Neratinib is an oral, irreversible tyrosine kinase inhibitor of HER1, HER2 and HER4. In China, neratinib was approved in 2020 in the extended adjuvant treatment for HER2+ EBC adult patients who completed prior adjuvant trastuzumab-based therapy. Neratinib is currently the only approved anti-HER2 extended adjuvant therapy for HER2+ EBC. The ExteNET phase III trial, that included patients after adjuvant trastuzumab, has provided concrete efficacy evidence of neratinib in the extended adjuvant setting, but the adjuvant treatment landscape has changed since. Diarrhoea was the most common grade 3 adverse event observed without mandated antidiarrheal prophylaxis (39,8 %). With the evolving landscape of adjuvant treatments, there is a great need to identify real-world treatment patterns of neratinib in HER2+ EBC, its use in clinical practice, its effectiveness and safety data in patients in China. This is a multi-center, open-label, single-arm, non-interventional study in patients with HER2+ EBC in China. 500 patients in 30 centers who completed adjuvant trastuzumab based treatment and scheduled to receive 1-year of extended adjuvant neratinib will be included. Patients will undergo 12 months of extended adjuvant neratinib treatment and 12 months follow-up. Due to its observational nature, treatment decisions will be independent of the registration to the study. The primary objective aims to describe the real-world treatment patterns with neratinib among HER2+ early-stage breast cancer patients. Primary endpoints are patterns of adjuvant treatment, including patient demographics, characteristics, and different prior adjuvant treatments; and patterns of neratinib use as extended adjuvant treatment. Secondary endpoints include incidence, type, severity, and action taken of all grades of AE of special interest. Exploratory endpoints are characterization of recurrence patterns and assessment of self-reported HRQoL. As of 10 Jan 2023, 49 patients have been enrolled from 14 initiated sites. NCT05491057. Medical writing support was provided by Buffy Li, Beijing MetHealth Technology Co., Ltd. Pierre Fabre Medicament. Pierre Fabre Medicament.
Notch receptors (Notch1-4) play critical roles in tumorigenesis and metastasis of malignant tumors, including breast cancer. Although abnormal Notch activation is related to various tumors, the importance of single receptors and their mechanism of activation in distinct breast cancer subtypes are still unclear. Previous studies by our group demonstrated that Notch3 may inhibit the emergence and progression of breast cancer. PTEN is a potent tumor suppressor, and its loss of function is sufficient to promote the occurrence and progression of tumors. Intriguingly, numerous studies have revealed that Notch1 is involved in the regulation of PTEN through its binding to CBF-1, a Notch transcription factor, and the PTEN promoter. In this study, we found that Notch3 and PTEN levels correlated with the luminal phenotype in breast cancer cell lines. Furthermore, we demonstrated that Notch3 transactivated PTEN by binding CSL-binding elements in the PTEN promoter and, at least in part, inhibiting the PTEN downstream AKT-mTOR pathway. Notably, Notch3 knockdown downregulated PTEN and promoted cell proliferation and tumorigenesis. In contrast, overexpression of the Notch3 intracellular domain upregulated PTEN and inhibited cell proliferation and tumorigenesis in vitro and in vivo. Moreover, inhibition or overexpression of PTEN partially reversed the promotion or inhibition of cell proliferation induced by Notch3 alterations. In general, Notch3 expression positively correlated with elevated expression of PTEN, ER, lower Ki-67 index, and incidence of involved node status and predicted better recurrence-free survival in breast cancer patients. Therefore, our findings demonstrate that Notch3 inhibits breast cancer proliferation and suppresses tumorigenesis by transactivating PTEN expression.
Abstract Extensive clinical trials indicate that patients with negative sentinel lymph node biopsy do not need axillary lymph node dissection (ALND). However, the ACOSOG Z0011 trial indicates that patients with clinically negative axillary lymph nodes (ALNs) and 1–2 positive sentinel lymph nodes having breast conserving surgery with whole breast radiotherapy do not benefit from ALND. The aim of this study is therefore to identify those patients with 0–2 positive nodes who might avoid ALND. A total of 486 patients were eligible for the study with 212 patients in the modeling group and 274 patients in the validation group, respectively. Clinical lymph node status, histologic grade, estrogen receptor status, and human epidermal growth factor receptor 2 status were found to be significantly associated with ALN metastasis. A negative binomial regression (NBR) model was developed to predict the probability of having 0–2 ALN metastases with the area under the curve of 0.881 (95% confidence interval 0.829–0.921, P < 0.001) in the modeling group and 0.758 (95% confidence interval 0.702–0.807, P < 0.001) in the validation group. Decision curve analysis demonstrated that the model was clinically useful. The NBR model demonstrated adequate discriminative ability and clinical utility for predicting 0–2 ALN metastases.
