Efficacy and safety of eribulin mesylate in patients with locally advanced or metastatic breast cancer previously treated with anthracycline/taxanes.

BACKGROUND: This prospective real-world study aimed to assess the efficacy and safety of eribulin in the clinical practice against advanced breast cancer (ABC) in China. PATIENTS AND METHODS: In this study, eligible patients with inoperable locally advanced or metastatic breast cancer who had experienced prior neo-/adjuvant or failed the palliative treatment with anthracycline/taxanes were included. Eribulin (1.4 mg/m2) was infused intravenously on Day 1 and Day 8 every 3 weeks until disease progression or intolerable toxicity occurred. The progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), and safety of the treatment were assessed. RESULTS: One hundred and thirty-four patients were enrolled. The median PFS (mPFS) was 4.3 months (95% CI: 0.3-15.4). The ORR and DCR was 32.1% and 79.1%, respectively. The mPFS of patients who received eribulin as first- or second-line treatment was significantly better than those who received eribulin as ≥3-line treatment (6.9 months [95% CI: 3.2-8.8] vs. 4.0 months [95% CI: 3.4-4.6], p = 0.006). The mPFS of patients with triple-negative, HER2-positive, and HER2(-)/HR(+) was 3.4 (95% CI: 2.7-4.1), 6.2 (95% CI: 2.3-10.1) and 5.0 months (95% CI: 4.1-5.9), respectively. HER2(+) patients had significantly longer PFS than TNBC patients (p = 0.022). Patients received combination therapy had a significantly longer mPFS than those who received eribulin monotherapy (5.0 months [95% CI 3.6-6.3] vs. 4.0 months [95% CI: 3.3-4.7] [p = 0.016]). Multivariate analysis revealed that MBC patients with a molecular typing of non-TNBC receiving eribulin as ≤2-line therapy and combination therapy had a low risk of disease progression. Neutropenia (33.58%), leukopenia (11.94%), and thrombocytopenia (4.48%) were the most common treatment-related adverse events. CONCLUSION: Eribulin demonstrated effective clinical activity and a favorable tolerability profile in Chinese patients with ABC in the real-world. The efficacy and safety profile were consistent with those reported in previous randomized phase 3 trials.

Visual SLAM for Unmanned Aerial Vehicles: Localization and Perception.

Localization and perception play an important role as the basis of autonomous Unmanned Aerial Vehicle (UAV) applications, providing the internal state of movements and the external understanding of environments. Simultaneous Localization And Mapping (SLAM), one of the critical techniques for localization and perception, is facing technical upgrading, due to the development of embedded hardware, multi-sensor technology, and artificial intelligence. This survey aims at the development of visual SLAM and the basis of UAV applications. The solutions to critical problems for visual SLAM are shown by reviewing state-of-the-art and newly presented algorithms, providing the research progression and direction in three essential aspects: real-time performance, texture-less environments, and dynamic environments. Visual-inertial fusion and learning-based enhancement are discussed for UAV localization and perception to illustrate their role in UAV applications. Subsequently, the trend of UAV localization and perception is shown. The algorithm components, camera configuration, and data processing methods are also introduced to give comprehensive preliminaries. In this paper, we provide coverage of visual SLAM and its related technologies over the past decade, with a specific focus on their applications in autonomous UAV applications. We summarize the current research, reveal potential problems, and outline future trends from academic and engineering perspectives.

Is postmastectomy radiotherapy necessary for breast cancer patients with clinically node-positive downstaging to ypN0 after neoadjuvant chemotherapy?

