Prognostic factors and benefit populations of ovarian function suppression in premenopausal HR+/HER2+ early-stage breast cancer patients who received trastuzumab: Evidence from a real-world study with long-term follow-up.

BACKGROUND: Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-positive (HER2+) breast cancer exhibits considerable heterogeneity, and it is of great interest whether patients with premenopausal HR+/HER2+ breast cancer treated with trastuzumab can benefit from ovarian function suppression (OFS) therapy similarly to HR+/HER2- breast cancer. Here, we conducted a real-world study in this population to identify both who would derive substantial benefits from the addition of OFS and clinicopathological factors with potential prognostic value. METHODS: Multicenter data from 253 premenopausal patients with HR+/HER2+ early-stage breast cancer who received trastuzumab from October 2009 to October 2018 were retrospectively included. The Kaplan-Meier method was used for survival analysis, while the log-rank test was used to compare the survival rates. Univariate and multifactor Cox regression analyses were performed to analyze the independent risk factors affecting invasive disease-free survival (IDFS). RESULTS: After a median follow-up of 98.50 months, compared with tamoxifen/toremifene alone, tamoxifen/toremifene/aromatase inhibitors plus OFS demonstrated significant benefits in the overall study population (HR = 0.289, 95% CI: 0.100-0.835, p = 0.022, 8-year IDFS rate: 90.78% vs. 95.54%), especially in the lymph node-positive subgroup and age ≤40 years subgroup. Age ≤40 years, histological grade >2, lymph node involvement, PR ≤50%, and tamoxifen alone were independent prognostic factors. CONCLUSIONS: For premenopausal HR+ breast cancer patients, HER2 positivity alone is an indication for the addition of OFS in adjuvant endocrine therapy. Age, histological grade, lymph node status, the expression of PR, and OFS treatment were independent prognostic factors in this population.

Prognostic factors and adjuvant systemic therapy for patients with HER2-positive T1N0 breast cancer: evidence from a real-world study with long-term follow-up.

PURPOSE: The optimal adjuvant systemic treatment and potential prognostic factors for patients with T1N0 HER2-positive breast cancer are still unclear. We conducted a real-world study in this relatively low-risk population to identify the clinical-pathological factors of potential prognostic value and to compare the efficacy of different adjuvant strategies. METHODS: We included patients with HER2-positive T1N0 breast cancer of infiltrating ductal carcinoma (IDC) histology treated at the Cancer Hospital, Chinese Academy of Medical Sciences from April 2010 to April 2017. We performed Cox multivariate analysis to identify the potential prognostic factors for invasive disease-free survival (IDFS). We also compared survival outcomes of (1) patients treated with adjuvant chemotherapy alone, or chemotherapy plus trastuzumab, or observation; (2) patients receiving adjuvant anthracycline-based and non-anthracycline regimens, both combined with trastuzumab. Inverse probability of treatment weighting (IPTW) propensity score was used to reduce selection bias. RESULTS: Overall, 692 consecutive patients were included, with a median follow-up of 78.0 months for IDFS. Age ≤ 40, T1c, ER + PR + , and adjuvant trastuzumab were identified as independent prognostic factors. For adjuvant treatment, compared with observation and chemotherapy alone, chemotherapy plus trastuzumab could significantly benefit patients (HR = 2.70, P = 0.034; HR = 3.95, P < 0.001). Meanwhile, compared with observation, chemotherapy alone did not significantly benefit patients (HR = 1.37, P = 0.424). For the comparison of anthracycline-based versus non-anthracycline regimens when combined with trastuzumab, patients in both groups had similar IDFS (HR = 1.74, P = 0.242). CONCLUSIONS: HER2-positive T1N0 IDC patients could benefit from adjuvant chemotherapy plus trastuzumab. Age ≤ 40, T1c, ER + PR + , and adjuvant trastuzumab are independent prognostic factors for this population.

Assessing early changes in plasma HER2 levels is useful for predicting therapeutic response in advanced breast cancer: A multicenter, prospective, noninterventional clinical study.

