A systemic pan-cancer analysis of MPZL3 as a potential prognostic biomarker and its correlation with immune infiltration and drug sensitivity in breast cancer

BackgroundThis study aimed to analyze the role of myelin protein zero-like 3 (MPZL3), a single membrane glycoprotein, in prognosis, tumor immune infiltration, and drug susceptibility in human cancers.MethodsData regarding MPZL3 were extracted from the TCGA, GTEx, CellMiner, CCLE, TIMER, GSEA, and USCS Xena databases. The expression difference, survival outcomes, DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR), tumor microenvironment (TME), immune cell infiltration, and drug sensitivity of MPZL3 were analyzed by R language software. Cell proliferation and drug sensitivity tests were applied to analyze the biological role of MPZL3 and drug sensitivities in breast cancer.ResultsMPZL3 was highly expressed in most cancer types and correlated with unfavorable survival outcomes in several cancers. TMB, MSI, MMR, DNA methylation, and RNA modification played a significant role in mediating MPZL3 dysregulation in cancers, and MPZL3 was closely linked to CD8+ T cells and CD4+ T immune infiltration. The MPML3 mRNA level was associated with protein secretion, the Notch signaling pathway, and heme metabolism. In addition, drug sensitivity analysis and validation also indicated that MPZL3 expression influenced the sensitivity of therapeutics targeting EGFR, ABL, FGFR, etc. Additionally, MPZL3 overexpression contributed to proliferation and drug sensitivity in different subtypes of breast cancer.ConclusionsThis study provides a comprehensive analysis and understanding of the oncogenic roles of the pan-cancer gene MPZL3 across different tumors, including breast cancer. MPZL3 could be a potential prognostic biomarker and therapeutic target for breast cancer

Accuracy of ultrasonographic changes during neoadjuvant chemotherapy to predict axillary lymph node response in clinical node-positive breast cancer patients

PurposeTo evaluate whether changes in ultrasound features during neoadjuvant chemotherapy (NAC) could predict axillary node response in clinically node-positive breast cancer patients.MethodsPatients with biopsy-proven node-positive disease receiving NAC between February 2009 and March 2021 were included. Ultrasound (US) images were obtained using a 5-12-MHz linear array transducer before NAC, after two cycles, and at the completion of NAC. Long and short diameter, cortical thickness, vascularity, and hilum status of the metastatic node were retrospectively reviewed according to breast imaging-reporting and data system (BI-RADS). The included population was randomly divided into a training set and a validation set at a 2:1 ratio using a simple random sampling method. Factors associated with node response were identified through univariate and multivariate analyses. A nomogram combining clinical and changes in ultrasonographic (US) features was developed and validated. The receiver operating characteristic (ROC) and calibration plots were applied to evaluate nomogram performance and discrimination.ResultsA total of 296 breast cancer patients were included, 108 (36.5%) of whom achieved axillary pathologic complete response (pCR) and 188 (63.5%) had residual nodal disease. Multivariate regression indicated that independent predictors of node pCR contain ultrasound features in addition to clinical features, clinical features including neoadjuvant HER2-targeted therapy and clinical response, ultrasound features after NAC including cortical thickness, hilum status, and reduction in short diameter ≥50%. The nomogram combining clinical features and US features showed better diagnostic performance compared to clinical-only model in the training cohort (AUC: 0.799 vs. 0.699, P=0.001) and the validation cohort (AUC: 0.764 vs. 0.638, P=0.027).ConclusionsUltrasound changes during NAC could improve the accuracy to predict node response after NAC in clinically node-positive breast cancer patients

An exosome-based specific transcriptomic signature for profiling regulation patterns and modifying tumor immune microenvironment infiltration in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor that lacks effective treatment and has a poor prognosis. Exosomes carry abundant genomic information and have a significant role in tumorigenesis, metastasis, and drug resistance. However, further exploration is needed to investigate the relationship between exosome-related genes and the heterogeneity and tumor immune microenvironment of TNBC. Based on the exosome-related gene sets, multiple machine learning algorithms, such as Cox boost, were used to screen the risk score model with the highest C-index. A 9-gene risk score model was constructed, and the TNBC population was divided into high- and low-risk groups. The effectiveness of this model was verified in multiple datasets. Compared with the low-risk group, the high-risk group exhibited a poorer prognosis, which may be related to lower levels of immune infiltration and immune response rates. The gene mutation profiles and drug sensitivity of the two groups were also compared. By screening for genes with the most prognostic value, the hub gene, CLDN7, was identified, and thus, its potential role in predicting prognosis, as well as providing ideas for the clinical diagnosis, treatment, and risk assessment of TNBC, was also discussed. This study demonstrates that exosome-related genes can be used for risk stratification in TNBC, identifying patients with a worse prognosis. The high-risk group exhibited a poorer prognosis and required more aggressive treatment strategies. Analysis of the genomic information in patient exosomes may help to develop personalized treatment decisions and improve their prognosis. CLDN7 has potential value in prognostic prediction in the TNBC population

