Maintenance chemotherapy after 6 cycles of platinum-doublet regimen in anthracycline-and taxane-pretreated metastatic breast cancer.

BACKGROUND/AIMS: Sequential monotherapy is recommended for anthracycline-and taxane-resistant metastatic breast cancer (MBC), but combination chemotherapy is considered in patients with visceral crisis. Cisplatin-doublet chemotherapy is a combination regimen for MBC, but prolonged treatment is challenging because of toxicity. We analyzed the role of single-agent maintenance chemotherapy after cisplatin-doublet chemotherapy for MBC. METHODS: From January 2011 to December 2017, 96 anthracycline- and taxane- resistant MBC patients were retrospectively reviewed, and 49 patients with a sustained clinical benefit during the initial 6 cycles of cisplatin-doublet chemotherapy were enrolled for study. Patients were treated with gemcitabine-cisplatin (gemcitabine, 1,250 mg/m2, intravenously [IV], days 1 to 8; cisplatin 60 mg/m2, IV, day 1) or capecitabine-cisplatin (capecitabine 2,500 mg/m2, orally, days 1 to 14; cisplatin 60 mg/m2, IV, day 1) during the induction period. After 6 cycles, 16 patients were switched to single-maintenance treatment (gemcitabine or capecitabine) and the doublet regimen was continued in 24 patients. Survival outcomes (progression- free survival [PFS] and overall survival [OS]) were analyzed. RESULTS: Among the 49 patients who showed a clinical benefit during cisplatin- doublet therapy, 24 were maintained on the doublet regimen, 16 were switched to single-maintenance treatment, and chemotherapy was suspended until disease progression in nine patients. The single-maintenance chemotherapy group showed superior survival than the chemotherapy holiday and doublet regimen groups (median PFS 15.43 months vs. 8.37 and 10.67 months, respectively, p = 0.008; median OS 43.67 months vs. 22.17 and 22.33 months, respectively, p = 0.014). CONCLUSION: Patients showing a clinical benefit during 6 cisplatin-doublet chemotherapy cycles may have a sustained survival benefit from single-maintenance chemotherapy.

Sex Chromosomes Are Severely Disrupted in Gastric Cancer Cell Lines.

Sex has not received enough attention as an important biological variable in basic research, even though the sex of cells often affects cell proliferation, differentiation, apoptosis, and response to stimulation. Knowing and considering the sex of cells used in basic research is essential as preclinical and clinical studies are planned based on basic research results. Cell lines derived from tumor have been widely used for proof-of-concept experiments. However, cell lines may have limitations in testing the effect of sex on cell level, as chromosomal abnormality is the single most characteristic feature of tumor. To examine the status of sex chromosomes in a cell line, 12 commercially available gastric carcinoma (GC) cell lines were analyzed using several different methods. Loss of Y chromosome (LOY) accompanied with X chromosome duplication was found in three (SNU-484, KATO III, and MKN-1) out of the six male-derived cell lines, while one cell line (SNU-638) showed at least partial deletion in the Y chromosome. Two (SNU-5 and MKN-28) out of six female-derived cell lines showed a loss of one X chromosome, while SNU-620 gained one extra copy of the X chromosome, resulting in an XXX karyotype. We found that simple polymerase chain reaction (PCR)-based sex determination gives a clue for LOY for male-derived cells, but it does not provide detailed information for the gain or loss of the X chromosome. Our results suggest that carefully examining the sex chromosome status of cell lines is necessary before using them to test the effect of sex on cell level.

Notch1 in Tumor Microvascular Endothelial Cells and Tumoral miR-34a as Prognostic Markers in Locally Advanced Triple-Negative Breast Cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is associated with poor prognosis with limited treatment options. Angiogenesis is known to be involved in the progression of TNBC, and targeting this pathway results in modest clinical benefits. In this study, we analyzed the role of tumor microvascular endothelial Notch1 (EC Notch1) and tumoral miR-34a as prognostic markers in patients with TNBC. METHODS: The expression of miR-34a was analyzed using archival tumor tissues from 114 patients with TNBC. Simultaneously, archival tumor tissues were also checked for the expression of CD34 and Notch1 by immunostaining. The ratio of Notch1-microvascular density (MVD) to CD34-MVD was defined as EC Notch1. The association between the expression of miR-34a or EC Notch1 and clinicopathological characteristics was analyzed. RESULTS: In the overall patient population, patients with low expression of EC Notch1 was associated with better overall survival (OS, p = 0.041) than those with high expression of EC Notch1. In lymph node-positive TNBC patients, high levels of miR-34a and low levels of EC Notch1 correlated significantly with higher survival benefits in terms of OS (p = 0.026), disease-free survival (p = 0.009), and metastasis-free survival (p = 0.038) relative to that in other patients. Decreased expression of EC Notch1 and increased expression of miR-34a also showed a survival benefit in locally advanced TNBC. CONCLUSION: The fact that miR-34a and EC Notch1 are associated with the angiogenesis suggests that angiogenesis may play a role in the development and progression of TNBC.

MiR-199a/b-5p Inhibits Lymphangiogenesis by Targeting Discoidin Domain Receptor 1 in Corneal Injury.

Discoidin domain receptor 1 (DDR1) is involved in tumorigenesis and angiogenesis. However, its role in lymphangiogenesis has been unknown. Here, we tested whether downregulation of DDR1 expression by miR-199a/b can suppress lymphangiogenesis. We also aimed to identify miRNA target site(s) in the 3' untranslated region (UTR) of DDR1. Transfection with miR-199a/b-5p mimics reduced expression of DDR1 and tube formation in primary human dermal lymphatic endothelial cells, whereas miR-199a/b-5p inhibitors showed the opposite effects. Critically, injection of miR-199a/b-5p mimics suppressed DDR1 expression and lymphangiogenesis in a corneal alkali-burn rat model. The three well-conserved seed matched sites for miR-199a/b-5p in the DDR1 3'-UTR were targeted, and miRNA binding to at least two sites was required for DDR1 inhibition. Our data suggest that DDR1 promotes enhanced lymphangiogenesis during eye injury, and miR-199a/b-5p suppresses this activity by inhibiting DDR1 expression. Thus, this miRNA may be useful for the treatment of lymphangiogenesis-related eye diseases.