Elevated expression of TUBA1C in breast cancer predicts poor prognosis.

α1C-tubulin (TUBA1C) is a member of the α-tubulin family and has served as a potential biomarker in a variety of cancers in many studies. In this study, the gene expression profile of TUBA1C in The Cancer Genome Atlas (TCGA) was extracted for analysis, and the prognostic value of TUBA1C in breast cancer was comprehensively evaluated. The Wilcoxon signed-rank test, Kruskal-Wallis test, and logistic regression analysis were performed to confirm the correlations between TUBA1C expression and the clinical characteristics of breast cancer patients. The effect of TUBA1C expression on the survival of breast cancer patients was assessed by Kaplan-Meier curve, Cox regression analysis, and the Kaplan-Meier plotter (an online database). The TCGA data set was used for the Gene Set Enrichment Analysis (GSEA). The results confirmed that high TUBA1C expression in breast cancer was closely correlated with survival time, survival status, and tumor size. In addition, elevated TUBA1C expression can predict poor overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS). Univariate and multivariate analyses (Cox regression analyses) confirmed that TUBA1C was an independent prognostic factor for the OS of breast cancer patients. The GSEA identified that the high TUBA1C expression phenotype was differentially enriched in cell cycle, basal transcription factor, P53 signaling pathway, pathways in cancer, TOLL-like receptor signaling pathway, and NOD-like receptor signaling pathway. In summary, high messenger RNA (mRNA) expression of TUBA1C is an independent risk factor for poor prognosis of breast cancer.

Multi-omics analysis of expression profile and prognostic values of connexin family in LUAD.

PURPOSE: Our study first explored the expression differences and prognostic significance of Cx genes in pan-cancer and then focused on LUAD. Our objectives were to conducted a comprehensive analysis of the expression profile, prognostic significance, genetic alterations, potential biological functions and drug sensitivity of the Connexin gene family in LUAD. METHODS: We developed a comprehensive prognostic model for LUAD by combining risk scores with clinical features and created a nomogram to predict 1-, 3-, and 5-year overall survival. Using single-cell sequencing, we examined the expression and biological functions of the identified prognostic markers. RESULTS: Our risk model revealed that GJB2-5 play a critical role in the prognosis of LUAD patients, associated with many biological processes such as cell cycle, DNA damage, EMT, hypoxia, invasion, and metastasis. Furthermore, the connexin gene family is linked to transcriptional mechanisms such as the extracellular matrix (ECM), migration, mobility, angiogenesis, and the epithelial-mesenchymal transition (EMT) genetic program. CONCLUSION: The risk model can be used as a potential prognostic factor for LUAD patients and may provide new insights into cancer treatment from perspective of the expression of Cx genes.

Second-line Endocrine Therapy of Hormone Receptor-positive/HER2- negative Advanced Breast Cancer: A Systematic Review and Network Meta-analysis.

BACKGROUND: The optimal second-line therapy for hormone receptor-positive (HR+)/ human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer is yet to be established. Therefore, we conducted a network meta-analysis (NMA) of marketed drugs to compare their efficacy. METHODS: We searched the literature in PubMed, Embase, Web of Science databases, and the main international conferences in the past 5 years to find phase III clinical trials on drugs available in the market. Network meta-analysis of progression-free survival (PFS), overall survival (OS), and the objective response rate (ORR) was performed using R software. The efficiency of treatment options was compared using hazard ratios and 95% credibility intervals. RESULTS: Overall, 12 studies with 6120 patients were included in the analysis. In an indirect comparison of the five regimens, cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) plus 500 mg fulvestrant (Ful500) gave the best PFS results; palbociclib ranked first with a surface under the cumulative ranking (SUCRA) of 94.99%, followed by mammalian target of rapamycin inhibitor (mTORi) plus everolimus (SUCRA=73.07%), phosphoinositide 3-kinase inhibitor (PI3Ki) plus Ful500 (SUCRA=66.73%), Ful500 alone (SUCRA=44.55%), and histone deacetylase inhibitor (HDACi) plus exemestane (SUCRA= 43.49%). However, no significant difference was found in the PFS rates of CDK4/6i, mTORi, and PI3Ki. For OS, CDK4/6i plus Ful500 ranked first; the SUCRA of ribociclib, abemaciclib, and palbociclib were 86.20%, 83.98%, and 78.52%, respectively. Alpelisib plus Ful500 (SUCRA=66.91%) ranked second but was not statistically different from CDK4/6i. The mTORi plus everolimus group had the best ORR (SUCRA=88.73%). In terms of safety, 81.56% of patients in the tucidinostat plus exemestane regimen developed neutropenia, suggesting strong hematological toxicity; 13.40% of patients developed grade 3-4 diarrhea after using abemaciclib plus Ful500. CONCLUSION: For second-line endocrine therapy in HR+/HER2- advanced/metastatic breast cancer, CDK4/6i is a better choice than mTORi, PI3Ki, HDACi, and Ful; it shows good PFS and OS outcomes and a low probability for serious adverse events.>.

