Neoadjuvant Chemotherapy of Taxanes With or Without Anthracyclines in Different Molecular Subtypes of Breast Cancer: A Propensity Score Matching Study.

PURPOSE: To compare the efficacy of taxane (T) based neoadjuvant chemotherapy (NAC) with T and anthracycline (A) based NAC in different molecular types of breast cancer (BC). METHODS: We retrospectively analyzed the date of NAC for BC from 20 hospitals in China from January 2010 to December 2020, 7870 cases were enrolled. The propensity score matching was used to equalize the baseline characteristics. Pathological complete response (pCR) rate, clinical response rate and breast-conserving rate were analyzed. RESULTS: The efficacy of 2 regimens were similar in luminal A subtype. The breast-conserving rate was higher in T-based NAC in luminal B subtype (17.9% vs. 10.2%, P = .043).The pCR (T0/isN0M0) and tpCR (T0N0M0) rates in T-based NAC were higher than those in TA-based NAC for triple-negative subtype (pCR: 34.5% vs. 25.8%, P = .041, tpCR: 26.9% vs. 17.1%, P = .008). For HER2+(HR-) subtype, the pCR, and tpCR rates were higher in T-based NAC in insufficient anti-HER2 therapy (P < .05), and those were higher in TA-based NAC in dual-target anti-HER2 therapy (pCR: 69.2% vs. 53.8%, P = .254, tpCR: 61.5% vs. 42.3%, P = .165). For HER2+(HR+) breast cancer, both pCR and tpCR rates were higher in TA group, regardless of the adequacy of anti-HER2 treatment. CONCLUSIONS: T-based NAC could replace TA-based NAC for luminal A, luminal B, and triple-negative early-stage BC, but anthracyclines cannot be abandoned in HER2+ breast cancer. The development of anthracyclines with lower adverse reactions is one of the directions for the treatment of HER2+ breast cancer.

Design, strategies, and therapeutics in nanoparticle-based siRNA delivery systems for breast cancer.

Utilizing small interfering RNA (siRNA) as a treatment for cancer, a disease largely driven by genetic aberrations, shows great promise. However, implementing siRNA therapy in clinical practice is challenging due to its limited bioavailability following systemic administration. An attractive approach to address this issue is the use of a nanoparticle (NP) delivery platform, which protects siRNA and delivers it to the cytoplasm of target cells. We provide an overview of design considerations for using lipid-based NPs, polymer-based NPs, and inorganic NPs to improve the efficacy and safety of siRNA delivery. We focus on the chemical structure modification of carriers and NP formulation optimization, NP surface modifications to target breast cancer cells, and the linking strategy and intracellular release of siRNA. As a practical example, recent advances in the development of siRNA therapeutics for treating breast cancer are discussed, with a focus on inhibiting cancer growth, overcoming drug resistance, inhibiting metastasis, and enhancing immunotherapy.

COVID-induced 3 weeks' treatment delay may exacerbate breast cancer patient's psychological symptoms.

The delayed access to cancer treatment due to the outbreak of COVID-19 pandemic posed a unique challenge to breast cancer patients and caused a significant level of mental distress among them. In the current research, we examined the psychological impacts of COVID on a subpopulation of breast cancer patients from a hospital in Shaanxi province of China using Symptom Checklist-90-R (SCL-90-R). Participants were 195 breast cancer patients at the outpatient clinic of Xijing hospital, Xi'an, Shaanxi Province, China. We found that a treatment delay of more than 3 weeks may exacerbate breast cancer patients' psychological symptoms, such as somatization, obsessive-compulsive disorder, interpersonal sensitivity, depression, hostility, phobic anxiety, paranoid ideation, and psychoticism, whereas a short-term delay of less than 3 weeks is less likely to have a significant effect on one's mental well-being. Additionally, breast cancer survivors, especially those at more advance stages, tend to experience more elevated psychological symptoms with longer treatment delay, and whose treatments continues to be delayed reported stronger psychological symptoms than individuals whose treatment are resumed, regardless of treatment type.

Model development to predict central lymph node metastasis in cN0 papillary thyroid microcarcinoma by machine learning.

