Abemaciclib plus endocrine therapy versus chemotherapy after progression on prior palbociclib in HR+/HER2- metastatic breast cancer: A single center real-world study in China.

BACKGROUND: Cyclin-dependent kinase (CDK) 4/6 inhibitor plus endocrine therapy (ET) become standard-of-care for patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) metastatic breast cancer (MBC). However, the optimal therapeutic paradigm after progression on CDK4/6 inhibitor remains unclear. This study aimed to evaluate the efficacy and safety of abemaciclib with switching ET versus chemotherapy after progression on prior palbociclib-based ET in Chinese patients with HR+/HER2- MBC. METHODS: From 414 consecutive patients with HR+/HER2- MBC who had been treated with palbociclib plus ET from September 2018 to May 2022 in Peking University Cancer Hospital, we identified 80 patients who received abemaciclib plus switching ET or chemotherapy after progression on palbociclib, matched for age, original stage at diagnosis, disease-free interval, and tumor burden at 1:1 ratio. The primary endpoint was progression-free survival (PFS) compared using the Kaplan-Meier method. A Cox proportional hazard model was performed to identify clinical factors associated with PFS in the abemaciclib group. RESULTS: The median PFS was 6.0 months (95% confidence interval [CI]: 3.94-8.06) in abemaciclib group and 4.0 months (95% CI, 2.52-5.49) in chemotherapy group (p = 0.667). And, there was no difference in median PFS between the sequential and nonsequential arm (6.0 vs. 6.0 months) in the abemaciclib group though fewer lines of prior systemic therapy and longer PFS from prior palbociclib in the sequential arm. However, patients with prior palbociclib as the first-line therapy had a significantly longer median PFS versus prior palbociclib as ≥2nd-line therapy (11.0 vs. 5.0 months, p = 0.043). Based on multivariable analysis, ER+/PR+ was an independent factor associated with longer PFS. There was no significant difference in overall survival between the abemaciclib and chemotherapy groups (p = 0.069). CONCLUSION: Our findings indicate that abemaciclib plus switching ET might be one of feasible treatment options for Chinese patients with HR+/HER2- MBC after progression on prior palbociclib-based therapy in addition to chemotherapy.

Efficacy of apatinib 250 mg combined with chemotherapy in patients with pretreated advanced breast cancer in a real-world setting.

Objectives: This study evaluated the efficacy and safety of apatinib (an oral small-molecule tyrosine kinase inhibitor targeting VEGFR-2) 250 mg combined with chemotherapy in patients with pretreated metastatic breast cancer in a real-world setting. Patients and methods: A database of patients with advanced breast cancer who received apatinib between December 2016 and December 2019 in our institution was reviewed, and patients who received apatinib combined with chemotherapy were included. Progression-free survival (PFS), overall survival (OS), the objective response rate (ORR), the disease control rate (DCR), and treatment-related toxicity were analyzed. Results: In total, 52 evaluated patients with metastatic breast cancer previously exposed to anthracyclines or taxanes who received apatinib 250 mg combined with chemotherapy were enrolled in this study. Median PFS and OS were 4.8 (95% confidence interval [CI] = 3.2-6.4) and 15.4 months (95% CI = 9.2-21.6), respectively. The ORR and DCR were 25% and 86.5%, respectively. Median PFS for the previous line of treatment was 2.1 months (95% CI = 0.65-3.6), which was significantly shorter than that for the apatinib-chemotherapy combination (p < 0.001). No significant difference was identified in the ORR and PFS among the subgroups(subtypes, target lesion, combined regimens and treatment lines). The common toxicities related to apatinib were hypertension, hand-foot syndrome, proteinuria, and fatigue events. Conclusion: Apatinib 250 mg combined with chemotherapy provided favorable efficacy in patients with pretreated metastatic breast cancer regardless of molecular types and treatment lines. The toxicities of the regimen were well tolerated and manageable. This regimen could be a potential treatment option in patients with refractory pretreated metastatic breast cancers.

Empowering the Diversity and Individuality of Option: Residual Soft Option Critic Framework.