PURPOSE: The significance of postmastectomy radiotherapy (PMRT) in breast cancer patients who initially have clinically node-positive (cN +) status but achieve downstaging to ypN0 following neoadjuvant chemotherapy (NAC) remains uncertain. This study aims to assess the impact of PMRT in this patient subset. METHODS: Patients were enrolled from West China Hospital, Sichuan University from 2008 to 2019. Overall survival (OS), Locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and breast cancer-specific survival (BCSS) were estimated using the Kaplan-Meier method and assessed with the log-rank test. The impact of PMRT was further analyzed by the Cox proportional hazards model. Propensity score matching (PSM) was performed to reduce the selection bias. RESULTS: Of the 333 eligible patients, 189 (56.8%) received PMRT, and 144 (43.2%) did not. At a median follow-up period of 71 months, the five-year LRFS, DMFS, BCSS, and OS rates were 99.1%, 93.4%, 96.4%, and 94.3% for the entire cohort, respectively. Additionally, the 5-year LRFS, DMFS, BCSS, and OS rates were 98.9%, 93.8%, 96.7%, and 94.5% with PMRT and 99.2%, 91.3%, 94.9%, and 92.0% without PMRT, respectively (all p-values not statistically significant). After multivariate analysis, PMRT was not a significant risk factor for any of the endpoints. When further stratified by stage, PMRT did not show any survival benefit for patients with stage II-III diseases. CONCLUSION: In the context of comprehensive treatments, PMRT might be exempted in ypN0 breast cancer patients. Further large-scale, randomized controlled studies are required to investigate the significance of PMRT in this patient subset.

DDX58 deficiency leads to triple negative breast cancer chemotherapy resistance by inhibiting Type I IFN-mediated signalling apoptosis.

Introduction: Triple-negative breast cancer (TNBC) is characterized by its aggressive nature and absence of specific therapeutic targets, necessitating the reliance on chemotherapy as the primary treatment modality. However, the drug resistance poses a significant challenge in the management of TNBC. In this study, we investigated the role of DDX58 (DExD/H-box helicase 58), also known as RIG-I, in TNBC chemoresistance. Methods: The relationship between DDX58 expression and breast cancer prognosis was investigated by online clinical databases and confirmed by immunohistochemistry analysis. DDX58 was knockout by CRISPR-Cas9 system (DDX58-KO), knockdown by DDX58-siRNA (DDX58-KD), and stably over expressed (DDX58-OE) by lentivirus. Western blotting, immunofluorescence and qPCR were used for related molecules detection. Apoptosis was analyzed through flow cytometry (Annexin V/7AAD apoptosis assay) and Caspase 3/7 activity assay. Results: Patients with lower expression of DDX58 led to lower rate of pathological complete response (pCR) and worse prognosis by online databases and hospital clinical data. DDX58-KD cells showed multiple chemo-drugs resistance (paclitaxel, doxorubicin, 5-fluorouracil) in TNBC cell lines. Similarly, DDX58-KO cells also showed multiple chemo-drugs resistance in a dosage-dependent manner. In the CDX model, tumours in the DDX58-KO group had a 25% reduction in the tumour growth inhibition rate (IR) compared to wild-type (WT) group after doxorubicin (Dox) treatment. The depletion of DDX58 inhibited proliferation and promoted the migration and invasion in MDA-MB-231 cells. The findings of our research indicated that DDX58-KO cells exhibit a reduction in Dox-induced apoptosis both in vivo and in vitro. Mechanistically, Dox treatment leads to a significant increase in the expression of double-stranded RNAs (dsRNAs) and activates the DDX58-Type I interferon (IFN) signaling pathway, ultimately promoting apoptosis in TNBC cells. Discussion: In the process of TNBC chemotherapy, the deficiency of DDX58 can inhibit Dox-induced apoptosis, revealing a new pathway of chemotherapy resistance, and providing a possibility for developing personalized treatment strategies based on DDX58 expression levels.

HER2-targeted therapies in cancer: a systematic review.

Abnormal alterations in human epidermal growth factor receptor 2 (HER2, neu, and erbB2) are associated with the development of many tumors. It is currently a crucial treatment for multiple cancers. Advanced in molecular biology and further exploration of the HER2-mediated pathway have promoted the development of medicine design and combination drug regimens. An increasing number of HER2-targeted drugs including specific monoclonal antibodies, tyrosine kinase inhibitors (TKIs), and antibody-drug conjugates (ADCs) have been approved by the U.S. Food and Drug Administration. The emergence of ADCs, has significantly transformed the treatment landscape for various tumors, such as breast, gastric, and bladder cancer. Classic monoclonal antibodies and novel TKIs have not only demonstrated remarkable efficacy, but also expanded their indications, with ADCs in particular exhibiting profound clinical applications. Moreover the concept of low HER2 expression signifies a breakthrough in HER2-targeted therapy, indicating that an increasing number of tumors and patients will benefit from this approach. This article, provides a comprehensive review of the underlying mechanism of action, representative drugs, corresponding clinical trials, recent advancements, and future research directions pertaining to HER2-targeted therapy.

miR-942-5p Regulates Proliferation, Invasion and EMT of Trophoblast Cells in Gestational Diabetes by Targeting the CEBPA.

