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Objective: To construct a multi-region MRI radiomics model for predicting pathological complete response (pCR) in breast cancer (BCa) patients who received neoadjuvant chemotherapy (NACT) and provide a theoretical basis for the peritumoral microenvironment affecting the efficacy of NACT. Methods: A total of 133 BCa patients who received NACT, including 49 with confirmed pCR, were retrospectively analyzed. The radiomics features of the intratumoral region, peritumoral region, and background parenchymal enhancement (BPE) were extracted, and the most relevant features were obtained after dimensional reduction. Then, combining different areas, multivariate logistic regression analysis was used to select the optimal feature set, and six different machine learning models were used to predict pCR. The optimal model was selected, and its performance was evaluated using receiver operating characteristic (ROC) analysis. SHAP analysis was used to examine the relationship between the features of the model and pCR. Results: For signatures constructed using three individual regions, BPE provided the best predictions of pCR, and the diagnostic performance of the intratumoral and peritumoral regions improved after adding the BPE signature. The radiomics signature from the combination of all the three regions with the XGBoost machine learning algorithm provided the best predictions of pCR based on AUC (training set: 0.891, validation set: 0.861), sensitivity (training set: 0.882, validation set: 0.800), and specificity (training set: 0.847, validation set: 0.84). SHAP analysis demonstrated that LZ_log.sigma.2.0.mm.3D_glcm_ClusterShade_T12 made the greatest contribution to the predictions of this model. Conclusion: The addition of the BPE MRI signature improved the prediction of pCR in BCa patients who received NACT. These results suggest that the features of the peritumoral microenvironment are related to the efficacy of NACT. [ABSTRACT FROM AUTHOR]

Background: Non-invasive identification of breast cancer (BCa) patients with pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) is critical to determine appropriate surgical strategies and guide the resection range of tumor. This study aimed to examine the effectiveness of a nomogram created by combining radiomics signatures from both intratumoral and derived tissues with clinical characteristics for predicting pCR after NACT. Methods: The clinical data of 133 BCa patients were analyzed retrospectively and divided into training and validation sets. The radiomics features for Intratumoral, peritumoral, and background parenchymal enhancement (BPE) in the training set were dimensionalized. Logistic regression analysis was used to select the optimal feature set, and a radiomics signature was constructed using a decision tree. The signature was combined with clinical features to build joint models and generate nomograms. The area under curve (AUC) value of receiver operating characteristic (ROC) curve was then used to assess the performance of the nomogram and independent predictors. Results: Among single region, intratumoral had the best predictive value. The diagnostic performance of the intratumoral improved after adding the BPE features. The AUC values of the radiomics signature were 0.822 and 0.82 in the training and validation sets. Multivariate logistic regression analysis revealed that age, ER, PR, Ki-67, and radiomics signature were independent predictors of pCR in constructing a nomogram. The AUC of the nomogram in the training and validation sets were 0.947 and 0.933. The DeLong test showed that the nomogram had statistically significant differences compared to other independent predictors in both the training and validation sets (P < 0.05). Conclusion: BPE has value in predicting the efficacy of neoadjuvant chemotherapy, thereby revealing the potential impact of tumor growth environment on the efficacy of neoadjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Genetic testing plays an important role in guiding screening, diagnosis, and precision treatment of breast cancer (BC). However, the appropriate genetic testing criteria remain controversial. The current study aims to facilitate the development of suitable strategies by analyzing the germline mutational profiles and clinicopathological features of large‐scale Chinese BC patients. Methods: BC patients who had undergone genetic testing at the Sun Yat‐sen University Cancer Center (SYSUCC) from September 2014 to March 2022 were retrospectively reviewed. Different screening criteria were applied and compared in the population cohort. Results: A total of 1035 BC