Carbidopa suppresses estrogen receptor-positive breast cancer via AhR-mediated proteasomal degradation of ERα.

Estrogen receptor-α (ERα) promotes breast cancer, and ER-positive cancer accounts for ~ 80% of breast cancers. This subtype responds positively to hormone/endocrine therapies involving either inhibition of estrogen synthesis or blockade of estrogen action. Carbidopa, a drug used to potentiate the therapeutic efficacy of L-DOPA in Parkinson's disease, is an agonist for aryl hydrocarbon receptor (AhR). Pharmacotherapy in Parkinson's disease decreases the risk for cancers, including breast cancer. The effects of carbidopa on ER-positive breast cancer were evaluated in cell culture and in mouse xenografts. The assays included cell proliferation, apoptosis, cell migration/invasion, subcellular localization of AhR, proteasomal degradation, and tumor growth in xenografts. Carbidopa decreased proliferation and migration of ER-positive human breast cancer cells in vitro with no significant effect on ER-negative breast cancer cells. Treatment of ER-positive cells with carbidopa promoted nuclear localization of AhR and expression of AhR target genes; it also decreased cellular levels of ERα via proteasomal degradation in an AhR-dependent manner. In vivo, carbidopa suppressed the growth of ER-positive breast cancer cells in mouse xenografts; this was associated with increased apoptosis and decreased cell proliferation. Carbidopa has therapeutic potential for ER-positive breast cancer either as a single agent or in combination with other standard chemotherapies.

Free docosahexaenoic acid promotes ferroptotic cell death via lipoxygenase dependent and independent pathways in cancer cells.

PURPOSE: Ferroptosis is a form of regulated cell death that has the potential to be targeted as a cancer therapeutic strategy. But cancer cells have a wide range of sensitivities to ferroptosis, which limits its therapeutic potential. Accumulation of lipid peroxides determines the occurrence of ferroptosis. However, the type of lipid involved in peroxidation and the mechanism of lipid peroxide accumulation are less studied. METHODS: The effects of fatty acids (10 µM) with different carbon chain length and unsaturation on ferroptosis were evaluated by MTT and LDH release assay in cell lines derived from prostate cancer (PC3, 22RV1, DU145 and LNCaP), colorectal cancer (HT-29), cervical cancer (HeLa) and liver cancer (HepG2). Inhibitors of apoptosis, necroptosis, autophagy and ferroptosis were used to determine the type of cell death. Then the regulation of reactive oxygen species (ROS) and lipid peroxidation by docosahexaenoic acid (DHA) was measured by HPLC-MS and flow cytometry. The avtive form of DHA was determined by siRNA mediated gene silencing. The role of lipoxygenases was checked by inhibitors and gene silencing. Finally, the effect of DHA on ferroptosis-mediated tumor killing was verified in xenografts. RESULTS: The sensitivity of ferroptosis was positively correlated with the unsaturation of exogenously added fatty acid. DHA (22:6 n-3) sensitized cancer cells to ferroptosis-inducing reagents (FINs) at the highest level in vitro and in vivo. In this process, DHA increased ROS accumulation, lipid peroxidation and protein oxidation independent of its membrane receptor, GPR120. Inhibition of long chain fatty acid-CoA ligases and lysophosphatidylcholine acyltransferases didn't affect the role of DHA. DHA-involved ferroptosis can be induced in both arachidonate lipoxygenase 5 (ALOX5) negative and positive cells. Down regulation of ALOX5 inhibited ferroptosis, while overexpression of ALOX5 promoted ferroptosis. CONCLUSION: DHA can effectively promote ferroptosis-mediated tumor killing by increasing intracellular lipid peroxidation. Both ALOX5 dependent and independent pathways are involved in DHA-FIN induced ferroptosis. And during this process, free DHA plays an important role.

Major Postoperative Complications in Esophageal Cancer After Minimally Invasive Esophagectomy Compared With Open Esophagectomy: An Updated Meta-analysis.