Efficacy of anti-HER2 drugs in the treatment of patients with HER2-mutated cancers: a systematic review and meta-analysis.

Anti-human epidermal growth factor receptor-2 (anti-HER2) therapy has shown excellent efficacy in patients with HER2 overexpression and amplification. Although HER2 mutations are rarely expressed in several cancers, when they occur, they can activate the HER2 signaling pathway. In recent years, studies have shown that anti-HER2 drugs have promising efficacy in patients with HER2 mutations. Based on keywords, we searched databases, such as PubMed, Embase, and Cochrane Library, and the main conference abstracts. We extracted data on objective response rate (ORR), clinical benefit rate (CBR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) from studies on the efficacy of anti-HER2 therapies in patients with HER2-mutated cancers, and analyzed grade 3 or higher adverse events (AEs). We included 19 single-arm clinical studies and 3 randomized controlled trials (RCTs), containing a total of 1017 patients with HER2 mutations, involving seven drugs and nine cancers, and 18 studies enrolled a high proportion of heavily pretreated patients who had received multiple lines of therapy. Our results showed pooled ORR and CBR of 25.0% (range, 3.8-72.7%; 95% CI, 18-32%) and 36.0% (range, 8.3-63.0%; 95% CI, 31-42%) for anti-HER2 therapy in HER2-mutated cancers. The pooled median PFS, OS, DOR were 4.89 (95% CI, 4.16-5.62), 12.78 (95% CI, 10.24-15.32), and 8.12 (95% CI, 6.48-9.75) months, respectively. In a subgroup analysis, we analyzed the ORR for different cancers, showing 27.0, 25.0, 23.0, and 16.0% for breast, lung, cervical, and biliary tract cancers, respectively. ORR analyses were performed for different drugs as monotherapy or in combination, showing 60.0% for trastuzumab deruxtecan (T-DXd), 31.0% for pyrotinib, 26.0% for neratinib combined with trastuzumab, 25.0% for neratinib combined with fulvestrant, 19.0% for trastuzumab combined with pertuzumab, and 16.0% for neratinib. In addition, we found that diarrhoea, neutropenia, and thrombocytopenia were the most common grade ≥ 3 AEs associated with anti-HER2 therapeutic agents. In this meta-analysis of heavily pretreated patients with HER2 mutations, anti-HER2 therapies, DS-8201 and trastuzumab emtansine, showed promising efficacy and activity. Anti-HER2 therapies showed different efficacies in different or the same cancer settings and all had a tolerable safety profile.

Treatment options for patients with human epidermal growth factor 2-positive breast cancer brain metastases: A systematic review and meta-analysis.

Introduction: Many systemic treatment options are available for patients with human epidermal growth factor 2 (HER2)-positive breast cancer brain metastases. However, it is unclear which pharmacological treatment option is the most beneficial. Methods: We searched databases, such as PubMed, Embase, and Cochrane Library, and conference abstracts according to keywords. We extracted progression-free survival (PFS), overall survival (OS) data, and overall response rate (ORR) from randomized controlled trials and single-arm studies of HER2-positive breast cancer brain metastasis treatment for meta-analysis and analyzed different drug-related adverse events (AEs). Results: Three randomized controlled trials and seven single-arm clinical studies with 731 patients with HER2-positive brain metastases from breast cancer involving at least seven drugs were included. In randomized controlled trials, our results showed that trastuzumab deruxtecan significantly improved PFS and OS in patients and was superior to other drug regimens. In the single-arm study, the ORR was more pronounced for the trastuzumab deruxtecan and pyrotinib plus capecitabine regimens (ORR, 73.33%; 95% confidence intervals [CI], 44.90%-92.21%; ORR, 74.58%; 95% CI, 61.56%-85.02%, respectively). We found that the main AEs of antibody-drug conjugate (ADC) were nausea and fatigue, while the main AE of small-molecule tyrosine kinase inhibitor (TKI) drugs and large monoclonal antibodies was diarrhea. Conclusions: Trastuzumab deruxtecan was shown to be the most significant in improving survival in patients with HER2-positive breast cancer brain metastases in network meta-analysis, and in single-arm study, patients with HER2-positive breast cancer brain metastases treated with trastuzumab deruxtecan and pyrotinib plus capecitabine regimen had the highest ORR. The main AEs associated with ADC, large monoclonal antibodies, and TKI drugs were nausea, fatigue, and diarrhea, respectively.