Extracting temporal abstraction (option), which empowers the action space, is a crucial challenge in hierarchical reinforcement learning. Under a well-structured action space, decision-making agents can probe more deeply in the searching or plan efficiently through pruning irrelevant action candidates. However, automatically capturing a well-performed temporal abstraction is a nontrivial challenge due to its insufficient exploration and inadequate functionality. We consider alleviating this challenge from two perspectives, i.e., diversity and individuality. For the aspect of diversity, we propose a maximum entropy model based on ensembled options to encourage exploration. For the aspect of individuality, we propose to distinguish each option accurately, utilizing mutual formation minimization, so that each option can better express and function. We name our framework as an ensemble with soft option (ESO) critics. Furthermore, the residual algorithm (RA) with a bidirectional target network is introduced to stabilize bootstrapping, yielding a residual version of ESO. We provide detailed analysis for extensive experiments, which shows that our method boosts performance in commonly used continuous control tasks.

Surgical reduction in chest wall disease to prolong survival in breast cancer patients: a retrospective study.

Background: Patients with breast cancer (BC) may develop locoregional recurrence alone or with distant metastases. Results of previous studies discussing the benefit of local surgery among patients with chest wall disease were controversial. Whether surgical reduction for chest wall disease could influence survival outcome is still a question. The objective of this study was to compare overall survival (OS) in patients with recurrence involving the chest wall who did or did not undergo surgical reduction after previous treatment of the primary BC to explore the role of surgical reduction. Methods: We retrospectively reviewed BC patients with chest wall as the first recurrent/metastatic site selected between January 2012 and December 2018 to explore whether surgical reduction for chest wall disease could influence OS. Clinicopathological data, including age at initial diagnosis, TNM stage, the pathological parameters, and treatment were recorded and analyzed. OS was primarily described using the Kaplan-Meier estimator for each group, with the statistical significance between groups being tested by the log-rank test. Results: A total of 198 patients with a median age of 48 years (range, 22-73 years) were analyzed. Chest wall as the only site of recurrence occurred in 139 patients (70.2%), and the other 59 (29.8%) patients had other metastatic sites. There were 88 patients who underwent surgical reduction for chest wall recurrence. The median OS was significantly longer for the patients who had chest wall disease reduction than for those who did not {194.2 months [95% confidence interval (CI): 140.4-247.9 months] vs. 102.7 months (95% CI: 79.7-125.7 months), respectively, P=0.001}. From multivariate analysis, surgical reduction was an independent factor significantly influenced OS (HR =0.52, 95% CI: 0.33-0.81, P=0.004). Subgroup analyses showed that OS was statistically longer in the chest wall disease surgical reduction group than in the no reduction group with respect to hormone receptor (HR) negative (-), human epidermal growth factor receptor 2 (HER2) negative (-), triple-negative breast cancer (TNBC), disease-free survival (DFS) >24 months, and chest wall disease only. Conclusions: BC patients with chest wall recurrence could benefit from surgical reduction with a prolonged OS. In a certain selected group, surgical reduction may be warranted.

Modeling Hierarchical Uncertainty for Multimodal Emotion Recognition in Conversation.

Approximating the uncertainty of an emotional AI agent is crucial for improving the reliability of such agents and facilitating human-in-the-loop solutions, especially in critical scenarios. However, none of the existing systems for emotion recognition in conversation (ERC) has attempted to estimate the uncertainty of their predictions. In this article, we present HU-Dialogue, which models hierarchical uncertainty for the ERC task. We perturb contextual attention weight values with source-adaptive noises within each modality, as a regularization scheme to model context-level uncertainty and adapt the Bayesian deep learning method to the capsule-based prediction layer to model modality-level uncertainty. Furthermore, a weight-sharing triplet structure with conditional layer normalization is introduced to detect both invariance and equivariance among modalities for ERC. We provide a detailed empirical analysis for extensive experiments, which shows that our model outperforms previous state-of-the-art methods on three popular multimodal ERC datasets.

Phase II study of apatinib in combination with oral vinorelbine in heavily pretreated HER2-negative metastatic breast cancer and clinical implications of monitoring ctDNA.

