Altered cortical thickness and structural covariance networks in chronic low back pain.

BACKGROUND: Despite regional brain structural changes having been reported in patients with chronic low back pain (CLBP), the topological properties of structural covariance networks (SCNs), which refer to the organization of the SCNs, remain unclear. This study applied graph theoretical analysis to explore the alterations of the topological properties of SCNs, aiming to comprehend the integration and separation of SCNs in patients with CLBP. METHODS: A total of 38 patients with CLBP and 38 healthy controls (HCs), balanced for age and sex, were scanned using three-dimensional T1-weighted magnetic resonance imaging. The cortical thickness was extracted from 68 brain regions, according to the Desikan-Killiany atlas, and used to reconstruct the SCNs. Subsequently, graph theoretical analysis was employed to evaluate the alterations of the topological properties in the SCNs of patients with CLBP. RESULTS: In comparison to HCs, patients with CLBP had less cortical thickness in the left superior frontal cortex. Additionally, the cortical thickness of the left superior frontal cortex was negatively correlated with the Visual Analogue Scale scores of patients with CLBP. Furthermore, patients with CLBP, relative to HCs, exhibited lower global efficiency and small-worldness, as well as a longer characteristic path length. This indicates a decline in the brain's capacity to transmit and process information, potentially impacting the processing of pain signals in patients with CLBP and contributing to the development of CLBP. In contrast, there were no significant differences in the clustering coefficient, local efficiency, nodal efficiency, nodal betweenness centrality, or nodal degree between the two groups. CONCLUSIONS: From the regional cortical thickness to the complex brain network level, our study demonstrated changes in the cortical thickness and topological properties of the SCNs in patients with CLBP, thus aiding in a better understanding of the pathophysiological mechanisms of CLBP.

Characteristics of DNA macro-alterations in breast cancer with liver metastasis before treatment.

BACKGROUND: Whole-genome doubling (WGD) has been observed in 30% of cancers, followed by a highly complex rearranged karyotype unfavourable to breast cancer's outcome. However, the macro-alterations that characterise liver metastasis in breast cancer(BC) are poorly understood. Here, we conducted a whole-genome sequencing analysis of liver metastases to explore the status and the time frame model of these macro-alterations in pre-treatment patients with metastatic breast cancer. RESULTS: Whole-genome sequencing was conducted in 11 paired primary tumours, lymph node metastasis, and liver metastasis fresh samples from four patients with late-stage breast cancer. We also chose five postoperative frozen specimens from patients with early-stage breast cancer before any treatment as control. Surprisingly, all four liver metastasis samples were classified as WGD + . However, the previous study reported that WGD happened in 30% of cancers and 2/5 in our early-stage samples. WGD was not observed in the two separate primary tumours and one lymph node metastasis of one patient with metastatic BC, but her liver metastasis showed an early burst of bi-allelic copy number gain. The phylogenetic tree proves her 4 tumour samples were the polyclonal origin and only one WGD + clone metastasis to the liver. Another 3 metastatic BC patients' primary tumour and lymph node metastasis experienced WGD as well as liver metastasis, and they all showed similar molecular time-frame of copy number(CN) gain across locations within the same patient. These patients' tumours were of monoclonal origin, and WGD happened in a founding clone before metastasis, explaining that all samples share the CN-gain time frame. After WGD, the genomes usually face instability to evolve other macro-alterations. For example, a greater quantity and variety of complex structural variations (SVs) were detected in WGD + samples. The breakpoints were enriched in the chr17: 39 Mb-40 Mb tile, which contained the HER2 gene, resulting in the formation of tyfonas, breakage-fusion-bridge cycles, and double minutes. These complex SVs may be involved in the evolutionary mechanisms of the dramatic increase of HER2 copy number. CONCLUSION: Our work revealed that the WGD + clone might be a critical evolution step for liver metastasis and favoured following complex SV of breast cancer.