patients were enrolled, 237 pathogenic or likely pathogenic variants (P/LPV) were identified in 235 patients, including 41 out of 203 (19.6%) patients tested only for BRCA1/2 genes, and 194 out of 832 (23.3%) received 21 genes panel testing. Among the 235 P/LPV carriers, 222 (94.5%) met the NCCN high‐risk criteria, and 13 (5.5%) did not. While using Desai's criteria of testing, all females diagnosed with BC by 60 years and NCCN criteria for older patients, 234 (99.6%) met the high‐risk standard, and only one did not. The 21 genes panel testing identified 4.9% of non‐BRCA P/LPVs and a significantly high rate of variants of uncertain significance (VUSs) (33.9%). The most common non‐BRCA P/LPVs were PALB2 (11, 1.3%), TP53 (10, 1.2%), PTEN (3, 0.4%), CHEK2 (3, 0.4%), ATM (3, 0.4%), BARD1 (3, 0.4%), and RAD51C (2, 0.2%). Compared with BRCA1/2 P/LPVs, non‐BRCA P/LPVs showed a significantly low incidence of NCCN criteria listed family history, second primary cancer, and different molecular subtypes. Conclusions: Desai's criteria might be a more appropriate genetic testing strategy for Chinese BC patients. Panel testing could identify more non‐BRCA P/LPVs than BRCA1/2 testing alone. Compared with BRCA1/2 P/LPVs, non‐BRCA P/LPVs exhibited different personal and family histories of cancer and molecular subtype distributions. The optimal genetic testing strategy for BC still needs to be investigated with larger continuous population studies. [ABSTRACT FROM AUTHOR]

Purpose: We attempted to explore the prognostic value of baseline inflammatory and nutritional biomarkers at diagnosis in patients with early-stage breast cancer and develop a novel scoring system, the inflammatory-nutritional prognostic score (INPS). Patients and Methods: We collected clinicopathological and baseline laboratory data of 1259 patients with early-stage breast cancer between December 2010 and November 2012 from Sun Yat-sen University Cancer Center. Eligible patients were randomly divided into training and validation cohorts (n = 883 and 376, respectively) in a 7:3 ratio. We selected the most valuable biomarkers to develop INPS by the least absolute shrinkage and selection operator (LASSO) Cox regression model. A prognostic nomogram incorporating INPS and other independent clinicopathological factors was developed based on the stepwise multivariate Cox regression method. Then, we used the concordance index (C-index), calibration plot, and time-dependent receiver operating characteristic (ROC) analysis to evaluate the prognostic performance and predictive accuracy of the predictive nomogram. Results: Four inflammatory-nutritional biomarkers, including neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), prognostic nutritional index (PNI), and albumin-alkaline phosphatase ratio (AAPR), were selected using the LASSO Cox analysis to construct INPS, which remained an independent prognostic indicator per the multivariate Cox regression analysis. Patients were stratified into low- and high-INPS groups based on the cutoff INPS determined by the maximally selected rank statistics. The prognostic model for overall survival consisting of INPS and other independent clinicopathological indicators showed excellent discrimination with C-indexes of 0.825 (95% confidence interval [CI]: 0.786– 0.864) and 0.740 (95% CI: 0.657– 0.822) in the training and validation cohorts, respectively. The time-dependent ROC curves showed a higher predictive accuracy of our prognostic nomogram than that of traditional tumor-node-metastasis staging. Conclusion: Baseline INPS is an independent indicator of OS in patients with early-stage breast cancer. The INPS-based prognostic nomogram could be used as a practical tool for individualized prognostic predictions. [ABSTRACT FROM AUTHOR]

Background: Aging, an inevitable process characterized by functional decline over time, is a significant risk factor for various tumors. However, little is known about aging-related genes (ARGs) in breast cancer (BC). We aimed to explore the potential prognostic role of ARGs and to develop an ARG-based prognosis signature for BC. Methods: RNA-sequencing expression profiles and corresponding clinicopathological data of female patients with BC were obtained from public databases in The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). An ARG-based risk signature was constructed in the TCGA cohort based on results of least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis, and its prognostic value was further validated in the GSE20685 cohort. Results: A six ARG-based signature, including CLU, DGAT1, MXI1, NFKBI, PIK3CA and PLAU, was developed in the TCGA cohort and significantly stratified