Objective: Gestational diabetes mellitus (GDM) is a prevalent metabolic disorder caused by abnormal glucose metabolism during pregnancy. Trophoblast dysfunction induced by hyperglycemia during pregnancy is the main factor leading to the development of GDM. In this study, we evaluated the expression of miR-942-5p in the placenta of patients with GDM and its regulation of trophoblast cell biological function. Methods: HTR-8/SVneo trophoblast cells were incubated with glucose to establish in vitro models, and miR-942-5p mimics transfected cells were added. The expression levels of miR-942-5p, CCAAT-enhancer-binding protein alpha (CEBPA) and N-cadherin in tissues and cells were detected by reverse-transcription quantitative polymerase chain reaction (RT-qPCR), protein blotting and immunohistochemistry (IHC). MTT, flow cytometry and Transwell assays were used to determine changes in cell proliferation, apoptosis and invasion. Dual-luciferase reporter assay and Pearson analysis were used to confirm the association between miR-942-5p and CEBPA. Results: miR-942-5p and N-cadherin were decreased in placental tissue and in human placental trophoblast cells (HTR-8/SVneo) exposed to high glucose (HG) conditions, while CEBPA was increased in placental tissue and HTR-8/SVneo exposed to HG conditions. Elevated levels of miR-942-5p suppressed apoptosis induced by HG and facilitated the proliferative and invasive capacities of HTR-8/SVneo. Mechanistically, we confirmed that miR-942-5p overexpression directly targeted CEBPA and suppressed CEBPA expression, while upregulating N-cadherin expression, which is involved in the EMT process of trophoblast cells and alleviated the dysfunction of trophoblast cells induced by HG in GDM. Conclusion: Overexpression of miR-942-5p promotes proliferation, invasion and EMT of trophoblast cells by targeting and negatively regulating CEBPA. These findings offer novel understanding regarding the treatment of GDM.

HER2-low heterogeneity between primary and paired recurrent/metastatic breast cancer: Implications in treatment and prognosis.

BACKGROUND: With the largest sample size to date, the authors' objective was to investigate the incidence of primary-to-metastatic human epidermal growth factor 2 (HER2) conversion and the predictors for such conversion. Moreover, no previous studies have evaluated the prognosis of patients who have negative HER2 expression (HER2-0) versus low HER2 expression (HER2-low) when HER2 status was assessed based on all recurrent/metastatic lesions. METHODS: The authors included 1299 patients who had available HER2 status of primary breast tumors and paired recurrent/metastatic lesions at Fudan University Shanghai Cancer Center and West China Hospital. RESULTS: In total, 370 patients (28.5%) experienced primary-to-metastatic HER2 conversion. Intrapatient intermetastasis spatial heterogeneity and temporal heterogeneity of HER2 were detected. When assessing HER2 based on recurrent/metastatic tumors, patients who had HER2-0 tumors had significantly shorter overall survival than those who had HER2-low tumors in the overall population and in the estrogen receptor (ER)-negative subgroup. However, when assessing HER2 based on primary tumors, there was no difference in overall survival between patients who had HER2-0 versus HER2-low tumors. Moreover, patients who had tumors that converted from HER2-0 to HER2-low had longer overall survival than those who had consistent HER2-0 status in the ER-negative subgroup. By combining four predictors (ER status, Ki67 index, biopsy site, and disease-free interval), the authors established the first prediction tool to estimate the probability of HER2-0 tumors converting to HER2-low/positive tumors. CONCLUSIONS: Intrapatient primary-to-metastatic and intermetastatic HER2 heterogeneity were observed in this large-scale cohort study. When evaluating HER2 based on recurrent/metastatic tumors, an overall survival difference was observed between patients who had HER2-0 versus HER2-low, recurrent/metastatic breast tumors. The developed prediction tool might help clinicians screen out patients with primary HER2-0 tumors that have a high probability of HER2 status conversion and recommend them for re-biopsy, thus helping to screen out candidate patients for trastuzumab deruxtecan treatment.

Cost-Effectiveness Analysis of Adjuvant Endocrine Therapy With Ovarian Suppression in Premenopausal Patients With Hormone Receptor-Positive Early Breast Cancer in China.

