High hepatocyte growth factor expression in primary tumor predicts better overall survival in male breast cancer

Background Breast cancer is rare in men, but management is focused on tumor characteristics commonly found in female breast cancer. The tumor microenvironment of male breast cancer is less well understood, and insight may improve male breast cancer management. The hepatocyte growth factor (HGF)/c-MET axis and the stromal cell-derived factor-1 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis are prognostic in women with breast cancer. We aimed to investigate these factors in male breast cancer and correlate them with patient survival. Methods From 841 Dutch males with breast cancer who were enrolled in the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program (NCT01101425) and diagnosed between 1990 and 2010, archival primary tumor samples were collected. Tissue microarrays were constructed with 3 cores per sample and used for immunohistochemical analysis of HGF, c-MET, CXCL12, and CXCR4. Overall survival (OS) of the patients without metastases (M0) was analyzed using the Kaplan-Meier method. The value of the markers regarding OS was determined using univariable and multivariable Cox regression analyses, providing hazard ratios (HRs) and 95% confidence intervals (95% CIs). Results Of 720 out of 841 patients, sufficient tissue was available for analysis; 487 out of 720 patients had M0 disease. Patients with high HGF expression and high CXCL12 expression had a superior OS (low vs high expression of both markers, 7.5 vs 13.0 years, hazard ratio [HR] 0.64, 95% CI 0.49-0.84, P = 0.001 [HGF]; 9.1 vs 15.3 years, HR 0.63, 95% CI 0.45-0.87, P = 0.005 [CXCL12]). Multivariate analysis identified HGF as an independent predictor for OS (HR 0.64, 95% CI 0.47-0.88, P = 0.001). Conclusions HGF and CXCL12 tumor expression appear to identify male breast cancer patients with a relatively good prognosis. Possibly, this could support male breast cancer-specific management strategies in the future

Performance of BRCA1/2 mutation prediction models in male breast cancer patients

To establish whether existing mutation prediction models can identify which male breast cancer (MBC) patients should be offered BRCA1 and BRCA2 diagnostic DNA screening, we compared the performance of BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), BRCAPRO (BRCA probability) and the Myriad prevalence table ("Myriad"). These models were evaluated using the family data of 307 Dutch MBC probands tested for BRCA1/2, 58 (19%) of whom were carriers. We compared the numbers of observed vs predicted carriers and assessed the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) for each model. BOADICEA predicted the total number of BRCA1/2 mutation carriers quite accurately (observed/predicted ratio: 0.94). When a cut-off of 10% and 20% prior probability was used, BRCAPRO showed a non-significant better performance (observed/predicted ratio BOADICEA: 0.81, 95% confidence interval [CI]: [0.60-1.09] and 0.79, 95% CI: [0.57-1.09], vs. BRCAPRO: 1.02, 95% CI: [0.75-1.38] and 0.94, 95% CI: [0.68-1.31], respectively). Myriad underestimated the number of carriers in up to 69% of the cases. BRCAPRO showed a non-significant, higher AUC than BOADICEA (0.798 vs 0.776). Myriad showed a significantly lower AUC (0.671). BRCAPRO and BOADICEA can efficiently identify MBC patients as BRCA1/2 mutation carriers. Besides their general applicability, these tools will be of particular value in countries with limited healthcare resources

Tumor-specific uptake of fluorescent bevacizumab-IRDye800CW microdosing in patients with primary breast cancer:a phase I feasibility study

PURPOSE: to provide proof of principle of safety, breast tumor-specific uptake and positive tumor margin assessment of the systemically administered near-infrared fluorescent (NIRF) tracer bevacizumab-IRDye800CW targeting vascular endothelial growth factor (VEGF)-A in breast cancer patients. EXPERIMENTAL DESIGN: Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab-IRDye800CW as intravenous bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery and ex vivo in surgical specimens using an optical imaging system. Ex vivo multiplexed histopathology analyses were performed for evaluation of biodistribution of tracer uptake and co-registration of tumor tissue and healthy tissue. RESULTS: None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared to those in the tumor margin (P < 0.05) and healthy tissue (P < 0.0001). VEGF-A tumor levels also correlated with tracer levels (r = 0.63, P < 0.0002). All but one tumor showed specific tracer uptake. Two out of 20 surgically excised lumps contained microscopic positive margins detected ex vivo by fluorescent macro- and microscopy and confirmed at the cellular level. CONCLUSIONS: Our study shows that systemic administration of the bevacizumab-IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor-margin uptake as evaluated by a systematic validation methodology. The findings are a step towards a phase II dose-finding study aimed at in vivo margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in tumor tissue

Immunotherapeutic options on the horizon in breast cancer treatment

It is increasingly acknowledged that breast cancer can be an immunogenic disease. Immunogenicity appears to differ between subtypes. For instance, in triple negative breast cancer (TNBC) and HER2-positive breast cancer tumor infiltrating lymphocytes (TILs) are prognostic and predictive for response to chemotherapy containing anthracyclines, but in other subtypes they are not. Preclinical evidence suggests important immune based mechanisms of conventional chemotherapeutics, in particular anthracyclines. Early clinical studies with monoclonal antibodies targeting programmed death protein 1, programmed death-ligand 1 and cytotoxic T-lymphocyte-associated antigen 4 have shown anti-tumor efficacy. Tumor vaccines designed to increase the body's own anti-tumor immunity have shown an increased anti-tumor immunity, however clinical efficacy has not yet been demonstrated. Novel strategies will likely follow. In light of the increased interest in immune modulation, this review focuses on predictive immune-based biomarkers, immune-mediated effects from conventional therapies, as well as recent results and ongoing studies concerning immunotherapies in breast cancer. (C) 2015 Elsevier Inc. All rights reserved

Emil Kautzsch's letter to Ignaz Goldziher

Introduction: The intensified treatment of breast cancer improves survival but has a price in terms of side-effects. The main side-effects, such as vasomotor symptoms and impaired sexual functioning, are related to premature menopause due to chemotherapy and/or anti-hormonal therapy. Though for some women these symptoms are bearable, for others they have a large impact on their quality of life. The paper discusses the menopausal symptoms most frequently reported by breast cancer survivors and current treatment options. Methods: A literature review is presented of menopausal symptoms after breast cancer and management strategies, illustrated by two cases. Summary: Vasomotor symptoms can be relieved by lifestyle adaptation, acupuncture and non-hormonal agents such as venlafaxine, gabapentin or clonidine. Impaired sexual functioning can be treated by couple-based sexual counselling or psycho-educational therapy. Painful intercourse due to vaginal dryness can be alleviated by vaginal lubricants and moisturizers, but is most effectively treated by vaginal estriol. Local estriol seems safe if used for a short period (less than six weeks). Because of proven increased risk of recurrence with hormone replacement therapy (HRT), it should not be prescribed for breast cancer survivors, although exceptions could be made of selected cases of fully informed BRCA mutation carriers after ER-negative breast cancer and with severe menopausal symptoms due to prophylactic oophorectomy at a young age and (preferably) after mastectomy. Conclusion: The management of vasomotor symptoms and impaired sexual functioning in breast cancer survivors should focus on lifestyle and, if necessary, non-hormonal pharmacological interventions. (c) 2012 Elsevier Ireland Ltd. All rights reserved