Opportunities and Challenges in the Development of Antibody-Drug Conjugate for Triple-Negative Breast Cancer: The Diverse Choices and Changing Needs.

Triple-negative breast cancer (TNBC) is a highly heterogeneous breast cancer subtype, which is also characterized by the aggressive phenotype, high recurrence rate, and poor prognosis. Antibody-drug conjugate (ADC) is a monoclonal antibody with a cytotoxic payload connected by a linker. ADC is gaining more and more attention as a targeted anti-cancer agent. Clinical studies of emerging ADC drugs such as sacituzumab govitecan and trastuzumab deruxtecan in patients with metastatic breast cancer (including TNBC) are progressing rapidly. In view of its excellent clinical efficacy and good tolerability, Sacituzumab govitecan gained accelerated approval by the FDA for the treatment of advanced metastatic TNBC in 2020. This review discusses the treatment status and challenges in TNBC, with an emphasis on the current status of ADC development and clinical trials in TNBC and metastatic breast cancer. We also summarize the clinical experience and future exploration directions of ADC development for TNBC patients.

ATAS Acupuncture Reduces Chemotherapy Induced Fatigue in Breast Cancer Through Regulating ADROA1 Expression: A Randomized Sham-Controlled Pilot Trial.

OBJECTIVE: To investigate the feasibility and effectiveness of ATAS acupuncture (Acupoints-Time-Space Acupuncture) as a non-pharmacological intervention to prevent or relieve chemotherapy-induced fatigue in breast cancer patients undergoing taxane chemotherapy. METHODS: A pilot study in Kunming center with the aim of evaluating 40 patients randomized to 3 groups: ATAS, sham and non-acupuncture with an unequal randomization of 2:1:1. Participants with stage I-III breast cancer were scheduled to receive adjuvant EC4P4 chemotherapy. Participants in the ATAS and sham acupuncture arms received 20 sessions of acupuncture over 20 weeks, non-acupuncture arm received usual care. Evaluation scales, including VAS-F, MFI-20, HDAS, ISI, and blood samples were collected at four timepoints (T1-T4). mRNA sequencing was performed to detect the mechanism of acupuncture. RESULTS: A total of 581 sessions of acupuncture were performed on patients in the acupuncture group. There was no difference between the three groups in terms of clinical characteristics. Patients randomized to ATAS acupuncture had improved symptoms including fatigue, anxiety and insomnia during the whole process of chemotherapy compared with the other two groups. The VAS-F score of ATAS acupuncture group was decreased compared with non-acupuncture group (P=0.004). The score of MFI-20 in ATAS acupuncture group was kept at low level, while the other two groups' scores kept climbing during chemotherapy (P=0.016; P=0.028, respectively). The mechanism of ATAS acupuncture which reduced fatigue and depression may be related to ADROA1, by regulating cGMP/PKG pathway. CONCLUSION: This pilot study has demonstrated that ATAS acupuncture can significantly reduce fatigue induced by chemotherapy. TRIAL REGISTRATION: Chinese Clinical Trials Registry, ChiCTR-IPR-17,013,652, registered Dec 3, 2017. http://www.chictr.org.cn/. PROTOCOL VERSION: Version 3.2 dated from 2018/04/20.

Switching to anastrozole plus goserelin vs continued tamoxifen for adjuvant therapy of premenopausal early-stage breast cancer: preliminary results from a randomized trial.

PURPOSE: To assess the efficacy, safety, and quality-of-life impact of switching adjuvant treatment in hormone receptor-positive primary breast cancer patients who are still premenopausal after 2-3 years of tamoxifen therapy to anastrozole plus goserelin as compared with continuing tamoxifen over a total period of 5 years. PATIENTS AND METHODS: Hormone receptor-positive, premenopausal, lymph node-positive, or tumor size ≥4 cm breast cancer patients who had received tamoxifen for 2-3 years were randomly assigned to continue tamoxifen treatment (TAM group) or switch to adjuvant anastrozole plus goserelin (ADD group) and continue treatment for another 2-3 years (total treatment duration 5 years). Endpoints evaluated were adverse events (AEs), changes in bone mineral density, quality of life, and disease-free survival-related events. RESULTS: A total of 62 patients (33 in the ADD group and 29 in the TAM group) were evaluated. Grade 3-4 drug-related AEs occurred in five patients (15.2%) in the ADD group vs none in the TAM group. In the ADD group, arthralgias were the most common AEs (5/33 patients; 15.2%), and three patients in this group were discontinued because of AEs. Treatment was temporarily suspended due to AEs in three patients (9.1%) in the ADD group and one patient (3.4%) in the TAM group. Compared with continuing TAM therapy, switching to anastrozole plus goserelin did not result in any worsening of bone mineral density or quality of life. During a median follow-up of 34 months, five patients (15.2%) in the ADD group had disease-free survival events vs four patients (13.8%) in the TAM group. CONCLUSION: For early-stage breast cancer patients who remain premenopausal following 2-3 years of adjuvant tamoxifen therapy, switching to anastrozole plus goserelin therapy was safe with tolerable adverse effects. However, it did not show superior efficacy compared to remaining on tamoxifen treatment. TRIAL REGISTRATION: ClinicalTrials.gov (identifier NCT01352091).

Opposite response to hypoxia by breast cancer cells between cell proliferation and cell migration: A clue from microRNA expression profile.