Impact of platinum-based chemotherapy on the prognosis of early triple-negative breast cancer: a systematic review and meta-analysis.

Although platinum-based chemotherapy can improve pathologic complete response (pCR) in patients with triple-negative breast cancer (TNBC), the impact on survival of platinum-based neoadjuvant and adjuvant chemotherapy is still controversial. Our meta-analysis aimed at analyzing survival with platinum-based neoadjuvant and adjuvant chemotherapy in patients with TNBC. We searched PubMed, EMBASE, MEDLINE, Cochrane databases, and several major conferences up to January 2021. Fixed and random models were used for our meta-analysis. Disease-free survival (DFS), overall survival (OS), and side effects data were extracted from the included literature in addition to the corresponding pooled hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CIs). A total of nine studies involving 3247 patients were included. The pooled analysis suggested that compared with anthracycline- and/or paclitaxel-based chemotherapy, platinum-based chemotherapy could further improve DFS (HR = 0.56, 95% CI 0.45-0.67, p < 0.01) and OS (HR = 0.54, 95% CI 0.38-0.70, p < 0.01) in patients with TNBC. The subgroup analysis showed that platinum-based chemotherapy could further improve DFS (HR = 0.59, 95% CI 0.43-0.74, p < 0.01) and OS (HR = 0.61, 95% CI 0.40-0.83, p < 0.01) in neoadjuvant chemotherapy and DFS (HR = 0.53, 95% CI 0.37-0.69, p < 0.01) and OS (HR = 0.46, 95% CI 0.23-0.69, p < 0.01) in adjuvant chemotherapy compared with anthracycline- and/or paclitaxel-based chemotherapy in patients with TNBC. In addition, compared with anthracycline-based chemotherapy, platinum-based chemotherapy without anthracycline chemotherapy could further improve DFS (HR = 0.53, 95% CI 0.37-0.70, p < 0.01) and OS (HR = 0.46, 95%CI 0.19-0.72, p < 0.01) in patients with TNBC. Compared with anthracycline- and/or paclitaxel-based chemotherapy, all-grade diarrhea, fatigue, and grade ≥ 3 anemia were higher in platinum-based chemotherapy. In contrast, all-grade anemia, leukopenia, neutropenia, peripheral neuropathy, myalgia/arthralgia, cardiac toxicity were lower in platinum-based chemotherapy; grade ≥ 3 leukopenia, neutropenia and myalgia/arthralgia were also lower. Compared with anthracycline- and/or paclitaxel-based chemotherapy, platinum-based chemotherapy was more associated with improved DFS and OS in TNBC patients. The benefit of survival is consistent with platinum-based neoadjuvant and adjuvant chemotherapy. The side effects of platinum-based chemotherapy are tolerable.

Cyclin-dependent kinase 4 and 6 inhibitors in combination with neoadjuvant endocrine therapy in estrogen receptor-positive early breast cancer: a systematic review and meta-analysis.

The combination of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors and endocrine treatment has benefited patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER + /HER2-) metastatic breast cancer; however, its effects in the neoadjuvant setting for ER + /HER2- early breast cancer (EBC) are unclear. Systematic searches were performed in PubMed, Embase, Cochrane Library, and major oncological meetings for trials of CDK4/6 inhibitors plus neoadjuvant endocrine treatment (NET) vs. NET/neoadjuvant chemotherapy (NACT) alone up to January 30, 2021. We assessed the efficacy of CDK4/6 inhibitors plus NET vs. NET/NACT alone in ER + /HER2- EBC. Six studies that included 803 patients treated with CDK4/6 inhibitors plus NET vs. NET/NACT alone were used. Compared with NET/NACT alone, CDK4/6 inhibitors plus NET increased the complete cell cycle arrest (CCCA) rate (OR, 9.00; 95% CI, 5.42-14.96; P < 0.001). Nonsignificant differences between CDK4/6 inhibitors and NET/NACT alone occurred in the preoperative endocrine prognostic index (PEPI)-0 rate (OR, 1.13; 95% CI, 0.59-2.18; P = 0.71), pathological complete response (pCR) rate (OR, 0.75; 95% CI, 0.13-4.29; P = 0.74), objective response rate (ORR) (OR, 0.70; 95% CI, 0.21-2.29; P = 0.55), and disease control rate (DCR) (OR, 1.16; 95% CI, 0.47-2.89; P = 0.74). CDK4/6 inhibitors plus NET indicated a high risk of neutropenia (OR, 56.43; 95% CI, 15.76-202.11; P < 0.001) as an adverse effect (AE) and elevated alanine aminotransferase (ALT) level (OR, 15.30; 95% CI, 2.02-115.98; P = 0.008) as grade 3/4 AEs. Compared with NET/NACT alone, CDK4/6 inhibitors plus NET increased CCCA rate in ER + /HER2- EBC patients. CDK4/6 inhibitors plus NET did not substantially improve the PEPI-0 rate, pCR rate, ORR, or DCR. The combination increased the risk of neutropenia and elevated ALT levels. In the neoadjuvant setting, addition of CDK4/6 inhibitors to NET may be an option for treating ER + /HER2- EBC.

