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Pyrotinib, an irreversible pan‐ErbB inhibitor, has been approved for treating HER2‐positive advanced breast cancer in China. We conducted a nationwide, prospective observational study to examine the real‐world data of pyrotinib‐based therapy in this population. Patients from 61 sites across China were included. Pyrotinib‐based regimens were prescribed at local physician's discretion. Demographics, treatment patterns, prognosis and safety were evaluated. The primary outcome was real‐world progression‐free survival (rwPFS). Of 1129 patients, pyrotinib‐based therapy was prescribed as first‐, second‐ and third‐ or later‐line treatment in 437 (38.7%), 476 (42.2%) and 216 (19.1%) patients, respectively. Median rwPFS (mrwPFS) was 14.3 (95% CI, 13.3‐15.2) months in the total population, with the longest mrwPFS of 17.8 (95% CI, 15.2‐24.9) months in the first‐line setting, followed by 14.4 (95% CI, 12.9‐15.3) months in the second‐line setting. Patients with third‐ or later‐line treatment also achieved a mrwPFS of 9.3 (95% CI, 8.4‐11.8) months. Patients with trastuzumab‐ or trastuzumab‐pertuzumab‐treated disease achieved a mrwPFS of 14.3 and 13.6 months, respectively. Dual HER2 blockade with pyrotinib plus trastuzumab showed a mrwPFS of 16.2 months in the total population, with data not mature in the first‐line setting. For patients with baseline brain metastases, the mrwPFS was 11.7 months. The most common adverse event was diarrhea (any grade, 73.5%; grade ≥ 3, 15.3%). In real world, pyrotinib‐based therapy shows promising effectiveness in the first‐, as well as second‐ and later‐line treatment, with acceptable tolerability. Further investigations regarding front‐line use or novel combinations of pyrotinib might facilitate to maximize its anti‐tumor potential. [ABSTRACT FROM AUTHOR]

Background: Although neoadjuvant trastuzumab and pertuzumab (HP)-based regimens are recommended for human epidermal receptor-positive (HER2 +)/lymph node-positive (N +) breast cancer (BC) patients according to NCCN guidelines, it is undeniable that many patients achieved pathological complete response (pCR) after trastuzumab (H)-based regimens without adding pertuzumab to treatment. Patients who specifically benefit from pertuzumab must be identified. The aim of this retrospective study was to evaluate progesterone receptor (PR) status as a predictor of response to the addition of pertuzumab in HER2 + /N + breast cancer. Methods: One hundred forty-two patients who were diagnosed as HER2 + /N + BC without distant metastasis and followed by neoadjuvant HP-based or H-based therapy were retrospectively included. The endpoints were pCR and disease-free survival (DFS) times. Results: In total, the pCR occurred in 25 of 87 patients (28.74%) in group H compared with 32 of 55 (58.18%) in group HP. The results revealed that hormone receptor (HR) status was significantly different on pCR in group HP. The odds of pCR for patients who have HR-positive tumors were 0.160 times (P = 0.011) that for patients with HR-negative tumors by multivariable analysis. Moreover, a similar probability of PR-positive (PR +) patients, whatever estrogen receptor (ER) status was, achieving pCR in group HP was observed. The ROC curves showed different anti-HER2 regimens provide worst predictive value in the PR + cohort (N = AUC = 0.521, 95% CI: 0.348–0.694, P = 0.813) compared with the overall cohort (AUC = 0.644, 95% CI: 0.550–0.738, P = 0.004) and ER + cohort (AUC: 0.559, 95% CI: 0.405–0.713, P = 0.451). And PR status (AUC = 0.760, 95% CI: 0.626–0.894, P = 0.001) had a greater predictive value than ER status (AUC = 0.658, 95% CI: 0.508–0.807, P = 0.048) in group HP. DFS analyses were done on 141 patients. Although ER and PR status did not show significant difference in group HP (P = 0.789 and 0.088, respectively), HP-based therapy contributed to better DFS in the ER − and PR − cohorts (P = 0.035 and 0.015, respectively). Conclusions: Compared with ER status, PR status might be a more valuable factor predicting the efficacy of adding pertuzumab into neoadjuvant therapy for HER2 + /N + BC. PR + patients benefit little from the addition of pertuzumab. [ABSTRACT FROM AUTHOR]

