Mortality Risks Over 20 Years in Men With Stage I to III Hormone Receptor-Positive Breast Cancer.

Importance: In women with hormone receptor-positive (HR+) breast cancer, the risk of distant recurrence and death persists for at least 20 years from diagnosis. The risk of late mortality in men with HR+ breast cancer has not been reported. Objective: To report 20-year risks of breast cancer-specific mortality (BCSM) and non-BCSM in men with stage I to III HR+ breast cancer and identify factors associated with late BCSM. Design, Setting, and Participants: An observational cohort study was conducted of men diagnosed with HR+ breast cancer from 1990 to 2008, using population-based data from the Surveillance, Epidemiology, and End Results program. Men diagnosed with stage I to III HR+ breast cancer were included in the analysis. Cumulative incidence function was used to estimate the outcomes of baseline clinicopathologic variables regarding cumulative risk of BCSM and non-BCSM since diagnosis. Smoothed hazard estimates over time were plotted for BCSM. Fine and Gray multivariable regression evaluated the association of preselected variables with BCSM, conditional on having survived 5 years. Main Outcome Measure: BCSM. Results: A total of 2836 men with stage I to III HR+ breast cancer were included, with a median follow-up of 15.41 (IQR, 12.08-18.67) years. Median age at diagnosis was 67 (IQR, 57-76) years. The cumulative 20-year risk of BCSM was 12.4% for stage I, 26.2% for stage II, and 46.0% for stage III. Smoothed annual hazard estimates for BCSM revealed an increase in late hazard rates with each incremental node category, reaching a bimodal distribution in N3 and stage III, with each having peaks in hazard rates at 4 and 11 years. Among patients who survived 5 years from diagnosis, the adjusted BCSM risk was higher for those younger than 50 years vs older than 64 years, those with grade II or III/IV vs grade I tumors, and stage II or III vs stage I disease. Conclusions and Relevance: The findings of this study suggest that, in men with stage I to III HR+ breast cancer, the risk of BCSM persists for at least 20 years and depends on traditional clinicopathologic factors, such as age, tumor stage, and tumor grade. Among men with higher stages of disease, the kinetics of the BCSM risk appear different from the risk that has been reported in women.

Multidimensional Molecular Profiling of Metastatic Triple-Negative Breast Cancer and Immune Checkpoint Inhibitor Benefit.

PURPOSE: In metastatic triple-negative breast cancer (mTNBC), consistent biomarkers of immune checkpoint inhibitor (ICI) therapy benefit remain elusive. We evaluated the immune, genomic, and transcriptomic landscape of mTNBC in patients treated with ICIs. METHODS: We identified 29 patients with mTNBC treated with pembrolizumab or atezolizumab, either alone (n = 9) or in combination with chemotherapy (n = 14) or targeted therapy (n = 6), who had tumor tissue and/or blood available before ICI therapy for whole-exome sequencing. RNA sequencing and CIBERSORTx-inferred immune population analyses were performed (n = 20). Immune cell populations and programmed death-ligand 1 expression were assessed using multiplexed immunofluorescence (n = 18). Clonal trajectories were evaluated via serial tumor/circulating tumor DNA whole-exome sequencing (n = 4). Association of biomarkers with progression-free survival and overall survival (OS) was assessed. RESULTS: Progression-free survival and OS were longer in patients with high programmed death-ligand 1 expression and tumor mutational burden. Patients with longer survival also had a higher relative inferred fraction of CD8+ T cells, activated CD4+ memory T cells, M1 macrophages, and follicular helper T cells and enrichment of inflammatory gene expression pathways. A mutational signature of defective repair of DNA damage by homologous recombination was enriched in patients with both shorter OS and primary resistance. Exploratory analysis of clonal evolution among four patients treated with programmed cell death protein 1 blockade and a tyrosine kinase inhibitor suggested that clonal stability post-treatment was associated with short time to progression. CONCLUSION: This study identified potential biomarkers of response to ICIs among patients with mTNBC: high tumor mutational burden; presence of CD8+, CD4 memory T cells, follicular helper T cells, and M1 macrophages; and inflammatory gene expression pathways. Pretreatment deficiencies in the homologous recombination DNA damage repair pathway and the absence of or minimal clonal evolution post-treatment may be associated with worse outcomes.

Cardiac outcomes of subjects on adjuvant trastuzumab emtansine vs paclitaxel in combination with trastuzumab for stage I HER2-positive breast cancer (ATEMPT) study (TBCRC033): a randomized controlled trial.

The excellent outcomes seen in patients treated with adjuvant trastuzumab emtansine (T-DM1) in the ATEMPT trial and the favorable toxicity profile associated with this agent make T-DM1 a potential therapeutic option for select patients with stage I HER2-positive breast cancer. Moreover, T-DM1 is an established adjuvant treatment for patients with HER2-positive breast cancer with the residual invasive disease after neoadjuvant therapy. Given that cardiotoxicity is the most significant adverse event of trastuzumab, which is a main molecular component of T-DM1, we conducted a sub-analysis of the ATEMPT trial to determine the cardiac safety of adjuvant T-DM1. In this analysis, the incidence of grade 3-4 left ventricular systolic dysfunction (LVSD) in T-DM1 or trastuzumab plus paclitaxel arms were respectively 0.8 and 1.8%. In addition, three (0.8%) patients in the T-DM1 arm and six (5.3%) patients in the adjuvant paclitaxel with trastuzumab (TH) arm experienced a significant asymptomatic left ventricular ejection fraction (LVEF) decline that per-protocol required holding T-DM1 or trastuzumab. All patients with available follow-up data experienced full resolution of cardiac symptoms and LVEF normalization. Furthermore, we performed an exploratory analysis to assess the relationship between age, baseline LVEF, and body mass index with cardiac outcomes. No significant association between these baseline characteristics and the incidence of significant asymptomatic LVEF decline or symptomatic LVSD was identified. The low incidence of significant cardiac adverse events in this population during therapy with adjuvant T-DM1 suggests that studies on the cost-effectiveness of cardiac monitoring during adjuvant therapy using anthracycline-free regimens are needed.Clinical Trial Registration: ClinicalTrials.gov, NCT01853748.