patients into low- and high-risk groups. Patients in the former group showed significantly better prognosis than those in the latter. Multivariate Cox regression analysis demonstrated that the ARG risk score was an independent prognostic factor for BC. A predictive nomogram integrating the ARG risk score and three identified factors (age, N- and M-classification) was established in the TCGA cohort and validated in the GSE20685 cohort. Calibration plots showed good consistency between predicted survival probabilities and actual observations. Conclusion: A novel ARG-based risk signature was developed for patients with BC, which can be used for individual prognosis prediction and promoting personalized treatment. [ABSTRACT FROM AUTHOR]

Lessons Learned: Fulvestrant 500 mg maintenance therapy showed a clinical benefit rate of 76% and median progression‐free survival of 16.1 months in patients who achieved objective responses or disease control after first‐line chemotherapy.Adverse events with fulvestrant maintenance therapy were consistent with the known safety profile of the drug. Background: Evidence for maintenance hormonal therapy after chemotherapy for estrogen receptor (ER)–positive/human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer is scarce. This study aimed to evaluate the efficacy of fulvestrant 500 mg maintenance therapy in patients after first‐line chemotherapy. Methods: We enrolled postmenopausal women with ER‐positive/HER2‐negative advanced breast cancer who attained tumor responses or disease control with four to eight cycles of chemotherapy as first‐line treatment. Fulvestrant 500 mg was injected on days 1, 15, and 29 and every 28 (±3) days thereafter. The primary endpoint was the clinical benefit rate (CBR); the secondary endpoints included the objective response rate (ORR), progression‐free survival (PFS), and safety. Results: We included 58 patients; the median follow‐up duration was 32.6 months. The CBR since commencing fulvestrant maintenance therapy was 76% (95% confidence interval [CI], 63%–86%), and ORR was 14% (95% CI, 6%–25%); eight patients achieved partial response. The median PFS for fulvestrant maintenance therapy was 16.1 months (95% CI, 10.3–21.0 months). Thirty‐nine patients (67%) reported at least one adverse event, of which most were grade 1/2, whereas three patients (5%) reported grade 3 adverse events. Conclusion: Fulvestrant 500 mg is a feasible and promising hormonal maintenance strategy in patients with ER‐positive/HER2‐negative advanced breast cancer who have no disease progression after first‐line chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Tumor progression following endocrine therapy is considered to indicate resistance to endocrine drugs due to a variety of mechanisms. An insufficient dose of endocrine drugs is one of the causes for treatment failure in some patients with high hormone-receptor (HR)-expressing advanced breast cancer. This study aimed to explore the efficacy of high-dose tamoxifen (TAM) treatment in patients with advanced breast cancer with highly expressed HR. Materials & methods: This was a single-arm, phase II pilot study that enrolled patients with advanced breast cancer with high HR expression (estrogen receptor ⩾60% and/or progesterone receptor ⩾60%) following routine endocrine therapy. All enrolled patients received a high-dose of TAM (100 mg/day) until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety. Exploratory endpoints included the predictive value of 16α-18F-17β-fluoroestradiol quantitative positron emission tomography/computed tomography (18F-FES PET/CT) for treatment efficacy. Results: A total of 30 patients were enrolled between September 2017 and February 2019. The median PFS was 6 months [95% confidence interval (CI) 4.9–7.1] and the median OS was 15.6 months (95% CI 8.3–22.9). Five patients experienced a partial response (PR) and none experienced a complete response (CR), with an ORR of 16.7% and CBR of 33.3%. No severe adverse events were observed. Lesions with 18F-FES maximum standardized uptake value (SUVmax) ⩾4 had a significantly longer PFS [median 9.2 months, (95% CI 6.9–11.6)] compared with lesions with a 18F-FES SUVmax <4 [median 4.8 months, (95% CI 3.9–5.6); p = 0.022]. Conclusion: A high-dose of TAM is effective and safe for patients with advanced breast cancer with high HR expression. 18F-FES SUVmax values may predict the local clinical benefits of high-dose TAM. Trial Registration: [ClinicalTrials.gov identifier: NCT0304565] [ABSTRACT FROM AUTHOR]