A nomogram based on cuproptosis-related genes predicts 7-year relapse-free survival in patients with estrogen receptor-positive early breast cancer.

Introduction: Excess copper induces cell death by binding to lipoylated components of the tricarboxylic acid cycle. Although a few studies have examined the relationship between cuproptosis-related genes (CRGs) and breast cancer prognosis, reports on estrogen receptor-positive (ER+) breast cancer are lacking. Herein, we aimed to analyze the relationship between CRGs and outcomes in patients with ER+ early breast cancer (EBC). Methods: We conducted a case-control study among patients with ER+ EBC presenting poor and favorable invasive disease-free survival (iDFS) at West China Hospital. Logistic regression analysis was performed to establish the association between CRG expression and iDFS. A cohort study was performed using pooled data from three publicly available microarray datasets in the Gene Expression Omnibus database. Subsequently, we constructed a CRG score model and a nomogram to predict relapse-free survival (RFS). Finally, the prediction performance of the two models was verified using training and validation sets. Results: In this case-control study, high expression of LIAS, LIPT1, and ATP7B and low CDKN2A expression were associated with favorable iDFS. In the cohort study, high expression of FDX1, LIAS, LIPT1, DLD, PDHB, and ATP7B and low CDKN2A expression were associated with favorable RFS. Using LASSO-Cox analysis, a CRG score was developed using the seven identified CRGs. Patients in the low CRG score group had a reduced risk of relapse in both training and validation sets. The nomogram included the CRG score, lymph node status, and age. The area under the receiver operating characteristic (ROC) curve (AUC) of the nomogram was significantly higher than the AUC of the CRG score at 7 years. Conclusions: The CRG score, combined with other clinical features, could afford a practical long-term outcome predictor in patients with ER+ EBC.

Mammography radiomics features at diagnosis and progression-free survival among patients with breast cancer.

BACKGROUND: The associations between mammographic radiomics and breast cancer clinical endpoints are unclear. We aimed to identify mammographic radiomics features associated with breast cancer prognosis. METHODS: Nested from a large breast cancer cohort in our institution, we conducted an extreme case-control study consisting of 207 cases with any invasive disease-free survival (iDFS) endpoint <5 years and 207 molecular subtype-matched controls with >5-year iDFS. A total of 632 radiomics features in craniocaudal (CC) and mediolateral oblique (MLO) views were extracted from pre-treatment mammography. Logistic regression was used to identify iDFS-associated features with multiple testing corrections (Benjamini-Hochberg method). In a subsample with RNA-seq data (n = 96), gene set enrichment analysis was employed to identify pathways associated with lead features. RESULTS: We identified 15 iDFS-associated features from CC-view yet none from MLO-view. S(1,-1)SumAverg and WavEnLL_s-6 were the lead ones and associated with favourable (OR 0.64, 95% CI 0.42-0.87, P = 0.01) and poor iDFS (OR 1.53, 95% CI 1.31-1.76, P = 0.01), respectively. Both features were associated with eight pathways (primarily involving cell cycle regulation) in tumour but not adjacent normal tissues. CONCLUSION: Our findings suggest mammographic radiomics features are associated with breast cancer iDFS, potentially through pathways involving cell cycle regulation.

Neuroendocrine pathways and breast cancer progression: a pooled analysis of somatic mutations and gene expression from two large breast cancer cohorts.