Background: Whether prophylactic central lymph node dissection is necessary for cN0 papillary thyroid microcarcinoma (PTMC) patients remains highly debatable. Surgeons desperately need a way to help with surgical decision-making. While traditional predictive models can better explain changes in variables, machine learning (ML) models may have better predictive performance. This study aims to develop models for predicting the risk of central lymph node metastasis (CLNM) by utilizing ML algorithms. Methods: The clinical records of 1,121 patients with cN0 PTMC who underwent initial thyroid resection at our hospital between January 2014 and December 2018 were retrospectively retrieved. Univariate and multivariate analyses were performed to examine risk factors associated with CLNM. Six ML algorithms for predicting CLNM were established and internally validated. Indices including the area under the receiver operating characteristic (AUROC), sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated to test the performance of the model. Results: The results showed 33.5% (376 out of 1,121) of patients had CLNM. In multivariate logistic regression (LR) analyses, gender, age, tumor size, multifocal lesions, and extrathyroidal extension (ETE) were all independent predictors of CLNM. The AUROC predictive values of the six ML algorithms were between 0.664 and 0.794, with the random forest (RF) model performing the best with an AUROC of 0.794. Therefore, we used the RF model and uploaded the results to a web-based risk calculator to predict an individual's probability of CLNM (https://xijing-thyroid.shinyapps.io/ptmc_clnm). Conclusions: Developing predictive models of CLNM in cN0 PTMC patients using the ML algorithm is a feasible method. Our online risk calculator based on the RF model may be a useful tool for surgical decisions.

USP41 promotes breast cancer via regulating RACK1.

BACKGROUND: Breast cancer (BC) is the most common cancer diagnosed among women and is the second leading cause of cancer death. It is of great significance to explore potential candidate targets for BC. METHODS: The expression of ubiquitin-specific protease 41 (USP41) and its prognosis prediction function was firstly evaluated by TCGA database analysis. Using BC cell lines and specimens from 10 patients with primary BC, the upregulation of USP41 in BC was ensured. By USP41 overexpression or knockdown, its function was studied by cell function assays, small interfering RNA (siRNA), western blot, mass spectrometry, and flow cytometry. The potential mechanism of USP41 was explored via Co-Immunoprecipitation mass spectrometry, and western blot. RESULTS: TCGA database analysis revealed that in metastatic BC, USP41 expression was upregulated and negatively correlated with BC prognosis. In BC cancer cells and cancer specimens, USP41 was also upregulated. Overexpression of USP41 greatly enhanced BC colony-forming ability, proliferation, and migration. In contrast, USP41 knockdown significantly inhibited BC colony-forming ability, proliferation, and migration. Moreover, Co-Immunoprecipitation mass spectrometry results indicated that USP41 could interact with RACK1. USP41 promoted the protein expression of RACK1. The expression of RACK1 in BC tissues was upregulated. Knockdown of RACK1 inhibited cell growth and migration, and reversed the oncogenic function of USP41 in BC cells. CONCLUSIONS: USP41 can be a potential therapeutic target against BC via RACK1.

Analysis of sentinel lymph node biopsy and non-sentinel lymph node metastasis in invasive ductal and invasive lobular breast cancer: a nationwide cross-sectional study (CSBrS-001).

BACKGROUND: Information regarding the implementation of sentinel lymph node biopsy (SLNB) in invasive lobular carcinoma (ILC) is scarce, and whether ILC patients with 1-2 positive sentinel lymph nodes (SLNs) can be omitted from axillary lymph node dissection (ALND) remains controversial. This study aimed to compare involvement of SLNs and non-SLNs between patients with invasive ductal carcinoma (IDC) and ILC. METHODS: We retrospectively collected the clinical and pathological data of invasive breast cancer patients from 37 medical centers in China from January 2018 to December 2018. The number of resected SLNs, positive rate of SLNs, and non-SLNs metastasis were compared between patients with IDC and ILC. RESULTS: A total of 6,922 patients were included, comprising 6,650 with IDC (96.1%) and 272 with ILC (3.9%). No difference was observed in the number of resected SLNs between patients with IDC and ILC (IDC: 4.0±1.9 vs. ILC: 3.9±1.6, P=0.352). The positive rate of SLNs was significantly higher in patients with IDC than that in patients with ILC (19.3% in IDC vs. 12.9% in ILC, P=0.008). The difference in positive rate of SLNs between IDC and ILC was mainly attributed to macro-metastasis. For patients with positive SLNs who received ALND, and those with 1-2 positive SLNs, the metastatic rate of non-SLNs in the ILC group was higher than that in the IDC group (for patients with positive SLNs: 50.0% in ILC vs. 39.9% in IDC, P=0.317; for patients with 1-2 positive SLNs: 45.4% in ILC vs. 34.8% in IDC, P=0.366), but the differences were not statistically significant. CONCLUSIONS: Patients with ILC had similar number of resected SLNs and lower positive rate of SLNs compared to those with IDC. In participants with 1-2 positive SLNs, the ILC group had an increased tendency for non-SLNs metastasis compared with the IDC group. Surgeons may need to be more cautious about omitting ALND for ILC patients with 1-2 positive SLNs.