PURPOSE: Endocrine therapy combined with ovarian function suppression (OFS) is recommended in intermediate- or high-risk patients among premenopausal women with hormone receptor-positive early breast cancer. However, in China, the cost-effectiveness of this strategy compared with endocrine therapy alone is unclear. This study aimed to evaluate the long-term cost-effectiveness of tamoxifen (TAM), TAM+OFS, and exemestane plus OFS (EXE+OFS). METHODS: On the basis of prognostic data from the Suppression of Ovarian Function Trial (SOFT), cost data from the Hospital Information System of the West China Hospital of Sichuan University, and health utility values from the published literature, a Markov model was established. The incremental cost-effectiveness ratio (ICER) was used to compare the treatment strategies. RESULTS: In a 25-year simulation of adjuvant therapy in Chinese women with early breast cancer, the total costs of TAM, TAM+OFS, and EXE+OFS were $7821, $9318, and $9445, respectively. The quality-adjusted life-years (QALYs) were 11.615, 11.896, and 11.734 years, respectively. Compared with TAM, the ICERs of TAM+OFS and EXE+OFS were $5,327.4021/QALY and $13,647.0588/QALY, respectively. The ICERs of TAM+OFS and EXE+OFS were below the threshold of $32,517/QALY. The reliability and stability of the simulation results were verified using Monte Carlo simulation and sensitivity analysis. CONCLUSION: In the context of limited resources in China, TAM+OFS and EXE+OFS are cost-effective options compared with TAM.

Silencing HE4 alleviates the renal fibrosis in lupus nephritis mice by regulating the C3/MMPs/prss axis.

To explore the regulatory effect of human epididymis protein 4 (HE4) on renal fibrosis in mice with lupus nephritis (LN) and the underlying mechanism. Ten-week old MRL/LPR mice were injected with HE4 shRNA adenovirus vector through the renal pelvis for 5 days. Renal tissues were extracted for HE and Masson staining to evaluate pathological changes and fibrosis in lupus nephritis mice. The level of urine protein was measured using a biochemical analyzer, while the expression level of HE4 and p-NF-κB p65 in renal tissues was visualized using an immunofluorescence assay. The level of ß2-microglobulin (ß2-MG), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule 1 (Kim-1) was determined by the immunohistochemical assay. Western blotting was used to determine the levels of C3, HE4, matrix metalloproteinase-2 (MMP2), MMP9, p-p65, prss23, and prss35 in renal tissues. Compared to wild-type C57BL/6 mice, MRL/LPR mice showed a marked increase in the number of glomeruli, hyperplasic basement membrane, severe infiltration of inflammatory cells in renal tubules and glomeruli, obvious necrosis in glomeruli, elevated fibrosis levels, and increased levels of urine protein, ß2-MG, NGAL, Kim-1, C3, HE4, MMP2, MMP9, and p-p65; and decreased levels of prss23 and prss35 were observed in MRL/LPR mice. After the administration of the HE4 shRNA adenovirus vector, the repaired structure of renal tubules and glomeruli improved infiltration of inflammatory cells, reduced collagen fiber and urine protein, suppressed levels of C3, HE4, MMP2, MMP9, and p-P65, and facilitated the expression of prss23 and prss35 which were observed. Silencing HE4 improved renal fibrosis and inhibited inflammation in mice with lupus nephritis, which may play a role in inhibiting C3/MMPs and promoting prss-related protein expression.

Pyrotinib and chrysin synergistically potentiate autophagy in HER2-positive breast cancer.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) has been the most challenging subtype of BC, consisting of 20% of BC with an apparent correlation with poor prognosis. Despite that pyrotinib, a new HER2 inhibitor, has led to dramatic improvements in prognosis, the efficacy of pyrotinib monotherapy remains largely restricted due to its acquired resistance. Therefore, identifying a new potential antitumor drug in combination with pyrotinib to amplify therapeutic efficacy is a pressing necessity. Here, we reported a novel combination of pyrotinib with chrysin and explored its antitumor efficacy and the underlying mechanism in HER2-positive BC. We determined that pyrotinib combined with chrysin yielded a potent synergistic effect to induce more evident cell cycle arrest, inhibit the proliferation of BT-474 and SK-BR-3 BC cells, and repress in vivo tumor growth in xenograft mice models. This may be attributed to enhanced autophagy induced by endoplasmic reticulum stress. Furthermore, the combined treatment of pyrotinib and chrysin induced ubiquitination and glucose-6-phosphate dehydrogenase (G6PD) degradation by upregulating zinc finger and BTB/POZ domain-containing family protein 16 (ZBTB16) in tumorigenesis of BC. Mechanistically, we identified that miR-16-5p was a potential upstream regulator of ZBTB16, and it showed a significant inverse correlation with ZBTB16. Inhibition of miR-16-5p overexpression by restoring ZBTB16 significantly potentiated the overall antitumor efficacy of pyrotinib combined with chrysin against HER2-positive BC. Together, these findings demonstrate that the combined treatment of pyrotinib and chrysin enhances autophagy in HER2-positive BC through an unrecognized miR-16-5p/ZBTB16/G6PD axis.