BACKGROUND: Experimental studies indicate that neuroendocrine pathways might play a role in progression of breast cancer. We aim to test the hypothesis that somatic mutations in the genes of neuroendocrine pathways influence breast cancer prognosis, through dysregulated gene expression in tumor tissue. METHODS: We conducted an extreme case-control study including 208 breast cancer patients with poor invasive disease-free survival (iDFS) and 208 patients with favorable iDFS who were individually matched on molecular subtype from the Breast Cancer Cohort at West China Hospital (WCH; N = 192) and The Cancer Genome Atlas (TCGA; N = 224). Whole exome sequencing and RNA sequencing of tumor and paired normal breast tissues were performed. Adrenergic, glucocorticoid, dopaminergic, serotonergic, and cholinergic pathways were assessed for differences in mutation burden and gene expression in relation to breast cancer iDFS using the logistic regression and global test, respectively. RESULTS: In the pooled analysis, presence of any somatic mutation (odds ratio = 1.66, 95% CI: 1.07-2.58) of the glucocorticoid pathway was associated with poor iDFS and a two-fold increase of tumor mutation burden was associated with 17% elevated odds (95% CI: 2-35%), after adjustment for cohort membership, age, menopausal status, molecular subtype, and tumor stage. Differential expression of genes in the glucocorticoid pathway in tumor tissue (P = 0.028), but not normal tissue (P = 0.701), was associated with poor iDFS. Somatic mutation of the adrenergic and cholinergic pathways was significantly associated with iDFS in WCH, but not in TCGA. CONCLUSION: Glucocorticoid pathway may play a role in breast cancer prognosis through differential mutations and expression. Further characterization of its functional role may open new avenues for the development of novel therapeutic targets for breast cancer.

Association between age at initial diagnosis and post-metastasis mortality among women with recurrent metastatic breast cancer in China.

BACKGROUND: Little is known about whether age at initial diagnosis influences the prognosis of recurrent metastatic breast cancer (rMBC). Here, we analyzed the association between age at initial diagnosis and rMBC mortality in China. METHODS: A total of 1636 women diagnosed with rMBC between 1989 and 2020 at West China Hospital, Sichuan University were included in this study. The age at initial diagnosis was categorized as young (≤ 40 years), middle-aged (41-64 years) and elderly (≥ 65 years). Post-metastasis mortality was the primary outcome and its associated factors were analyzed by Cox proportional hazards models. RESULTS: During a median follow-up of 5.2 years after initial diagnosis of breast cancer, 620 deaths were identified. Compared with middle-aged patients, elderly patients had a 70% increased risk of post-metastasis mortality (95%CI, 1.24-2.33) after adjusting for demographics, tumor characteristics and treatment modes. Similarly, elderly patients were associated with a 75% increased risk of post-metastasis mortality (95%CI, 1.19-2.59) compared with young patients. Subgroup analyses also showed similar trends. CONCLUSION: Our findings suggest that in breast cancer, elderly patients at initial diagnosis face a higher risk of post-metastasis mortality.

Clinical characteristics and survival outcome of patients with estrogen receptor low positive breast cancer.

BACKGROUND: The benefit of endocrine therapy for patients with estrogen receptor (ER)-low (1%-10%) positive breast cancer is a matter for debate. We aimed to compare the clinical characteristics and survival outcome of ER-low patients with ER-high (＞10%) positive patients and ER-negative patients. METHODS: From the breast cancer database of our institution, we identified 5466 patients with known ER status who were diagnosed with early-stage breast cancer between January 2008 and December 2016. Variables associated with initiation of endocrine therapy were identified using multivariate logistic regression model. According to ER status, all patients were classified into ER-low (1%-10%), ER-high (>10%) and ER-negative subgroups. Fine and Gray competing risks regression was performed to compare the survival outcome of three subgroups. RESULTS: Age at diagnosis, ER status and progesterone receptor (PR) status were identified as correlates of initiation of endocrine therapy. ER-low patients were more likely to have advanced, PR-negative, human epidermal growth factor receptor 2 (HER2)-positive or grade Ⅲ disease compared to ER-high patients. Similar to ER-negative patients, ER-low patients presented increased rate of locoregional recurrence (LRR), distant recurrence (DR) and breast cancer mortality (BCM) than ER-high patients. Endocrine therapy showed nonsignificant trends toward lower LRR, DR and BCM in ER-low patients. CONCLUSION: Similar to ER-negative patients, ER-low patients had more aggressive clinical characteristics and worse survival outcome than ER-high patients. ER-low patients appeared to benefit less from endocrine therapy. Randomized studies are needed to further explore the endocrine responsiveness of ER-low patients.