Factors Associated With Surgical Modality Following Neoadjuvant Chemotherapy in Patients with Breast Cancer.

BACKGROUND: The breast-conserving surgery (BCS) rate for patients with breast cancer in China is much lower than that in Europe and the United States. This study aimed to identify factors affecting the choice of surgical modality following neoadjuvant chemotherapy (NAC) in patients with breast cancer in northwest China. PATIENTS AND METHODS: Patients who underwent mastectomy or BCS after NAC for invasive breast cancer from January 2013 to December 2017 were enrolled in the study. Single-factor and multivariate logistic regression analyses were applied to identify the association between the type of surgery and demographic characteristics or clinical pathological factors of patients. RESULTS: This study enrolled 916 patients. Among them, 191 patients (20.9%) and 725 patients (79.1%) underwent BCS and mastectomy, respectively. Patients with high education were less likely to undergo mastectomy compared with patients with less education (P < .001; odds ratio [OR] = 0.50; 95% confidence interval [CI], 0.35-0.71). Patients with cT3 tumors were nearly six times more likely to undergo mastectomy compared with patients with cT1 tumors (P = .003; OR = 5.74; 95% CI, 2.07-15.97). Moreover, patients older than 50 years of age (P < .001; OR = 2.84; 95% CI, = 1.93-4.16) were more likely to be offered mastectomy. No association between the type of surgery and pathological complete response (P = .351) was observed. CONCLUSION: Pretreatment clinical disease size remains a strong predictor of surgical management, whereas response to NAC appeared to play no role in the surgical decision, suggesting that the potential surgical benefits of NAC may be still under-recogonized in northwest China.

MMP-2 sensitive poly(malic acid) micelles stabilized by π-π stacking enable high drug loading capacity.

Poly(ß-l-malic acid) (PMLA) together with its derivatives is an aliphatic polyester with superior bio-properties for anti-tumor drugs. In order to surmount the obstacles of low drug loading and rapid premature release during the circulation of polyester-based micelles, micelles based on poly(ß-benzyl malate)-b-polyethylene glycol (PBM-PEG) were developed in this study. The micelles had high drug loading capacity (>20 wt%) and held robust stability, owing to the π-π stacking interactions between polymer chains, and between the polymer and drug. Computer simulation also confirmed that there was the strongest binding free energy between PBMs, and PBM and doxorubicin (DOX), compared with other polyesters. A cell-penetrating moiety (TAT) was employed, and furthermore, a protective outer shell (PEG5k) was also introduced via a matrix metalloproteinase-2 (MMP-2) cleavable peptide. Before reaching the tumor site, the TAT peptide was shielded by long chain PEG, and the micelles showed low bioactivity. While at the tumor tissues where MMP-2 was highly expressed, the cleavage of the linker leads to the exposure of TAT, thus enhancing the cellular internalization. The desired therapeutic consequent was also observed, with no accompanying systemic toxicity detected. Our findings indicated that this MMP-2 sensitive PBM polymeric micelle would be a promising antitumor drug carrier with enhanced therapeutic effects.

Clinical Practice Status of Sentinel Lymph Node Biopsy for Early-Stage Breast Cancer Patients in China: A Multicenter Study.

