Search Results (113)

Background/Objectives: Assigned female at birth (AFAB) individuals who identify as transgender or gender-diverse (TGD) with concurrent breast cancer or high-risk genetic mutations represent a unique population, requiring consideration of oncologic and aesthetic goals. These patients sought chest masculinization with oncologic gender-affirming mastectomy (OGAM) or non-binary reconstruction to alleviate gender dysphoria and treat their breast cancer. There is limited literature on surgical techniques in this patient population. Methods: A retrospective chart review of AFAB TGD adults (>18 years of age) who underwent OGAM or non-binary reconstruction at the University of Washington between 2019 and 2023 was conducted. All patients had a consultation with a plastic surgeon for reconstruction and a minimum of one year follow-up. Demographic data, oncologic status, post-operative complications, and revision surgical history were collected. Results: Eight AFAB TGD individuals met the inclusion criteria. The mean age at the time of mastectomy was 35.13 years (SD = 8.04), and the mean BMI was 29.88 (SD = 6.40). Indications for mastectomy included a breast cancer diagnosis (N = 4) or a strong family history of breast cancer or genetic predisposition (N = 4). Two (25%) patients underwent nipple-sparing mastectomies (NSM), two patients (25%) underwent skin-sparing mastectomy with Goldilocks reconstruction, and four patients (50%) underwent simple mastectomy (oncologic gender-affirming mastectomy), flat closure with free nipple graft (FNG). Two patients had staged nipple mastectomy with secondary nipple reduction and fat grafting. Six patients had immediate reconstruction, four (50%) patients underwent immediate double-incision OGAM with FNG, and two (25%) patients underwent Goldilocks procedures—one with and one without FNG. One patient (12.5%) experienced a surgical site infection, and three patients (37.5%) underwent revision surgery. No patients had positive margins following their mastectomy. Conclusions: This case series highlights the importance of a multidisciplinary and highly personalized approach for AFAB and TGD individuals undergoing oncologic gender-affirming mastectomy or non-binary reconstruction. We reviewed reconstructive options performed at our institution, demonstrating safe oncologic and reconstructive techniques that emphasized collaboration between breast and plastic surgeons. Full article

Background: Heritable breast cancer (BC) predisposition is strongly influenced by high-penetrance genes such as BRCA1 and BRCA2, but many moderate- and low-penetrance genes remain poorly characterized. Although over 100 loci have been reported, the causal genes often include false positives or uncertain associations. Methods: We applied a gene-centric, integrative approach to multi-ethnic genomic datasets, including the UK Biobank (UKB) and FinnGen (FG). We assessed consistency across multiple GWAS in Open Targets (OT) and additional complementary genetic association approaches, including ExPheWAS, TWAS, and PWAS. Collapsing variant-level effects to a gene-level view enhanced confidence and reaffirmed contributions from genes such as BRCA1, BRCA2, PALB2, CHEK2, and other DNA repair genes. Results: Using this integrative framework, we identified 38 high-confidence BC predisposition genes, including 8 previously reported drivers, 13 supported by multiple lines of evidence, and additional candidates (e.g., APOBEC3A, TNS1, PEX14) with emerging evidence. PWAS revealed several genes with potential recessive effects often missed by standard GWAS. Multi-cohort replication showed robust findings in European ancestry populations, while transferability to other populations was more limited. Conclusions: This work demonstrates the value of a gene-centric, integrative framework for prioritizing high-confidence BC predisposition genes, highlighting associated cellular pathways, and uncovering new candidates for further functional study, providing a reliable foundation for future research. Full article

Background/Objectives: Women who have genetic predisposition to breast cancer often opt for risk-reducing mastectomy with immediate reconstruction. Evaluating their satisfaction and quality of life is essential for guiding shared decision-making. Methods: This exploratory study assessed quality-of-life outcomes in two cohorts of patients undergoing bilateral prophylactic nipple-sparing mastectomy with immediate prepectoral implant-based reconstruction. Only patients without postoperative complications (necrosis, infection) were included. Each patient completed the BREAST-Q questionnaire both preoperatively (1–2 days before surgery) and postoperatively. Results: Postoperative BREAST-Q scores demonstrated significant improvement, with self-confidence increasing from 40.75 to 44.33, satisfaction with breast size and appearance from 50.42 to 58.50, and general esthetic/functional satisfaction from 26.92 to 33.17 (all p < 0.01). In contrast, physical comfort decreased from 48.00 to 32.42 (p < 0.001). Preoperative responses may have been influenced by anticipatory stress related to the imminent surgery and concern regarding the breast area to be operated. In contrast, postoperative results reflect psychological relief and satisfaction following a successful surgery, with no complications. Conclusions: Nipple-sparing mastectomy with immediate prepectoral reconstruction is associated with high patient-reported satisfaction and perceived improvements in quality of life, particularly regarding body image and emotional well-being. However, functional limitations such as reduced physical comfort should also be acknowledged. These findings further support evidence-based recommendations for prophylactic surgery in high-risk patients. Full article