The majority of tumors possess the features of hypoxia. It is generally accepted that hypoxia is a negative prognostic factor for cancer. Low levels of oxygen are able to modify basic cell metabolism status. Elucidating the basic response, including cell proliferation and migration, to hypoxia by cancer cells is important for understanding the role of hypoxia in the development of cancer. In the present study, CoCl2 stimulation was used to simulate hypoxia. A microRNA (miRNA/miR) array was used to systematically detect the changes in miRNA expression profiles. Following treatment with CoCl2 for 12 h, 15 miRNAs were markedly upregulated and 10 miRNAs were markedly decreased compared with the control. After 24 h CoCl2 incubation, 15 miRNAs were increased and 3 miRNAs were decreased compared with the control. Among them, 7 miRNAs were upregulated and 2 miRNAs were downregulated at 12 and 24 h following CoCl2 stimulation. The potential roles of these miRNA were reviewed and it was identified that the majority of them are associated with cell proliferation and migration. Additional experiments demonstrated that CoCl2 incubation inhibited the proliferation of MCF-7 cells but promoted cell migration. miR-491 may be a key miRNA for hypoxia-inhibited cell proliferation, as it was identified that hypoxia induced the downregulation of B-cell lymphoma-extra large in a miR-491-dependent manner. As the target of miR-302a, CXCR4 may be a key protein for hypoxia-promoted cell migration. In the present study, it was identified that in the early stage of hypoxia, cell proliferation was inhibited but cell migration was promoted. These results support the hypothesis that hypoxia may be a driving force for tumor cell escape from the primary tumor site to other organs, or other sites of the same organ.

Microarray based analysis of gene regulation by mesenchymal stem cells in breast cancer.

Breast cancer is one of the most common malignant tumors with a high case-fatality rate among women. The present study aimed to investigate the effects of mesenchymal stem cells (MSCs) on breast cancer by exploring the potential underlying molecular mechanisms. The expression profile of GSE43306, which refers to MDA-MB-231 cells with or without a 1:1 ratio of MSCs, was downloaded from Gene Expression Omnibus database for differentially expressed gene (DEG) screening. The Database for Annotation, Visualization and Integrated Discovery was used for gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for DEGs. The protein-protein interactional (PPI) network of DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins. The data was subsequently analyzed using molecular complex detection for sub-network mining of modules. Finally, DEGs in modules were analyzed using GO and KEGG pathway enrichment analyses. A total of 291 DEGs including 193 upregulated and 98 downregulated DEGs were obtained. Upregulated DEGs were primarily enriched in pathways including response to wounding (P=5.92×10-7), inflammatory response (P=5.92×10-4) and defense response (P=1.20×10-2), whereas downregulated DEGs were enriched in pathways including the cell cycle (P=7.13×10-4), mitotic cell cycle (P=6.81×10-3) and M phase (P=1.72 ×10-2). The PPI network, which contained 156 nodes and 289 edges, was constructed, and Fos was the hub node with the degree of 29. A total of 3 modules were mined from the PPI network. In total, 14 DEGs in module A were primarily enriched in GO terms, including response to wounding (P=4.77×10-6), wounding healing (P=6.25×10-7) and coagulation (P=1.13 ×10-7), and these DEGs were also enriched in 1 KEGG pathway (complement and coagulation cascades; P=0.0036). Therefore, MSCs were demonstrated to exhibit potentially beneficial effects for breast cancer therapy. In addition, the screened DEGs, particularly in PPI network modules, including FN1, CD44, NGF, SERPINE1 and CCNA2, may be the potential target genes of MSC therapy for breast cancer.

Polymorphisms of human histamine receptor H4 gene are associated with breast cancer in Chinese Han population.

Previous investigations indicated that histamine receptor H4 (HRH4) played important roles in many aspects of breast cancer pathogenesis, and that the polymorphisms of HRH4 gene may result in expression and functional changes of HRH4 proteins. However, the relationship between polymorphisms of HRH4 and breast cancer risk and malignant degree is unclear. In the present study, we conducted a case-control investigation among 185 Chinese Han breast cancer patients and 199 ethnicity-matched health controls. Four tag-SNPs (i.e. rs623590, rs16940762, rs11662595 and rs1421125) of HRH4 were genotyped and association analysis was performed. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the association. We found that the T allele of rs623590 had a decreased risk of breast cancer (adjusted OR, 0.667; 95% CI, 0.486-0.913; P=0.012) while the A allele of rs1421125 had an increased risk (adjusted OR, 1.653; 95% CI, 1.139-2.397; P=0.008). Further haplotype analysis showed that the CAA haplotype of rs623590-rs11662595-rs1421125 was more frequent among patients with breast cancer (adjusted OR, 1.856; 95% CI, 1.236-2.787; P=0.003). Additionally, polymorphisms of rs623590 and rs11662595 were also correlated with clinical stages, lymph node involvement, and HER2 status. These findings indicated that the variants of rs623590, rs11662595 and rs1421125 genotypes of HRH4 gene were significantly associated with the risk and malignant degree of breast cancer in Chinese Han populations, which may provide us novel insight into the pathogenesis of breast cancer although further studies with larger participants worldwide are still needed for conclusion validation.

[Development of the system of quality of life instruments for patients with breast cancer (QLICP-BR)].

BACKGROUND & OBJECTIVE: The general module of the system of quality of life instruments for cancer patients, QLICP-GM, has been developed by us. Based on it, this study was to develop and evaluate the quality of life instrument for patients with breast cancer (QLICP-BR). METHODS: Using the structured group methods of instrument development, the instrument with Chinese cultural background was developed, and evaluated by analyzing the data from 186 breast cancer patients. RESULTS: The test-retest reliability for the overall scale and 5 domains were all above 0.75. The internal consistency alpha for each domain was higher than 0.65 except social domain (0.58). Most correlation coefficients between each item and the domain (that the item belongs to) were above 0.60. The differences between the scores before treatment and the scores after treatment for overall scale, general module, physical domain, psychologic domain, and social domain were significant. CONCLUSION: The QLICP-BR is of good validity, reliability and reasonable responsiveness, and can be used to assess quality of life for breast cancer patients.