BACKGROUND: To evaluate the existing literature comparing cardiopulmonary complications after minimally invasive esophagectomy (MIE) with open esophagectomy (OE) and conduct a meta-analysis based on the relevant studies. METHODS: A systematic search for articles was performed in Medline, Embase, Wiley Online Library, and the Cochrane Library. The relative risks or odds ratios (ORs) were calculated by using fixed or random-effects models. The I2 and X2 tests were used to test for statistical heterogeneity. We performed a metaregression for the pulmonary complications with the adenocarcinoma proportion and tumor stage. Publication bias and small-study effects were assessed using Egger's test and Begg's funnel plot. RESULTS: A total of 30,850 participants were enrolled in the 63 studies evaluated in the meta-analysis. Arrhythmia, pulmonary embolism, pulmonary complications, gastric tip necrosis, anastomotic leakage, and vocal cord palsy were chosen as outcomes. The occurrence rate of arrhythmia was significantly lower in patients receiving MIE than in patients receiving OE (OR = 0.69; 95% CI = 0.53-0.89), with heterogeneity (I2 = 30.7%, P = 0.067). The incidence of pulmonary complications was significantly lower in patients receiving MIE (OR = 0.54, 95% CI = 0.45-0.63) but heterogeneity remained (I2 = 72.1%, P = 0.000). The risk of gastric tip necrosis (OR = 1.48, 95% CI = 1.07-2.05) after OE was lower than that after MIE. Anastomotic leakage, pulmonary embolism, and vocal cord palsy showed no significant differences between the two groups. CONCLUSIONS: MIE has advantages over OE, especially in reducing the incidence of arrhythmia and pulmonary complications. Thus, MIE can be recommended as the preferred alternative surgery method for resectable esophageal cancer.

Increased SIX-1 expression promotes breast cancer metastasis by regulating lncATB-miR-200s-ZEB1 axis.

Patients with advanced breast cancer (BC) showed a higher incidence of regional and distant metastases. Sine oculis homeobox homolog 1 (SIX-1) has been confirmed to be a key tumorigenic and metastatic regulator in BC progression. Yet, molecular mechanisms behind SIX-1-induced BC metastases remain largely unknown. Here we found that SIX-1 was frequently up-regulated in BC and correlated with poor outcomes when tested in human BC tissue microarray. Then, we manipulated the expression of SIX-1 by via shRNA-mediated knockdown and lentivirus-mediated overexpression. Transwell assay in vitro and lung metastases model of nude mice in vivo showed that SIX-1 promoted BC cell invasion and migration in vitro, and facilitated metastases in vivo. Mechanistically, SIX-1 could promote the transcription of lncATB, which exerts critical pro-metastatic role in BC by directly binding to the miR-200 family, especially for miR-200c, to induce EMT and promote metastases. In conclusion, SIX-1 exerts its pro-metastatic role in BC through lncATB/miR-200s axis of EMT signalling pathway and could act as an important diagnostic marker as well as a significant therapeutic target for clinically advanced BC.

Resolvin D1 and D2 inhibit tumour growth and inflammation via modulating macrophage polarization.

Plastic polarization of macrophage is involved in tumorigenesis. M1-polarized macrophage mediates rapid inflammation, entity clearance and may also cause inflammation-induced mutagenesis. M2-polarized macrophage inhibits rapid inflammation but can promote tumour aggravation. ω-3 long-chain polyunsaturated fatty acid (PUFA)-derived metabolites show a strong anti-inflammatory effect because they can skew macrophage polarization from M1 to M2. However, their role in tumour promotive M2 macrophage is still unknown. Resolvin D1 and D2 (RvD1 and RvD2) are docosahexaenoic acid (DHA)-derived docosanoids converted by 15-lipoxygenase then 5-lipoxygenase successively. We found that although dietary DHA can inhibit prostate cancer in vivo, neither DHA (10 µmol/L) nor RvD (100 nmol/L) can directly inhibit the proliferation of prostate cancer cells in vitro. Unexpectedly, in a cancer cell-macrophage co-culture system, both DHA and RvD significantly inhibited cancer cell proliferation. RvD1 and RvD2 inhibited tumour-associated macrophage (TAM or M2d) polarization. Meanwhile, RvD1 and RvD2 also exhibited anti-inflammatory effects by inhibiting LPS-interferon (IFN)-γ-induced M1 polarization as well as promoting interleukin-4 (IL-4)-mediated M2a polarization. These differential polarization processes were mediated, at least in part, by protein kinase A. These results suggest that regulation of macrophage polarization using RvDs may be a potential therapeutic approach in the management of prostate cancer.