Efficacy and Safety of PARP Inhibitors in Advanced or Metastatic Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in metastatic triple-negative breast cancers (TNBCs). We therefore performed a systematic review and meta-analysis to evaluate the efficacy and safety of this drug in patients with advanced or metastatic TNBC. METHODS: A systematic literature search of PubMed, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials for synonyms of "PARP inhibitors" and "breast cancer" was carried out. All published phase II/III clinical studies of PARP inhibitors in patients with advanced/metastatic TNBC were screened. Data were extracted independently by two authors and analyzed using Review Manager software version 5.3. End points include overall response rate (ORR), progression-free survival (PFS), and adverse events. RESULTS: Ten clinical trials were identified, with a total of 1,495 patients included. Pooled analyses showed that PARP inhibitors could provide a significant improvement of ORR [risk ratio (RR) = 2.00; 95% confidence interval (CI), 1.14-3.50; p = 0.02) and PFS [hazard ratio (HR) = 0.68; 95%Cl, 0.59-0.77; p < 0.0001) compared to chemotherapy in the whole population. In subgroup analysis, patients with BRCA mutation had a higher objective response to PARP inhibitor, with an RR of 2.85 (95%CI, 1.34-6.06; p = 0.007) compared to BRCA wild-type patients. However, no significant difference in ORR was observed between the homologous recombination deficiency (HRD) positive and non-HRD subgroups (RR = 1.82; 95%CI, 0.81-4.08; p = 0.14). Hematological toxicity is a common adverse event of PARP inhibitors. CONCLUSIONS: PARP inhibitors are effective options for the treatment of patients with advanced or metastatic TNBC. Compared with patients without germline BRCA mutation, patients with germline BRCA mutation could benefit more from PARP inhibitors. In clinical setting, hematological toxicity associated with PARP inhibitors should be monitored regularly.

Cardiovascular mortality among cancer survivors who developed breast cancer as a second primary malignancy.

BACKGROUND: To assess the risk of cardiovascular mortality among cancer survivors who developed breast cancer as a second malignancy (BCa-2) compared with patients with first primary breast cancer (BCa-1) and the general population. METHODS: Using the Surveillance, Epidemiology, and End Results database, we conducted a population-based cohort study including 1,024,047 BCa-1 and 41,744 BCa-2 patients diagnosed from the age 30 between 1975 and 2016, and the corresponding US female population (994,415,911 person-years; 5,403,551 cardiovascular deaths). Compared with the general population and BCa-1 patients, we calculated incidence rate ratios (IRRs) of cardiovascular deaths among BCa-2 patients using Poisson regression. To adjust for unmeasured confounders, we performed a nested, case-crossover analysis among BCa-2 patients who died from cardiovascular disease. RESULTS: Although BCa-2 patients had a mildly increased risk of cardiovascular mortality compared with the population (IRR 1.08) and BCa-1 patients (IRR 1.15), the association was pronounced among individuals aged 30-49 years (BCa-2 vs. population: IRR 6.61; BCa-2 vs. BCa-1: IRR 3.03). The risk elevation was greatest within the first month after diagnosis, compared with the population, but comparable with BCa-1 patients. The case-crossover analysis confirmed these results. CONCLUSION: Our findings suggest that patients with BCa-2 are at increased risk of cardiovascular mortality.

Postmastectomy radiation therapy and survival outcome in older patients with T1-2N1 breast cancer.