Objectives: The NCCN guidelines recommend that the addition of bevacizumab should be considered in metastatic breast cancers in some circumstances, but there are no recommendations for the similar antiangiogenic drug apatinib. The aim of this study was to evaluate the safety and efficacy of apatinib in metastatic breast cancer patients pretreated with multiline treatment in a real-world setting. Materials and Methods: Metastatic breast cancer patients pretreated with multiline treatment who had apatinib treatment initiated from September 2015 to August 2019 at Shandong Cancer Hospital and Institute were included. The primary endpoints included PFS and OS, and the secondary endpoint was treatment-related toxicity. Results: A total of 66 patients with metastatic breast cancer received apatinib treatment after failure of multiline chemotherapy in this study. The median PFS and OS of all 66 patients were 6.0 months and 10.0 months, respectively. The clinical beneficial rate was 40.9%. All patients tolerated treatment well, and no patients died of toxicity. The common toxicities of apatinib were hand and foot syndrome, secondary hypertension and fatigue events. The number of prior chemotherapy regimens was significantly associated with DFS and OS. Capecitabine may be a better choice for combination with a longer median OS of 19 months, while apatinib combined with other drugs was 9 months, and the apatinib monotherapy was 10 months. Conclusion: Apatinib produced moderate efficacy in metastatic breast cancer patients pretreated with multiline treatment with no significant treatment-related adverse events. Apatinib might be a choice for women as a maintenance salvage therapy following multiline chemotherapy failure. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the role of EGFR and STAT3 in breast cancer development and progression. Methods: Through bioinformatics analysis differently expressed genes (DEGs) including EGFR and STAT3 were identified in breast cancer tissue. QRT-PCR and Western blot analysis were used to investigate EGFR and STAT3 levels in breast cancer tissues and cells. The influence of EGFR and STAT3 on the breast cancer cell proliferation (CCK-8 assay, clone formation assays), migration (wound healing assays) and invasion (transwell assays) were investigated. The influence of EGFR on breast cancer in vivo was examined by Nude mouse transplantation tumor experiments and immunohistochemistry (IHC) staining. The effects of EGFR on breast cancer signaling were assessed via Western blot. Results: Both EGFR and p-STAT3 were up-regulated in breast cancer tissues and cell lines. EGFR expression was positively associated with p-STAT3. Moreover, EGFR and p-STAT3 activity enhanced the proliferation and invasion of tumor cells. Breast cancer cell growth was dramatically inhibited by EGFR silencing in vivo. Conclusion: EGFR promotes breast cancer progression via STAT3 phosphorylation and JAK/STAT3 signaling. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) is over-expressed in about 50% of Triple negative breast cancers (TNBCs), but EGFR inhibitors have not been effective in treating TNBC patients. Increasing evidence supports that autophagy was related to drug resistance at present. However, the role and the mechanism of autophagy to the treatment of TNBC remain unknown. In the current study, we investigated the effect of autophagy inhibitor to gefitinib (Ge) in TNBC cells in vitro and in nude mice vivo. Our study demonstrated that inhibition of autophagy by 3-Methyladenine or bafilomycin A1 improved Ge’s sensitivity to MDA-MB-231 and MDA-MB-468 cells, as evidence from stronger inhibition of cell vitality and colony formation, higher level of G0/G1 arrest and DNA damage, and these effects were verified in nude mice vivo. Our data showed that the mitochondrial-dependent apoptosis pathway was activated in favor of promoting apoptosis in the therapy of Ge combined autophagy inhibitor, as the elevation of BAX/Bcl-2, Cytochrome C, and CASP3. These results demonstrated that targeting autophagy should be considered as an effective therapeutic strategy to enhance the sensitivity of EGFR inhibitors on TNBC. [ABSTRACT FROM AUTHOR]