Background: Breast cancer (BC) is the most common malignancy among women, and genetic predisposition plays a critical role in its development. Among DNA mismatch repair (MMR) genes, MLH1 is essential for maintaining genomic stability, and promoter variants may influence its transcriptional regulation. Variants in MMR genes, including MLH1, have been implicated in cancer susceptibility; however, evidence regarding the promoter polymorphism −93G>A (rs1800734) and its association with BC remains limited and inconsistent across populations. Methods: We conducted a case–control study of 143 breast cancer patients and 161 cancer-free controls of Azerbaijani origin. Genotyping of MLH1 −93G>A was performed using PCR-RFLP and validated by next-generation sequencing (NGS). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under different genetic models by logistic regression, followed by false discovery rate (FDR) correction for multiple testing. Results: The genotype distribution among patients was 25.9% GG, 58.7% GA, and 15.4% AA, compared with 37.9%, 46.6%, and 15.5% in controls. A significant association was observed between the GA genotype and BC risk (OR = 1.855, 95% CI: 1.104–3.085, p = 0.019). In the dominant model (GA + AA vs. GG), carriers of the A allele showed increased breast cancer risk (OR = 1.747, 95% CI: 1.069–2.856, p = 0.026). Genotype distribution was also associated with tumor grade (p = 0.047) and stage (p = 0.013). However, none of the associations remained significant after FDR adjustment. Conclusions: This pilot study provides the first evidence from Azerbaijan suggesting a potential role of the MLH1 −93G>A variant in breast cancer susceptibility. Although the associations were nominal and require validation in larger cohorts, the findings point to a biologically plausible link between MLH1 promoter variation and impaired MMR activity, which may contribute to polygenic breast cancer risk. These preliminary results emphasize the importance of evaluating MMR gene variants in underrepresented populations and support further studies integrating functional assays and broader gene coverage. Full article

Hereditary breast and ovarian cancer (HBOC) syndrome accounts for 5–10% of all breast and ovarian cancers, with BRCA1 and BRCA2 pathogenic variants being the most common genetic alterations. However, additional genes such as BARD1, whose protein product interacts with BRCA1 via its N-terminal RING domain, have been implicated as low-penetrance contributors to cancer risk. This study aimed to investigate the frequency and distribution of the BARD1 variant c.1518_1519delinsCA (p.Val507Met) in a cohort of 920 patients undergoing genetic testing for hereditary cancer predisposition. Next Generation Sequencing (NGS) was performed using a 28-gene panel, and allelic frequencies of BARD1 were analyzed. Among 920 patients, 159 (17.28%) were pure heterozygous for the c.1518_1519delinsCA variant. Notably, c.1519G>A was never observed without c.1518T>C, suggesting a strong linkage between the two variants. The allele frequencies observed (34.51% for A at c.1519 and 77.88% for C at c.1518) challenge current reference genome expectations. Data from the ALFA database confirmed that these frequencies are consistent with population-level variation, not sample bias. Our findings raise the hypothesis that the reference allele at position c.1518 may not reflect the true wild-type sequence. While both c.1518T>C and c.1519G>A are individually classified as benign, their combined occurrence as a dinucleotide substitution (c.1518_1519delinsCA) warrants further investigation. These results underscore the importance of accurate variant annotation and population-specific frequency data for clinical interpretation of NGS findings. Although BARD1 remains a low-frequency contributor to HBOC compared to BRCA1/2, its inclusion in multigene panels is supported by the potential relevance of such complex variants. Full article