BACKGROUND: Sentinel lymph node biopsy (SLNB) was introduced over 30 years ago, but the application of SLNB in China is unclear. This study aimed to explore the real-world implementation of SLNB among early-stage breast cancer patients in China. METHODS: A multi-center, retrospective study was conducted among primary breast cancer patients from 37 hospitals in China in 2018. Their clinical data were collected and analyzed, including the implementation status of SLNB in China, subsequent processing of sentinel lymph nodes (SLNs) containing metastases, and the effect of neoadjuvant chemotherapy (NAC) on SLNB. RESULTS: SLNB surgery was performed on 43.5% of early-stage breast cancer patients in China and 11,942 patients who underwent SLNB were enrolled in this study. The majority of SLNBs were performed using a single mapping agent. A combination of blue dye and radiotracer or fluorescence imaging was used in only 14.9% of patients. The mean (SD) number of resected SLNs was 4.0 (2.1). For the patients with 1 or 2 positive SLNs, 83.0% of them continued to receive axillary lymph node dissection (ALND), while others did not. For the patients with three or more positive SLNs, 97.2% of them continued to receive ALND, among which 82.9% accepted radiotherapy simultaneously. Of the patients who underwent SLN surgery, 5.5% (654/11,942) were receiving NAC. Among them, 51.9% received SLNB before NAC, and the rest received SLNB after NAC. In biopsy-proven positive nodes, 64.7% positive SLNs turned negative after NAC. CONCLUSION: SLNB has been promoted in China, but it is not widely used compared to in developed countries. Furthermore, the usage of the dual tracer technique in SLNB is not high. Chinese breast surgeons are more conservative regarding the omission of ALND in 1 or 2 SLNs-positive patients.

Regulation of docetaxel chemosensitivity by NR2F6 in breast cancer.

Docetaxel (DTX)-based chemotherapy significantly eliminates rest cancerous cells and decreases the risk of death, thus remaining the mainstay of treatment for operable breast cancer (BCa). However, resistance or incomplete response to DTX occurs frequently, resulting in disease recurrence and poor prognosis. There is an urgent need to identify and understand the key factors and corresponding molecular bases driving this complicated pathogenesis. Herein, both data mining and profiling analysis using clinical BCa biopsies showed that expression levels of the nuclear receptor subfamily 2, group F, member 6 (NR2F6), a recently characterized central transcription factor for cancer immune surveillance, were significantly downregulated in DTX-resistant BCa. This downregulation, possibly regulated by leptin signaling, predicted a poor postoperative chemotherapy survival in DTX-resistant BCa. In both genetically engineered cell models and patient-derived xenograft models, we provided evidence that BCa cells with insufficient NR2F6 expression were less responsive to DTX treatment. Mechanistically, NR2F6 functioned as a potent corepressor of platelet-derived growth factor B receptor gene (PDGFRB) transcription by recruiting HDAC2 onto the PDGFRB promoter. Stable PDGFRB inhibition ameliorated NR2F6 deficiency-impaired response to DTX in BCa cells, indicating that NR2F6's effect on DTX response is mediated, at least in part, through transcriptional repression of PDGFRB. Collectively, our findings define NR2F6 as an negative regulator of cell survival and DTX resistance, probably by serving as a convergent point linking leptin signaling and PDGF-B/PDGFRß axis, in BCa cells.

Small molecule HDAC inhibitors: Promising agents for breast cancer treatment.

Breast cancer, a heterogeneous disease, is the most frequently diagnosed cancer and the second leading cause of cancer-related death among women worldwide. Recently, epigenetic abnormalities have emerged as an important hallmark of cancer development and progression. Given that histone deacetylases (HDACs) are crucial to chromatin remodeling and epigenetics, their inhibitors have become promising potential anticancer drugs for research. Here we reviewed the mechanism and classification of histone deacetylases (HDACs), association between HDACs and breast cancer, classification and structure-activity relationship (SAR) of HDACIs, pharmacokinetic and toxicological properties of the HDACIs, and registered clinical studies for breast cancer treatment. In conclusion, HDACIs have shown desirable effects on breast cancer, especially when they are used in combination with other anticancer agents. In the coming future, more multicenter and randomized Phase III studies are expected to be conducted pushing promising new therapies closer to the market. In addition, the design and synthesis of novel HDACIs are also needed.