Background: Tumor progression following endocrine therapy is considered to indicate resistance to endocrine drugs due to a variety of mechanisms. An insufficient dose of endocrine drugs is one of the causes for treatment failure in some patients with high hormone-receptor (HR)-expressing advanced breast cancer. This study aimed to explore the efficacy of high-dose tamoxifen (TAM) treatment in patients with advanced breast cancer with highly expressed HR. Materials & methods: This was a single-arm, phase II pilot study that enrolled patients with advanced breast cancer with high HR expression (estrogen receptor ⩾60% and/or progesterone receptor ⩾60%) following routine endocrine therapy. All enrolled patients received a high-dose of TAM (100 mg/day) until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), and safety. Exploratory endpoints included the predictive value of 16α-18F-17β-fluoroestradiol quantitative positron emission tomography/computed tomography (18F-FES PET/CT) for treatment efficacy. Results: A total of 30 patients were enrolled between September 2017 and February 2019. The median PFS was 6 months [95% confidence interval (CI) 4.9–7.1] and the median OS was 15.6 months (95% CI 8.3–22.9). Five patients experienced a partial response (PR) and none experienced a complete response (CR), with an ORR of 16.7% and CBR of 33.3%. No severe adverse events were observed. Lesions with 18F-FES maximum standardized uptake value (SUVmax) ⩾4 had a significantly longer PFS [median 9.2 months, (95% CI 6.9–11.6)] compared with lesions with a 18F-FES SUVmax <4 [median 4.8 months, (95% CI 3.9–5.6); p = 0.022]. Conclusion: A high-dose of TAM is effective and safe for patients with advanced breast cancer with high HR expression. 18F-FES SUVmax values may predict the local clinical benefits of high-dose TAM. Trial Registration: [ClinicalTrials.gov identifier: NCT0304565] [ABSTRACT FROM AUTHOR]

Objective: Cavin3 is a putative tumor suppressor protein. However, its molecular action on tumor regulation is largely unknown. The aim of the current study is to explore the implication of cavin3 alteration, its clinical significance, and any potential molecular mechanisms in the regulation of breast cancer (BC). Methods: TCGA (The Cancer Genome Atlas) and GTEx (Genotype-Tissue Expression) data bases, and 17 freshly paired BC and adjacent normal tissues were analyzed for mRNA levels of Cavin3. Furthermore, cavin3 protein expression from 407 primary BC samples were assessed by immunohistochemistry (IHC) and measured by H-score. The clinical significance of cavin3 expression was explored by Kaplan-Meier analysis and the Cox regression method. In vitro biological assays were performed to elucidate the function and underlying mechanisms of cavin 3 in BC cell lines. Results: Cavin3 mRNA was dramatically down-regulated in BC compared with the negative control. The median H-score of cavin3 protein by IHC was 50 (range 0-270). There were 232 (57%) and 175 (43%) cases scored as low (H-score≤50) and high (H-score >50) levels of cavin3, respectively. Low cavin3 was correlated with a higher T and N stage, and worse distant metastasis-free survival (DMFS) and overall survival (OS). Multivariate survival analysis revealed low cavin3 was an independent fact for worse DMFS. In BC cells, an overexpression of cavin3 could inhibit cell migration and invasion, and significantly decreased the level of p-Akt. Knockout of cavin3, meanwhile, promoted cell invasion ability and increased the level of p-AKT. Conclusion: Cavin3 expression is significantly lower in BC and is correlated with distant metastasis and worse survival. Cavin3 functions as a metastasis suppressor via inhibiting the AKT pathway, suggesting cavin3 as a potential prognostic biomarker and a target for BC treatment. [ABSTRACT FROM AUTHOR]

Purpose: Ovarian function is important for optimizing endocrine treatment in patients with hormone receptor-positive (HR+) early breast cancer (eBC). The aim of the study was to determine whether patients' pretreatment levels of anti-Mullerian hormone (AMH) were associated with menses status after chemotherapy and to build a predictive nomogram model for amenorrhea in women with HR+ eBC.Methods: Between August 2013 and December 2014, 120 premenopausal patients with HR+ eBC were included retrospectively. The associations among age, prechemotherapy levels of AMH, follicle-stimulating hormone (FSH),and estradiol (E2) and the 2-year postchemotherapy menses status were analyzed. We determined the cutoff values of hormone levels by using the biostatistical tool (Cutoff Finder). A novel nomogram was established to predict the 2-year amenorrhea status based on the logistic analysis. Concordance index (C-index) was used to validate the capacity.Results: One hundred nine women (90.8%) experienced amenorrhea after chemotherapy. AMH < 0.965 ng/ml predicted amenorrhea at 2 years (AUC 0.84, sensitivity 74% and specificity 81.8%), independent of age. The predictive nomogram based on age and pretreatment AMH and FSH levels was developed to predict the probability of 2-year postchemotherapy amenorrhea with a C-index of 0.88 (95% CI 0.84-0.91).Conclusions: In premenopausal patients with HR+ eBC, prechemotherapy AMH concentration was associated with the patient's 2-year amenorrhea status, independent of age. The nomogram model based on age and pretreatment AMH and FSH levels accurately predicted the 2-year amenorrhea status. [ABSTRACT FROM AUTHOR]