Targeting glutamine metabolic reprogramming of SLC7A5 enhances the efficacy of anti-PD-1 in triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) is a heterogeneous disease that is characterized by metabolic disruption. Metabolic reprogramming and tumor cell immune escape play indispensable roles in the tumorigenesis that leads to TNBC.MethodsIn this study, we constructed and validated two prognostic glutamine metabolic gene models, Clusters A and B, to better discriminate between groups of TNBC patients based on risk. Compared with the risk Cluster A patients, the Cluster B patients tended to exhibit better survival outcomes and higher immune cell infiltration. In addition, we established a scoring system, the glutamine metabolism score (GMS), to assess the pattern of glutamine metabolic modification.ResultsWe found that solute carrier family 7 member 5 (SLC7A5), an amino acid transporter, was the most important gene and plays a vital role in glutamine metabolism reprogramming in TNBC cells. Knocking down SLC7A5 significantly inhibited human and mouse TNBC cell proliferation, migration, and invasion. In addition, downregulation of SLC7A5 increased CD8+ T-cell infiltration. The combination of a SLC7A5 blockade mediated via JPH203 treatment and an anti-programmed cell death 1 (PD-1) antibody synergistically increased the immune cell infiltration rate and inhibited tumor progression.ConclusionsHence, our results highlight the molecular mechanisms underlying SLC7A5 effects and lead to a better understanding of the potential benefit of targeting glutamine metabolism in combination with immunotherapy as a new therapy for TNBC

Impact of clinicopathological factors on extended endocrine therapy decision making in estrogen receptor–positive breast cancer

PurposeIn our study, we aim to analyze the impact of clinicopathological factors on the recommendation of extended endocrine therapy (EET) in patients with ER+ breast cancer and to retrospectively validate the value of CTS5 in EET decision making.Patients and methodsThe retrospective analysis was performed in patients with ER+ breast cancer who have finished 4.5–5 years of adjuvant endocrine therapy and undergone MDT discussion from October 2017 to November 2019. Multivariate logistic regression was used to identify the independent factors for treatment recommendation. CTS5 was calculated for retrospective validation of the EET decision making.ResultsTwo hundred thirty-five patients were received; 4.5–5 years of adjuvant endocrine therapy were included in the study. Multivariate analysis suggested that age (OR 0.460, 95% CI 0.219–0.965, p = 0.04), pN (OR 39.350, 95% CI 9.831–157.341, P < 0.001), and receipt of chemotherapy (OR 3.478, 95% CI 1.336–9.055, p = 0.011) were independent predictors for the recommendation of EET. In the previously selective estrogen receptor modulator (SERM)–treated subgroup, pN and receipt of chemotherapy were independent predictors for the recommendation of EET. In the previously AI-treated subgroup, age, pN, and receipt of chemotherapy were independent predictors. Adverse events did not affect the recommendation in patients previously treated with adjuvant endocrine treatment nor in the previously SERM or AI-treated subgroups. CTS5 (OR 21.887, 95% CI 2.846–168.309, p = 0.003) remained an independent predictor for the recommendation of EET.ConclusionsOur study indicated that age, lymph nodal status, and receipt of chemotherapy were independent predictors for the recommendation of EET. The application of the CTS5 on EET decision making might be valuable among ER+ breast cancer patients

Retrospective analysis of 119 Chinese noninflammatory locally advanced breast cancer cases treated with intravenous combination of vinorelbine and epirubicin as a neoadjuvant chemotherapy: a median follow-up of 63.4 months