Nomogram-derived prediction of pathologic complete response (pCR) in breast cancer patients treated with neoadjuvant chemotherapy (NCT).

BACKGROUND: Previous research results on the predictive factors of neoadjuvant chemotherapy (NCT) efficacy in breast cancer are inconsistent, suggesting that the ability of a single factor to predict efficacy is insufficient. Combining multiple potential efficacy-related factors to build a model may improve the accuracy of prediction. This study intends to explore the clinical and biological factors in breast cancer patients receiving NCT and to establish a nomogram that can predict the pathologic complete response (pCR) rate of NCT. METHODS: We selected 165 breast cancer patients receiving NCT from July 2017 to May 2019. Using pretreatment biopsy materials, immunohistochemical studies to assess estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 expression. The correlation between biological markers and pCR was analyzed. These predictors were used to develop a binary logistic regression model with cross-validation and to show the established predictive model with a nomogram. RESULTS: The nomogram for pCR based on lymphovascular invasion, anemia (hemoglobin≤120 g/L), ER, Ki67 expression levels and NCT regimen had good discrimination performance (area under the curve [AUC], 0.758; 95% confidence interval [CI], 0.675-0.841) and calibration coordination. According to the Hosmer-Lemeshow test, the calibration chart showed satisfactory agreement between the predicted and observed probabilities. The final prediction accuracy of cross-validation was 76%. CONCLUSIONS: We developed a nomogram based on multiple clinical and biological covariations that can provide an early prediction of NCT response and can help to quickly assess the individual benefits of NCT.

Identifying subtypes and developing prognostic models based on N6-methyladenosine and immune microenvironment related genes in breast cancer.

Breast cancer (BC) is the most prevalent cancer in women globally. The tumor microenvironment (TME), comprising epithelial tumor cells and stromal elements, is vital for breast tumor development. N6-methyladenosine (m6A) modification plays a key role in RNA metabolism, influencing its various aspects such as stability and translation. There is a notable link between m6A methylation and immune cells in the TME, although this relationship is complex and not fully deciphered. In this research, BC expression and clinicopathological data from TCGA were scrutinized to assess expression profiles, mutations, and CNVs of 31 m6A genes and immune microenvironment-related genes, examining their correlations, functions, and prognostic impacts. Lasso and Cox regression identified prognostic genes for constructing a nomogram. Single-cell analyses mapped the distribution and patterns of these genes in BC cell development. We investigated associations between gene-derived risk scores and factors like immune infiltration, TME, checkpoints, TMB, CSC indices, and drug response. As a complement to computational analyses, in vitro experiments were conducted to confirm these expression patterns. We included 31 m6A regulatory genes and discovered a correlation between these genes and the extent of immune cell infiltration. Subsequently, a 7-gene risk score was generated, encompassing HSPA2, TAP1, ULBP2, CXCL1, RBP1, STC2, and FLT3. It was observed that the low-risk group exhibited better overall survival (OS) in BC, with higher immune scores but lower tumor mutational burden (TMB) and cancer stem cell (CSC) indices, as well as lower IC50 values for commonly used drugs. To enhance clinical applicability, age and stage were incorporated into the risk score, and a more comprehensive nomogram was constructed to predict OS. This nomogram was validated and demonstrated good predictive performance, with area under the curve (AUC) values for 1-year, 3-year, and 5-year OS being 0.848, 0.807, and 0.759, respectively. Our findings highlight the profound impact of prognostic-related genes on BC immune response and prognostic outcomes, suggesting that modulation of the m6A-immune pathway could offer new avenues for personalized BC treatment and potentially improve clinical outcomes.

The outcome of neoadjuvant chemotherapy and the current trend of surgical treatment in young women with breast cancer: A multicenter real-world study (CSBrS-012).