Breast cancer associated with BRCA1 and BRCA2 mutations presents unique therapeutic challenges, traditionally favoring mastectomy due to concerns over recurrence and new primaries. However, evolving evidence and advances in multimodal therapy have reshaped this paradigm, positioning breast-conserving surgery (BCS) as a viable option for selected carriers. This narrative review synthesizes current data from meta-analyses, retrospective cohorts, and pivotal studies, including a multicenter analysis which affirmed oncologic equivalence between BCS and mastectomy when combined with radiotherapy and systemic therapy. While meta-analyses confirm higher local events following BCS, survival remains comparable, indicating that recurrence reflects genetic predisposition rather than surgical inadequacy. Optimized systemic treatments, including chemotherapy, endocrine therapy, risk-reducing salpingo-oophorectomy, and PARP inhibitors, further mitigate recurrence risk. Meanwhile, patient-centered outcomes favor BCS: studies consistently link it to improved body image, psychosocial well-being, and quality of life, especially for younger BRCA carriers. Fertility-preserving options remain viable, with evidence supporting the safety of pregnancy, breastfeeding, and assisted reproductive technologies in BRCA-mutated survivors. These findings support individualized surgical planning for BRCA carriers within multidisciplinary care, balancing oncologic safety, systemic strategies, and psychosocial priorities. BCS should be considered a standard option for well-selected patients in hereditary breast cancer management. Full article

Breast cancer affects women at an increasingly younger age, with genetic predispositions and other factors contributing to its second-highest cancer mortality rate. The diversity of pharmacological treatment stems from its heterogeneity, which favors a more precise approach to each subtype. Despite the extensive advances in medicine in recent decades, the problem of treating cancer patients remains significant. The problem with modern therapeutic methods is low effectiveness, emerging side effects, difficulty in eliminating all cancer cells, and the quite common use of monotherapy and the associated drug resistance, which may lead to disease progression. The aim of this review is to present the latest therapeutic strategies (combination therapies) used in the treatment of breast cancer. PubMed databases and clinical data from ClinicalTrials.gov were used for this purpose. The review included characteristics of the latest clinical trials from the last year (2024–2025), which present currently recruiting studies of breast cancer treatment with immunotherapy. The review also presented characteristics of clinical trials from the last 5 years (2020–2025) using nanoparticles as an adjunct to breast cancer treatment. Articles published between 2016 and August 2025 (excluding articles that describe the first use of a given drug) were included in the review. The review analyzed drugs targeting molecular targets, including intracellular pathways responsible for cell cycle regulation, as well as new directions such as nanotechnology in treatment breast cancer. Full article

Background/Objectives: Male breast cancer (MBC) is a rare malignancy representing less than 1% of all breast cancer cases, with rising incidence worldwide. Current treatment strategies largely rely on extrapolation from female breast cancer, despite clear biological and clinical distinctions. This review aims to summarize current knowledge on non-metastatic MBC, with a particular focus on genetic predisposition, tumor biology, and recent therapeutic advances. Methods: A systematic literature search was conducted using PubMed and PMC databases to identify clinical trials, observational studies and systematic reviews related to MBC published up to 1st June, 2025. Studies were selected for their relevance to genetic and molecular features, as well as treatment outcomes in non-metastatic disease. Results: Fifty-one studies were included in the review. Findings confirm the predominance of hormone receptor–positive tumors in MBC and underscore the central role of BRCA2 mutations. Germline mutations in BRCA2 and BRCA1 were reported in approximately 1 and 2% of male cases, respectively. Additional germline alterations were identified in PALB2, CHEK2, and other DNA repair genes. Comparative analyses of surgical approaches showed no significant difference in survival between breast-conserving surgery and mastectomy. Postmastectomy radiotherapy improved overall survival compared to surgery alone. Adjuvant tamoxifen therapy was independently associated with significant survival benefits, although adherence remains a challenge. Conclusions: MBC is a biologically distinct and molecularly heterogeneous disease. Breast-conserving surgery appears safe and effective in selected patients. Adjuvant radiotherapy and tamoxifen confer clear survival advantages. The lack of male-specific clinical trials remains a major limitation in optimizing evidence-based care for MBC. Full article

Background: The national guidelines, informed by evidence from the National Institutes of Health (NIH), define the criteria for genetic testing of BRCA1/2 and other genes associated with Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS). When a germline pathogenic variant (PV) is identified in an index case, clinical recommendations advise informing at-risk relatives about the availability of predictive genetic testing, as early identification of carriers allows for timely implementation of preventive measures. Methods: This retrospective observational study examined data collected between 2017 and 2024 at the Medical Genetics Unit of the “Renato Dulbecco” University Hospital in Catanzaro, Italy. The analysis focused on trends in the identification of individuals carrying PVs in cancer predisposition genes (CPGs) and the subsequent uptake of cascade genetic testing (CGT) among their family members. Results: Over the study period, from 116 probands were performed 257 CGTs on 251 relatives. A notable reduction of approximately ten years in median age was observed, 39% were found to carry familial mutation and were referred to personalized cancer prevention programs. Among these, 62% accessed Oncological Genetic Counselling (CGO) within one year of the proband’s diagnosis, suggesting effective communication and outreach. Conclusions: The findings highlight the critical role of effective CGO and intrafamilial communication in hereditary cancer prevention. The identification of PVs, followed by timely CGTs and implementation of preventive strategies, significantly contributes to early cancer risk management. Periodic monitoring of CGT uptake and outcome trends, as demonstrated in this study, is essential to refine and optimize genetic services and public health strategies. Full article