Watson for oncology decision system for treatment consistency study in breast cancer.

The Watson for Oncology (WFO) decision system has been rolled out in many cancers. However, the consistency of treatment for breast cancer is still unclear in relatively economically disadvantaged areas. Patients with postoperative adjuvant stage (January 2017 to December 2017) and advanced-stage breast cancer (January 2014 to December 2018) in northwest of China were included in this study. Patient information was imported to make treatment decisions using Watson version 19.20 analysis and subsequently compared with clinician decisions and analyzed for influencing factors. A total of 263 patients with postoperative adjuvant breast cancer and 200 with advanced breast cancer were included in this study. The overall treatment modality for WFO was in 80.2% and 50.5% agreement with clinicians in the adjuvant and advanced-stage population, respectively. In adjuvant treatment after breast cancer surgery, menopausal status (odds ratio (OR) = 2.89, P = 0.012, 95% CI, 1.260-6.630), histological grade (OR = 0.22, P = 0.019, 95% CI, 0.061-0.781) and tumor stage (OR = 0.22, P = 0.042, 95% CI, 0.050-0.943) were independent factors affecting the concordance between the two stages. In the first-line treatment of advanced breast cancer, hormone receptor status was a factor influencing the consistency of treatment (χ2 = 14.728, P < 0.001). There was good agreement between the WFOs and clinicians' treatment decisions in postoperative adjuvant breast cancer, but poor agreement was observed in patients with advanced breast cancer.

Comparative efficacy and safety of first-line neoadjuvant treatments in triple-negative breast cancer: systematic review and network meta-analysis.

Neoadjuvant treatment options for triple-negative breast cancer (TNBC) are abundant, but the efficacy of different combinations of treatment options remains unclear. Our network meta-analysis aimed to evaluate the effectiveness and safety of various neoadjuvant treatment options in patients with TNBC. Literature reports published before March 31, 2022, were retrieved from the PubMed, Embase, Cochrane Library, main oncology conference of the European Society of Medical Oncology, American Society of Clinical Oncology, and San Antonio Breast Cancer Symposium databases. Pairwise and Bayesian network meta-analyses were performed to compare direct and indirect evidence, respectively. The primary outcome was pathological complete response (pCR). Comparison of efficiency between different treatment regimens was made by HRs and 95% confidence intervals (CIs). Overall, 26 studies, including 9714 TNBC patients, were assessed in this network meta-analysis. Results indicated that the pCR of immune checkpoint inhibitors plus platinum-containing regimens is better than other joint regimens. PCR rate of neoadjuvant chemotherapy regimens containing bevacizumab, platinum, poly(ADP-ribose) polymerase inhibitors, and immune checkpoint inhibitors was higher than those of standard chemotherapy agents. By performing a conjoint analysis of the pCR rate and safety endpoints, we found that immune checkpoint inhibitors plus platinum-containing regimens were well balanced in terms of efficacy and toxicity. Considering the efficacy and acceptable adverse events, neoadjuvant chemotherapy based on immune checkpoint inhibitors plus platinum may be considered as an option for patients with TNBC.

Impact of intestinal dysbiosis on breast cancer metastasis and progression.