BACKGROUND: Early prediction of treatment response is crucial for the optimal treatment of advanced breast cancer. We aimed to explore whether monitoring early changes in plasma human epidermal growth factor receptor 2 (HER2) levels using digital PCR (dPCR) could predict the treatment response in advanced breast cancer. METHODS: This was a multicenter, prospective, noninterventional clinical study of patients with advanced breast cancer. All enrolled patients underwent blood testing to measure the HER2 levels by digital PCR before treatment initiation and once every 3 weeks during the study. The primary endpoints werea the diagnostic value of dPCR for detecting HER2 status in the blood andb the relevance of potential changes in the plasma HER2 level at 3 weeks from baseline for predicting treatment response. RESULTS: Overall, 85 patients were enrolled between October 9, 2018, and January 23, 2020. dPCR had a specificity of 91.67% (95% CI: 80.61% to 97.43%) for detecting HER2 amplification, and the area under the receiver operating characteristic (ROC) curve was 0.84 (p < 0.01). A clinically relevant specificity threshold of approximately 90%, which was equivalent to a ≥15% decrease in the plasma HER2 ratio at 3 weeks from baseline, showed a positive predictive value of 97.37% (95% CI: 77.11% to 98.65%) in terms of predicting clinical benefit. Patients whose plasma HER2 ratio was reduced by ≥15% had a longer median progression-free survival (PFS) than those whose ratio was reduced by <15% (9.20 months vs. 4.50 months, p < 0.01). CONCLUSIONS: Early changes in the plasma HER2 ratio may predict the treatment response in patients with advanced breast cancer and could facilitate optimal treatment selection.

Combined analysis of receptor expression reflects inter-and intra-tumor heterogeneity in HR+/HER2+ breast cancer.

BACKGROUND: Hormone receptor-positive and human epidermal growth factor receptor 2-positive (HR+/HER2+ breast cancer comprise approximately 5-10% of all invasive breast cancers. However, the lack of knowledge regarding the complexity of tumor heterogeneity in HR+/HER2+ disease remains a barrier to more accurate therapies. This study aimed to describe the tumor heterogeneity of HR+/HER2+ breast cancer and to establish a novel indicator to identify the HER2-enriched subtype in patients with HR+/HER2+ breast cancer. METHODS: First of all, a comprehensive analysis was performed on HR+/HER2+ breast cancer samples from the TCGA (n = 141) and METABRIC (n = 104) databases. We determined the distribution of PAM50 intrinsic subtypes within the two cohorts and compared the somatic mutational profile and RNA expression features between HER2-enriched and non-HER2-enriched subtypes. From this, we constructed a novel marker termed rH/E, which was calculated as ERBB2 expression quantity/(ESR1 expression quantity + 1). Secondly, we performed multiplex immunofluorescence (mIF) to evaluate HER2 and estrogen receptor (ER) expression simultaneously in the third cohort, enrolling 43 cases of early HR+/HER2+ breast cancer from Cancer Hospital, Chinese Academy of Medical Sciences (CAMS). When using mIF, rH/E was adjusted to prH/E, which was calculated as HER2-positive cells%/(ER-positive cells + 1)%. RESULTS: All four main intrinsic subtypes were identified in HR+/HER2+ breast cancer, of which the luminal B subtype was the most common, followed by the HER2-enriched and luminal A subtypes. Significantly increased TP53 and ERBB3 and decreased PIK3CA somatic mutation frequency were observed in the HER2-enriched subtype compared with the non-HER2-enriched subtype. In addition, the HER2-enriched subtype was characterized by significantly higher ERBB2 and lower ESR1 expression. We then constructed a marker termed rH/E to reflect the relative expression of ERBB2 to ESR1 in each patient. rH/E discriminates the HER2-enriched subtype from the better than the expression of ERBB2 or ESR1 alone. In the CAMS cohort, we observed four subtypes of tumor cells: ER+/HER2-, ER+/HER2+, ER-/HER2+, and ER-/HER2-. Tumor cell diversity was common, with 86% of patients having all four subtypes of tumor cells. Moreover, prH/E showed a significant prognostic association in the CAMS cohort. CONCLUSIONS: This study furthers our understanding of the complexity of tumor heterogeneity in HR+/HER2+ breast cancer, and suggests that the combined analysis of ERBB2 and ESR1 expression may contribute to identifying patients with specific subtypes in this population.