Background and objectives: The relationship between age and the outcome of breast cancer neoadjuvant chemotherapy (NAC) remains controversial, and little is known about the choice of surgical treatment for young patients. In this multicenter real-world study, we sought to analyze the outcome of NAC as well as the current status and trend of surgical decision-making after NAC in young breast cancer patients. Methods: The medical records of patients from 20 hospitals in different regions of China were collected retrospectively. The study population included females diagnosed with cT1-4N0-3M0 breast cancer who received NAC from January 2010 to December 2020. Results: A total of 9,643 eligible patients were included, 1,945 (20.2%) of whom were ≤40 years old. Young patients tend to have a higher tumor stage and a higher proportion of Luminal B and triple-negative breast cancer (TNBC) tumors compared with the >40-year-old group. The breast pathological complete response (pCR) rate in the young group was 20.3%, and Luminal B tumor was more likely to obtain pCR in young patients. The implementation rate of breast-conserving surgery (BCS) and breast reconstruction surgery was higher in young patients and tended to increase over time. In different regions of China, there were great differences in the choice of surgical treatment after NAC among young patients. Conclusion: Breast cancer in young women has unique clinical characteristics, but age does not affect the overall pCR rate. In China, the BCS rate after NAC is increasing over time but is still at a low level.

Evaluation of outcome of chemotherapy for breast cancer patients older than 70 years: A SEER-based study.

Background: With the aging of the population, the number of elderly breast cancer cases has increased. However, there is a lack of effective randomized clinical trial data to support whether elderly patients should receive chemotherapy. Our goal was to observe the relationship between chemotherapy and breast cancer-specific survival (BCSS) in elderly breast cancer patients and to identify those who could benefit from chemotherapy. Methods: We collected the data of patients who were diagnosed with invasive ductal carcinoma and older than 70 years in the SEER database from 1995 to 2016. The independent predictors of BCSS were identified by Cox regression analysis. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to eliminate confounding factors. Results: A total of 142,537 patients were collected, including 21,782 patients in the chemotherapy group and 120,755 patients in the non-chemotherapy group. We identified the same potential predictors of BCSS after PSM and IPTW, such as age, race, grade, stage, therapy, subtype. A nomogram for predicting 3-year, 5-year and 10-year BCSS was constructed. The 3-year, 5-year and 10-year AUCs of the nomogram were 0.842, 0.819, and 0.788. According to the risk stratification of model predictive scores, patients in the high-risk group achieved the greatest improvement in BCSS after receiving chemotherapy. Conclusions: Our study suggests that women older than 70 years with larger tumors, higher grade, positive nodes, negative hormone receptor and inactive local therapy gain prognostic benefits from chemotherapy, but for those with low- and median-risk, conventional chemotherapy should be administered cautiously.

A risk stratification model to predict chemotherapy benefit in medullary carcinoma of the breast: a population-based SEER database.

Whether patients with medullary breast carcinoma (MBC) receive chemotherapy is controversial. Therefore, the aim of our study was to screen out patients with MBC who benefit from chemotherapy. We enrolled 618 consecutive patients with MBC from The Surveillance, Epidemiology, and End Results (SEER) database (2010-2018). Cox regression analysis was used to identify independent prognostic factors. Next, a nomogram was constructed and evaluated using calibration plots and the area under the curve (AUC) of receiver operating characteristic (ROC) curves. Kaplan‒Meier curves were used to evaluate the overall survival (OS) benefit of chemotherapy in different risk groups. A total of 618 MBC patients were involved in our study, and an 8:2 ratio was used to randomly split them into a training cohort (n = 545) and a validation cohort (n = 136). Next, a nomogram predicting 3- and 5-year OS rates was constructed based on the five independent factors (age at diagnosis, T stage, N status, subtype and radiation). The nomogram AUCs for 3- and 5-year OS (training set: 0.793 and 0.797; validation set: 0.781 and 0.823) and calibration plots exhibited good discriminative and predictive ability. Additionally, a novel risk classification system for MBC patients demonstrated that we do not have enough evidence to support the benefit effect of chemotherapy for the high-risk group as the result is not statistically significant (total population: p = 0.180; training set: p = 0.340) but could improve OS in the low-risk group (total population: p = 0.001; training set: p = 0.001). Our results suggested that chemotherapy should be selected more carefully for high-risk groups based on a combination of factors and that the possibility of exemption from chemotherapy should be confirmed by more clinical trials in the future.

Elevated ADAM-like Decysin-1 (ADAMDEC1) expression is associated with increased chemo-sensitivity and improved prognosis in breast cancer patients.

