The efficacy of human epidermal growth factor receptor 2 (HER2) blockade switching mode in refractory patients with HER2-positive metastatic breast cancer: a phase II, multicenter, single-arm study (SYSUCC-005).

BACKGROUND: Despite significant survival improvement in human epidermal growth factor receptor 2 (HER2) blockade for HER2-positive breast cancer, resistance to anti-HER2 remains inevitable. Subsequent anti-HER2 with continuing trastuzumab beyond progression is acceptable with limited efficacy when other anti-HER2 treatment is unavailable. This single-arm, phase II study (SYSUCC-005) aimed to explore the efficacy of switching mode for HER2-positive refractory metastatic breast cancer. METHODS: Patients with HER2-positive metastatic breast cancer rapidly progressing during pre-trastuzumab from six hospitals in China were designed to switch to lapatinib 1,250 mg orally once per day continuously plus capecitabine (1,000 mg/m2 orally twice per day on days 1-14) or vinorelbine (25 mg/m2 intravenously once per day on days 1 and 8) of each 21-day cycle. The primary endpoint was progression-free survival (PFS). RESULTS: Between January 5, 2015 and May 31, 2020, 159 patients were eligible in this study. The median follow-up was 33.1 months, a median PFS of 8.5 months was achieved. Brain metastases (hazard ratio [HR] = 1.582, 95% confidence interval [CI] 1.019- 2.453, P = 0.041) and ≥ 2 metastatic sites (HR = 1.679, 95% CI 1.151-2.450, P = 0.007) were independent prognostic factors for PFS. The most common grade ≥ 3 adverse events were diarrhea (3.8%) and hand-foot syndrome (9.4%). CONCLUSION: The switching mode showed predominant efficacy, which might be a prior therapeutic option over continuing mode in subsequent anti-HER2 therapy for patients with HER2-positive refractory metastatic breast cancer. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov ( NCT02362958 ) on 13/02/2015.

MiR-17- 5p/RRM2 regulated gemcitabine resistance in lung cancer A549 cells.

The main objective of this study is to investigate the regulatory roles of the miR-17-5p/RRM2 axis in A549/G+ cells' gemcitabine resistance. The cell viability was determined using CCK8 and clonogenic assays. Gene expression level analysis by RT-qPCR and Western blotting. Cell cycle analysis by flow cytometry. The dual luciferase activity assay was used to verify the target gene of miR-17-5p. In gemcitabine-resistant cell line A549G+, the drug resistance decreased after up-regulation of MiR-17-5p expression. The proportion of cell cycle G1 phase increased, and the S phase decreased. The expression level of cell cycle-related proteins CCNE1, CCNA2, and P21 decreased. The opposite results emerged after the down-regulation of MiR-17-5p expression in gemcitabine-sensitive cell line A549G-. The expression levels of PTEN and PIK3 in A549G+ cells were higher than in A549G-cells, but p-PTEN was lower than that in A549G-. After up-regulating the expression of MiR-17-5p in A549G+, the expression levels of p-PTEN increased, and the expression level of p-AKT decreased. After down-regulating miR-17-5p expression, the opposite results emerged. The dual-luciferase reporter assay and restorative experiments proved that RRM2 is one of the target genes for MiR-17-5p. Our results suggested that the miR-17-5p/RRM2 axis could adjust gemcitabine resistance in A549 cells, and the p-PTEN/PI3K/AKT signal pathway might be involved in this regulatory mechanism.

Current status and prospect of ZIF-based materials for breast cancer treatment.

Breast cancer, one of the three most life-threatening cancers in modern times, must be explored for treatments with low side effects and practical efficacy. Metal organic framework materials (MOFs) is made by metal ions as the center for point and organic ligands as a bridge connecting a new type of porous nano-materials, among them, the zinc base zeolite imidazole skeleton material series (ZIFs) because of its excellent biocompatibility and pH slow controlled release ability, is widely used in the tumor microenvironment in basic research and achieved remarkable curative effect. Inspired by this, in this review, we focus on the recent research progress on the application of ZIFs in the treatment of breast cancer, mainly studying the structure of ZIFs such as ZIF-8, ZIF-90 and ZIF-67 and their application in novel therapies for breast cancer treatment, such as targeted drug delivery, photothermal therapy, immunotherapy and gene therapy.We will more fully demonstrate the potential of zif in breast cancer treatment, hoping to provide an avenue for exploring breast cancer treatment.

The Iron-Inflammation Axis in Early-Stage Triple-Negative Breast Cancer.

The iron-related homeostasis and inflammatory biomarker have been identified as prognostic factors for cancers. We aimed to explore the prognostic value of a novel comprehensive biomarker, the iron-monocyte-to-lymphocyte ratio (IronMLR) score, in patients with early-stage triple-negative breast cancer (TNBC) in this study. We retrospectively analysed a total of 257 early-stage TNBC patients treated at Sun Yat-sen University Cancer Center (SYSUCC) between March 2006 and October 2016. Their clinicopathological information and haematological data tested within 1 week of the diagnosis were collected. According to the IronMLR score cutoff value of 6.07 µmol/L determined by maximally selected rank statistics, patients were stratified into the low- and high-IronMLR groups, after a median follow-up of 92.3 months (95% confidence interval [CI] 76.0-119.3 months), significant differences in 5-years disease-free survival (DFS) rate (81.2%, 95% CI 76.2%-86.5% vs. 65.5%, 95% CI 50.3%-85.3%, p = 0.012) and 5-years overall survival (OS) rate (86.0%, 95% CI 81.6%-90.7% vs. 65.5%, 95% CI 50.3%-85.3%, p = 0.011) were seen between two groups. Further multivariate Cox regression analysis revealed the IronMLR score as an independent predictor for DFS and OS, respectively, we then established a prognostic nomogram integrating the IronMLR score, T stage and N stage for individualized survival predictions. The prognostic model showed good predictive performance with a C-index of DFS 0.725 (95% CI 0.662-0.788) and OS 0.758 (95% CI 0.689-0.826), respectively. Besides, calibration curves for 1-, 3-, 5-DFS, and OS represented satisfactory consistency between actual and nomogram predicted survival. In conclusion, the Iron-inflammation axis might be a potential prognostic biomarker of survival outcomes for patients with early-stage TNBC, prognostic nomograms based on it with good predictive performance might improve individualized survival predictions.