NF-κB signaling in therapy resistance of breast cancer: Mechanisms, approaches, and challenges.

Breast cancer is the most common type of cancer and is the second leading cause of cancer-related mortality in women. Chemotherapy, targeted therapy, endocrine therapy, and radiotherapy are all effective in destroying tumor cells, but they also activate the defense and protection systems of cancer cells, leading to treatment resistance. Breast cancer is characterized by a highly inflammatory tumor microenvironment. The NF-κB pathway is essential for connecting inflammation and cancer, as well as for tumor growth and therapy resistance. An increase in NF-κB signaling boosts the growth potential of breast cancer cells and facilitates the spread of tumors to bone, lymph nodes, lungs, and liver. This review focuses on the mechanisms by which chemotherapy, targeted therapy, endocrine therapy, and radiotherapy induce breast cancer resistance through NF-κB signaling. Additionally, we investigate therapeutic regimens, including single agents or in combination with target inhibitors, plant extracts, nanomedicines, and miRNAs, that have been reported in clinical trials, in vivo, and in vitro to reverse resistance. In particular, NF-κB inhibitors combined with tamoxifen were shown to significantly increase the sensitivity of breast cancer cells to tamoxifen. Combination therapy of miRNA-34a with doxorubicin was also found to synergistically inhibit the progression of doxorubicin-resistant breast cancer by inhibiting Notch/NF-κB signaling.

NF-κB in biology and targeted therapy: new insights and translational implications.

NF-κB signaling has been discovered for nearly 40 years. Initially, NF-κB signaling was identified as a pivotal pathway in mediating inflammatory responses. However, with extensive and in-depth investigations, researchers have discovered that its role can be expanded to a variety of signaling mechanisms, biological processes, human diseases, and treatment options. In this review, we first scrutinize the research process of NF-κB signaling, and summarize the composition, activation, and regulatory mechanism of NF-κB signaling. We investigate the interaction of NF-κB signaling with other important pathways, including PI3K/AKT, MAPK, JAK-STAT, TGF-ß, Wnt, Notch, Hedgehog, and TLR signaling. The physiological and pathological states of NF-κB signaling, as well as its intricate involvement in inflammation, immune regulation, and tumor microenvironment, are also explicated. Additionally, we illustrate how NF-κB signaling is involved in a variety of human diseases, including cancers, inflammatory and autoimmune diseases, cardiovascular diseases, metabolic diseases, neurological diseases, and COVID-19. Further, we discuss the therapeutic approaches targeting NF-κB signaling, including IKK inhibitors, monoclonal antibodies, proteasome inhibitors, nuclear translocation inhibitors, DNA binding inhibitors, TKIs, non-coding RNAs, immunotherapy, and CAR-T. Finally, we provide an outlook for research in the field of NF-κB signaling. We hope to present a stereoscopic, comprehensive NF-κB signaling that will inform future research and clinical practice.

Treatment patterns and clinical outcomes of chidamide combined with endocrine therapy in hormone receptor-positive, HER2-negative metastatic breast cancer: A real-world multicenter study.

BACKGROUND: Chidamide is a selective histone deacetylase inhibitor approved for patients with hormone receptor (HoR)-positive and HER2-negative metastatic breast cancer (MBC). We aimed to investigate the efficacy, safety, and treatment patterns of chidamide and identify clinicopathological factors that predict the efficacy of chidamide in real-world scenarios. METHODS: Consecutive MBC patients treated with chidamide from January 2020 to August 2021 across 11 institutions were enrolled in this multicenter, retrospective study. Eligible patients were pre- and postmenopausal women who had clinically or histologically confirmed ER-positive, HER2-negative MBC, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with multiple primary malignancies or missing baseline characteristics were excluded. Patients received 30 mg chidamide orally twice a week, combined with aromatase inhibitors (AIs) or non-AIs. Efficacy analyses included progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). Univariate and multivariate Cox regression analyses were performed to identify the potential efficacy predictors. RESULTS: A total of 157 patients were finally included for analysis. The median number of lines prior to chidamide was four. In the whole cohort, the median PFS was 4.2 months (95% confidence interval [CI] 3.8-4.5). The ORR was 7.5% and the CBR was 31.3%. The efficacy of chidamide was consistent in patients pretreated with CDK4/6 inhibitors and patients treated with different endocrine combinations. Multivariate analysis indicated that patients who had liver metastases (adjusted HR = 1.66, 95% CI 1.14-2.43, adjusted p = 0.008) or ≥3 prior lines of treatment (adjusted HR = 1.80, 95% CI 1.17-2.77, adjusted p = 0.008) had significantly worse PFS. The most common AEs with chidamide were thrombocytopenia, leucopenia, neutropenia, and anemia. CONCLUSION: This study provided real-world data for the use of chidamide in patients with HoR-positive and HER2-negative MBC. Our data endorsed the use of chidamide in patients pretreated with CDK4/6 inhibitors and patients treated with different endocrine combinations.