Cardiotoxicity is a leading cause of mortality in the growing populations of elderly breast cancer (BC) patients. Breast cancer treatment in the elderly is highly challenging due to its heterogeneous nature and the lack of specific evidence, as this population is usually underrepresented in randomized clinical trials. Decision making requires a comprehensive approach, considering the type and stage of BC, the patient’s overall health status, life expectancy, geriatric and frailty assessment, the risk of cancer recurrence, comorbidities, cardiotoxicity risk, and the patient’s preferences. The cardiotoxic effects of BC treatments cover the whole spectrum of cardiovascular diseases: heart failure, hypertension, arrhythmias, and myocardial ischemia. Cardiotoxicity risk in these patients is defined by several factors: anticancer therapies, polypharmacy, established cardiovascular disease, comorbidities, frailty, cellular senescence, hormonal changes, and genetic predisposition. Preventive oncological and cardio-oncological strategies, as well as patients’ education, are critical for improved outcomes. Prospective clinical trials in this population are urgently needed. Full article

Background: Gene variants of unknown significance (VUSs) present a challenge in genetic counselling. The primary aim of this study was to describe the spectrum of genetic findings in a cohort of 5923 Danish patients with suspected predisposition to hereditary breast and/or ovarian cancer, with a focus on classifying gene variants and investigating their distribution. Methods: The gene variants were classified using the American College of Medical Genetics (ACMG) guidelines as well as gene-specific guidelines where applicable. The identified VUSs were further examined through association analysis, comparison of the frequencies in this Danish population to those in the Swedish population using gnomAD 2.1, and splice analysis using RNA sequencing. Results: Of 167 variants that were clinically classified as VUSs prior to this research study, 38 (22.8%) were either up- or downgraded based on the guidelines that were used. We found that 630 patients (10.6%) carried a likely pathogenic or pathogenic variant, mainly in BRCA1 (31.9%) and BRCA2 (26.0%). VUSs were carried by 1606 (27.1%) patients, mainly in BARD1 (27.6%) and ATM (19.3%). Our association study assigned criteria for 10 gene variants, while our splice analysis assigned criteria for 3 gene variants but did not reclassify the variants. Conclusions: A total of 22.8% of the 167 variants that were observed in this study and which were previously classified as VUSs in a clinical setting were reclassified in this study. In total, 10.6% of the patients with a suspected predisposition to hereditary breast and/or ovarian cancer carried a likely pathogenic or pathogenic variant. The high incidence of VUSs observed in this study reflects the challenges faced in the daily clinical setting. Full article

Pathogenic variants in breast cancer predisposition genes are associated with poor clinical outcomes but also offer an opportunity for more individualized therapeutic pathways. Given increasing knowledge, improvements in germline genetic testing efficiency, and the availability of novel systemic targeted treatment options, the importance of appropriately identifying patients for testing has never been greater. A pan-Canadian expert working group (EWG) consisting of 10 healthcare professionals (HCPs) was convened to review recent international guidelines for germline genetic testing in breast cancer and develop Canadian recommendations. The group identified four clinical questions to address which patients should undergo testing, what approaches should be used, how patients should be counselled, and what steps are needed for implementation. In response to these questions, the EWG agreed upon 12 recommendations that emphasized broader incorporation of germline genetic testing and more standardized, streamlined testing and counselling approaches. The group also offered multiple suggestions to support effective and equitable implementation across Canada. These recommendations provide guidance for HCPs and represent a call to action for the Canadian government and other organizations to support genetic testing pathways, drug access, and ultimately improved outcomes for patients with breast cancer and their families. Full article