The Effects of Endocrine Therapies on Lipid Profiles in Chinese Young Women With Early Breast Cancer.

This study aimed to evaluate and compare the effects of various endocrine therapies on lipid profiles in young patients with breast cancer. A retrospective, single-center study was performed to investigate the effects of tamoxifen (TAM), tamoxifen plus ovarian function suppression (TAM+OFS), and aromatase inhibitors plus ovarian function suppression (AI+OFS) on lipid profiles during the 60 months of endocrine therapy in hormone receptor-positive patients aged <40 with early breast cancer. The primary endpoint was the cumulative incidence of lipid events, and the secondary endpoints were the changes in lipid profiles. A total of 230 young patients were included with the mean age of 35.7 years old. The patients in TAM group had significantly lower incidence of 5-year lipid events than those in TAM+OFS group (7.4% versus 21.3%; P=0.016) and AI+OFS group (7.4% versus 21.6%; P=0.009). The incidence of fatty liver was significantly higher in TAM+OFS group than TAM group (52.5%versus 30.9%; P=0.043). Lipid events were associated with younger age (odds ratio (OR)=0.865, 95% confidence interval (CI): 0.780-0960; P=0.006), higher baseline LDL-C (OR=14.959, 95% CI: 4.379-51.105; P<0.001), and use of OFS (OR=3.557, 95% CI: 1.151-10.989; P=0.027). Therefore, application of OFS, with younger age and higher baseline LDL-C, may increase the incidence of lipid events in premenopausal breast cancer. More care should be taken for lipid profiles during the endocrine therapy for young breast cancer patients.

Efficacy and safety of cyclophosphamide in anthracycline- and taxane-based neoadjuvant chemotherapy in breast cancer: a meta-analysis.

BACKGROUND: Our study aimed to compare the efficacy and safety of anthracycline plus taxane (AT)-based neoadjuvant chemotherapy (NAC) with or without cyclophosphamide in the treatment of breast cancer. METHODS: We searched PubMed, Embase, Web of Science and the Cochrane Library for randomized controlled studies comparing the efficacy and safety of AT-based NAC with or without cyclophosphamide in breast cancer patients. RESULTS: Four eligible studies with 2,302 individuals were ultimately included in the quantitative analysis. After applying the AT-based NAC regimen, the overall rates of pathologic complete response (pCR) and breast conserving surgery in all included subjects were 26.5% and 70.6%, respectively. The rates of pCR [risk ratio (RR): 1.35; 95% CI: 0.75, 2.45; P=0.32], breast-conserving surgery (RR: 1.07; 95% CI: 0.97, 1.19; P=0.17) and clinical response (RR: 1.08; 95% CI: 0.97, 1.19; P=0.15) in patients in the cyclophosphamide group were similar to those in the control group. However, participants in the cyclophosphamide group had a lower no clinical response rate than those in the control group (RR: 0.72; 95% CI: 0.60, 0.87; P<0.001). Subjects in the cyclophosphamide group had significantly lower rates of infection (RR: 0.57; 95% CI: 0.41, 0.79; P<0.001) and diarrhea (RR: 0.46; 95% CI: 0.30, 0.68; P<0.001) and higher rates of thrombocytopenia (RR: 3.38; 95% CI: 1.96, 5.84; P<0.001), sensory/motor neuropathy (RR: 1.57; 95% CI: 1.03, 2.39; P=0.03) and nausea/vomiting (RR: 1.51; 95% CI: 1.11, 2.06; P=0.009) than those in the control group. CONCLUSIONS: The AT-based NAC regimen with or without cyclophosphamide had similar clinical outcomes in breast cancer patients. The addition of cyclophosphamide might increase the risks of thrombocytopenia, sensory/motor neuropathy and nausea/vomiting.