<p>Abstract</p> <p>Background</p> <p>This study is a retrospective evaluation of the efficacy of neoadjuvant chemotherapy (NC) with a vinorelbine (V) and epirubicin (E) intravenous combination regimen and is aimed at identification of predictive markers for the long-term outcome in noninflammatory locally advanced breast cancer (NLABC).</p> <p>Methods</p> <p>One-hundred-and-nineteen patients with NLABC were identified from September 2001 to May 2006. Analysis was performed in March 2008, with a median follow-up of 63.4 months (range, 9-76 months). All patients were diagnosed with invasive breast cancer using 14 G core needle biopsy and treated with three cycles of VE before surgery. Local-regional radiotherapy was offered to all patients after the completion of chemotherapy followed by hormonal therapy according to hormone receptor status. Tissue sections cut from formalin-fixed paraffin-embedded blocks from biopsy specimens and postoperative tumor tissues were stained for the presence of estrogen receptor (ER), progesterone receptor (PgR), HER-2 (human epidermal growth factor receptor-2), and MIB-1(Ki-67).</p> <p>Results</p> <p>Patients characteristics were median age 52 years (range: 25-70 years); clinical TNM stage, stage IIB (n = 32), stage IIIA (n = 56), stage IIIB (n = 22) and stage IIIC (n = 9). All patients were evaluable for response: clinically complete response was documented in 27 patients (22.7%); 78 (65.6%) obtained partial response; stable disease was observed in 13 (10.9%); 1 patient (0.8%) had progressive disease. Pathological complete response was found in 22 cases (18.5%). Seventy-five patients were alive with no recurrence after a median follow-up of 63.4 months, the 5-year rates for disease-free survival and overall survival were 58.7% and 71.3%, respectively, after the start of NC. On multivariate analysis, the independent variables associated with increased risk of relapse and death were high pre-Ki-67(p = 0.012, p = 0.017, respectively), high post-Ki-67 expression (p = 0.045, p = 0.001, respectively), and non-pCR (p = 0.034, p = 0.027, respectively). A significantly increased risk of death was associated with lack of pre-ER expression (p = 0.002). Among patients with non-pCR, those with a pathological response at the tumor site with special involvement (i.e. skin, vessel and more than one quadrant) were at a higher risk of disease relapse and death (p < 0.001, p = 0.001, respectively).</p> <p>Conclusion</p> <p>This study suggests the promising use of a VE regimen as NC for Chinese NLABC after a median follow-up of 63.4 months. Pathological response in the tumor site, pre-Ki-67 and post-Ki-67 expression, and pre-ER expression were the important variables that predicted long-term outcome. Patients with pathological special involvement at the primary site after NC had the lowest survival rates.</p

Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1) : a phase 3, randomised, double-blind, multicentre trial