Lymphangiogenesis is thought to contribute to promote tumor cells to enter lymphatic vessels and plant at a secondary site. Endothelial cells are the cornerstone of the generation of new lymphatic vessels. NADPH oxidase 4 (Nox4) is the most abundant one of NADPH oxidases in endothelial cells and the most studied one in relevance with cancer. Our purpose is to analyze the relationship between Nox4 and lymphangiogenesis and find out whether the newborn lymphatic vessels lead to cancer metastasis. We first explored the expression of Nox4 in lymphatic endothelial cells of primary invasive breast tumors and human normal mammary glands using GEO databases and found that Nox4 was upregulated in primary invasive breast tumors samples. In addition, its high expression correlated with lymph node metastasis in breast cancer patients. Nox4 could increase the tube formation and lymphatic vessel sprouting in a three‐dimensional setting. In vivo, inhibition of Nox4 in 4T1 tumor‐bearing mice could significantly decrease the tumor lymphangiogenesis and metastasis. Nox4 may increase tumor lymphangiogenesis via ROS/ERK/CCL21 pathway and attract CCR7‐positive breast cancer cells to entry lymphatic vessels and distant organs. In conclusion, our results show that Nox4 is a factor that promotes lymphangiogenesis and is a potential target of antitumor metastasis. [ABSTRACT FROM AUTHOR]

We managed to explore the function of HFY-4A, a novel histone deacetylases (HDACs) inhibitor, on breast cancer as well as its potential mechanisms. MCF7 and T47D cells were treated with 0.8, 1.6 or 3.2 μM HFY-4A for 0–72 h, following of which CCK-8, colony formation, EdU staining, flow cytometry, Transwell, and wound healing assays were carried out. Western blot, immunohistochemistry, and ELISA were conducted for assaying the expression of immunogenic cell death (ICD)-related proteins. The interaction between HFY-4A, HDAC1, and tumor suppressor candidate 2 (TUSC2) was evaluated by chromatin immunoprecipitation assay. Further, the function of HFY-4A in breast cancer progression in vivo was evaluated using xenograft mouse models. HFY-4A inhibited the proliferation, migration, and invasion, and induced apoptosis of breast cancer cells in a dose-dependent manner. HFY-4A dose-dependently caused the ICD of breast cancer cells, as evidenced by the significant high levels of high-mobility group box 1 (HMGB1), calreticulin (CRT), heat shock protein 70 (HSP70), and HSP90. Interestingly, HFY-4A could facilitate TUSC2 transcription by promoting acetylation of histones on the TUSC2 promoter. The results of rescue assays revealed that HFY-4A repressed proliferation and mobility, but enhanced apoptosis and ICD through facilitating TUSC2 transcription in breast cancer. In breast cancer xenograft mouse models, HFY-4A was verified to inhibit tumor growth via upregulating TUSC2. HFY-4A could inhibit breast cancer cell proliferation and mobility, and enhanced apoptosis and ICD through facilitating TUSC2 transcription. • HFY-4A promotes TUSC2 transcription by promoting the acetylation of H3K56. • HFY-4A represses breast cancer malignant behavior by promoting TUSC2 transcription. • HFY-4A causes ICD of breast cancer cells by facilitating TUSC2 transcription. [ABSTRACT FROM AUTHOR]

Ras-related protein in brain (Rab) proteins are dysregulated in cancer cells and affect the proliferation and metastasis of cancer cells, thereby reducing the survival rate of cancer patients. Brain-derived neurotrophic factor (BDNF) and its receptor Tropomyosin-related kinase B (TrkB) play an important role in the occurrence and development of tumors. In this research, we investigate the interaction of Rab8A and TrkB in regulating the progression of breast cancer. Rab8A is upregulated in breast cancer tissues. The knockdown of Rab8A inhibits the proliferation, migration, and invasion of breast cancer cells through inhibiting TrkB. Moreover, the phosphorylation of AKT and ERK1/2 is suppressed by Rab8A knockdown. Rab8A interacts with TrkB, as revealed by co-immunoprecipitation assay to promote the surface expression of TrkB. However, Rab8A induced no significant changes in TrkB internalization. Functionally, BDNF promotes the expression of Rab8A through inhibiting Rab8A degradation. The TrkB inhibitor K252a blocks cell proliferation, migration and invasion as well as the activation of the AKT and ERK1/2 signaling pathway, which is induced by Rab8A in breast cancer cells. Our results reveal that Rab8A is upregulated by BDNF, and that Rab8A increases the surface expression of TrkB to promote the growth of breast cancer through the activation of the AKT and ERK1/2 signaling pathway. These results suggest that inhibiting Rab8A level could inhibit the progression of breast cancer. [ABSTRACT FROM AUTHOR]