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.

Incidence and prognostic significance of receptor discordance between primary breast cancer and paired bone metastases.

ER, PgR and HER-2 status are the cornerstones of choosing systemic therapy for breast cancer, but can change during the disease course. Guidelines recommended the biopsy of the metastatic tumor to reassess receptor status. Bone is the most frequent metastatic site of breast cancer but remained technically difficult to biopsy. Our study aimed to evaluate the incidence and prognostic significance of receptor discordance between primary breast cancer and paired bone metastases. One hundred and fifty-five breast cancer patients were diagnosed with pathology-confirmed bone metastasis at Fudan University Shanghai Cancer Center. Ninety-three patients with receptor status available on both primary tumor and bone metastases were included in our study. ER, PgR and HER-2 status converted from positive to negative in 10.8% (10/93), 28.0% (26/93) and 8.6% (8/93) of the patients, while ER, PgR and HER-2 status converted from negative to positive in 3.2% (3/93), 4.3% (4/93) and 1.1% (1/93) of the patients, respectively. 40.4% (17/42) of the HER2-0 tumors converted to HER2-low, which enabled them to receive the treatment of new antibody-drug conjugates (ADCs). Prior endocrine and anti-HER2 therapy were the independent risk factors for receptor conversion. Loss of HR expression in bone metastases was significantly associated with worse first-line PFS (adjusted hazard ratio = 3.271, P-value = .039) and OS (adjusted hazard ratio = 6.09, P-value = .011). In conclusion, our study confirmed that patients may experience receptor conversion between primary breast cancer and bone metastases, possibly influenced by prior treatments, which significantly influenced prognosis. The rebiopsy of bone metastases in patients with primary HER2-0 tumors may benefit from the new ADC drugs.

Age- and Severity-Associated Humoral Immunity Response in COVID-19 Patients: A Cohort Study from Wuhan, China.

Age has been found to be the single most significant factor in COVID-19 severity and outcome. However, the age-related severity factors of COVID-19 have not been definitively established. In this study, we detected SARS-CoV-2-specific antibody responses and infectious disease-related blood indicators in 2360 sera from 783 COVID-19 patients, with an age range of 1−92 years. In addition, we recorded the individual information and clinical symptoms of the patients. We found that the IgG responses for S1, N, and ORF3a and the IgM for NSP7 were associated with severe COVID-19 at different ages. The IgM responses for the S-protein peptides S1-113 (aa 673−684) and S2-97 (aa 1262−1273) were associated with severe COVID-19 in patients aged <60. Furthermore, we found that the IgM for S1-113 and NSP7 may play a protective role in patients aged <60 and >80, respectively. Regarding clinical parameters, we analyzed the diagnostic ability of five clinical parameters for severe COVID-19 in six age groups and identified three-target panel, glucose, IL-6, myoglobin, IL-6, and NT proBNP as the appropriate diagnostic markers for severe COVID-19 in patients aged <41, 41−50, 51−60, 61−70, 71−80, and >80, respectively. The age-associated severity factors revealed here will facilitate our understanding of COVID-19 immunity and diagnosis, and eventually provide meaningful information for combating the pandemic.

SARS-CoV-2-specific antibody response characteristics in COVID-19 patients of different ages.