BACKGROUND: The prognostic impact of postmastectomy radiation therapy (PMRT) on contemporary older patients with T1-2N1 breast cancer is unclear. We aimed to investigate the effect of PMRT in this setting. METHODS: Leveraging the Surveillance, Epidemiology, and End Results (SEER) program data from 2004 to 2015, 7052 patients aged 70 years or older with T1-2N1 breast cancer were identified for this propensity-matched analysis. Fine and Gray competing risks regression was conducted to explore the correlation between PMRT and breast cancer-specific survival, in subgroups defined by tumor size and positive lymph nodes. RESULTS: The median follow-up was 60.1 months (interquartile range, 28.0 to 87.0). Among propensity-matched patients, multivariate analysis identified an association between PMRT and decreased breast cancer mortality (BCM; HR 0.637; 95 % CI 0.436-0.931; P = 0.020) in patient subset with three positive nodes and tumors 2-5 cm in size, and this benefit was limited to patients with three positive nodes and tumors 2-5 cm in size who did not receive chemotherapy. In patient subsets who received chemotherapy, no association between PMRT and BCM was found. CONCLUSION: PMRT was not associated with BCM in older patients with T1-2N1 breast cancer who received chemotherapy. The benefit of PMRT was limited to those with three positive nodes and tumors 2-5 cm in size who did not receive chemotherapy.

The effect of postmastectomy radiation therapy on high-risk patients with T1-2N0 breast cancer.

BACKGROUND: The prognostic impact of postmastectomy radiation therapy (PMRT) on high-risk patients with T1-2N0 breast cancer is controversial. We aimed to investigate the effect of PMRT on high-risk patients with T1-2N0 breast cancer. METHODS: A total of 3439 patients diagnosed with T1-2N0 breast cancer who received mastectomy between 2000 and 2016 in our institute were retrospectively analyzed. Leveraging the Fine and Gray competing risks regression in unirradiated patients, risk factors of locoregional recurrence (LRR) were identified. All patients were stratified into high-risk (3 or 4 risk factors) and low-risk (no more than 2 risk factors) groups. The prognostic effect of PMRT was estimated in two subgroups. This subgroup analysis was also performed in patients with T2N0 breast cancer. RESULTS: The median follow-up was 89 months. The 5-year cumulative incidence of LRR was 2.2% in unirradiated patients. Tumor size, estrogen receptor (ER) status, histologic grade and lymphovascular invasion (LVI) were identified as independent risk factors of LRR. In the high-risk group, PMRT was correlated with a 8.3% risk reduction of 5-year LRR, 7.8% risk reduction of 5-year distant recurrence (DR), and 6.4% risk reduction of 5-year breast cancer mortality (BCM), whereas it was not correlated with LRR, DR, or BCM in low-risk group. In patients with T2N0 breast cancer, PMRT was associated with decreased LRR, DR and BCM in high-risk group, other than low-risk group. CONCLUSIONS: PMRT presented heterogenous effect on patients with T1-2N0 breast cancer. Patients at high risk of LRR were more likely to benefit from PMRT.

Treatment patterns and outcomes in older women with early breast cancer: a population-based cohort study in China.

BACKGROUND: Despite the proportion of elderly breast cancer patients has been consistently increasing, the optimal treatment modalities for this population have not been well explored. We summarized the treatment outcomes of these patients in our hospital. METHODS: Older patients with early breast cancer were identified from the Breast Cancer Information Management System at West China Hospital, Sichuan University (2000-2019). We compared tumor characteristics and treatment outcomes between the older group (65-74 years old) and the elderly group (≥75 years old). The Kaplan-Meier and Cox regression analysis were conducted to determine significant prognostic factors. RESULTS: In total, 1094 patients were included. The median follow-up time for this cohort was 59 months. The majority of patients underwent surgery and benefited from surgical treatment. Elderly group patients were less likely to receive adjuvant chemotherapy or postmastectomy radiotherapy (PMRT) compared to the older group. However, adjuvant chemotherapy was associated with improved overall survival (OS) (hazard ratio [HR] 0.521, 95% confidence interval [CI] 0.284-0.955, P = 0.035). Subgroup analysis revealed that patients with grade III disease best benefited from adjuvant chemotherapy. PMRT offered a significant improvement in local disease control, but not in OS. Furthermore, endocrine therapy improved the OS of HR-positive patients (HR 0.440, 95%CI 0.261-0.741, P = 0.002), especially for cases aged 65-74 years. Also, receipt of trastuzumab in HER2-positive patients was associated with better OS (HR 0.168, 95%CI 0.029-0.958, P = 0.045). CONCLUSIONS: Our findings suggest that surgery, adjuvant chemotherapy, endocrine and targeted therapy are associated with improved OS in older breast cancer patients. Moreover, clinicopathological characteristics should be comprehensively considered when making treatment decisions for these patients.