OBJECTIVE: Apatinib is an oral TKI targeting VEGFR-2. Single-agent apatinib treatment has been shown to produce an objective response in patients with pretreated mBC. Oral vinorelbine also holds promise as a treatment of choice in patients with mBC. This study aimed to investigate the efficacy and safety of the oral vinorelbine-apatinib combination in patients with pretreated mBC. In addition, we detected gene variants in ctDNA to explore the therapeutic implications. METHODS: This study enrolled patients with HER2-negative mBC who were pretreated with anthracycline/taxanes. Patients were treated with apatinib at 500 mg/425 mg daily plus oral vinorelbine 60 mg/m2 on days 1, 8, and 15 of every cycle (3 weeks). The primary endpoint was PFS. The secondary endpoints were ORR, CBR, OS, and safety. Patients eligible for ctDNA detection were evaluated before and during treatment. RESULTS: Forty patients were enrolled. The median PFS was 5.2 months (95% CI, 3.4-7.0 months), and the median OS was 17.4 months (95% CI, 8.0-27.0 months). The ORR was 17.1% (6/35), and the CBR was 45.7% (16/35). The most common AEs included gastrointestinal reaction, myelosuppression, and hypertension. In 20 patients, ctDNA was detected at baseline and during treatment. A significant difference was found in PFS for undetected vs. detected baseline ctDNA (13.9 months vs. 3.6 months, P = 0.018). CONCLUSIONS: All-oral therapy with apatinib plus vinorelbine displayed objective efficacy in patients with heavily pretreated HER2-negative mBC, with acceptable and manageable toxicity profiles. Patients with no gene variant detected and lower variant allele frequencies in ctDNA at baseline showed longer PFS.

Steroidal aromatase inhibitors have a more favorable effect on lipid profiles than nonsteroidal aromatase inhibitors in postmenopausal women with early breast cancer: a prospective cohort study.

BACKGROUND: Aromatase inhibitors (AIs) influence blood lipid profiles. However, relatively few studies have directly compared the treatment effects of steroidal and nonsteroidal AIs. METHODS: A prospective single-center cohort study was conducted to investigate the effects of steroidal and nonsteroidal AIs on lipid profiles during the first 24 months of endocrine therapy in hormone receptor-positive postmenopausal patients with early breast cancer. The primary endpoint was the cumulative incidence of lipid events, while the secondary endpoints were changes in lipid profiles and lipid event-free survival. RESULTS: Comparison of the lipid profiles of the two groups showed that triglycerides (TGs) and total cholesterol (TC) levels were significantly higher in the nonsteroidal AI group over 24 months (p < 0.05), whereas low-density lipoprotein cholesterol (LDL-C) was significantly higher only at 3 months (p = 0.017) and 6 months (p = 0.026). High-density lipoprotein cholesterol (HDL-C) was significantly lower in the steroidal group at all time points (p < 0.05), except at 18 months (p = 0.085). The cumulative incidence of lipid events in the steroidal and nonsteroidal groups at 24 months was 25.3% and 37.0%, respectively. Multivariate analysis results indicated that TG, LDL-C, and steroidal AIs were independently associated with blood lipid events. CONCLUSION: This trial showed that a significantly higher cumulative incidence of lipid events occurred in the nonsteroidal AI group than in the steroidal AI group, which indicated that steroidal AIs exerted a protective effect against blood lipid events in postmenopausal women receiving an AI as adjuvant therapy for breast cancer. CLINICALTRIALSGOV IDENTIFIER: NCT02765373.

Carboplatin plus taxanes are non-inferior to epirubicin plus cyclophosphamide followed by taxanes as adjuvant chemotherapy for early triple-negative breast cancer.