Age has been found to be one of the main risk factors for the severity and outcome of COVID-19. However, differences in SARS-CoV-2 specific antibody responses among COVID-19 patients of different age groups remain largely unknown. In this study, we analyzed the IgG/IgM responses to 21 SARS-CoV-2 proteins and 197 peptides that fully cover the spike protein against 731 sera collected from 731 COVID-19 patients aged from 1 to We show that there is no overall difference in SARS-CoV-2 antibody responses in COVID-19 patients in the 4 age groups. By antibody response landscape maps, we find that the IgG response profiles of SARS-CoV-2 proteins are positively correlated with age. The S protein linear epitope map shows that the immunogenicity of the S-protein peptides is related to peptide sequence, disease severity and age of the COVID-19 patients. Furthermore, the enrichment analysis indicates that low S1 IgG responses are enriched in patients aged <50 and high S1 IgG responses are enriched in mild COVID-19 patients aged >60. In addition, high responses of non-structural/accessory proteins are enriched in severe COVID-19 patients aged >70. These results suggest the distinct immune response of IgG/IgM to each SARS-CoV-2 protein in patients of different age, which may facilitate a deeper understanding of the immune responses in COVID-19 patients.

Identification of Key Genes Associated with Brain Metastasis from Breast Cancer: A Bioinformatics Analysis.

BACKGROUND As the second most frequent factor of brain metastasis worldwide, breast cancer and its pathogenesis have been researched intensively. Nevertheless, the molecular mechanisms of brain metastasis from breast cancer (BMBC) remain uncertain. The purpose of this study was to explore the key genes concerning the prognosis of BMBC and identify their predictive value. MATERIAL AND METHODS Obtained from the Gene Expression Omnibus (GEO) database, microarray datasets GSE125989, GSE52604, and GSE159956 were used to identify the differentially expressed genes (DEGs) and perform function enrichment analysis. RESULTS Of a total of 240 DEGs, 113 genes were upregulated and 127 genes were downregulated. The protein-protein interaction (PPI) was performed through STRING, and 29 hub genes were screened through Cytoscape. After being examined through the cBioportal online platform and the Oncomine database, 8 key genes were finally obtained, including COL14A1, COL3A1, COL6A3, THY1, MMP14, GAP43, PTPRN, and SNAP25. In the validation dataset GSE46928, COL14A1 was shown to have predictive significance of brain metastasis in breast cancer. CONCLUSIONS The key genes explored in this article could assist in identifying the molecular mechanism of BMBC. Also, COL14A1, COL3A1, COL6A3, THY1, MMP14, GAP43, PTPRN, and SNAP25 might be candidate targets for diagnosis and treatment of BMBC, and COL3A1 might have predictive value.

COVID-ONE-hi: The One-stop Database for COVID-19-specific Humoral Immunity and Clinical Parameters.

Coronavirus disease 2019 (COVID-19), which is caused by SARS-CoV-2, varies with regard to symptoms and mortality rates among populations. Humoral immunity plays critical roles in SARS-CoV-2 infection and recovery from COVID-19. However, differences in immune responses and clinical features among COVID-19 patients remain largely unknown. Here, we report a database for COVID-19-specific IgG/IgM immune responses and clinical parameters (named COVID-ONE-hi). COVID-ONE-hi is based on the data that contain the IgG/IgM responses to 24 full-length/truncated proteins corresponding to 20 of 28 known SARS-CoV-2 proteins and 199 spike protein peptides against 2360 serum samples collected from 783 COVID-19 patients. In addition, 96 clinical parameters for the 2360 serum samples and basic information for the 783 patients are integrated into the database. Furthermore, COVID-ONE-hi provides a dashboard for defining samples and a one-click analysis pipeline for a single group or paired groups. A set of samples of interest is easily defined by adjusting the scale bars of a variety of parameters. After the "START" button is clicked, one can readily obtain a comprehensive analysis report for further interpretation. COVID-ONE-hi is freely available at www.COVID-ONE.cn.

Determination and clinical significance of bone pseudoprogression in hormone receptor-positive metastatic breast cancer.