Breast cancer is the most common cancer in women worldwide. Anthracyclines (doxorubicin, epirubicin, daunorubicin, idarubicin) are among the most used drugs for the treatment of breast cancer. Unfortunately, anthracyclines cause cardiotoxicity, which is a limiting factor for its use, and the lifetime cumulative dose of anthracyclines is the major risk factor for cardiotoxicity. In our study, we focused on acute and subacute heart damage. One of the main factors is a genetic predisposition, which determines individual susceptibility to anthracycline cardiotoxicity. The main idea of this study was, for the first time, to evaluate drug metabolism-related genes as a risk factor for developing cardiovascular toxicity in breast cancer patients. The main objective of our study was to identify the impact of drug metabolism-related gene SNPs on the development of subclinical heart damage during and/or after doxorubicin-based chemotherapy in breast cancer patients. The data of 81 women with breast cancer treated with doxorubicin-based chemotherapy in an outpatient clinic were analyzed, and SNP RT-PCR tests were performed. The drug metabolism-related gene variants SULT2B1 rs10426377, UGT1A6 rs17863783, CBR1 rs9024, CBR3 rs1056892, NCF4 rs1883112, and CYBA rs1049255 did not reach a statistically important impact on ABCC in multivariate logistic regression analysis. However, we identified that NCF4 rs1883112 had a risk reduction tendency for ABCC (OR = 0.49, 95% CI 0.27–0.87, p = 0.015). Our findings suggest that some SNPs, such as NCF4 rs1883112, may be associated with a reduced risk of cardiotoxicity, while no variants in this study showed a statistically significant increased risk. Even though, NCF4 rs1883112 showed a risk reduction tendency, suggesting the potential for personalized risk stratification. We can conclude that multiple genes are involved in ABCC, with different impacts, and it is unlikely that there is a single driver gene in ABCC pathogenesis. Full article

Background and Objectives: Despite the well-established role of the BRCA and mismatch repair (MMR) genes in DNA damage repair pathways, a substantial proportion of familial cancer cases still lack pathogenic variants in those genes. Next Generation Sequencing (NGS) panels have emerged as a powerful tool to identify hereditary cancer at-risk individuals and subsequently provide them with accurate management. Materials and Methods: Families harbouring PVs in RAD50, RAD51C, RAD51D, and BRIP1 were identified by analysing a cancer-predisposing genes panel using Ion S5 system technology. A retrospective cohort of 155 families tested only for the BRCAs of MMR genes were reanalysed, prompted by an increase in familial cases or new cancer diagnoses among index cases. Results: We identified 40 families through molecular reanalysis (33 with Hereditary Breast and Ovarian Cancer (HBOC) and 7 with Lynch Syndrome (LS)), with positive test results among 155 families lacking BRCA or MMR mutations. The most frequently mutated genes after ATM and CHEK2 were BRIP1, RAD51D, and RAD51C with 16, 13, and 9 positive families, respectively. The phenotype–genotype correlations not only revealed ovarian and HER-negative breast cancer predispositions but also other cancer types, particularly lung and gastric, and individuals with a second or third distinct cancer episode. Conclusions: Broader ranges of malignancies, including gastric, lung, and bladder, have been identified among BRIP1, RAD51D, and RAD51C positive families. The results generated using NGS provide a comprehensive genetic landscape in each patient that could explain the diversity of phenotypes shown in PV families that, combined with non-genetic factors, might enable accurate surveillance and personalized treatments. NGS reanalysis doubled our diagnostic yield and was a good strategy to identify hereditary cancer families that would otherwise be overlooked. Full article

Chemotherapy-induced neutropenia (CIN) and chemotherapy-induced alopecia (CIA) are significant toxicities affecting cancer patients. CIN is a potentially fatal complication of chemotherapy caused by myelosuppression and increased infection susceptibility, while CIA, although not fatal, severely affects treatment adherence and mental health. This study provides a comprehensive comparative analysis of CIN and CIA, focusing on patient, disease, treatment, and genetic risk factors. Key risk factors for CIN and CIA include age, poor performance status, body mass index (BMI), laboratory abnormalities, and pre-existing comorbidities. Both toxicities were significantly associated with breast cancer patients, although CIN patients were more likely to have hematological cancer, and CIA patients were more likely to have solid tumors. Notably, anthracyclines, alkylators, and taxanes frequently induce both toxicities, although their timelines and clinical implications differed. There was no clear overlap between genetic predispositions and toxicities beyond single-nucleotide polymorphisms (SNPs) in the ABCB1 gene. This is the first study to directly compare CIN and CIA, offering insights into personalized oncology care. Understanding the risk factors implicated in the development of CIN and CIA will enable physicians to manage patient outcomes. Full article