Amphiregulin and ocular axial length.

PURPOSE: To assess the potential role of amphiregulin as messenger molecule in ocular axial elongation. METHODS: The experimental study included guinea pigs (total n = 78) (age: 3-4 weeks) which underwent bilateral lens-induced myopization and received 15 days later three intraocular injections in weekly intervals of amphiregulin antibody (doses:5 µg, 10 µg, 20 µg) into their right eyes, and three phosphate-buffered saline injections into their left eyes; and guinea pigs without lens-induced myopization and which received three unilateral intraocular injections of amphiregulin antibody (dose: 20 µg) or amphiregulin (doses: 1 ng; 10 ng; 20 ng) into their right eyes, and three phosphate-buffered saline injections into their left eyes. Seven days later, the animals were sacrificed. Intravitally, we performed biometry, and histology and immunohistochemistry post-mortem. RESULTS: In animals with bilateral lens-induced myopization, the right eyes receiving amphiregulin antibody showed reduced axial elongation in a dose-dependent manner (dose: 5 µg: side difference: 0.14 ± 0.05 mm;10 µg: 0.22 ± 0.06 mm; 20 µg: 0.32 ± 0.06 mm; p < 0.001), thicker sclera (all p < 0.05) and higher cell density in the retinal nuclear layers and retinal pigment epithelium (RPE) (all p < 0.05). In animals without lens-induced myopia, the right eyes with amphiregulin antibody application (20 µg) showed reduced axial elongation (p = 0.04), and the right eyes with amphiregulin injections experienced increased (p = 0.02) axial elongation in a dose-dependent manner (1 ng: 0.04 ± 0.06 mm; 10 ng: 0.10 ± 0.05 mm; 20 ng: 0.11 ± 0.06 mm). Eyes with lens-induced axial elongation as compared to eyes without lens-induced axial elongation revealed an increased visualization of amphiregulin upon immunohistochemistry and higher expression of mRNA of endogenous amphiregulin and epidermal growth factor receptor, in particular in the outer part of the retinal inner nuclear layer and in the RPE. CONCLUSION: Amphiregulin may be associated with axial elongation in young guinea pigs.

The efficacy of dietary Spirulina as an adjunct to chemotherapy to improve immune function and reduce myelosuppression in patients with malignant tumors.

BACKGROUND: Recent studies have demonstrated functional benefits of Spirulina (Arthrospira sp.) in the treatment and prevention of cancer. However, it is unclear if Spirulina can be used to limit the side effects of chemotherapy in patients with malignant tumors. METHODS: In this study, cancer patients receiving four cycles of chemotherapy were randomized into control or treatment groups. The treated group consumed Spirulina for the first two cycles while the control group did not. The extent of myelosuppression and immune function were assessed after each cycle of chemotherapy, and patients were monitored for myelosuppression-related adverse events throughout the study period. RESULTS: In total, 100 patients were recruited and randomized into control (n=40) or treatment (n=60) groups. The white blood cell (WBC) and neutrophil (NEU) levels were similar in both groups at baseline while they were higher in the treated group relative to controls after Cycle1 (P=0.028 for WBC; P=0.006 for NEU) and Cycle2 (P=0.023 for WBC; P=0.013 for NEU). Hemoglobin (HGB) and platelet counts (PLT) were not statistically different between the groups at baseline or after treatment. Patients in the treatment group had a significantly lower rate of severe myelosuppression (P=0.034) and less modification of the chemotherapy regimen was necessary (P=0.012). After four cycles of chemotherapy, the IgM level and number of CD8+ T cells increased in the treatment group, but decreased in the control group (P=0.004 for IgM; P=0.022 for CD8+ T cells). CONCLUSIONS: Spirulina reduces myelosuppression and improves immune function after chemotherapy in patients with malignant tumors.

Short-term clinical outcomes of enteral nutrition versus parenteral nutrition after surgery for pancreatic cancer: a meta-analysis.