BACKGROUND: 99mTechnetium labeled methylene diphosphonate bone scans (BSs) are commonly used to monitor disease progression in bone for patients with metastatic breast cancer (MBC). However, new BS lesions may represent osteoblastic bone healing, which we now define as bone pseudoprogression. In this study, we aimed to assess the clinical significance and determination methods of bone pseudoprogression. METHODS: This retrospective analysis was conducted among 48 patients with hormone receptor-positive MBC treated with first-line endocrine therapy. Four months after initiating therapy, all the participants did not show extraosseous disease progression. Participants were divided into two groups according to the presence of new BS lesions. All the patients continued on treatment until explicit disease progression (extraosseous disease progression or progressive lysis on bone lesions). Explicit progression-free survival (PFS) and extraosseous objective response rate were analyzed between the two groups. RESULTS: New BS lesions were observed in 11 of 48 (22.9%) patients. All the new BS lesions appeared as osteoblastic bone lesions on computed tomography. For patients with new BS lesions, the median PFS was 26.57 months [95% confidence interval (CI) 15.46-37.68], which was similar to that (29.57 months; 95% CI 19.24-39.90) in patients without new BS lesions [hazard ratio: 1.098 (95% CI 0.482-2.503), p = 0.818]. Notably, 82.9% of patients without new BS lesions showed an extraosseous objective response, whereas 85.7% of patients with new BS lesions demonstrated an extraosseous objective response [odds ratio: 0.806 (95% CI 0.061-5.682), p = 0.999]. The median interval between bone pseudoprogression and true disease progression was 21.26 months (95% CI 10.11-32.42). CONCLUSIONS: Osteoblastic new BS lesions detected on follow-up BSs may represent bone pseudoprogression. Clinicians should raise awareness of bone pseudoprogression, thereby avoiding premature discontinuation of therapy and maximizing the opportunity to benefit from endocrine therapy. Due to the small sample size and retrospective nature of the study, large prospective clinical trials are needed to confirm our findings.

Development and validation of a nomogram for predicting overall survival of patients with cancer of unknown primary: a real-world data analysis.

BACKGROUND: Cancer of unknown primary (CUP) has a variable prognosis and lacks any standard staging systems. We aim to improve the prediction of survival in patients with CUP by constructing a nomogram based on a real-world, population analysis. METHODS: We performed a population analysis of patients diagnosed with CUP between 2010 and 2016 in the Surveillance, Epidemiology, and End Results (SEER) database. Patients with complete study variables were respectively assigned to training and validation cohorts by diagnostic time. A prognostic nomogram was established based on the multivariate Cox proportional hazards model and was evaluated through calculating the Harrell's C-index and plotting calibration curves. RESULTS: In total, 19,543 patients were identified under the selection criteria, and 3,347 cases with complete study variables were included for developing and validating the nomogram. Covariates incorporated in the final nomogram were sex, age, histological type, surgery, radiotherapy, chemotherapy, and the number of metastatic organs. The Harrell's C-index of nomogram was 0.705 (95% CI: 0.692-0.717) for the training cohort and 0.727 (95% CI: 0.703-0.752) for the validation cohort. CONCLUSIONS: We developed and validated the first nomogram based on a large population, which showed good prediction ability for predicting overall survival of patients with CUP. The risk stratification based on this nomogram could also help clinicians in treatment planning. This nomogram requires further validation in external cohorts, since important clinical factors such as favorable/unfavorable subset, performance status, lactate dehydrogenase, blood cell counts, or metastatic patterns limited to multiple lymph nodes could not be considered due to the lack of availability of these data.

Comparative Overall Survival of CDK4/6 Inhibitors Plus Endocrine Therapy vs. Endocrine Therapy Alone for Hormone receptor-positive, HER2-negative metastatic breast cancer.

