Neoadjuvant Treatment with HER2-Targeted Therapies in HER2-Positive Breast Cancer: A Systematic Review and Network Meta-Analysis

SIMPLE SUMMARY: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer causes more aggressive progression of disease and poorer outcomes for patients. HER2-targeted medicines used as neoadjuvant systemic therapy could improve clinical outcomes in early-stage or locally advanced breast cancer patients. The purpose of this systematic review and network meta-analysis was to identify the neoadjuvant anti-HER2 therapy with the best balance between efficacy and safety. We found that trastuzumab emtansine + pertuzumab + chemotherapy had a high pathologic complete response with a low risk of adverse events compared to other neoadjuvant anti-HER2 regimens, while the pertuzumab + trastuzumab + chemotherapy regimen showed the highest disease-free survival. However, further trial data on neoadjuvant regimens with trastuzumab emtansine are needed to confirm these findings. ABSTRACT: This systematic review aimed to identify neoadjuvant anti-human epidermal growth factor receptor 2 (HER2) therapies with the best balance between efficacy and safety. Methods: A network meta-analysis was applied to estimate the risk ratios along with 95% confidence intervals (CIs) for pathological complete response (pCR) and serious adverse events (SAE). A mixed-effect parametric survival analysis was conducted to assess the disease-free survival (DFS) between treatments. Results: Twenty-one RCTs with eleven regimens of neoadjuvant anti-HER2 therapy (i.e., trastuzumab + chemotherapy (TC), lapatinib + chemotherapy (LC), pertuzumab + chemotherapy (PC), pertuzumab + trastuzumab (PT), trastuzumab emtansine + pertuzumab (T-DM1P), pertuzumab + trastuzumab + chemotherapy (PTC), lapatinib + trastuzumab + chemotherapy (LTC), trastuzumab emtansine + lapatinib + chemotherapy (T-DM1LC), trastuzumab emtansine + pertuzumab + chemotherapy(T-DM1PC), PTC followed by T-DM1P (PTC_T-DM1P), and trastuzumab emtansine (T-DM1)) and chemotherapy alone were included. When compared to TC, only PTC had a significantly higher DFS with a hazard ratio (95% CI) of 0.54 (0.32–0.91). The surface under the cumulative ranking curve (SUCRA) suggested that T-DM1LC (91.9%) was ranked first in achieving pCR, followed by the PTC_T-DM1P (90.5%), PTC (74.8%), and T-DM1PC (73.5%) regimens. For SAEs, LTC, LC, and T-DM1LC presented with the highest risks (SUCRA = 10.7%, 16.8%, and 20.8%), while PT (99.2%), T-DM1P (88%), and T-DM1 (83.9%) were the safest regimens. The T-DM1PC (73.5% vs. 71.6%), T-DM1 (70.5% vs. 83.9%), and PTC_T-DM1P (90.5% vs. 47.3%) regimens offered the optimal balance between pCR and SAE. Conclusions: The T-DM1PC, T-DM1, and PTC_T-DM1P regimens had the optimal balance between efficacy and safety, while DFS was highest for the PTC regimen. However, these results were based on a small number of studies, and additional RCTs assessing the efficacy of regimens with T-DM1 are still needed to confirm these findings

IFN-?–induced protein 10 is a novel biomarker of rhinovirus-induced asthma exacerbations

Background: Rhinovirus-induced acute asthma is the most frequent trigger for asthma exacerbations.Objective: We assessed which inflammatory mediators were released from bronchial epithelial cells (BECs) after infection with rhinovirus and then determined whether they were also present in subjects with acute virus-induced asthma, with the aim to identify a biomarker or biomarkers for acute virusinduced asthma.Methods: BECs were obtained from bronchial brushings of steroid-naive asthmatic subjects and healthy nonatopic control subjects. Cells were infected with rhinovirus 16. Inflammatory mediators were measured by means of flow cytometry with a cytometric bead array. Subjects with acute asthma and virus infection were recruited; they were characterized clinically by using lung function tests and had blood taken to measure the inflammatory mediators identified as important by the BEC experiments.Results: IFN-g–induced protein 10 (IP-10) and RANTES were released in the greatest quantities, followed by IL-6, IL-8, and TNF-a. Dexamethasone treatment of BECs only partially suppressed IP-10 and TNF-a but was more effective at suppressing RANTES, IL-6, and IL-8. In acute clinical asthma serum IP-10 levels were increased to a greater extent in those with acute virus-induced asthma (median of 604 pg/mL compared with 167 pg/mL in those with non–virus-induced acute asthma, P <.01). Increased serum IP-10 levels were predictive of virus-induced asthma (odds ratio, 44.3 [95% CI, 3.9-100.3]). Increased serum IP-10 levels were strongly associated with more severe airflow obstruction (r520.8; P < .01).Conclusions: IP-10 release is specific to acute virus-induced asthma.Clinical implications: Measurement of serum IP-10 could be used to predict a viral trigger to acute asthma

A Clinical Decision Rule to Aid Ordering of Serum and Urine Protein Electrophoresis for Case-Finding of Paraproteins in Hospitalized Inpatients

Objective: To develop a simple clinical decision rule that could increase the yield of serum and urine protein electrophoresi(SPE/UPE) without loss of sensitivity. Design: A cross-sectional study of inpatients with a SPE/UPE performed over a 5-year period (2001–2006) with complete data on electrolytes, globulins, full blood count, creatinine, age, and gender. Setting: A tertiary-care general teaching hospital serving the Hunter Valley in New South Wales, with a referral population of over 1 million. Participants: A total of 14,374 adult patients admitted between January 2001–November 2006. Main outcome measures Paraprotein on serum and/or urine protein electrophoresis (SPE/UPE). Results: Five points were assigned for globulin >41 g/l, 3 points for age ≥60, 2 points for each of hemoglobin <121 and male gender, and 1 point for estimated glomerular filtration rate (eGFR) <60.Total scores of 0–5, 6–10, and ≥11 corresponded to positive likelihood ratios of an abnormal SPE/UPE of 1, 2.5, and 6.6, respectively. The predictive ability of this model was strong, with an area under the curve of ~0.8. Results in the validation set were almost identical. Conclusion: A clinical decision rule using simple clinical variables has the potential to improve the yield of SPE/UPE.This rule however needs to be verified prospectively