Breast cancer has a high mortality rate among malignant tumors, with metastases identified as the main cause of the high mortality. Dysbiosis of the gut microbiota has become a key factor in the development, treatment, and prognosis of breast cancer. The many microorganisms that make up the gut flora have a symbiotic relationship with their host and, through the regulation of host immune responses and metabolic pathways, are involved in important physiologic activities in the human body, posing a significant risk to health. In this review, we build on the interactions between breast tissue (including tumor tissue, tissue adjacent to the tumor, and samples from healthy women) and the microbiota, then explore factors associated with metastatic breast cancer and dysbiosis of the gut flora from multiple perspectives, including enterotoxigenic Bacteroides fragilis, antibiotic use, changes in gut microbial metabolites, changes in the balance of the probiotic environment and diet. These factors highlight the existence of a complex relationship between host-breast cancer progression-gut flora. Suggesting that gut flora dysbiosis may be a host-intrinsic factor affecting breast cancer metastasis and progression not only informs our understanding of the role of microbiota dysbiosis in breast cancer development and metastasis, but also the importance of balancing gut flora dysbiosis and clinical practice.

Case report of double superior vena cava and double odd vein with hypoplastic left brachiocephalic vein.

Persistent left superior vena cava (PLSVC) is a common venous variation that is usually accompanied by an absence of the left brachiocephalic vein, and displays a higher incidence in patients with congenital heart disease. Here, the case of a 57-year-old male patient who was found to have PLSVC on chest computed tomography (CT) during screening for gastric cancer metastasis at the Affiliated Hospital of Qinghai University, is described. Further coronal CT and three-dimensional reconstruction of the chest revealed the patient's double superior vena cava (DSVC), double odd veins, and left brachiocephalic vein dysplasia. The patient did not have congenital heart disease and the case was associated with dysplasia of the left brachiocephalic vein, indicating an unusual and rare venous abnormality. At the time of writing, the patient was receiving antitumour therapy.

Identification of the GTPase IMAP family as an immune-related prognostic biomarker in the breast cancer tumor microenvironment.

INTRODUCTION: Breast cancer is the most common malignancy threatening women's health worldwide. The GTPase IMAP family genes are proteins belonging to the immune-associated nucleotide subfamily of the GTP-binding superfamily and nucleotide-binding proteins. However, little is known about the role of different GTPase IMAP family genes in breast cancer. METHODS: We obtained differential genes from the GEPIA and UALCAN databases and then used the Kaplan-Meier plotter, The Human Protein Atlas, NetworkAnalyst, STRING, and TIMER to analyze the prognostic value, protein expression, and immune cell infiltration of the GTPase IMAP family in patients with breast cancer. RESULTS: Among the GIMAP family genes, the expression levels of GIMAP1, GIMAP5, GIMAP6, GIMAP7, and GIMAP8 were significantly low in breast tumor tissues. In the overall population, patients with high expression of all genes of the GIMAP family had a significantly higher overall survival (OS), with the most significant increase correlated with the GIMAP2 gene (hazard ratio [HR] = 0.45, 95% confidence interval [CI], 0.34-0.59, P = 3.1e-09). However, patients with high expression of the GIMAP family genes in triple-negative breast cancer compared to those with low expression had a significant OS benefit, with the most pronounced benefit correlated with the GIMAP2 gene (HR = 0.37, 95% CI, 0.23-0.59, P = 1.4e-05). GIMAP7 and GIMAP8 were significantly upregulated in breast tumor tissues. The expression of genes in different GIMAP families was positively correlated with the infiltration and expression of six immune cell types (B cells, CD4+ T cells, CD8+ T cells, macrophages, neutrophils, and dendritic cells). CONCLUSION: This study may provide novel insights into the selection of GIMAP family prognostic biomarkers for breast cancer.

Immune checkpoint inhibitors plus neoadjuvant chemotherapy in early triple-negative breast cancer: a systematic review and meta-analysis.

