Investigating Male Breast Cancer Using Transcriptomics and Immunohistochemistry

Background: The rare nature of male breast cancer (MBC) has led to its management being guided by the extensive research conducted in the field of female breast cancer (FBC). The aim of this study was to evaluate MBC at both protein and molecular level to improve understanding of its pathology. Methodology: Immunohistochemistry analysis was performed in MBC (n=428) TMAs for 18 biomarkers (ERα, ERβ1, ERβ2, ERβ5, Total PR, AR, CK5/6, CK14, CK18, CK19, p53, Bcl-2, Her2, E-cadherin, Ki67, Survivin, Prolactin and FOXA1). The manual scoring of ERα and Ki67 was correlated with a fully automated immunohistochemistry image analysis system (ImmunoRatio™). Finally gene expression profiling (GEP) was undertaken in matched MBC (n=15) and FBC (n=10) samples. Results: There was poor 5 year overall survival (OS) in CK18 and CK19 negative patients (p= 0.05; p= 0.003), as well as poor 10 year OS in CK19 negative patients (p= 0.002). Age (p= 0.001) and nodal status (p= 0.04) was found to be independent predictors of OS at 5 years. There was significant correlations between manual and ImmunoRatio™ ERα (ρ= 0.872; p= 0.000) and Ki67 (r= 0.675; p= 0.000) scores. However due to a low measure of agreement it was not possible to validate Ki67 scoring using ImmunoRatio™. The functional enrichment analysis of GEP data using less stringent criteria (p < 0.05) identified 735 differentially expressed genes. The data analysis showed up-regulation of genes involved in ECM synthesis, degradation and re-modelling in MBC. The end product of one of the up-regulated genes (Fibronectin (FN1)) was validated in the MBC cohort with high fibronectin expression (60%) being positively associated with nodal status and showed a trend towards poor 5 year OS (p= 0.06). Conclusion: In MBC, epithelial cytokeratins, especially CK19 was found to be of prognostic significance. The extracellular matrix remodelling associated genes were found to be up-regulated in MBC. Fibronectin, end product of one of the up-regulated gene was found to have prognostic significance in MBC

A Case Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic and Tractable Biomarkers in Male Breast Cancer

Purpose: Breast cancer (BC) affects both genders, but is understudied in men. Although still rare, male BC is being diagnosed more frequently. Treatments are wholly informed by clinical studies conducted in women, based on assumptions that underlying biology is similar. Experimental design: A transcriptomic investigation of male and female BC was performed, confirming transcriptomic data in silico. Biomarkers were immunohistochemically assessed in 697 MBCs (n=477, training; n=220, validation set) and quantified in pre- and post-treatment samples from a male BC patient receiving Everolimus and PI3K/mTOR inhibitor. Results: Gender-specific gene expression patterns were identified. eIF transcripts were up-regulated in MBC. eIF4E and eIF5 were negatively prognostic for overall survival alone (Log rank; p=0.013; HR=1.77, 1.12-2.8 and p=0.035; HR=1.68, 1.03-2.74, respectively), or when co-expressed (p=0.01; HR=2.66, 1.26-5.63), confirmed in the validation set. This remained upon multivariate Cox regression analysis (eIF4E p=0.016; HR 2.38 (1.18-4.8), eIF5 p=0.022; HR 2.55 (1.14-5.7); co-expression p=0.001; HR=7.04 (2.22-22.26)). Marked reduction in eIF4E and eIF5 expression was seen post BEZ235/Everolimus, with extended survival. Conclusions: Translational initiation pathway inhibition could be of clinical utility in male BC patients overexpressing eIF4E and eIF5. With mTOR inhibitors which target this pathway now in the clinic, these biomarkers may represent new targets for therapeutic intervention, although further independent validation is required

Chest wall perforator flap to partially reconstruct central mound of breast tissue - evolution of the technique.