A nomogram for predicting breast cancer specific survival in elderly patients with breast cancer: a SEER population-based analysis.

BACKGROUND: The number of elderly patients diagnosed with breast cancer is increasing worldwide. However, treatment decisions for these patients are highly variable. Although researchers have identified the effects of surgery, radiotherapy, endocrine therapy, and chemotherapy in elderly patients with breast cancer, clinicians still struggle to make appropriate decisions for these patients. METHODS: We identified 75,525 female breast cancer patients aged ≥ 70 years in the Surveillance, Epidemiology, and End Results (SEER) database treated between January 1, 2010, and December 31, 2016. The patients were further divided into training and testing cohorts. The cumulative occurrence of breast cancer-specific deaths (BCSDs) and other cause-specific deaths (OCSD) was calculated using the cumulative incidence function. In the univariate analysis, risk factors were screened using the Fine-Gray model. In the multivariate analysis for competing risks, the sub-distribution hazard ratio with a 95% confidence interval for each independent predictor associated with BCSD was calculated for the construction of nomograms. Based on the above analyses, a competing risk nomogram was constructed to predict the probability of BCSD in the 1st, 3rd, and 5th years after treatment. During validation, the concordance index (C-index) was selected to quantify the predictive ability of the competing risk model. RESULTS: A total of 33,118 patients were included in this study, with 24,838 in the training group and 8,280 in the testing group. Age, race, marital status, cancer grade, tumor stage, node stage, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor--2 status, and treatment including surgery, radiation, and chemotherapy were used to establish a nomogram. The C-index of 0.852 (0.842-0.862) in the training cohort and 0.876 (0.868-0.892) in the testing cohort indicated satisfactory discriminative ability of the nomogram. Calibration plots showed favorable consistency between the nomogram predictions and actual observations in both the training and validation cohorts. CONCLUSIONS: Our study identified independent predictors of BCSD in elderly patients with breast cancer. A prognostic nomogram was developed and validated to aid clinical decision-making.

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.

The disparities in prognostic prediction and annualized hazard function in different molecular subtypes between young Chinese and White American women with breast cancer.

Background and objectives: The prognostic disparities in different molecular subtypes between young Chinese and White American breast cancer patients remain unclear. The goal of this study was to explore the prognostic differences in different molecular subtypes between Chinese and White American patients aged ≤ 40 years. Methods: We included Chinese and White female breast cancer patients at or under the age of 40 from the Surveillance, Epidemiology, and End Results database (SEER) and the West China Hospital of Sichuan University. The chi-square test, log-rank test, and Cox proportional hazards model were employed to evaluate the distribution and survival disparities in the two racial/ethnic cohorts and different molecular subtypes. An annualized hazard function was used to calculate the annual failure rate among different molecular subtypes. Results: This study included 20,859 female breast cancer patients at or under the age of 40, of whom 18,400 were White women and 2,459 were Chinese women. With a median follow-up time of 47 months, the 5-year breast cancer-specific survival (BCSS) rates for young Chinese and White women were 93.9% and 90.0%, respectively (P< 0.001). Molecular subtype was found to be a significant predictor in both young Chinese and White patients (P< 0.001), but different trends were observed in the two racial/ethnic cohorts when exploring the association between BCSS and molecular subtypes. Among young White patients, the hormone receptor (HoR) (+)/epidermal growth factor receptor 2 (HER2) (+) subtype had the best 5-year BCSS rate, while in young Chinese patients, the HoR (+)/HER2 (+) and HoR (+)/HER2 (-) showed comparable survival curves and both showed superior 5-year BCSS than other subtypes. Stratification by molecular subtypes, young Chinese patients demonstrated a superior 5-year BCSS in HoR (+)/HER2 (-) (96.3% vs 92.9%, P< 0.001) and triple-negative subtypes (88% vs 81.7%, P= 0.006) compared to young White American patients, while no significant differences were found in HoR (+)/HER2 (+) and HER2 enriched tumors. The annual hazard function for BCSS showed that there were significantly different trends in the HoR (+)/HER2 (-) and HoR (+)/HER2 (+) subtypes between young Chinese and White patients. Conclusions: There are disparities in prognosis and annualized hazard function between young Chinese and White females with breast cancer in different molecular subtypes.