Background: Chemoresistance is problematic and its mechanisms are unclear in breast cancer. More predictive markers are urgently required. Methods: GSE32646, GSE34138, and GSE20271 were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs) between chemosensitive and chemoresistant tumors. LinkedOmics was used to analyze ADAM-like Decysin-1 (ADAMDEC1) expression among patients with different clinical characteristics and detect co-expression genes for functional analysis. Tumor Immune Estimation Resource (TIMER) and an integrated repository portal for tumor-immune system interactions (TISIDB) were used to investigate the association between the target gene and the immune response. Gene Set Cancer Analysis (GSCA) was utilized to explore the related pathways of ADAMDEC1 and evaluate the correlation between the expression of ADAMDEC1 and drug sensitivity. RNA22, miRWalk, and miRmap were used to predict the upstream micro ribonucleic acids (miRNAs) regulating ADAMDEC1 expression, while DIANA-LncBase v2 was applied to predict the upstream long non-coding ribonucleic acids (lncRNAs). Kaplan-Meier curve analysis was applied to determine the survival time. Results: We identified that ADAMDEC1 was upregulated among chemosensitive triple-negative breast cancer (TNBC) tissues in GSE32646, GSE34138, and GSE20271. Higher expression of ADAMDEC1 indicated longer survival in breast cancer. Next, we found that ADAMDEC1 was significantly related to the immune response in breast cancer through functional enrichment analysis and further meta-data validation. Moreover, we recognized that hsa-miR-4534 was the potential upstream miRNA regulating ADAMDEC1 expression and Taurine Up-Regulated 1 (TUG1) was the most likely upstream lncRNA of ADAMDEC1 and hsa-miR-4534. Finally, the correlation between ADAMDEC1 and chemosensitivity was confirmed through drug database analysis. Conclusions: Elevated ADAMDEC1 expression is associated with increased chemosensitivity and better prognosis in breast cancer patients.

The nodal positivity rate in breast pCR patients with initially, clinically node-negative breast cancer after neoadjuvant systemic therapy: A systematic review and meta-analysis.

Background: The axillary lymph node positive (ypN+) rate in patients with clinically node-negative (cN0) breast cancer who have achieved breast pathologic complete response (bpCR) after neoadjuvant systemic therapy (NST) is extremely low, and this population has the potential to be exempt from sentinel lymph node biopsy (SLNB). However, an overview of the ypN+ rate in this population for different breast cancer subtypes is lacking. Objective: To provide the pooled ypN+ rate in cN0 patients who achieved bpCR after NST in different breast cancer subtypes defined by hormone receptor (HR) status and human epidermal growth factor receptor 2 (HER2) status. Methods: A systematic literature search was conducted in Embase and PubMed on July 20, 2022. Two authors independently selected studies that met the inclusion criteria and extracted all data. The pooled ypN+ rates for each subtype were calculated by a random-effects model using the Stata 16.0 metaprop command. Results: The pooled analysis of 9609 cN0 patients who achieved bpCR showed that the ypN+ rate was lowest for the HR+/HER2+ (0%) subtype, followed by HR+/HER2- (5.1%), HR-/HER2+ (0.6%), and HR-/HER2- (0.3%). Additionally, 6571 cT1-T2N0 patients who achieved bpCR had a pooled ypN+ rate of 0.6%, and the ypN+ rates for different subtypes were as follows: HR+/HER2+ (1.7%), HR+/HER2- (2.7%), HR-/HER2+ (0.1%), and HR-/HER2- (0.8%). Conclusion: Our results suggested that cN0 patients who achieve bpCR may be exempt from axillary surgery in the HR+/HER2-, HR+/HER2+, and HR-/HER2- subtypes because of the extremely low probability of residual axillary lymph node disease. However, the safety of omitting axillary surgery needs to be further confirmed by prospective studies. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/#recordDetails, identifier CRD42022351739.

Efficacy analysis of neoadjuvant chemotherapy with or without anthracyclines in female patients with HER2-positive breast cancer in China: a nationwide, multicenter, 10-year retrospective study (CSBrS-012).