We describe the use of chest wall perforator flap (CWPF) to reconstruct the central mound of breast tissue in women presenting with central/retro areolar breast cancer. We describe the results of seven patients (median age, 59 years) with a median follow-up of 9 months. We were able to conserve the breast in all except one woman who was found to have extensive DCIS. Two patients were taken back to theatre, one for a washout of infected seroma and second for a wound debridement. There was no flap loss or donor site complications in our series. We were able to conserve the breast, maintain aesthetic contour of the central mound along with projection and achieve excellent cosmetic outcome for our patients. Partial breast reconstruction using CWPF provides an oncologically safe and cosmetically superior alternative in selected women with breast cancer needing central wide local excision

Post-mastectomy radiotherapy for women with early breast cancer and one to three positive lymph nodes.

BACKGROUND: Continual improvement in adjuvant therapies has resulted in a better prognosis for women diagnosed with breast cancer. A surrogate marker used to detect the spread of disease after treatment of breast cancer is local and regional recurrence. The risk of local and regional recurrence after mastectomy increases with the number of axillary lymph nodes affected by cancer. There is a consensus to use radiotherapy as an adjuvant treatment after mastectomy (postmastectomy radiotherapy (PMRT)) in women diagnosed with breast cancer and found to have disease in four or more positive axillary lymph nodes. Despite data showing almost double the risk of local and regional recurrence in women treated with mastectomy and found to have one to three positive lymph nodes, there is a lack of international consensus on the use of PMRT in this group. OBJECTIVES: To assess the effects of PMRT in women diagnosed with early breast cancer and found to have one to three positive axillary lymph nodes. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's Specialised Register, CENTRAL, MEDLINE, Embase, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov up to 24 September 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs). The inclusion criteria included women diagnosed with breast cancer treated with simple or modified radical mastectomy and axillary surgery (sentinel lymph node biopsy (SLNB) alone or those undergoing axillary lymph node clearance with or without prior SLNB). We included only women receiving PMRT using X-rays (electron and photon radiation), and we defined the radiotherapy dose to reflect what is currently being recommended (i.e. 40 Gray (Gy) to 50 Gy in 15 to 25/28 fractions in 3 to 5 weeks. The included studies did not administer any boost to the tumour bed. In this review, we excluded studies using neoadjuvant chemotherapy as a supportive treatment before surgery. DATA COLLECTION AND ANALYSIS: We used Covidence to screen records. We collected data on tumour characteristics, adjuvant treatments and the outcomes of local and regional recurrence, overall survival, disease-free survival, time to progression, short- and long-term adverse events and quality of life. We reported on time-to-event outcome measures using the hazard ratio (HR) and subdistribution HR. We used Cochrane's risk of bias tool (RoB 1), and we presented overall certainty of the evidence using the GRADE approach. MAIN RESULTS: The RCTs included in this review were subgroup analyses of original RCTs conducted in the 1980s to assess the effectiveness of PMRT. Hence, the type and duration of adjuvant systemic treatments used in the studies included in this review were suboptimal compared to the current standard of care. The review involved three RCTs with a total of 829 women diagnosed with breast cancer and low-volume axillary disease. Amongst the included studies, only a single study pertained to the modern-day radiotherapy practice. The results from this one study showed a reduction of local and regional recurrence (HR 0.20, 95% confidence interval (CI) 0.13 to 0.33, 1 study, 522 women; low-certainty evidence) and improvement in overall survival with PMRT (HR 0.76, 95% CI 0.60 to 0.97, 1 study, 522 women; moderate-certainty evidence). One of the other studies using radiotherapy techniques that do not reflect modern-day practice reported on disease-free survival in women with low-volume axillary disease (subdistribution HR 0.63, 95% CI 0.41 to 0.96, 1 study, 173 women). None of the included studies reported on PMRT side effects or quality-of-life outcome measures. AUTHORS' CONCLUSIONS: Based on one study, the use of PMRT in women diagnosed with breast cancer and low-volume axillary disease indicated a reduction in locoregional recurrence and an improvement in survival. There is a need for more research to be conducted using modern-day radiotherapy equipment and methods to support and supplement the review findings