A prospective cohort study of clinical characteristics and outcomes in Chinese patients with estrogen receptor-negative/progesterone receptor-positive early breast cancer.

PURPOSE: This study aimed to examine the clinical characteristics and outcomes of patients with estrogen receptor-negative (ER-)/progesterone receptor-positive (PR+) early breast cancer. We also aimed to investigate the benefits of adjuvant endocrine therapy (ET) in this patient population. METHODS: Patients with early breast cancer diagnosed at West China Hospital were divided into the ER-/PR+, ER+, and ER-/PR- groups. The chi-square test was used to analyze differences in clinical and pathological features among the groups. Multivariable Cox and Fine-Gray regression models were used to compare mortality and locoregional recurrence (LRR)/distant recurrence (DR), respectively. We performed a subgroup analysis to determine which ER-/PR+ patients can benefit more from ET. RESULTS: From 2008 to 2020, we enrolled 443, 7104, and 2892 patients into the ER-/PR+, ER+, and ER-/PR- groups, respectively. The ER-/PR+ group showed more unfavorable clinical features and aggressive pathological characteristics than the ER+ group. The mortality, LRR, and DR rates were higher in the ER-/PR+ than in the ER+ group. Most clinical features and pathological characteristics were similar between the ER-/PR+ and ER-/PR- group and their outcomes were comparable. In the ER-/PR+ group, patients who received ET showed significantly lower LRR and mortality rates than those who did not; however, no difference was observed in DR. Subgroup analysis suggested that ER-/PR+ patients age ≥ 55 years, and postmenopausal status can benefit from ET. CONCLUSION: ER-/PR+ tumors have more aggressive pathological characteristics and more unfavorable clinical features than ER+ tumors. ET can reduce the LRR and mortality rates in ER-/PR+ patients. Postmenopausal and age ≥ 55 years ER-/PR+ patients can benefit from ET.

Global longitudinal strain at 3 months after therapy can predict late cardiotoxicity in breast cancer.

BACKGROUND: Cancer therapy-related cardiovascular toxicity (CTR-CVT) is a major contributor to poor prognosis in breast cancer (BC) patients undergoing chemotherapy. Left ventricular global longitudinal strain (LV GLS) has predictive value for CTR-CVT, while few researchers take into account late-onset CTR-CVT. This study sought to provide a guide for the prediction of late-onset CTR-CVT in primary BC over the 2 years follow-up via strain and contrast-enhanced echocardiography. METHODS: Anthracycline and anthracycline + targeted medication groups were created from 111 patients with stage I-III primary BC who were prospectively included. The left ventricular diastolic function, LV global long-axis strain (GLS); left ventricular ejection fraction by contrast-enhanced echocardiography (c-LVEF), and electrocardiograms were collected at baseline, 3, 6, 12, and 24 months after the start of cancer treatment. The high-sensitivity troponin-T and NT-pro BNP at baseline and 3 months after chemotherapy were measured. RESULTS: (1) LV GLS decreased in BC patients over time. (2) After 12 months' follow-up, the LV GLS in the anthracycline+ targeted group was lower than in the anthracycline group. After 24 months' follow-up, the GLS and c-LVEF in the anthracycline + targeted group declined while the E/e' increased. (3) Decreased LVEF (56%) and arrhythmia (38%) are the common causes of CTR-CVT. Lower LVEF was a major factor in late-onset CTR-CVT. (4) Combination of LV GLS and c-LVEF at 3 months were used as predictors for CTR-CVT and exhibited a higher AUC than either one alone (AUC = 0.929, 95% CI: 0.863-0.970). LV GLS at 3 months can predict the late-onset CTR-CVT (AUC = 0.745, p < 0.001), and the cut-off is 20.32%. CONCLUSIONS: As time went on, the systolic and diastolic dysfunction of BC patients get worsened. The combination of LV GLS and c-LVEF is better in the prediction of CTR-CVT. Only the LV GLS at 3 months can predict the late-onset CTR-CVT.