BACKGROUND: The short-term clinical outcomes between early enteral nutrition (EEN) and total parenteral nutrition (TPN) after pancreaticoduodenectomy (PD) for pancreatic cancer were not clear. METHODS: We searched the PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases to identify randomized controlled studies comparing EEN and TPN after PD for pancreatic cancer. Then a meta-analysis was conducted. RESULTS: Seven studies with 486 patients were included in the analysis. After surgery, patients in EEN group had higher level of plasma total protein (TP) [weighted mean difference (WMD): 1.83, 95% confidence interval (CI): 0.33-3.32, P=0.02], while the albumin (ALB) level was similar between the two groups (WMD: 0.25, 95% CI: -4.07-4.56, P=0.91). As for the bowel function, EEN group had shorter exhaust time (WMD: -0.66, 95% CI: -0.81 to -0.51, P<0.001) and bowel movement time (WMD: -2.27, 95% CI: -2.61 to -1.94, P<0.001) than TPN group. EEN group also had lower short-term total complication rate [relative risk (RR): 0.68, 95% CI: 0.51-0.92, P=0.01] and postoperative hemorrhage rate (RR: 0.22, 95% CI: 0.06-0.75, P=0.02), while there was no significant difference in infection rate (RR: 0.68, 95% CI: 0.38-1.22, P=0.20), pancreatic fistula rate (RR: 0.63, 95% CI: 0.35-1.16, P=0.14) and delayed gastric emptying (DGE) rate (RR: 0.72, 95% CI: 0.39-1.33, P=0.29) between the groups. In addition, EEN group had shorter hospital stay (WMD: -1.53, 95% CI: -2.12 to -0.94, P<0.001). CONCLUSIONS: Compared to TPN, EEN showed better outcomes in improving the nutritional status and bowel function as well as decreasing complication rate and hospital stay after PD in patients with pancreatic cancer.

Short-Term and Mid-Term Clinical Outcomes Following Hybrid Coronary Revascularization Versus Off-Pump Coronary Artery Bypass: A Meta-Analysis / Resultados Clínicos de Curto e Médio Prazo após Revascularização Coronariana Híbrida versus Revascularização Miocárdica sem Circulação Extracorpórea: Uma Meta-Análise

Abstract Background: Off-pump coronary artery bypass grafting (OPCAB) is one of the standard treatments for coronary artery disease (CAD) while hybrid coronary revascularization (HCR) represents an evolving revascularization strategy. However, the difference in outcomes between them remains unclear. Objective: We performed a meta-analysis to compare the short-term and mid-term outcomes of HCR versus OPCAB for the treatment of multivessel or left main CAD. Methods: We searched the PubMed, EMBASE, Web of Science and Cochrane databases to identify related studies and a routine meta-analysis was conducted. Results: Nine studies with 6121 patients were included in the analysis. There was no significant difference in short-term major adverse cardiac and cerebrovascular event (MACCE) rate (RR: 0.55, 95% CI: 0.30-1.03, p = 0.06) or mortality (RR: 0.51, 95% CI: 0.17-1.48, p = 0.22). HCR required less ventilator time (SMD: -0.36, 95% CI: -0.55- -0.16, p < 0.001), ICU stay (SMD: -0.35, 95% CI: -0.58 - -0.13, p < 0.01), hospital stay (SMD: -0.29, 95% CI: -0.50- -0.07, p < 0.05) and blood transfusion rate (RR: 0.57, 95% CI: 0.49-0.67, p < 0.001), but needed more operation time (SMD: 1.29, 95% CI: 0.54-2.05, p < 0.001) and hospitalization costs (SMD: 1.06, 95% CI: 0.45-1.66, p < 0.001). The HCR group had lower mid-term MACCE rate (RR: 0.49, 95% CI: 0.26-0.92, p < 0.05) but higher rate in mid-term target vessel revascularization (TVR, RR: 2.20, 95% CI: 1.32-3.67, p < 0.01). Conclusions: HCR had similar short-term mortality and morbidity comparing to OPCAB. HCR decreased the ventilator time, ICU stay, hospital stay, blood transfusion rate and increased operation time and hospitalization costs. HCR has a lower mid-term MACCE rate while OPCAB shows better in mid-term TVR.