The Effect of Postmastectomy Radiotherapy on Breast Cancer Patients After Neoadjuvant Chemotherapy by Molecular Subtype.

BACKGROUND: The effect of postmastectomy radiotherapy (PMRT) on patient outcomes after neoadjuvant chemotherapy (NAC) remains controversial. We aimed to establish a model to identify the subsets benefiting from PMRT and to examine the effect of PMRT according to molecular subtype. PATIENTS AND METHODS: We retrospectively analyzed 1118 cT1-4cN0-3M0 breast cancer patients treated with NAC and mastectomy. A nomogram predicting locoregional recurrence (LRR) was established based on 418 unirradiated patients, and X-tile analysis was performed to divide the patients into two risk groups. The effect of PMRT on LRR, distant recurrence (DR), and breast cancer mortality (BCM) was estimated for patients with different molecular subtypes in two risk groups. RESULTS: A nomogram predicting LRR was developed using six factors: histologic classification, lymphovascular invasion, ypT stage, ypN stage, estrogen receptor status, and Ki-67 expression. Our study found that PMRT correlated with lower 5-year LRR, DR, and BCM rates for the high-risk group; however, no significant improvement in these endpoints was observed in the low-risk group. Among patients with high risk, subgroup analysis showed that LRR control was improved after PMRT for the human epidermal growth factor receptor 2 (HER2)-negative/hormone receptor (HR)-positive (HER2-/HR+), HER2-positive (HER2+)/HR+, and HER2-/HR-negative (HR-) subtypes, with hazard ratios of 0.113 (95% confidence [CI] 0.034-0.379; p < 0.001), 0.159 (95% CI 0.038-0.671; p = 0.017), and 0.243 (95% CI 0.088-0.676; p = 0.007), respectively, but not for the HER2+/HR- subtype (p = 0.468). CONCLUSIONS: We built a nomogram showing favorable risk quantification and patient stratification. Patients in the high-risk group benefited from PMRT, but patients in the low-risk group did not. PMRT may show different benefits for each molecular subtype.

Multidimensional Machine Learning Personalized Prognostic Model in an Early Invasive Breast Cancer Population-Based Cohort in China: Algorithm Validation Study.