Background: In the era of targeted therapy, whether patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are exempted from anthracycline usage in the neoadjuvant setting is controversial. Objectives: Our objective was to retrospectively analyze the differences in pathological complete remission (pCR) rates between the anthracycline group and the nonanthracycline group. Design: The CSBrS-012 study (2010-2020) included female primary breast cancer patients with neoadjuvant chemotherapy (NAC) who underwent standard breast and axillary surgery post-NAC. Methods: A logistic proportional hazard model was applied to estimate the association of covariates with pCR. Propensity score matching (PSM) was performed to balance the differences in baseline characteristics, and subgroup analyses were performed using the Cochran-Mantel-Haenszel test. Results: A total of 2507 patients were enrolled: the anthracycline group (n = 1581, 63%) and the nonanthracycline group (n = 926, 37%). A pCR was recorded in 17.1% (271/1581) of patients in the anthracycline group and in 29.3% (271/926) in the nonanthracycline group, and the difference in the pCR rate between the two groups was statistically significant [odds ratio (OR) = 2.00, 95% confidence interval (CI) (1.65-2.43); p < 0.001). In the subsequent subgroup analysis, substantial differences in pCR rates between the anthracycline and nonanthracycline groups were detected in the nontargeted [OR = 1.91, 95% CI (1.13-3.23); p = 0.015] and dual-HER2-targeted populations [OR = 0.55, 95% CI (0.33-0.92); p = 0.021) before PSM, whereas differences vanished after PSM. The pCR rates between the anthracycline and nonanthracycline groups did not differ for the single target population, either before or after PSM. Conclusion: In the presence of trastuzumab and/or pertuzumab, the pCR rate of patients with HER2-positive breast cancer receiving anthracycline was not superior to that of patients receiving nonanthracycline. Thus, our study further provides clinical evidence for exempting anthracycline treatment in HER2-positive breast cancer in the era of targeted therapy.

ATB0,+-targeted nanoparticles initiate autophagy suppression to overcome chemoresistance for enhanced colorectal cancer therapy.

Oxaliplatin (OXA) resistance remains the major obstacle to the successful chemotherapy of colorectal cancer (CRC). As a self-protection mechanism, autophagy may contribute to tumor drug resistance, therefore autophagy suppression could be regarded as a possible treatment option in chemotherapy. Cancer cells, especially drug-resistant tumor cells, increase their demand for specific amino acids by expanding exogenous supply and up-regulating de novo synthesis, to meet the needs for excessive proliferation. Therefore, it is possible to inhibit cancer cell proliferation through pharmacologically blocking the entry of amino acid into cancer cells. SLC6A14 (ATB0,+) is an essential amino acid transporter, that is often abnormally up-regulated in most cancer cells. Herein, in this study, we designed oxaliplatin/berbamine-coloaded, ATB0,+-targeted nanoparticles ((O + B)@Trp-NPs) to therapeutically target SLC6A14 (ATB0,+) and inhibit cancer proliferation. The (O + B)@Trp-NPs utilize the surface-modified tryptophan to achieve SLC6A14-targeted delivery of Berbamine (BBM), a compound that is found in a number of plants used in traditional Chinese medicine, which could suppress autolysosome formation though impairing autophagosome-lysosome fusion. We verified the feasibility of this strategy to overcome the OXA resistance during colorectal cancer treatment. The (O + B)@Trp-NPs significantly inhibited the proliferation and decreased the drug resistance of resistant colorectal cancer cells. In vivo, (O + B)@Trp-NPs greatly suppressed the tumor growth in tumor-bearing mice, which is consistent with the in vitro data. This research offers a unique and promising chemotherapeutic treatment for colorectal cancer.

Nomogram for predicting axillary upstaging in clinical node-negative breast cancer patients receiving neoadjuvant chemotherapy.

PURPOSE: The prediction of axillary lymph node status after neoadjuvant chemotherapy (NAC) becoming critical because of the advocation of the de-escalation of axillary management. We investigate associated factors of axillary upstaging in clinical node-negative (cN0) breast cancer patients receiving NAC to develop and validate an accurate prediction nomogram. METHODS: We retrospectively analyzed 1892 breast cancer patients with stage of cT1-3N0 treated by NAC and subsequent surgery between 2010 and 2020 in twenty hospitals across China. Patients randomly divided into a training set and validation set (3:1). Univariate and multivariate logistic regression analysis were performed, after which a nomogram was constructed and validated. RESULTS: In total, pathologic node negativity (ypN0) achieved in 1406 (74.3%) patients and another 486 (25.7%) patients upstaged to pathologic node positive (ypN+). Breast pathologic complete response (bpCR) was achieved in 445 (23.5%) patients and non-bpCR in 1447 (76.5%) patients. A nomogram was established by ER, tumor histology, HER2 status, cycle of NAC treatment, and the bpCR, which were confirmed by multivariate logistic analysis as independent predictors of nodal upstaging in the training cohort (n = 1419). The area under the receiver operating characteristic curve (AUC) of the training cohort and validation cohort (n = 473) were 0.73 (95% CI 0.693-0.751) and 0.77 (95% CI 0.723-0.812) respectively. CONCLUSION: We present a nomogram with a nationwide large sample data which can effectively predict axillary upstaging after neoadjuvant chemotherapy to give better advice for individualized axillary lymph node management of breast cancer.