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.

Real-world efficacy and safety of pyrotinib in patients with HER2-positive metastatic breast cancer: A prospective real-world study.

Background: Pyrotinib, a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor, shows encouraging anticancer activity and acceptable tolerability in multiple phase II and phase III randomized clinical trials, but the real-world data of pyrotinib, especially the outcomes in HER2-positive metastatic breast cancer, have been rarely reported. Here, we evaluated the treatment outcomes of pyrotinib in real-world practice in patients with HER2-positive metastatic breast cancer (MBC). Methods: This was a prospective, real-world, observational cohort study. Through the Breast Cancer Information Management System, HER-2 positive MBC patients treated with pyrotinib between 2017/06 and 2020/09 were included. Provider-reported objective response rate, progression-free survival (PFS), and overall survival (OS) were considered in the assessment of treatment outcomes. Tumor responses to pyrotinib treatment were calculated using RECIST 1.1. Adverse events were evaluated using clinical records. Results: The trial involved 113 individuals who were receiving pyrotinib treatment, with an average age of 51 years. Complete response, partial response and stable disease were observed in 9 (8.0%), 66 (58.4%), and 17 (15.0%) patients, respectively, while progressive disease was recorded in 20 (17.7%) patients. After a median follow-up of 17.2 months, the median PFS was 14.1. The most common adverse events of any grade were diarrhea (87.6%), vomiting (31.9%), and palmar-plantar erythrodysesthesia (26.6%). Among the patients with brain metastases, the median PFS and OS were 15.2 and 19.8 months, respectively. In addition, pyrotinib has similar efficacy in various subtypes of HER2-positive MBC patients, as shown by the lack of a significant difference of PFS and OS among pyrotinib-treated patients with or without brain metastases, or patients using pyrotinib as first-line, second-line, third-line or beyond therapies. Conclusion: Our real-world results demonstrated equivalent clinical efficacy in HER-2 positive MBC patients compared to phase II and phase III clinical trials with pyrotinib, and promising outcomes in patients with brain metastases.

Global longitudinal strain assessment in contrast-enhanced echocardiography in breast cancer patients: a feasibility study.

BACKGROUND: Left ventricular global longitudinal strain (GLS) obtained from two-dimensional speckle-tracking echocardiography (2D-STE) can reflect cancer therapy-related cardiac dysfunction in breast cancer (BC) patients, however, the accuracy and reproducibility of 2D-STE are restricted due to poor image quality. METHODS: Between January 2019 and October 2021, 160 consecutive BC patients aged ≥ 18 years were recruited. The 160 BC patients (mean age: 48.41 ± 9.93 years, 100% women) underwent both 2D-STE and Contrast-enhanced echocardiography (CEcho), 125 of whom were included in the measurement of GLS. The intraclass correlation coefficient (ICC) was used to determine the intra- and inter-observer reproducibility of 2D-STE and CEcho-STE. Correlation (r) was calculated using Pearson correlation. Statistical significance was set at P < 0.05. RESULTS: Among 160 BC patients, more segments were recognized by CEcho-STE than by 2D-STE (2,771, 99.53% vs. 2,440, 84.72%). The left ventricular ejection fraction (LVEF) obtained by 2D was lower than CEcho (61.75 ± 6.59% vs. 64.14 ± 5.97%, P < 0.0001). The GLS obtained by 2D-STE was lower than CEcho-STE (-21.74 ± 2.77% vs. -26.79 ± 4.30%, P = 0.001). The ICC of the intraobserver and interobserver agreements in the CEcho-STE group was lower than that in the 2D-STE group. GLS measurements were in good agreement between the 2D-STE and CEcho-STE groups (r = 0.773). CONCLUSIONS: CEcho can overcome some imaging limitations and recognize more segments than 2D, which may provide an LVEF and GLS closer to the true value. Based on AutoStrain, CEcho-STE may serve as a complementary method for those with poor image quality.

