allowing for censoring. AAM, menstrual cycle length, BMI, and height in carriers and non-carriers were compared using linear and multinomial logistic regression. Analyses were adjusted for potential confounders, and weighted analyses carried out to account for non-random sampling with respect to cancer status. Results No statistically significant difference in ANM between carriers and non-carriers was observed in analyses accounting for censoring. Linear regression effect sizes for ANM were -0.002 (95%CI: -0.401, 0.397) and -0.172 (95%CI: -0.531, 0.188), for BRCA1 and BRCA2 PV carriers respectively, compared with non-carrier women. The distributions of AAM, menstrual cycle length and BMI were similar between PV carriers and non-carriers, but BRCA1 PV carriers were slightly taller on average than non-carriers (0.5 cm difference, p  = 0.003). Conclusion Information on the distribution of cancer risk factors in PV carriers is needed for incorporating these factors into multifactorial cancer risk prediction algorithms. Contrary to previous reports, we found no evidence that BRCA1 or BRCA2 PV are associated with hormonal or anthropometric factors, except for a weak association with height. We highlight methodological considerations and data limitations inherent in studies aiming to address this question.

Longitudinal history of mammographic breast density and breast cancer risk by familial risk, menopausal status, and initial mammographic density level in a high risk cohort: a nested case–control study

Evaluation and management of incomplete ovarian function suppression in premenopausal breast cancer patients receiving anti-hormone therapy

Cold-inducible RNA-binding protein is associated with subtype-specific breast cancer patient outcomes

TMEM120B strengthens breast cancer cell stemness and accelerates chemotherapy resistance via β1-integrin/FAK-TAZ-mTOR signaling axis by binding to MYH9

Abstract Background Breast cancer stem cell (CSC) expansion results in tumor progression and chemoresistance; however, the modulation of CSC pluripotency remains unexplored. Transmembrane protein 120B (TMEM120B) is a newly discovered protein expressed in human tissues, especially in malignant tissues; however, its role in CSC expansion has not been studied. This study aimed to determine the role of TMEM120B in transcriptional coactivator with PDZ-binding motif (TAZ)-mediated CSC expansion and chemotherapy resistance. Methods Both bioinformatics analysis and immunohistochemistry assays were performed to examine expression patterns of TMEM120B in lung, breast, gastric, colon, and ovarian cancers. Clinicopathological factors and overall survival were also evaluated. Next, colony formation assay, MTT assay, EdU assay, transwell assay, wound healing assay, flow cytometric analysis, sphere formation assay, western blotting analysis, mouse xenograft model analysis, RNA-sequencing assay, immunofluorescence assay, and reverse transcriptase-polymerase chain reaction were performed to investigate the effect of TMEM120B interaction on proliferation, invasion, stemness, chemotherapy sensitivity, and integrin/FAK/TAZ/mTOR activation. Further, liquid chromatography–tandem mass spectrometry analysis, GST pull-down assay, and immunoprecipitation assays were performed to evaluate the interactions between TMEM120B, myosin heavy chain 9 (MYH9), and CUL9. Results TMEM120B expression was elevated in lung, breast, gastric, colon, and ovarian cancers. TMEM120B expression positively correlated with advanced TNM stage, lymph node metastasis, and poor prognosis. Overexpression of TMEM120B promoted breast cancer cell proliferation, invasion, and stemness by activating TAZ-mTOR signaling. TMEM120B directly bound to the coil-coil domain of MYH9, which accelerated the assembly of focal adhesions (FAs) and facilitated the translocation of TAZ. Furthermore, TMEM120B stabilized MYH9 by preventing its degradation by CUL9 in a ubiquitin-dependent manner. Overexpression of TMEM120B enhanced resistance to docetaxel and doxorubicin. Conversely, overexpression of TMEM120B-∆CCD delayed the formation of FAs, suppressed TAZ-mTOR signaling, and abrogated chemotherapy resistance. TMEM120B expression was elevated in breast cancer patients with poor treatment outcomes (Miller/Payne grades 1–2) than in those with better outcomes (Miller/Payne grades 3–5). Conclusions Our study reveals that TMEM120B bound to and stabilized MYH9 by preventing its degradation. This interaction activated the β1-integrin/FAK-TAZ-mTOR signaling axis, maintaining stemness and accelerating chemotherapy resistance.