PURPOSE: Platinum plays an important role in the treatment of triple-negative breast cancer (TNBC) in neoadjuvant and metastatic settings. However, its role in an adjuvant setting remains unclear. METHODS: In this non-inferior randomized phase 2 trial, we randomly assigned 308 chemotherapy-naive patients with histologically confirmed TNBC after primary surgery to receive either six cycles of TP (docetaxel: 75 mg/m2 or paclitaxel 175 mg/m2 d1; carboplatin AUC = 5, day 1), or four cycles of EC (epirubicin: 90 mg/m2; cyclophosphamide: 600 mg/m2, day 1) followed by four cycles of T (docetaxel: 75 mg/m2 or paclitaxel 175 mg/m2, day 1). The primary end point was the disease-free survival (DFS) rate at 5 years. Both regimens were repeated every 3 weeks. The prognostic and predictive value of germline breast cancer gene mutations and programmed death ligand-1 (PD-L1) expression was evaluated. RESULTS: At a median follow-up of 66.9 months, the 5-year DFS rate was 85.8% in the EC-T arm, and 84.4% in the TP arm (p non-inferiority = 0.034, p log-rank = 0.712). The 5-year overall survival (OS) rate was 94.4% in the EC-T arm and 93.5% in the TP arm (p = 0.770). Patients in the TP arm showed better compliance and experienced significantly lower frequencies of G3/4 neutrocytopenia and G3/4 alopecia, but higher rates of G1-4 thrombocytopenia than those in the EC-T arm. Patients with PD-L1 expressing tumors showed significantly improved DFS and OS. CONCLUSIONS: This study indicates that carboplatin plus taxanes could be a feasible adjuvant chemotherapy for patients with early TNBC who are cannot tolerate intensive chemotherapy with anthracycline.

A Phase II, Single-Arm Study of Apatinib and Oral Etoposide in Heavily Pre-Treated Metastatic Breast Cancer.

INTRODUCTION: We performed this clinical trial to evaluate the efficacy and safety of apatinib and oral etoposide in patients with HER2-negative locally advanced or metastatic breast cancer (MBC). METHODS: Patients with HER2-negative MBC previously treated with anthracycline and taxanes and failed ≥1 prior chemotherapy regimens were recruited. The starting dose of apatinib was 500 and 425 mg in patients with ECOG scores of 0-1 and 2, respectively. The etoposide capsules were given at 50 mg/m2 on days 1 to 10 for 21 days. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. RESULTS: Thirty-one eligible patients were enrolled. The median follow-up time was 11 months. The median PFS for all patients was 6.9 months [95% confidence interval (CI) 6.0-7.9], and 6.9 months (95% CI 5.3-8.6) and 6.6 months (95% CI 1.4-11.7) for patients with apatinib 425 and 500mg once daily, respectively. The ORR was 35.5% (11/31). The DCR was 87.1% (27/31). The median OS was 20.4 months (95% CI 11.4-29.3). The median PFS of patients who had hypertension and proteinuria was longer than that for those without hypertension and proteinuria. The most common grade 3/4 treatment-related AEs were hypertension (12/31, 38.7%), fatigue (3/31, 9.7%), thrombocytopenia (3/31, 9.7%). CONCLUSION: Apatinib combined with etoposide capsules is effective and tolerable in heavily pretreated, metastatic HER2-negative breast cancer patients. A lower apatinib dose provide equivalent efficacy and reduced toxicity. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/, identifier NCT03535961.

Apatinib combined with chemotherapy in patients with previously treated advanced breast cancer: An observational study.

Locally advanced or metastatic disease accounts for the majority of breast cancer-associated cases of mortality. Treatment options for patients with locally advanced or metastatic disease are limited. The current study aimed to explore the efficacy and safety of apatinib combined with chemotherapy in patients with previously treated advanced breast cancer in real-world clinical practice. A total of 85 patients with advanced breast cancer, who had previously been exposed to anthracyclines or taxanes, received combined treatment. Tumor response was evaluated by a computed tomography scan based on the Response Evaluation Criteria in Solid Tumors. Adverse events were graded based on the Common Terminology Criteria for Adverse Events. The Kaplan-Meier method and a log-rank test were used to analyze the univariate discrimination of progression-free survival (PFS) and overall survival (OS) by demographic data, baseline clinical information and toxicities. The combined effects of these variables were analyzed by a Cox proportional hazards regression model. At a median follow-up time of 9.7 months, 73 patients exhibited disease progression and 48 had succumbed to the disease. During the follow-up, 19 patients demonstrated a partial response (PR) and 53 patients achieved stable disease (SD), with an objective response rate of 23.2%. Additionally, 39 patients demonstrated a PR or SD for ≥24 weeks, with a clinical benefit rate of 47.6%. The median PFS was 4.4 months [95% confidence interval (CI)=2.8-6.0] and the median OS was 11.3 months (95% CI=8.9-13.8). No treatment-associated mortalities occurred. The most common adverse events of all grades included myelosuppression (49.4%), gastrointestinal reaction (45.9%) and fatigue (43.5%). Proteinuria was an independent predictive factor for PFS and OS. Apatinib combined with chemotherapy appeared to be efficacious for pretreated advanced breast cancer, with acceptable toxicity for real-world clinical practice.