BACKGROUND: Current online prognostic prediction models for breast cancer, such as Adjuvant! Online and PREDICT, are based on specific populations. They have been well validated and widely used in the United States and Western Europe; however, several validation attempts in non-European countries have revealed suboptimal predictions. OBJECTIVE: We aimed to develop an advanced breast cancer prognosis model for disease progression, cancer-specific mortality, and all-cause mortality by integrating tumor, demographic, and treatment characteristics from a large breast cancer cohort in China. METHODS: This study was approved by the Clinical Test and Biomedical Ethics Committee of West China Hospital, Sichuan University on May 17, 2012. Data collection for this project was started in May 2017 and ended in March 2019. Data on 5293 women diagnosed with stage I to III invasive breast cancer between 2000 and 2013 were collected. Disease progression, cancer-specific mortality, all-cause mortality, and the likelihood of disease progression or death within a 5-year period were predicted. Extreme gradient boosting was used to develop the prediction model. Model performance was assessed by calculating the area under the receiver operating characteristic curve (AUROC), and the model was calibrated and compared with PREDICT. RESULTS: The training, test, and validation sets comprised 3276 (499 progressions, 202 breast cancer-specific deaths, and 261 all-cause deaths within 5-year follow-up), 1405 (211 progressions, 94 breast cancer-specific deaths, and 129 all-cause deaths), and 612 (109 progressions, 33 breast cancer-specific deaths, and 37 all-cause deaths) women, respectively. The AUROC values for disease progression, cancer-specific mortality, and all-cause mortality were 0.76, 0.88, and 0.82 for training set; 0.79, 0.80, and 0.83 for the test set; and 0.79, 0.84, and 0.88 for the validation set, respectively. Calibration analysis demonstrated good agreement between predicted and observed events within 5 years. Comparable AUROC and calibration results were confirmed in different age, residence status, and receptor status subgroups. Compared with PREDICT, our model showed similar AUROC and improved calibration values. CONCLUSIONS: Our prognostic model exhibits high discrimination and good calibration. It may facilitate prognosis prediction and clinical decision making for patients with breast cancer in China.

Downregulation of CXXC Finger Protein 4 Leads to a Tamoxifen-resistant Phenotype in Breast Cancer Cells Through Activation of the Wnt/ß-catenin Pathway.

Tamoxifen is a successful endocrine therapy drug for estrogen receptor-positive (ER+) breast cancer. However, resistance to tamoxifen compromises the efficacy of endocrine treatment. In the present study, we identified potential tamoxifen resistance-related gene markers and investigated their mechanistic details. First, we established two ER + breast cancer cell lines resistant to tamoxifen, named MCF-7/TMR and BT474/TMR. Gene expression profiling showed that CXXC finger protein 4 (CXXC4) expression is lower in MCF-7/TMR cells than in MCF-7 cells. Furthermore, CXXC4 mRNA and protein expression are lower in the resistant cell lines than in the corresponding parental cell lines. We also investigated the correlation between CXXC4 and endocrine resistance in ER + breast cancer cells. CXXC4 knockdown accelerates cell proliferation in vitro and in vivo and renders breast cancer cells insensitive to tamoxifen, whereas CXXC4 overexpression inhibits cancer cell growth and increases tamoxifen sensitivity of resistant cells. In addition, we demonstrated that CXXC4 inhibits Wnt/ß-catenin signaling in cancer cells by modulating the phosphorylation of GSK-3ß, influencing the integrity of the ß-catenin degradation complex. Silencing the CXXC4 gene upregulates expression of cyclinD1 and c-myc (the downstream targets of Wnt signaling) and promotes cell cycle progression. Conversely, ectopic expression of CXXC4 downregulates the expression of these proteins and arrests the cell cycle in the G0/G1 phase. Finally, the small-molecule inhibitor XAV939 suppresses Wnt signaling and sensitizes resistant cells to tamoxifen. These results indicate that components of Wnt pathway that are early in response to tamoxifen could be involved as an intrinsic factor of the transition to endocrine resistance, and inhibition of Wnt signaling may be an effective therapeutic strategy to overcome tamoxifen resistance.

Prognostic nomogram for patients with non-metastatic HER2 positive breast cancer in a prospective cohort.

PURPOSE: A nomogram is a reliable tool to generate individualized risk prediction by combining prognostic factors. We aimed to construct a nomogram for predicting the survival in patients with non-metastatic human epidermal growth factor receptor 2 (HER2) positive breast cancer in a prospective cohort. METHODS: We analyzed 1304 consecutive patients who were diagnosed with non-metastatic HER2 positive breast cancer between January 2008 and December 2016 in our institution. Independent prognostic factors were identified to build a nomogram using the COX proportional hazard regression model. The prediction of the nomogram was evaluated by concordance index (C-index), calibration and subgroup analysis. External validation was performed in a cohort of 6379 patients from the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: Through the COX proportional hazard regression model, five independent prognostic factors were identified. The nomogram predicting overall survival achieved a C-index of 0.78 in the training cohort and 0.74 in the SEER cohort. The calibration plot displayed favorable accordance between the nomogram prediction and the actual observation for 3-year overall survival in both cohorts. The quartiles of the nomogram score classified patients into subgroups with distinct overall survival. CONCLUSION: We developed and validated a novel nomogram for predicting overall survival in patients with non-metastatic HER2 positive breast cancer, which presented a favorable discrimination ability. This model may assist clinical decision making and patient-clinician communication in clinical practice.