PURPOSE: Some studies have shown that Immune checkpoint inhibitors (ICIs) have a favorable efficacy in advanced triple negative breast cancer (TNBC) patients, but the results are controversial in neoadjuvant chemotherapy (NACT) stage. The purpose of this study is to evaluate the efficacy and safety after NACT plus ICIs in early TNBC patients. METHODS: After searching PubMed, EMBASE, the Cochrane library and several mainly oncology conferences up to 30 January 2021 systematically, and define randomized controlled trials (RCTs) exploring the efficacy and safety of programmed death protein-1/programmed cell death-Ligand 1(PD-1/PD-L1) inhibitors plus neoadjuvant chemotherapy in TNBC patients. The primary endpoint was the pathological complete response (pCR) in intention-to-treat populations (ITT), and the secondary endpoints were event-free survival (EFS) and safety analysis in the ITT populations. RESULTS: Six RCTs (N = 2142) were included in our meta-analysis; NACT plus ICIs increased pCR rates compared with NACT in intention-to-treat (ITT) populations (OR: 1.91; 95% CI: 1.32-2.78, P < 0.001). The pCR rate also increased in both PD-L1 positive (OR: 1.65; 95% CI: 1.26-2.16, P < 0.001) and PD-L1 negative patients (OR: 1.56; 95% CI: 1.04-2.33, P = 0.03), especially in PD-L1 positive patients. The benefit was also observed in nodal-positive populations (OR: 2.52; 95% CI: 1.69-3.77, P < 0.001) and Eastern Cooperative Oncology Group performance-status score (ECOG PS) 0 subgroup (OR: 1.90; 95% CI: 1.42-2.53, P < 0.001). Three RCTs (N = 1615) reported EFS and the results showed that adding PD-1/PD-L1 inhibitors increased EFS (HR 0.65, 95% CI 0.50-0.83, P = 0.0007) in ITT populations with a short follow-up time. In the safety analysis of 2205 patients with early TNBC from five eligible studies, NACT plus ICIs had a higher risk of grade 3-4 diarrhea (OR: 2.54; 95% CI: 1.21-5.32; P = 0.01), any grade of adverse effects(AEs)including vomiting (OR: 1.37; 95% CI: 1.00-1.86; P = 0.05), hyperthyroidism (OR: 6.04; 95% CI: 2.39-15.29; P < 0.001), and hypothyroidism (OR: 5.04; 95% CI: 3.02-8.39; P < 0.001). CONCLUSIONS: PD-1/PD-L1 inhibitors combined with chemotherapy can improve pCR rates and EFS, and with an increased incidence of some immune-related AEs compared with chemotherapy alone. NACT plus ICIs might be an option in patients with in PD-L1 positive and high-risk populations with positive nodal disease early TNBC.

Addition of immunotherapy to chemotherapy for metastatic triple-negative breast cancer: A systematic review and meta-analysis of randomized clinical trials.

BACKGROUND: One of the front treatment regimens used for metastatic triple-negative breast cancer (mTNBC) is treatment with programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) blockade combine with chemotherapy. However, the results of such studies have been controversial. METHODS: A systematic searched of PubMed, Embase, Cochrane Library, and the proceedings of the last 5 years of several meetings until February 18, 2021. The primary endpoint was the progression-free survival (PFS) of PD-L1-positive patients treated with PD1/PD-L1 blockade plus chemotherapy compare with chemotherapy. RESULTS: Overall, 4 studies that included a total of 3007 mTNBC patients were analyzed in this meta-analysis. PFS was significantly improved in the PD1/PD-L1 blockade plus chemotherapy group compared with the chemotherapy group in PD-L1-positive mTNBC patients (hazard ratios, (HR), 0.69; 95% CI, 0.59-0.80; P < .001), also in intention-to-treat (ITT) population (HR, 0.82; 95% CI, 0.74-0.90; P < .001). However, no significant benefit in overall survival (OS) was observed regardless of PD-L1 status or ITT population. The immunotherapy plus chemotherapy has higher adverse events (AEs) compared with chemotherapy (all AEs, Odds ratios (ORs), 2.33; 95% CI, 1.50-3.62; P < .001; grade 3-5 AEs, OR, 1.27; 95% CI, 1.04-1.55; P = .019). CONCLUSIONS: This meta-analysis showed that the addition of PD1/PD-L1 blockade to chemotherapy improved PFS in PD-L1 positive mTNBC patients, also in the ITT population. However, no significant benefit in OS was observed in patients of PD-L1 positive or in the ITT population after adding PD1/PD-L1 blockade. We found a higher rate of AEs with the addition of PD1/PD-L1 blockers to chemotherapy.

Comparing Biomarkers for Predicting Pathological Responses to Neoadjuvant Therapy in HER2-Positive Breast Cancer: A Systematic Review and Meta-Analysis.