The prognostic differences and the effect of postmastectomy radiotherapy between post-chemotherapy ypT1-2ypN1 and de novo pT1-2N1 breast cancer.

BACKGROUND: The prognosis and the value of postmastectomy radiotherapy (PMRT) between post-chemotherapy ypT1-2ypN1 and de novo pT1-2N1 breast cancer (BC) remain controversial. We aimed to evaluate the prognostic differences and the effect of PMRT between the two patient subsets. METHODS: Patients diagnosed with pT1-2N1M0 BC were identified between 2010 and 2018. The study endpoints were overall survival (OS), breast cancer-specific survival (BCSS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and disease-free survival (DFS). The chi-square test, Kaplan-Meier method and Cox regression analysis were used for data analysis. RESULTS: Total number of 2103 pT1-2N1M0 BC patients were included in the study, including 270 post-chemotherapy (97 without PMRT, 173 with PMRT) and 1833 de novo cases (993 without PMRT, 840 with PMRT). No significant differences were found between post-chemotherapy ypT1-2ypN1 and de novo pT1-2N1 BC patients in 5-year OS (p = 0.068), BCSS (p = 0.054), LRFS (p = 0.241), DMFS (p = 0.104) or DFS (p = 0.08). PMRT did not improve any survival outcome in patients receiving neoadjuvant chemotherapy; however, the PMRT group had a better 5-year BCSS (97.0% vs. 95.8%, p = 0.033) in de novo pT1-2N1 BC. Cox multivariate analysis demonstrated that PMRT was a significant independent predictor of BCSS (HR 0.628; 95% CI, 0.403-0.978; p = 0.04) in de novo pT1-2N1 patients. CONCLUSIONS: There seemed no survival difference in post-chemotherapy ypT1-2ypN1 and de novo pT1-2N1 BC patients with contemporary systemic therapy. In addition, PMRT might be exempted in patients with post-chemotherapy ypT1-2ypN1 BC, while not in patients with de novo pT1-2N1 BC.

Suspension culture strategies to enrich colon cancer stem cells.

How to efficiently obtain high-purity cancer stem cells (CSCs) has been the basis of CSC research, but the optimal conditions for serum-free suspension culture of CSCs are still unclear. The present study aimed to define the optimal culture medium composition and culture time for the enrichment of colon CSCs via suspension culture. Suspension cell cultures of colon cancer DLD-1 cells were prepared using serum-free medium (SFM) containing variable concentrations of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) to produce spheroids. Culture times were set at 10, 20 and 30 days. A total of nine different concentrations of EGF and bFGF were added to SFM to generate nine experimental groups. The proportions of CD44+, CD133+, and CD44+CD133+ double-positive spheroid cells were detected via flow cytometry. mRNA expression of stemness-, epithelial-mesenchymal transition- and Wnt/ß-catenin pathway-associated genes was determined via reverse transcription-quantitative PCR. Self-renewal ability was evaluated by a sphere-forming assay. Tumorigenesis was studied in vitro using a colony formation assay and in vivo via subcutaneous cell injection in nude mice. It was found that the highest expression proportions of CD133+ and CD44+ spheroid cells were observed in group (G)9 (20 ng/ml EGF + 20 ng/ml bFGF) at 30 days (F=123.554 and 99.528, respectively, P<0.001), CD133+CD44+ cells were also observed in G9 at 30 days (and at 10 days in G3 and 20 days in G6; F=57.897, P<0.001). G9 at 30 days also displayed the highest expression of Krüppel-like factor 4, leucine-rich repeat-containing G protein-coupled receptor 5, CD44, CD133, Vimentin and Wnt-3a (F=22.682, 25.401, 3.272, 7.852, 13.331 and 17.445, respectively, P<0.001) and the lowest expression of E-cadherin (F=10.851, P<0.001). G9 at 30 days produced the highest yield of cell spheroids, as determined by a sphere forming assay (F=19.147, P<0.001); colony formation assays also exhibited the greatest number of colonies derived from G9 spheroids at 30 days (F=60.767, P<0.01), which also generated the largest mean tumor volume in the subcutaneous tumorigenesis xenograft model (F=12.539, P<0.01). In conclusion, 20 ng/ml EGF + 20 ng/ml bFGF effectively enriched colon CSCs when added to suspension culture for 30 days, and conferred the highest efficiency compared with other combinations.