A nomogram to identify appropriate candidates for breast-conserving surgery among young women with breast cancer: A large cohort study.

Background: There is a gradual increase of female breast cancer under 35 years old, who was characterized as poor prognosis. Whether young patients could obtain greater survival benefits from breast-conserving surgery (BCS) than mastectomy remains controversial. Methods: Breast cancer patients (≤35 years old) were selected from the Surveillance, Epidemiology, and End Results (SEER) database and divided into BCS and mastectomy group. Propensity score matching (PSM) was used to eliminate the distributional imbalance of variables among two groups. The influence of BCS on overall survival (OS) and breast cancer-specific survival (BCSS) was evaluated by Cox regression. Logistic regression was used to identify factors related to the benefit of BCS and to construct a nomogram. The nomogram was validated by the First Affiliated Hospital of Xi'an Jiaotong University cohort. Results: Totally, 15,317 cases in the SEER database and 149 cases of external validation cohort were included. BCS was an independent protective factor for OS (P = 0.028) and BCSS (P = 0.042). A nomogram was established, and the AUC values both in the internal and external validation set were 0.780. The applicability of the model was verified in the PSM cohort and indicated that the survival advantage in the BCS-Benefit group was higher than that in the BCS-Nonbenefit and mastectomy group (P <0.001). Conclusions: For young breast cancer patients, BCS may bring better OS and BCSS than mastectomy, but not all benefit from it. We constructed a model for young patients (≤35 years old) that could identify appropriate candidates who benefit from BCS.

Identification of prognostic biomarkers among ICAMs in the breast cancer microenvironment.

BACKGROUND: Intercellular adhesion molecules (ICAMs) in the tumor microenvironment are closely related to immunity and affect the prognosis of cancer patients. OBJECTIVE: The aim of our study is to explore the correlation between ICAM expression, mutation, methylation and immunity and their prognostic value in breast cancer (BC) is not clear. METHODS: Online databases and tools such as UALCAN, COSMIC, cBioPortal, MethSurv, PrognoScan, Kaplan-Meier Plotter, GSCA and TIMER were utilized in this study. RESULTS: We found that the mRNA and protein expression levels of ICAM1 were upregulated in triple-negative breast cancer (TNBC) compared with normal tissues, and TNBC patients with high expression of ICAM1 had better overall survival (OS) and recurrence-free survival (RFS). The main types of ICAM1 gene variants were missense mutation and amplification, and ICAM1 showed a lower level of methylation in TNBC cancer tissues than in normal tissues, which was contrary to the high expression levels of ICAM1 mRNA and protein. Next, the function of ICAM1 was mainly related to the activation of apoptosis, epithelial-mesenchymal transition (EMT) and inhibition of the androgen receptor (AR) and estrogen receptor (ER) pathways. Meanwhile, functional pathway enrichment results showed that ICAM1 was also involved in the immune regulation process of BC. Furthermore, the expression of ICAM1 was positively associated with 6 types of tumor-infiltrating immune cells (CD8+ T cells, CD4+ T cells, B cells, neutrophils, macrophages and dendritic cells) and was also positively related to the expression of programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA4). CONCLUSIONS: Our research indicated that ICAM1 was likely to be a potential therapeutic target in TNBC.

A Novel Risk-Scoring System to Identify the Potential Population Benefiting From Adjuvant Chemotherapy for Node-Negative TNBC Patients With Tumor Size Less Than 1 cm.

