Pyrotinib is effective in both trastuzumab-sensitive and primary resistant HER2-positive breast tumors

Objective: Primary resistance to trastuzumab frequently occurs in human epidermal growth factor receptor 2(HER2)-positive(+) breast cancer patients and remains a clinical challenge. Pyrotinib is a novel tyrosine kinase inhibitor that has shown efficacy in the treatment of HER2+ breast cancer. However, the efficacy of pyrotinib in HER2+ breast cancer with primary trastuzumab resistance is unknown.Methods: HER2+ breast cancer cells sensitive or primarily resistant to trastuzumab were treated with trastuzumab, pyrotinib, or the combination. Cell proliferation, migration, invasion, and HER2 downstream signal pathways were analyzed. The effects of pyrotinib plus trastuzumab and pertuzumab plus trastuzumab were compared in breast cancer cells in vitro and a xenograft mouse model with primary resistance to trastuzumab.Results: Pyrotinib had a therapeutic effect on trastuzumab-sensitive HER2+ breast cancer cells by inhibiting phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT) and rat sarcoma virus(RAS)/rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)/extracellular-signal regulated kinase(ERK)pathways. In primary trastuzumab-resistant cells, pyrotinib inhibited cell growth, migration, invasion, and HER2 downstream pathways, whereas trastuzumab had no effects. The combination with trastuzumab did not show increased effects compared with pyrotinib alone. Compared with pertuzumab plus trastuzumab, pyrotinib plus trastuzumab was more effective in inhibiting cell proliferation and HER2 downstream pathways in breast cancer cells and tumor growth in a trastuzumab-resistant HER2+ breast cancer xenograft model.Conclusions: Pyrotinib-containing treatments exhibited anti-cancer effects in HER2+ breast cancer cells sensitive and with primary resistance to trastuzumab. Notably, pyrotinib plus trastuzumab was more effective than trastuzumab plus pertuzumab in inhibiting tumor growth and HER2 downstream pathways in HER2+ breast cancer with primary resistance to trastuzumab. These findings support clinical testing of the therapeutic efficacy of dual anti-HER2 treatment combining an intracellular small molecule with an extracellular antibody.

Adipocyte-derived SFRP5 inhibits breast cancer cells migration and invasion through Wnt and epithelial-mesenchymal transition signaling pathways

Objective:Obesity is closely associated with metastasis in breast cancer patients.Secreted frizzled-related protein 5(SFRP5),one of the novel adipokines with anti-inflammatory properties,is associated with obesity.This study aims to study the role of SFRP5 in the crosstalk between obesity and breast cancer metastasis and identify the underlying mechanism.Methods:3T3-L1 pre-adipocytes were differentiated to mature adipocytes and a hypertrophic adipocyte model was induced with palmitic acid(PA).Cell motility was measured in MDA-MB-231 and MCF-7 breast cancer cells co-cultured with adipocytes conditioned medium(CM)with or without SFRP5 protein.Wnt and epithelialmesenchymal transition(EMT)signal pathways were investigated by western blot.Circulating SFRP5 level in 218 breast cancer patients and the association with clinicopathologic characteristics of breast cancer were further determined.Online databases ENCORI and PREDICT Plus were used to exam the link between SFRP5 and prognosis.Results:Reduced SFRP5 level was detected in the hypertrophic adipocyte model.Recombinant SFRP5 protein inhibited MDA-MB-231 and MCF-7 cells invasion and migration induced by PA-treated adipocyte CM,and SFRP5 inhibition by specific antibody reversed the effect of SFRP5.Furthermore,SFRP5 significantly inhibited Wnt and downstream EMT in breast cancer cells.Low circulating SFRP5 level correlated with body mass index(BMI),lymph node(LN)metastasis,TNM stage and high Ki67 expression in breast cancer patients.Increased SFRP5 level was associated with favorable predicted survival.Kaplan-Meier curves showed high SFRP5 level in tumor tissue was associated with better outcome of breast cancer patients.Conclusions:Our findings demonstrated SFRP5 is a vital adipokine that mediates the crosslink between obesity and the metastatic potential of breast cancer.Promotion of SFRP5 expression in the adipose microenvironment may represent a novel approach for preventing breast cancer metastasis.

An Improved Training Algorithm Based on Ensemble Penalized Cox Regression for Predicting Absolute Cancer Risk

Introduction:Biases in cancer incidence characteristics have led to significant imbalances in databases constructed by prospective cohort studies.Since they use imbalanced databases,many traditional algorithms for training cancer risk prediction models perform poorly.Methods:To improve prediction performance,we introduced a Bagging ensemble framework to an absolute risk model based on ensemble penalized Cox regression(EPCR).We then tested whether the EPCR model outperformed other traditional regression models by varying the censoring rate of the simulated data.Results:Six different simulation studies were performed with 100 replicates.To assess model performance,we calculated mean false discovery rate,false omission rate,true positive rate,true negative rate,and the areas under the receiver operating characteristic curve(AUC)values.We found that the EPCR procedure could reduce the false discovery rate(FDR)for important variables at the same true positive rate(TPR),thereby achieving more accurate variable screening.In addition,we used the EPCR procedure to build a breast cancer risk prediction model based on the Breast Cancer Cohort Study in Chinese Women database.AUCs for 3-and 5-year predictions were 0.691 and 0.642,representing improvements of 0.189 and 0.117 over the classical Gail model,respectively.Discussion:We conclude that the EPCR procedure can overcome challenges posed by imbalanced data and improve the performance of cancer risk assessment tools.

Breast Cancer Awareness and Association with Frequency of Screening Among Women—China,2020

Summary What is already known about this topic?Breast cancer awareness plays a crucial role in promoting screening attendance,enabling early detection,and improving survival rates associated with breast cancer.Nevertheless,a persistent issue is the low public awareness of breast cancer warning signs and risk factors.

Depressive Symptoms and Sleep Duration as Risk Factors for Breast Cancer—China,2020

Summary What is already known about this topic?Psychological and lifestyle factors are known to potentially play a significant role in the development of breast cancer.However,current evidence-based studies present controversial findings on the associations between depression,sleep duration,and breast cancer risk.

Rice productivity and profitability with slow-release urea containing organic-inorganic matrix materials

Applying slow-release fertilizers is possible means for reducing nitrogen(N) loss in rice production. Matrix-based fertilizers represent novel slow-release fertilizers. To date, there is little consensus about the effect of combined addition of organic and inorganic matrix materials on rice production. We developed a slow-release urea fertilizer with selected organic and inorganic matrix materials. The study aimed to: i) determine the effect of the slow-release urea on rice yield, profit, and agronomic efficiency and ii) elucidate its possible mechanisms. A two-year field experiment was conducted during 2015–2016. Besides,laboratory experiments were conducted to determine the potential N loss risk. Three treatments were set up: control without N application(CK), regular urea treatment(RU, 150 kg N ha^(-1)), and slow-release urea treatment(SU, 150 kg N ha^(-1)). The results showed that rice biomass and grain yield were significantly higher in SU than in RU(P < 0.05). The higher panicle density in SU was largely responsible for the greater grain yield. Net profit in SU was US$450 ha^(-1), higher than in RU. Agronomic efficiency was significantly greater in SU than in RU(P < 0.05). Rice height, root area, leaf chlorophyll, leaf nitrate reductase activity, and leaf glutamine synthetase activity were larger in SU than in RU. Less N loss and greater soil N availability were partly responsible for the improvements in rice growth traits and physiological parameters in SU. Overall, the slow-release urea is a promising fertilizer for rice production.