Relevance and clinicopathologic relationship of BRAF V600E, TERT and NRAS mutations for papillary thyroid carcinoma patients in Northwest China.

BACKGROUND: To determine the relevance of the single or combination mutations of BRAF V600E, TERT, and NRAS genes and the clinicopathologic relationship in papillary thyroid cancer (PTC). METHODS: Patients with PTC were enrolled into the study between February 2018 and April 2019. Based on the number of mutant genes, we classified the participants into single BRAF V600E mutation group, double mutations group and no mutation group. Single factor and multiple logistic regression analyses were applied to explore the independent factors. Review Manager 5.3 was used for meta-analysis to review the clinical efficacy of gene co-mutations. RESULTS: Finally, 483 patients were enrolled into the study and 419 (86.7%) of them harbored BRAF V600E mutation. TERT or NRAS mutation was likely to coexist with BRAF V600E mutation in PTC. BRAF V600E and NRAS promoter co-mutations was identified in 6 patients, with a prevalence of 1.2%. Prevalence of BRAF V600E and TERT coexistence in PTC was 2.1%. Significant differences were found among age, pathology, multifocality, bilateral lesions, lymph node metastasis, and 131I radiotherapy, P < 0.01. Multiple logistic regression analyses demonstrated that age [odds ratio (OR) = 1.044, 95% confidence interval (CI) = 1.013-1.076; P = 0.006], lymph node metastasis [OR = 0.094, 95% CI = 0.034-0.264; P < 0.001], 131I radiotherapy [OR = 7.628, 95% CI = 2.721-21.378; P < 0.001] were risk factors for BRAF V600E mutation. Besides, age [OR = 1.135, 95% CI = 1.069-1.205; P < 0.001], multiple leisions [OR = 4.128, 95% CI = 1.026-16.614; P = 0.046], pathology [OR = 3.954, 95% CI = 1.235-12.654; P = 0.021] were independent factors for combination mutations. Meta-analysis showed significant association of BRAF V600E+/TERT+ co-mutations with lymph node metastasis, multifocality, distant metastasis, tumor recurrence, extrathyroidal extension, and dead of disease. CONCLUSIONS: Prevalence of BRAF V600E mutation in Northwest China was higher than other areas. Age, multiple lesions, and pathology were independent factors for double mutation of BRAF V600E/TERT or BRAF V600E/NRAS. Coexistence of BRAF V600E and TERT promoter mutations was significantly correlated with poor outcome.

Relationship between BRAF V600E and clinical features in papillary thyroid carcinoma.

OBJECTIVE: To investigate the mutant status of BRAF gene and analyze its relationship to epidemiological risk factors and clinical outcomes among patients with papillary thyroid cancer (PTC) in the largest, single-institution Chinese cohort to date. METHODS: The medical records of 2048 PTC patients were reviewed in this retrospective study. Single-factor and multiple logistic regression analyses were applied to identify risk factors for BRAF V600E mutation. Survival outcomes including distant metastatic and persistent or recurrent PTC were examined, with a mean follow-up time of 23.4 (5-47) months. RESULTS: The BRAF V600E mutation was present in 83.7% of patients (1715 of 2048). Correlation was found between BRAF V600E mutation and several epidemiological features, including age, concomitant hypertension and Hashimoto thyroiditis (HT). For the clinicopathological features, BRAF V600E was significantly associated with bilateral multifocality (odds ratio (OR) 1.233, 95% confidence interval (CI) 1.063-1.431, P < 0.01) and less lateral lymph node metastases (OR 0.496, 95% CI 0.357-0.689, P < 0.01). Smaller tumor size and advanced disease stage were significant in single-factor analyses but became insignificant after multivariate adjustment. No association was found between BRAF V600E mutation and extrathyroidal invasion, distant metastatic and disease persistence or recurrence. CONCLUSION: Part of epidemiological features are independent risk or protective factors for BRAF V600E mutation. The presence of BRAF V600E mutation is not an aggressive prognosis on poor clinical outcomes in PTC. However, the high prevalence of BRAF V600E may provide guidance for surgery strategy and opportunity for targeted treatment in recurrent and advanced stage disease.