Abstract Brachial plexus injury is a rare complication during operation and anesthesia; it can occur as a result of various mechanisms such as inappropriate positioning, over-abduction and stretching the upper limbs. Brachial plexus injury can cause the poor function of the upper limb before recovery, and sometimes serious injury is unable to completely recovered the function permanently. Here, we report a female breast cancer patient who sustained a left brachial plexus palsy after modified radical mastectomy with immediate breast reconstruction with latissimusdorsi flap (LDF). The patient had fully recovered with normal function of her left upper limb six months postoperation after conservative treatment.
We analyzed the clinicopathological characteristics of 1,425 primary breast cancer patients admitted to the Cancer Hospital of Shantou University Medical College from 1995 to 2008. The peak age group was 45-49 years old and median age was 49 years old. Sixty-two percent of the patients were pre-menopausal, while the remaining was postmenopausal. In the present study, 53% of the patients were in stage I-II of TNM staging. Immunohistochemical detection demonstrated that estrogen receptor (ER), progestrone receptor (PR) and human epidermal growth factor receptor 2 (Her-2) were 59%, 56% and 32% positive, respectively. The most common histological type was invasive ductal carcinoma accounting for 76% of total patients. Most patients received surgical treatment (97.2%) and chemotherapy (74.4%). The overall five-year and ten-year survival rates were 63% and 56% respectively. Multivariate analyses revealed that the tumor size, axillary lymph node involvement, and clinical staging were independent risk factors for overall survival (OS). In summary, the largest cohort of breast cancer patients in Eastern Guangdong was analyzed with their clinicopathological characteristics. We demonstrated that the similar clinical outcomes were obtained by multi-modality therapy, and the tumor size and lymph node involvement are the independent prognostic factors being same as the previous reports. Keywords: Breast cancer, clinicopathological characteristics, lymph node involvement, overall survival, prognosis, tumor size.
Abstract No current in vitro tumor model replicates a tumor’s in vivo microenvironment. A culturing technique that better preserves a tumor’s pathophysiological conditions is needed for some important clinical applications, including personalized drug-sensitivity/resistance assays. In this study, we utilized autologous serum or body fluid to build a 3D scaffold and grow a patient’s tumor. We named this technique “3D-ACM” (autologous culture method). Forty-five clinical samples from biopsies, surgically removed tumor tissues and malignant body fluids were cultured with 3D-ACM. Traditional 3D-FBS (fetal bovine serum) cultures were performed side-by-side for comparison. The results were that cells cultured in 3D-ACM rebuilt tissue-like structures, and retained their immuno-phenotypes and cytokine productions. In contrast, the 3D-FBS method promoted mesenchymal cell proliferation. In preliminary chemo drug-sensitivity assays, significantly higher mortality was always associated with FBS-cultured cells. Accordingly, 3D-ACM appears to more reliably preserve a tumor’s biological characteristics, which might improve the accuracy of drug-testing for personalized cancer treatment.
The purpose of the present study was to investigate the significance of C-X-C motif chemokine receptor type 4 (CXCR4) and epidermal growth factor receptors (EGFRs) in triple-negative breast cancer (TNBC). CXCR4 and EGFR expression levels were immunohistochemically determined in 207 primary breast cancer specimens. The associations between receptor expression and clinicopathological characteristics were analyzed, and receptor expression was also assessed as a prognostic factor. In the human MDA-MB-231 TNBC cell line, CXCR4 or EGFR was stably knocked down by short hairpin RNA, and the biological behavior of the cells, including migration, invasion and tumorigenesis, was investigated. The results revealed that TNBC was associated with younger age, higher histological grade and an aggressive phenotype. CXCR4 and EGFR were highly expressed in patients with TNBC, and those with high CXCR4 or EGFR expression exhibited an unfavorable prognosis in terms of disease-free survival and overall survival. In MDA-MB-231 cells, the expression of CXCR4 protein was decreased following EGFR silencing, while CXCR4 knockdown also caused a decrease in EGFR protein levels. The migratory and invasive capabilities of MDA-MB-231 cells were decreased following the knockdown of CXCR4 or EGFR expression. A strong correlation between CXCR4 and EGFR expression was identified in patients with TNBC. The results suggest that elevated expression levels of these two receptors may serve as predictive factors for poor prognosis in patients with TNBC. In addition, tumor proliferation, migration, invasion and tumorigenesis are weakened in MDA-MB-231 cells following suppression of CXCR4 or EGFR expression. Therefore, EGFR and CXCR4 may be potential therapeutic targets for TNBC.