INTRODUCTION: The predictive strength and accuracy of some biomarkers for the pathological complete response (pCR) to neoadjuvant therapy for HER2-positive breast cancer remain unclear. This study aimed to compare the accuracy of the HER2-enriched subtype and the presence of PIK3CA mutations, namely, TILs, HRs, and Ki-67, in predicting the pCR to HER2-positive breast cancer therapy. METHODS: We screened studies that included pCR predicted by one of the following biomarkers: the HER2-enriched subtype and the presence of PIK3CA mutations, TILs, HRs, or Ki-67. We then calculated the pooled sensitivity, specificity, positive and negative predictive values (PPVs and NPVs, respectively), and positive and negative likelihood ratios (LRs). Summary receiver operating characteristic (SROC) curves and areas under the curve (AUCs) were used to estimate the diagnostic accuracy. RESULTS: The pooled estimates of sensitivity and specificity for the HER2-enriched subtype and the presence of PIK3CA mutations, namely, TILs, HRs, and Ki-67, were 0.66 and 0.62, 0.85 and 0.27, 0.49 and 0.61, 0.54 and 0.64, and 0.68 and 0.51, respectively. The AUC of the HER2-enriched subtype was significantly higher (0.71) than those for the presence of TILs (0.59, p = 0.003), HRs (0.65, p = 0.003), and Ki-67 (0.62, p = 0.005). The AUC of the HER2-enriched subtype had a tendency to be higher than that of the presence of PIK3CA mutations (0.58, p = 0.220). Moreover, it had relatively high PPV (0.58) and LR+ (1.77), similar NPV (0.73), and low LR- (0.54) compared with the other four biomarkers. CONCLUSIONS: The HER2-enriched subtype has a moderate breast cancer diagnostic accuracy, which is better than those of the presence of PIK3CA mutations, TILs, HRs, and Ki-67.

Meta-Analysis of HER2-Enriched Subtype Predicting the Pathological Complete Response Within HER2-Positive Breast Cancer in Patients Who Received Neoadjuvant Treatment.

BACKGROUND: This meta-analysis aimed to better elucidate the predictive value of human epidermal growth factor receptor 2 (HER2)-enriched subtype of pathological complete response (pCR) rate within HER2-positive breast cancer patients receiving neoadjuvant treatment. METHODS: We identified prospective trials that evaluated the correlation between an HER2-enriched subtype and pCR rate in HER2-positive breast cancer. Pooled odds ratio (OR) values with 95% confidence intervals (CIs) were computed. RESULTS: Fifteen studies comprising 2,190 patients met the inclusion criteria. The HER2-enriched subtype was associated with increased odds of achieving a pCR (OR = 4.12, 95% CI = 3.38 to 5.03, P < 0.001) in patients overall. Moreover, it was correlated with improved pCR when single or dual HER2-targeted agent-based therapy was employed (OR = 3.36, 95% CI = 2.25 to 5.02, P < 0.001; OR = 4.66, 95% CI = 3.56 to 6.10, P < 0.001, respectively), but not when HER2-targeted agent-free chemotherapy was used (OR = 2.52, 95% CI = 0.98 to 6.49, P = 0.05). Moreover, an HER2-enriched subtype predicted higher pCR rates irrespective of HER2-targeted agents (trastuzumab, lapatinib, pertuzumab, or T-DM1); chemotherapy agents (taxane-based, or anthracyclines plus taxane-based); endocrine therapy and hormone receptor [all the differences were statistically significant (P all ≤ 0.001)]. CONCLUSIONS: The HER2-enriched subtype can more effectively and specifically predict pCR for HER2-targeted agent-based neoadjuvant treatment, irrespective of the number (single or dual) or category of HER2-targeted agent, including chemotherapy and endocrine therapy, or hormone receptor in cases of HER2-positive breast cancer.

The role of capecitabine-based neoadjuvant and adjuvant chemotherapy in early-stage triple-negative breast cancer: a systematic review and meta-analysis.

BACKGROUND: The role of capecitabine in neoadjuvant and adjuvant chemotherapy for early-stage triple-negative breast cancer (TNBC) is highly controversial. Our meta-analysis was designed to further elucidate the effects of capecitabine on survival in early-stage TNBC patients and its safety. METHODS: PubMed, Embase, and papers presented at several main conferences were searched up to December 19, 2019, to investigate capecitabine-based versus capecitabine-free neoadjuvant and adjuvant chemotherapy in TNBC patients. Heterogeneity was assessed using I2 test, combined with hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CI) computed for disease-free survival (DFS), overall survival (OS), and over grade 3 adverse events (AEs). RESULTS: A total of 9 randomized clinical trials and 3842 TNBC patients were included. Overall, the combined capecitabine regimens in neoadjuvant and adjuvant chemotherapy showed significantly improved DFS (HR = 0.75; 95% CI, 0.65-0.86; P < 0.001) and OS (HR = 0.63; 95% CI, 0.53-0.77; P < 0.001). In subgroup analysis, there were improvements in DFS in the groups with addition of capecitabine (HR = 0.64; 95% CI, 0.53-0.78; P < 0.001), adjuvant chemotherapy (HR = 0.73; 95% CI, 0.63-0.85; P < 0.001), and lymph node positivity (HR = 0.62; 95% CI, 0.44-0.86; P = 0.005). Capecitabine regimens were related to higher risks of diarrhea (OR = 2.88, 95% CI 2.23-3.74, P < 0.001), stomatitis (OR = 2.01, 95% CI 1.53-2.64, P < 0.001) and hand-foot syndrome (OR = 8.67, 95% CI 6.70-11.22, P < 0.001). CONCLUSION: This meta-analysis showed that neoadjuvant and adjuvant chemotherapy combined with capecitabine significantly improved both DFS and OS in early-stage TNBC patients with tolerable AEs. There were benefits to DFS in the groups with the addition of capecitabine, adjuvant chemotherapy, and lymph node positivity.