Oncoplastic technique using a lateral mammary adipofascial flap for the breast-conserving reconstruction.

Achieving satisfactory cosmetic results after breast-conserving surgery (BCS) can be difficult for breast cancer patients with large tumors. To avoid breast asymmetries and deformation, we present a case of breast reconstruction after BCS with a lateral mammary adipofascial flap, which was dissociated along the sentinel lymph node biopsy incision. During the procedure, the pedicled flap was transferred into the residual tumor cavity through a tunnel between them and then matched the residual cavity. The sufficient blood supply of the transferred flap was observed in ultrasound at follow-up. The operative is straightforward to perform and less invasive. No operative complications were observed. The cosmetic results were found to be good with a natural shape, volume, and symmetry, and with which the patient has reported high satisfaction. This procedure offers a new possibility in breast reconstruction and is worth considering as a new option for immediate repair after BCS.

Clinicopathological characteristics and prognosis of thyroid cancer in northwest China: A population-based retrospective study of 2490 patients.

BACKGROUND: The specific clinical features of thyroid cancer patients in northwest China are unclear; therefore, we analyzed the clinicopathological characteristics and prognosis of this population. METHODS: Clinical characteristics including age, gender, blood type, histological type, and BRAFV600E gene mutation; and incidence; risk factors; surgical treatment; and prognosis were recorded. RESULTS: A total of 2490 thyroid cancer patients were included; 98% were diagnosed with papillary thyroid cancer (PTC). Weight, blood type, histological type, and BRAFV600E gene mutation rates were significantly different. Pediatric thyroid cancer patients had higher lymph node metastasis, lower BRAFV600E mutation, and 6.2-9.2% greater recurrence rates than adult patients. PTC and papillary thyroid microcarcinoma displayed similar features, while in other types, such as follicular and medullary thyroid cancer, there were variations. Multiple logistic analyses showed that age (odds ratio [OR] 0.957, 95% confidence interval [CI] 0.944-0.970; P < 0.001), focal status (OR 16.174, 95% CI 9.257-28.262; P < 0.001), pathology (OR 0.642, 95% CI 0.473-0.871; P = 0.004) and lymph node metastasis (OR 0.059, 95% CI 0.033-0.107; P < 0.001) were independent factors for BRAFV600E mutation. CONCLUSION: Most real world clinicopathological features, treatment, and prognosis of thyroid cancer are similar to reported data, such as the higher incidence of disease in women and the larger proportion of PTC. However, the results in pediatric patients and those with BRAF gene mutations are controversial and require more clinical incidence.

Synthesis and properties of poly(DEX-GMA/AAc) microgel particle as a hemostatic agent.

Immediate hemorrhage control without secondary injury is pivotal for saving lives. In this study, polymerized glycidyl methacrylate derivative dextran/acrylic acid (poly(DEX-GMA/AAc)) microgel particles were prepared via emulsion polymerization method as a hemostatic agent. Microgel particles with size distribution of 500-800 nm were chosen because they showed more appropriate characteristics of swelling ratio and gelation time. The results revealed that the microgel particles had excellent swelling ratio of 68.95 g g-1 (w/w), which was 8.4 times that of counterpart clinically used microporous polysaccharide hemospheres, Arista. And poly(DEX-GMA/AAc) showed very short gelation time of 10-13 s. As a result, a gelled film could be formed rapidly after poly(DEX-GMA/AAc) absorbed water in blood when used on wounds, and then staunched bleeding. Poly(DEX-GMA/AAc) microgel particles showed better clotting ability than commercial hemostatic agent Flashclot in vitro. In addition, poly(DEX-GMA/AAc) did not cause exothermic burn when absorbing liquid, which was superior to Flashclot. No obvious toxicity was found in cytotoxicity study and skin irritancy test. Blood loss and hemostasis time were dramatically reduced by poly(DEX-GMA/AAc) microgel particles in hemorrhage models of ear vein, ear artery, liver and femoral artery in rabbits. These results indicated that the poly(DEX-GMA/AAc) microgel particles are a potential hemostatic agent with almost no cytotoxicity and good biocompatibility.