Background: The combination of CDK4/6 inhibitors and endocrine therapy has greatly improved progression-free survival (PFS) in patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer in many randomized controlled trials (RCTs). However, the key issue was the extent to which the benefit in PFS could translate into a prolongation of OS. Methods: We performed a systematical literature search of PubMed, Web of Science, Cochrane Central Register of Clinical Trials and Embase, as well as meeting online archives up to February 2020. The primary outcome was OS, and we performed indirect treatment comparisons depend on a meta-analysis. Results: Six RCTs were eligible including 3421 breast cancer patients. Compared to the endocrine therapy alone group, adding CDK4/6 inhibitors to endocrine therapy had significantly improved OS (HR=0.76, 95% CI=0.68-0.85, P<0.001). Moreover, the OS advantage was consistent in patients with different combined endocrine therapy, endocrine sensitivity status, sites of distant metastasis, menopausal status and age. Nevertheless, more adverse events were observed in patients treated with CDK4/6 inhibitors. The most common grade 3-4 adverse events were neutropenia (risk ratio [RR]=37.15, 95% CI=15.33-90.04), leucopenia (RR=25.58, 95% CI=13.23-49.46) and anaemia (RR=2.24, 95% CI=1.38-3.85). Conclusions: Our meta-analysis suggested that compared with endocrine therapy alone, the addition of CDK4/6 inhibitors significantly improved OS in patients with hormone receptor-positive, HER2-negative metastatic breast cancer. However, the addition of CDK4/6 inhibitors also increased the incidences of grade 3-4 adverse events.

A risk stratification model for predicting brain metastasis and brain screening benefit in patients with metastatic triple-negative breast cancer.

BACKGROUND: Patients with metastatic triple-negative breast cancer (mTNBC) frequently experience brain metastasis. This study aimed to identify prognostic factors and construct a nomogram for predicting brain metastasis possibility and brain screening benefit in mTNBC patients. METHODS: Patients with mTNBC treated at our institution between January 2011 and December 2018 were retrospectively analyzed. Fine and Gray's competing risks model was used to identify independent prognostic factors. By integrating these prognostic factors, a competing risk nomogram and risk stratification model were developed and evaluated with concordance index (C-index) and calibration curves. RESULTS: A total of 472 patients were retrospectively analyzed, including 305 patients in the training set, 78 patients in the validation set I and 89 patients in the validation set II. Four clinicopathological factors were identified as independent prognostic factors in the nomogram: lung metastasis, number of metastatic organ sites, hilar/mediastinal lymph node metastasis and KI-67 index. The C-indexes and calibration plots showed that the nomogram exhibited a sufficient level of discrimination. A risk stratification was further generated to divide all the patients into three prognostic groups. The cumulative incidence of brain metastasis at 18 months was 5.3% (95% confidence interval [CI], 2.5%-9.7%) for patients in the low-risk group, while 14.3% (95% CI, 9.3%-20.4%) for patients with intermediate risk and 34.3% (95% CI, 26.8%-41.9%) for patients with high risk. Routine brain MRI screening improved overall survival in high-risk group (HR 0.67, 95% CI 0.46-0.98, P = .039), but not in low-risk group (HR 0.93, 95% CI 0.57-1.49, P = .751) and intermediate-risk group (HR 0.83, 95% CI 0.55-1.27, P = .386). CONCLUSIONS: We have developed a robust tool that is able to predict subsequent brain metastasis in mTNBC patients. Our model will allow selection of patients at high risk for brain metastasis who might benefit from routine bran MRI screening.

Cisplatin given at three divided doses for three consecutive days in metastatic breast cancer: an alternative schedule for one full dose with comparable efficacy but less CINV and hypomagnesaemia.

PURPOSE: Cisplatin, an effective medication for metastatic breast cancer (MBC), is recommended to be applied at the dose of 75 mg/m2 on day 1 every 3 weeks. However, the 75 mg/m2 schedule is often associated with a variety of side effects (such as vomiting and kidney toxicity), and time-consuming hydration treatment is usually needed. Divided dose (25 mg/m2 on day 1-3) without hydration is an alternative. This study aimed to compare the efficacy and toxicity profiles between these two dosage regimens. METHODS: Patients with MBC treated with cisplatin-based regimens in Fudan University Shanghai Cancer Center between December 2008 and June 2019 were retrospectively analyzed. Objective response rate (ORR), progression-free survival (PFS), and toxicity profiles were analyzed. RESULTS: 227 patients receiving a 1-day schedule and 256 patients receiving a 3-day schedule were included. Median PFS was 6.68 (5.66-7.70) months for patients in the 1-day schedule group and 6.70 (5.89-7.52) months for patients in the 3-day schedule group. There was no statistically significant difference in PFS between the two treatment groups (hazard ratio, 0.942; 95% CI 0.759 to 1.170; P = 0.589). The ORRs were comparable between the two groups. ORRs were 44.9% in 1-day schedule group and 44.5% in 3-day schedule group, respectively (P = 0.929). Compared with patients in the 3-day schedule group, patients in the 1-day schedule group experienced higher rates of chemotherapy-induced nausea and vomiting (CINV) (139 [61.2%] vs. 132 [51.6%], P = 0.033). The risk of hypomagnesaemia was also significantly higher (43.2% vs. 28.3%, P = 0.016) among patients receiving 1-day schedule (without magnesium supplementation). No other differences in adverse events were observed between the two groups. CONCLUSIONS: Cisplatin given at three divided doses with no hydration in MBC is a less toxic (less CINV and hypomagnesaemia) schedule with comparable efficacy. Thus, it may be a good alternative for one full-dose (75 mg/m2) schedule.