Nomogram Predicting Locoregional Recurrence to Assist Decision-Making of Postmastectomy Radiation Therapy in Patients With T1-2N1 Breast Cancer.

PURPOSE: Postmastectomy radiation therapy (PMRT) had heterogeneous effects on survival outcome of patients with T1-2N1 breast cancer. A reliable model to estimate individuals' risk of locoregional recurrence (LRR) and the potential benefit derived from PMRT is needed. METHODS AND MATERIALS: We retrospectively analyzed 1141 patients with T1-2N1 breast cancer who underwent mastectomy between January 2001 and December 2012. Based on the Fine and Gray competing risks regression in 623 unirradiated patients, a nomogram predicting LRR was conducted for risk quantification. Decision tree analysis was performed for patient grouping. The impact of PMRT was evaluated among 3 subgroups. RESULTS: With a median follow-up of 74.9 months, the 5-year cumulative incidence of LRR, distant recurrence (DR) and breast cancer mortality (BCM) were 3.9%, 8.8%, and 6.0%, respectively, for the entire cohort. Based on nomogram scores, patients were classified into 3 risk groups in decision tree analysis. In the high-risk group, PMRT was found to be associated with a 12.7% risk reduction of 5-year LRR, 9.2% risk reduction of 5-year DR, and 7.0% risk reduction of 5-year BCM, whereas it was not significantly associated with LRR, DR, or BCM in low- and intermediate-risk groups. CONCLUSIONS: The nomogram performed individualized risk quantification of LRR in patients with T1-2N1 breast cancer. A newly identified patient subgroup with high risk of LRR were found to derive survival benefit from PMRT.

Surgery of the primary tumor improves survival in women with stage IV breast cancer in Southwest China: A retrospective analysis.

The International Consensus Guidelines for advanced breast cancer (ABC) considers that the surgery of the primary tumor for stage IV breast cancer patients does not usually improve the survival. However, studies have showed that resection of the primary tumor may benefit these patients. The correlation between surgery and survival remains unclear.The impact of surgery and other clinical factors on overall survival (OS) of stage IV patients is investigated in West China Hospital. Female patients diagnosed with stage IV breast cancer between 1999 and 2014 were included (N = 223). Univariate and multivariate analysis assessed the association between surgery and OS.One hundred seventy-seven (79.4%) underwent surgery for the primary tumor, and 46 (20.6%) had no surgery. No significant differences were observed in age at diagnosis, T-stage, N-stage, histological grade, molecular subtype, hormone receptor (HR), and number of metastatic sites between 2 groups. Patients in the surgery group had dramatically longer OS (45.6 vs 21.3 months, log-rank P < .001). In univariate analysis, survival was associated with surgical treatment, residence, tumor size, lymph node, HR status, hormonal therapy, and radiotherapy. In multivariate analysis, surgery was an independent prognostic factor for OS [hazard ratio (HR), 0.569; 95% confidence interval (CI) 0.329-0.984, P = .044]. Additional independent prognostic factors were hormonal therapy (HR, 0.490; 95% CI 0.300-0.800) and radiotherapy (HR, 0.490; 95% CI 0.293-0.819). In addition, a favorable impact of surgery was observed by subgroup analysis.Our study showed that surgery of the primary breast tumor has a positive impact on OS in with stage IV breast cancer patients.