Purpose: Endocrine therapy is associated with improved disease-free survival (DFS) in hormone receptor-positive breast cancer, but it is also associated with many adverse events. The aim of this study was to clarify the association between endocrine treatment-related symptoms and treatment efficacy in patients receiving adjuvant endocrine therapy. Method: EMBASE, Web of Science, PubMed, and CENTRAL databases were searched for studies that compared treatment efficacy between patients in whom adverse events did and did not occur during hormone therapy. Hazard ratios (HRs) and associated 95 % confidence intervals (CIs) for DFS and overall survival were estimated and pooled using random-effects models. Results: Of 4665 citations identified, ten studies incorporating 32,192 patients were included in the meta-analysis. The presence of endocrine treatment-related symptoms was associated with improved DFS (HR 0.76; 95 % CI 0.68-0.85). Similar results were observed in patients with vasomotor symptoms (HR 0.76; 95 % CI 0.66-0.87) or musculoskeletal symptoms (HR 0.75; 95 % CI 0.60-0.94), in patients taking an aromatase inhibitor (HR 0.69; 95 % CI 0.57-0.85) or tamoxifen (HR 0.74; 95 % CI 0.60-0.93), and in patients with symptoms at 3-month (HR 0.74; 95 % CI 0.66-0.83), 6-month (HR 0.80; 95 % CI 0.66-0.96), or 12-month follow-up visits (HR 0.75; 95 % CI 0.68-0.83). However, no significant difference in overall survival was observed between patients with or without endocrine treatment-related symptoms (HR 0.82; 95 % CI 0.60-1.11). Sensitivity analysis excluding studies with heterogeneous factors yielded consistent results. No evidence of publication bias was observed. Conclusion: In our meta-analysis, endocrine treatment-related symptoms were shown to correlate with superior DFS and may therefore be useful in predicting treatment efficacy in patients with breast cancer receiving hormone therapy. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignancy in females. The presence of cancer stem cells ( CSCs) is the main cause of local and distant tumour recurrence and is associated with poor outcome in breast cancer. However, the molecular mechanisms underlying the maintenance of CSCs remain largely unknown. This study demonstrates that prostate tumour overexpressed-1 ( PTOV1) enhances the CSC population and augments the tumourigenicity of breast cancer cells both in vitro and in vivo. Moreover, PTOV1 suppresses transcription of Dickkopf-1 ( DKK1) by recruiting histone deacetylases and subsequently reducing DKK1 promoter histone acetylation, followed by activation of Wnt/β-catenin signalling. Restoration of DKK1 expression in PTOV1-overexpressing cells counteracts the effects of PTOV1 on Wnt/β-catenin activation and the CSC population. Collectively, these results suggest that PTOV1 positively regulates the Wnt/β-catenin signalling pathway and enhances tumourigenicity in breast cancer; this novel mechanism may represent a therapeutic target for breast cancer. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The role of adjuvant ovarian suppression or ablation (OS/OA) in premenopausal women with hormone receptor-positive breast cancer remains controversial. The purpose of our study was to examine which patients might benefit from the addition of OS/OA to tamoxifen. We analyzed the data of 2065 premenopausal patients with hormone receptor-positive invasive ductal carcinomas who were treated at Sun Yat-Sen University Cancer Center from 2000 to 2008. The five-year disease-free survival rate (DFSR) and overall survival rate (OSR) were compared by menstrual status and treatment. Compared with patients older than forty years of age, patients younger than forty years old had significant lower DFSRs and OSRs. The addition of OS/OA to tamoxifen increased the DFSR and OSR of patients with normal menstrual cycles after chemotherapy, regardless of their age at diagnosis. Patients with normal menstrual cycles after chemotherapy are the main beneficiaries of an adjuvant OS/OA. [ABSTRACT FROM AUTHOR]