Real-World Data of Pyrotinib-Based Therapy in Metastatic HER2-Positive Breast Cancer: Promising Efficacy in Lapatinib-Treated Patients and in Brain Metastasis.

PURPOSE: Pyrotinib is a newly-developed irreversible pan-ErbB receptor tyrosine kinase inhibitor. This study reported the first real-world data of pyrotinib-based therapy in metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), focusing on efficacy in lapatinib-treated patients and in brain metastasis. MATERIALS AND METHODS: One hundred thirteen patients with metastatic HER2-positive BC treated with pyrotinib-based therapy in Fudan University Shanghai Cancer Center under non-clinical trial settings from September 1, 2018 to March 1, 2019 were included. RESULTS: Over half patients have received more than two lines of systematic therapy and exposed to two or more kinds of anti-HER2 agents. Most patients received a combined therapy, commonly of pyrotinib plus capecitabine, or vinorelbine or trastuzumab. Median progression-free survival (PFS) was 6.3 months (range, 5.54 to 7.06 months) and objective response rate (ORR) was 29.5%, with two patients (1.9%) achieving complete response. Lapatinib-naïve patients had significantly longer PFS than lapatinib-treated patients (9.0 months vs. 5.4 months, p=0.001). ORR for lapatinib-treated patients was 23.2%. Thirty-one of 113 patients have brain metastasis. Median PFS was 6.7 months and intracranial ORR was 28%. For patients without concurrent radiotherapy and/or brain surgery, the ORR was very low (6.3%). But for patients receiving concurrent radiotherapy and/or brain surgery, the ORR was 66.7%, and three patients achieved complete response. Most common adverse event was diarrhea. CONCLUSION: Pyrotinib-based therapy demonstrated promising effects in metastatic HER2-positive BC and showed activity in lapatinib-treated patients. For patients with brain metastasis, pyrotinib-based regimen without radiotherapy showed limited efficacy, but when combined with radiotherapy it showed promising intracranial control.

Mutation analysis of 19 autosomal short tandem repeats in Chinese Han population from Shanghai.

The mutation of short tandem repeat (STR) loci is affected by several factors, such as sex, age, and DNA architectures. Previous studies have shown a different profile of mutation rates at autosomal STR loci among populations. It is important to provide population data and reveal underlying factors influencing the evaluation of STR mutation rates. In this study, we performed a comprehensive analysis on the mutation of 19 autosomal STR loci through 124,773 parent-child allelic transfers from 5846 paternity testing cases. A total of 197 mutations were observed including 187 single-step mutations. The observed mutation rates ranged from 0.15 × 10-3 (TH01) to 4.57 × 10-3 (FGA), and the average mutation rate across all the 19 loci was 1.58 × 10-3. Furthermore, the average mutation rate of STR loci increases with the paternal conception ages and remains relatively stable in different maternal age groups, which suggest the profile of paternal conception ages as a potential factor influencing the evaluation of STR mutation rates and the ratio of paternal versus maternal mutation rate in populations. Multidimensional scaling analysis (MDS) shows a difference in the profile of mutation rates at 13 CODIS STR loci among ethnical groups. Based on our data, our results support that short alleles are biased towards expansion mutation and longer alleles favor contraction mutation. In conclusion, our results provide useful information for further investigation on STR mutation in forensic genetics and population genetics.