Checkpoint inhibitor therapy has become increasingly important and has been endorsed as a treatment regimen in breast cancer. But benefits were limited to a small proportion of patients. We aimed to develop an improved signature on the basis of immune genes for detection of potential benefit from immunotherapy. Gene expression data of patients with breast cancer initially extracted from The Cancer Genome Atlas were analyzed. Ten genes were selected from the interaction of differentially expressed genes as well as immune-related genes to develop a survival signature. We compared the high-risk and low-risk groups by gene set enrichment analysis, immune infiltration, checkpoint molecule expression and immunophenoscore. Ten genes were extracted from interactions of differentially expressed and immune-related genes. The immune risk score was determined on the basis of the Cox regression coefficient of hub genes and validated with the GSE96058 dataset. Immune cell infiltrates, including CD8 + T cells, plasma cells, follicular helper T cells, CD4 + memory T cells, M1 macrophages, regulatory T cells and resting NK cells, were more highly infiltrated in the high-risk group as compared to the low-risk group. Checkpoint molecules, including CTLA-4, PD-L1, TIM-3, VISTA, ICOS, PD-1, and PD-L2, were expressed at markedly lower levels in the high-risk group as compared to the low-risk group. Immunophenoscores, as a surrogate of response to immune checkpoint therapy, was observed significant lower in the high-risk group. The 10-gene prognostic signature could identify patients’ survival and was correlated with the biomarkers of immune checkpoint inhibitor therapy, which may guide precise therapeutic decisions in clinical practice.
Triple-negative breast cancer (TNBC) accounts for 15–20% of all breast cancer cases. Due to the lack of expression of well-known molecular targets [estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)], there is a need for more alternative treatment approaches in TNBC. Chimeric antigen receptor (CAR)-T cell-based immunotherapy treatment is one of the latest treatment technologies with outstanding therapeutic advances in the past decade, especially in the treatment of hematologic malignancies, but the therapeutic effects of CAR-T cells against solid tumors have not yet shown significant clinical benefits. Identification of highly specific CAR-T targets in solid tumors is also crucial for its successful treatment. CD22 is reported to be a multifunctional receptor that is mainly expressed on the surface of mature B-cells (lymphocytes) and is also highly expressed in most B-cell malignancies. This study aimed to investigate the expression of CD22 in TNBC. Bioinformatic analysis was performed to evaluate the expression of CD22 in breast carcinoma and normal tissues. RNA-seq data of normal and breast carcinoma patients were downloaded from The Cancer Genome Atlas (TCGA), and differential gene expression was performed using R language. Additionally, online bioinformatics web tools (GEPIA and TNM plot) were used to evaluate the expression of CD22 in breast carcinoma and normal tissues. Western blot (WB) analysis and immunofluorescence (IF) were performed to characterize the expression of CD22 in TNBC cell lines. Immunohistochemical (IHC) staining was performed on tumor specimens from 97 TNBC patients for CD22 expression. Moreover, statistical analysis was performed to analyze the association of clinical pathological parameters with CD22 expression. Correlation analysis between overall survival data of TNBC patients and CD22 expression was also performed. Differential gene expression analysis of TCGA data revealed that CD22 is among the upregulated differentially expressed genes (DEGs) with high expression in breast cancer, as compared to normal breast tissues. WB and IF analysis revealed high expression of CD22 in TNBC cell lines. IHC results also showed that approximately 62.89% (61/97) of TNBC specimens were stained positive for CD22. Cell membrane expression of CD22 was evident in 23.71% (23/97) of TNBC specimens, and 39.18% (38/97) of TNBC specimens showed cytoplasmic/membrane expression, while 37.11% (36/97) specimens were negative for CD22. Furthermore, significant associations were found between the size of tumors in TNBC patients and CD22 expression, which unveils its potential as a prognostic biomarker. No significant correlation was found between the overall survival of TNBC patients and CD22 expression. In conclusion, we demonstrated for the first time that CD22 is highly expressed in TNBC. Based on our findings, we anticipated that CD22 could be used as a prognostic biomarker in TNBC, and it might be a potential CAR-T target in TNBC for whom few therapeutic options exist. However, more large-scale studies and clinical trials will ensure its potential usefulness as a CAR-T target in TNBC.
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