Progress in targeted therapy for breast cancer.

Breast cancer is a multistep, multifactorial, and heterogeneous disease. Significant transformations have occurred in the systemic management of breast cancer in the past decade. Due to the further understanding of pathogenesis, scientists have found plenty of signaling pathways and correspondingly therapeutic targets in breast cancer, such as hormone receptor, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), phosphoinositide-3-kinase (PI3K), v-akt murine thymoma viral oncogene homolog (AKT), mechanistic target of rapamycin (mTOR), cyclin-dependent kinase 4/6 (CDK4/6), poly (adenosine diphosphate-ribose) polymerase (PARP), and programmed death-1 (PD-1). Targeted therapy, which optimizes the accuracy of antitumor activity and minimizes toxicity to normal tissues, plays a crucial role in breast cancer treatment in the era of precision medicine. In this review, we aimed to summarize the latest developments in targeted therapy for breast cancer and discuss the existing problems.

SPARC overexpression in primary tumors correlates with disease recurrence and overall survival in patients with triple negative breast cancer.

SPARC/osteonectin expression is reportedly altered in various malignancies. However, little is known regarding to the prognostic value of SPARC in triple-negative breast cancer (TNBC) patients. In this study, immunohistochemistry and immunoreactive scores (IRSs) were used to evaluate SPARC protein expression in primary tumors from 211 TNBC patients with up to 10 years of clinical follow-up data. High SPARC expression (IRS ≥3) was detected in 52.1% of primary tumors. Patients expressing high SPARC levels had worse disease-free survival (DFS) (HR=1.58, 95% CI: 1.01-2.47, P=0.044) and overall survival (OS) (HR=1.74, 95% CI: 1.06-2.85, P=0.029) than patients with lower SPARC levels. Furthermore, high SPARC expression was an independent prognostic factor for both DFS (HR=1.73, 95% CI: 1.10-2.73, P=0.018) and OS (HR=1.90, 95% CI: 1.14-3.16, P=0.014) in TNBC patients. These results suggest that increased SPARC expression may be an indicator of greater aggressiveness, and may serve as a prognostic factor for triple-negative breast cancer.

A single-nucleotide polymorphism in the 3'-UTR region of the adipocyte fatty acid binding protein 4 gene is associated with prognosis of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor prognosis and high heterogeneity. The aim of this study was to screen patients for single-nucleotide polymorphisms (SNPs) associated with the prognosis of TNBC. Database-derived SNPs (NextBio, Ensembl, NCBI and MirSNP) located in the 3'-untranslated regions (3'-UTRs) of genes that are differentially expressed in breast cancer were selected. The possible associations between 111 SNPs and progression risk among 323 TNBC patients were investigated using a two-step case-control study with a discovery cohort (n=162) and a validation cohort (n=161). We identified the rs1054135 SNP in the adipocyte fatty acid binding protein 4 (FABP4) gene as a predictor of TNBC recurrence. The G allele of rs1054135 was associated with a reduced risk of disease progression as well as a prolonged disease-free survival time (DFS), with a hazard ratio (HR) for recurrence in the combined sample of 0.269 [95%CI: 0.098-0.735;P=0.001]. Notably, for individuals having the rs1054135 SNP with the AA/AG genotype, the magnitude of increased tumour recurrence risk for overweight patients (BMI≥25kg/m2) was significantly elevated (HR2.53; 95%CI: 1.06-6.03). Immunohistochemical staining of adipocytes adjacent to TNBC tissues showed that the expression level of FABP4 was statistically significantly lower in patients with the rs1054135-GG genotype and those in the disease-free group (P=0.0004 and P=0.0091, respectively). These results suggested that the expression of a lipid metabolism-related gene and an important SNP in the 3'-UTR of FABP4 are associated with TNBC prognosis, which may aid in the screening of high-risk patients with TNBC recurrence and the development of novel chemotherapeutic agents.