Tumor subtypes and survival in male breast cancer.

PURPOSE: Male breast cancer is an uncommon disease, and population-based information regarding prognostic factors is limited. Most cases are hormone receptor (HR) positive; however, the association of tumor subtype with overall survival (OS) and breast cancer-specific survival (BCSS) is unclear. METHODS: Using SEER data, we identified men with invasive breast cancer between 2010 and 2017 with known HR and HER2 status. We examined tumor subtypes by patient characteristics and performed multivariate Cox proportional hazards analyses to determine the associations of each variable with OS and BCSS. RESULTS: We included 2389 men with a median follow-up of 43 months (IQR 19-68). Median age was 66 years. Tumor subtype distribution was 84.1% HR+/HER2-, 12.7% HR+/HER2+ , 0.8% HR-/HER2+, and 2.3% triple-negative (TN). In univariate analysis, OS at 5 years was 76.5% for HR+/HER2-, 65.1% for HR+/HER2+ , 84.2% for HR-/HER2+, and 48.1% for TN (p < 0.0001). Of all subtypes, TN had the worst BCSS (p < 0.0001). Stage, tumor subtype and race were significantly associated with OS and BCSS in multivariate analysis. Adjusted Cox hazard ratios for OS by tumor subtype with HR+/HER2- as reference were 1.55 for HR+/HER2+ (p = 0.001), 1.1 for HR-/HER2+ (p = 0.888), and 3.59 for TN (p < 0.001). CONCLUSION: We observed significant differences in survival outcomes by tumor subtype. Poor outcomes among men with HER2+ and TN disease suggest possible under-treatment, aggressive tumor biology, and/or more advanced disease at presentation. Studies to better understand the inferior survival for men with these subtypes are warranted and will likely require international collaboration.

A Phase II Study of Pembrolizumab in Combination With Palliative Radiotherapy for Hormone Receptor-positive Metastatic Breast Cancer.

BACKGROUND: The purpose of this study was to investigate whether combining pembrolizumab with palliative radiation therapy (RT) improves outcomes in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). PATIENTS AND METHODS: Eligible patients had HR+/human epidermal growth factor receptor 2-negative MBC; were candidates for RT to ≥ 1 bone, soft tissue, or lymph node lesion; and had ≥ 1 lesion outside the RT field. Patients received 200 mg pembrolizumab intravenously 2 to 7 days prior to RT and on day 1 of repeating 21-day cycles. RT was delivered to a previously unirradiated area in 5 treatments each of 4 Gy. The primary endpoint was objective response rate. The study used a 2-stage design: 8 women were enrolled into the first stage, and if at least 1 of 8 patients experienced an objective response, 19 more would be enrolled. Secondary endpoints included progression-free survival, overall survival, and safety. Exploratory endpoints included association of overall response rate with programmed death-ligand 1 status and tumor-infiltrating lymphocytes. RESULTS: Eight patients were enrolled in stage 1. The median age was 59 years, and the median prior lines of chemotherapy for metastatic disease was 2. There were no objective responses, and the study was closed to further accrual. The median progression-free survival was 1.4 months (95% confidence interval, 0.4-2.1 months), and the median overall survival was 2.9 months (95% confidence interval, 0.9-3.6 months). All-cause adverse events occurred in 87.5% of patients, including just 1 grade 3 event (elevation of aspartate aminotransferase). CONCLUSIONS: RT combined with pembrolizumab did not produce an objective response in patients with heavily pre-treated HR+ MBC. Future studies should consider alternative radiation dosing and fractionation in patients with less heavily pre-treated HR+ MBC.

ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature.

BACKGROUND: Anaplastic lymphoma kinase-positive diffuse large B-cell lymphoma (ALK-DLBCL) is a rare lymphoma with several clinicopathological differences from ALK-positive anaplastic large cell lymphoma (ALCL). The latest WHO classification of lymphomas recognizes ALK-DLBCL as a separate entity. METHODS: A comprehensive comparison was made between the clinical and pathological features of the 4 cases reported and those found in an extensive literature search using MEDLINE through December 2008. RESULTS: In our series, three cases were adults and one was pediatric. Two cases had primary extranodal disease (multifocal bone and right nasal fossa). Stages were I (n = 1), II (n = 1), III (n = 1) and IV (n = 1). Two cases had increased LDH levels and three reported B symptoms. IPI scores were 0 (n = 1), 2 (n = 2) and 3 (n = 1). All cases exhibited plasmablastic morphology. By immunohistochemistry, cases were positive for cytoplasmic ALK, MUM1, CD45, and EMA; they marked negative for CD3, CD30 and CD20. Studies for EBV and HHV-8 were negative. The survival for the patients with stage I, II, III and IV were 13, 62, 72 and 11 months, respectively. CONCLUSION: ALK-DLBCL is a distinct variant of DLBCL with plasmacytic differentiation, which is characterized by a bimodal age incidence curve, primarily nodal involvement, plasmablastic morphology, lack of expression of CD20, aggressive behavior and poor response to standard therapies, although some cases can have prolonged survival as the cases reported in this study. ALK-DLBCL does not seem associated to immunosuppression or the presence of EBV or HHV8. Further prospective studies are needed to optimize therapies for this entity.