BACKGROUND : mTOR inhibition has been shown to reverse trastuzumab resistance from hyperactivated the PIK/AKT/mTOR pathway due to PTEN loss, by sensitizing PTEN-deficient tumors towards trastuzumab. The BOLERO-1 study evaluated the efficacy and safety of adding everolimus to trastuzumab and paclitaxel as first-line therapy for HER2+ advanced breast cancer (ABC). METHODS : In this phase III, randomized, double-blind trial, patients were enrolled across 141 sites in 28 countries. Eligible patients were ≥18 years of age, with locally assessed HER2+ advanced breast cancer (ABC), with Eastern Cooperative Oncology Group performance status of 0-1, who had not received prior trastuzumab or chemotherapy for ABC, had measurable disease as per Response Evaluation Criteria in Solid Tumors or bone lesions in the absence of measurable disease, without prior systemic therapy for advanced disease except endocrine therapy. The patients were randomized 2:1 (with an interactive voice and web response system) to receive either daily everolimus (10 mg/day) orally or placebo plus weekly trastuzumab intravenously at 4 mg/kg loading dose on Day-1 with subsequent weekly doses of 2 mg/kg of each 4-week cycle plus paclitaxel intravenously at a dose of 80 mg/m2 on days 1, 8, and 15 of each 4- week cycle. Randomization was stratified according to prior use of trastuzumab and visceral metastasis. Patients and investigators were blinded to the assigned treatments. Identity of experimental treatments was concealed by use of everolimus and placebo that were identical in packaging, labelling, appearance, and administration schedule. The two primary objectives were investigator-assessed progression-free survival (PFS) in the full study population and in the subset of patients with hormone receptor-negative (HR) breast cancer at baseline; the latter was added during the course of the study, prior to unblinding based on new clinical and biological findings from other studies. All efficacy analyses were based on the intention-to-treat population. Enrolment for this trial is closed and results of the final PFS analyses are presented here. Clinicaltrials.gov identifier: NCT00876395. FINDINGS : Between 10-Sep-2009 and 16-Dec-2012, 719 patients were randomized to receive everolimus (n=480) or placebo (n=239). Median follow-up was 41.3 months (IQR: 35.4 – 46.6 months). INTERPRETATION : The primary objective in the full population was not met; median PFS was 15.0 months with everolimus vs 14.5 months with placebo (hazard ratio, 0.89; 95% CI, 0.73-1.08; p=0.1166). In the HR subpopulation (n=311), median PFS with everolimus was 20.3 months vs 13.1 months with placebo (hazard ratio, 0.66; 95% CI, 0.48-0.91; p=0.0049), however, the protocol-specified statistical significance threshold (p=0.0044) was not crossed. The most common adverse events (AEs) with everolimus vs placebo were stomatitis (314 [66.5%] vs 77 [32.4%] patients), diarrhea (267 [56.6%] vs 111 [46.6%] patients), and alopecia (221 [46.8%] vs 125 [52.5%]). The most frequently reported grade 3/4 AEs in the EVE arm vs PBO arm were neutropenia (117 [24.8%] of 472 patients vs 35 [14.7%] of 238 patients), stomatitis (59 [12.5%] of 472 patients vs 3 [1.3%] of 238 patients), anemia (46 [9.7%] of 472 patients vs 6 [2.5%] of 238 patients) and diarrhea (43 [9.1%] of 472 patients vs 10 [4.2%] of 238 patients) On-treatment AE-related deaths were reported in 17 [3.6%] vs 0% of patients respectively.Interpretation: The primary objective of PFS was not met. However, consistent with the preliminary observations from BOLERO-3, everolimus prolonged median PFS by 7.2 months in patients with HR, HER2+ ABC, which warrants further investigation. The safety profile was generally consistent with what was previously reported in BOLERO-3. Proactive monitoring and early management of AEs in patients treated with everolimus and chemotherapy is critical..Novartis Pharmaceuticals Corporation.http://www.journals.elsevier.com/the-lancet-oncology2016-07-31hb201

Association of serum lipid levels and clinical outcomes in early breast cancer patients

Background: The association between dyslipidaemia and breast cancer remains controversial, especially regarding the dynamic changes in lipid levels. Objectives: This study aimed to elucidate the role of serum lipid levels and the changes in disease outcomes in patients with breast cancer. Methods: The lipid profiles of patients with breast cancer who underwent surgery between 2013 and 2017 were retrospectively reviewed. The lipid profiles comprised triglyceride (TG), total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein. Serum lipid levels were categorized into three groups based on the tertiles. The Wilcoxon test was used to compare changes in serum lipid levels during follow-up. Hazard ratios (HRs) for survival outcomes were estimated using a multivariate Cox regression analysis. Results: A total of 3499 women diagnosed with nonmetastatic invasive breast cancer were included in this study, with a median follow-up of 60.4 months. We confirmed that each 1-tertile increased TG at baseline [HR = 1.19, 95% confidence interval (CI) 1.02–1.39] and 1-year follow-up (HR = 1.46, 95% CI 1.07–1.98) led to worse relapse-free survival (RFS). A lower risk of disease relapse was observed with each 1-tertile upregulation in HDL at 1-year follow-up (HR = 0.72, 95% CI 0.56–0.92). Receiving systemic therapies tends to induce an elevation in plasma lipid levels 1 year after surgery, especially in terms of TG. Regarding the prognostic value of dynamic changes in lipid levels, patients with sustained high levels of TG had poorer RFS (HR = 1.90, 95% CI 1.16–3.11), whereas maintaining high levels of HDL led to better survival (HR = 0.60, 95% CI 0.37–0.97). Conclusion: High TG at baseline and during follow-up was associated with worse disease outcome in early breast cancer patients. Systemic treatment would lead to an elevation of serum lipid levels. Patients with sustained high HDL level at 1-year follow-up after surgery had a superior prognosis, warranting further clinical evaluation