Association of Cyclin-Dependent Kinases 4 and 6 Inhibitors With Survival in Patients With Hormone Receptor-Positive Metastatic Breast Cancer: A Systematic Review and Meta-analysis.

Importance: One of the most recent treatment regimens used for hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative metastatic breast cancer is treatment with the cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors and endocrine therapy (ET). Objective: To assess overall survival (OS), progression-free survival (PFS), objective response rate, and adverse events, especially grades 3 and 4 adverse events, among patients with HR-positive, ERBB2-negative metastatic breast cancer who were treated with CDK4/6 inhibitors plus ET vs ET alone. Data Sources: A systematic search of PubMed, Embase, the main oncology conference of the European Society of Medical Oncology, and the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium databases for randomized clinical trials of CDK4/6 inhibitors plus ET vs ET for HR-positive, ERBB2-negative metastatic breast cancer. Searches were performed up to March 30, 2020. Study Selection: A total of 472 records were assessed in PubMed and Embase by 2 authors, including studies, international meeting reports, and reviews. Inclusion criteria were English-language phase 2 or 3 randomized clinical trials of HR-positive, ERBB2-negative metastatic breast cancer, with patients randomly assigned to receive CDK4/6 inhibitors plus ET or ET alone, and having OS or PFS outcomes. The exclusion criteria were phase 1 trials, retrospective studies, or studies without survival outcomes. Excluding the references, 16 articles were relevant. After excluding studies based on exclusion criteria, 9 studies were considered eligible for this meta-analysis. Data Extraction and Synthesis: Two researchers independently extracted data and assessed potential bias. Data assessment followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline. The results were pooled using a fixed-effect model. Main Outcomes and Measures: Study heterogeneity was assessed using the I2 statistic. Hazard ratios (HRs) and 95% CIs were used to evaluate PFS, OS, and subgroup analyses. Overall response and 95% CIs were used to evaluate the objective response rate and grade 3 or 4 adverse events. The primary outcome was OS. Results: In total, 9 studies that included a total of 5043 patients with metastatic breast cancer were assessed in this meta-analysis. Overall, the addition of CDK4/6 inhibitors to ET was associated with a statistically significant benefit to OS (HR, 1.33; 95% CI, 1.19-1.48; P < .001). Compared with ET alone, treatment with CDK4/6 inhibitors plus ET was associated with improved OS for the following subgroups: first-line therapy (HR, 1.35; 95% CI, 1.18-1.54; P < .001), second-line therapy (HR, 1.30; 95% CI, 1.09-1.54; P < .001), premenopausal women (HR, 1.32; 95% CI, 1.04-1.66; P < .001), postmenopausal women (HR, 1.34; 95% CI, 1.18-1.52; P < .001), visceral metastasis (HR, 1.31; 95% CI, 1.12-1.53; P < .001), bone-only metastasis (HR, 1.22; 95% CI, 0.88-1.68; P < .001), age younger than 65 years (HR, 1.25; 95% CI, 1.06-1.49; P < .001), and age 65 years or older (HR, 1.38; 95% CI, 1.11-1.72; P < .001). The addition of CDK4/6 inhibitors to ET was also associated with significant PFS benefit (HR, 1.84; 95% CI, 1.70-1.98; P < .001) and objective response rate benefit (odds ratio, 2.02; 95% CI, 1.61-2.53; P < .001). However, the use of CDK4/6 inhibitors in combination with ET was associated with significantly increased risk of grade 3 or 4 adverse events compared with ET alone, including neutropenia (HR, 57.05; 95% CI, 38.26-85.05; P < .001), leukopenia (HR, 36.36; 95% CI, 19.35-68.34; P < .001), and diarrhea (HR, 4.97; 95% CI, 2.84-8.69; P < .001). Conclusions and Relevance: This meta-analysis indicated that, compared with ET alone, treatment with CDK4/6 inhibitors plus ET was associated with significantly improved OS, PFS, and objective response rate among patients with HR-positive, ERBB2-negative metastatic breast cancer.