Background and Objectives: Whether chemotherapy is needed in node-negative triple-negative breast cancer (TNBC) patients with tumor size less than 1 cm is still controversial. In our research, we constructed a novel risk-scoring system to identify the potential TNBC patients benefiting from adjuvant chemotherapy in T1miN0M0, T1aN0M0, and T1bN0M0 stages. Methods: Relevant data were extracted from the SEER database. We applied Kaplan-Meier curves and the Cox hazards model for survival analysis and developed a nomogram of overall survival. The X-tile software was used for risk stratification. The information of TNBC patients treated in the First Affiliated Hospital of Xi'an Jiaotong University was used for the application of the model. Results: A total of 4266 patients who met the criteria of our study were included. T stage, age, race, surgery, and radiotherapy state were used to create the nomogram of overall survival. According to the total risk score, the patients were divided into high-risk (score g 73), median-risk (38 ≤ score < 73), and low-risk (score <38) groups. Chemotherapy can prolong the overall survival of patients in the median-risk and high-risk groups, while patients in the low-risk group can be exempted from chemotherapy. In addition, we also used the risk-scoring system in real-world patients as application and verification. Conclusion: We constructed a novel risk-scoring system that can be used as a chemotherapy decision-making tool for node-negative TNBC patients with tumor size less than 1 cm. Tumor size should not be the only criterion for chemotherapy treatment decision-making.

Effect of the Nipple-Excising Breast-Conserving Therapy in Female Breast Cancer: A Competing Risk Analysis and Propensity Score Matching Analysis of Results Based on the SEER Database.

Introduction: Due to the lack of randomized controlled trial, the effectiveness and oncological safety of nipple-excising breast-conserving therapy (NE-BCT) for female breast cancer (FBC) remains unclear. We aimed to explore and investigate the prognostic value of NE-BCT versus nipple-sparing breast-conserving therapy (NS-BCT) for patients with early FBC. Methods: In this cohort study, data between NE-BCT and NS-BCT groups of 276,661 patients diagnosed with tumor-node-metastasis (TNM) stage 0-III FBC from 1998 to 2015 were retrieved from the Surveillance, Epidemiology, and End Results database. Propensity score matching analysis, Kaplan-Meier, X-tile, Cox proportional hazards model, and competing risk model were performed to evaluate the effectiveness and oncological safety for patients in NE-BCT and NS-BCT groups. Results: A total of 1,731 (0.63%) patients received NE-BCT (NE-BCT group) and 274,930 (99.37%) patients received NS-BCT (NS-BCT group); 44,070 subjects died after a median follow-up time of 77 months (ranging from 1 to 227 months). In the propensity score matching (PSM) cohort, NE-BCT was found to be an adversely independent prognostic factor affecting overall survival (OS) [hazard ratio (HR), 1.24; 95% CI, 1.06-1.45, p=0.0078]. Subjects in NE-BCT group had similar breast-cancer-specific survival (BCSS) (HR, 1.15; 95%CI, 0.88-1.52, p=0.30) and worse other-causes-specific death (OCSD) (HR, 1.217; 95%CI, 1.002-1.478, p=0.048<0.05) in comparison with those in the NS-BCT group. Conclusions: Our study demonstrated that the administration of NE-BCT is oncologically safe and reliable and can be widely recommended in clinics for women with non-metastatic breast cancer.

A Comprehensive Pan-Cancer Analysis of RBM8A Based on Data Mining.

BACKGROUND: As a member of the exon junction complex (EJC), RNA-binding motif protein 8A (RBM8A) plays a crucial role in the maintenance of mRNA and multiple activities of an organism. Immunotherapy has been proven to be a staple type of cancer treatment. However, the role of RBM8A and immunity across cancer types is unclear. OBJECTIVE: This study aims to visualize the expression, prognosis, mutations, and coexpressed gene results of RBM8A across cancer types and to explore the link between RBM8A expression and immunity. METHODS: In this study, data were collected from multiple online databases. We analyzed the data using the HPA, UALCAN Database, COSMIC, cBioPortal, Cancer Regulome tools, Kaplan-Meier Plotter, and TIMER website. RESULTS: For the expression of RBM8A in normal tissues, higher expression of RBM8A was observed in immune-related cells than in nonimmune organs. The expression level of RBM8A was related to tumor type. Missense mutations in RBM8A were found in most tumors and affected the prognosis of carcinomas with coexpressed genes. RBM8A was strongly associated with immune-infiltrating cells and immune checkpoint inhibitors, especially in LIHC. CONCLUSIONS: RBM8A is a gene worth exploring and may be a unique immune target in the future.