Resumo Fundamentos: A revascularização do miocárdio sem circulação extracorpórea (CRM sem CEC) é um dos tratamentos padrão para a doença arterial coronária (DAC), enquanto que a revascularização coronária híbrida (RCH) é uma estratégia de revascularização em evolução. No entanto, a diferença nos resultados entre eles ainda não está clara. Objetivo: Realizamos uma meta-análise para comparar os resultados a curto e médio prazo da RCH versus a CRM sem CEC para o tratamento de DAC de múltiplos vasos ou artéria principal esquerda. Métodos: Pesquisamos as bases de dados PubMed, EMBASE, Web of Science e Cochrane para identificar estudos relacionados e realizamos uma meta-análise de rotina. Resultados: Nove estudos com 6121 pacientes foram incluídos na análise. Não houve diferença significativa na taxa de eventos cardíacos e cerebrovasculares adversos maiores de curto prazo (ECCAM) (RR de 0,55, IC de 95% 0,30-1,03, p = 0,06) ou mortalidade (RR: 0,51, IC 95%: 0,17-1,48, p = 0,22). A RCH requereu menos tempo de ventilação (DMP -0,36; IC de 95%: -0,16 -0,55-, p < 0,001), tempo de UTI (DMP: -0,35, IC de 95%: -0,58- -0,13, p < 0,01), estadia hospitalar (DMP: -0,29; IC de 95%: -0.50 - -0,07, p < 0,05) e taxa de transfusão de sangue (RR: Cl 0,57, 95% de 0,49-0,67, p < 0,001), mas necessitou mais tempo de cirurgia (DMP): 1,29, IC de 95% 0,54-2,05, p < 0,001) e custos de hospitalização (DMP: 1,06, 95 %: 0,45-1,66, p < 0,001). O grupa RCH tinha uma taxa mais baixa de ECCAM a médio prazo (RR de 0,49, IC de 95% 0,26-0,92, p < 0,05), mas uma taxa mais elevada a médio prazo em revascularização de vaso alvo (RVA, RR: 2,20, IC 95%: 1,32). 3,67, p < 0,01). Conclusões: A RCH teve mortalidade e morbidade semelhantes no curto prazo comparada ao CRM sem CEC. A RCH diminuiu o tempo de ventilação, a internação na UTI, a internação hospitalar, a taxa de transfusão de sangue e o aumento do tempo de operação e os custos de hospitalização. A RCH tem uma taxa ECCAM mais baixa no médio prazo, enquanto a CRM sem CEC se mostra melhor em RVA a médio prazo.

Epidemiology of chronic airway disease: results from a cross-sectional survey in Beijing, China.

BACKGROUND: Although the epidemiology of chronic airway disease (CAD) has been investigated in several population-based studies, the findings of these studies are diverse. We aimed to investigate the prevalence of CAD and its associated factors in urban northern China. METHODS: A cross-sectional study was conducted among 29,359 Chinese adults aged ≥20 years. All participants were randomly recruited from two urban communities in Beijing and asked to complete a self-administered questionnaire that enquired about the demographic characteristics as well as the diagnosis of CAD and CAD-related symptoms. RESULTS: In all, 26,166 participants completed the questionnaire, with the response rate being 89.1%. The prevalence of diagnosed CAD was 9.0% among men and 7.2% among women, with a total prevalence of 8.1%. Furthermore, 11.5% of the investigated subjects had CAD-related symptoms. Women had a lower risk of developing wheezing, cough, dyspnea, and diagnosed CAD than men (P<0.05). The frequency of CAD-related symptoms and diagnosed CAD was greater among elderly persons than among those who were younger (P<0.01). Subjects with a smoking habit were more susceptible to CAD-related symptoms and diagnosed CAD (P<0.01). Additionally, individuals with CAD-related symptoms were more likely to be diagnosed with CAD, compared to those without these symptoms (P<0.01). CONCLUSIONS: CAD is a common respiratory disease in urban northern China. Female gender might be a protective factor against CAD, while age and smoking are risk factors for the disease.