Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: final long-term results of the Hellenic Cooperative Oncology Group Phase III HE10/05 Trial.

BACKGROUND: Dose-dense sequential chemotherapy with anthracyclines and taxanes achieved an 18% reduction of recurrence risk in early breast cancer (BC). The optimal chemotherapy schedule and interval between cycles remain under investigation. METHODS: Overall, 990 patients were randomised to receive either three cycles of epirubicin (E, 110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by three cycles of intensified CMF (Control Arm A, E-T-CMF) that was previously used in BC or three cycles of epirubicin followed by three cycles of CMF followed by nine consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Arm B, E-CMF-wD) or nine consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Arm C, E-CMF-wT). Trastuzumab was administered for HER2-positive disease. RESULTS: At a median follow-up of 13.3 years, 330 disease-free survival (DFS) events (33.3%) were reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus arm A either in the entire cohort (HR = 0.90, P = 0.38 and HR = 0.85, P = 0.20) or among trastuzumab-treated patients (HR = 0.69, P = 0.13 and HR = 0.67, P = 0.13). Thirty-four patients (3.4%) developed secondary neoplasms. CONCLUSIONS: Overall, no significant differences in survival were found amongst the studied regimens after a long-term observational period. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000151033.

Prognostic Significance of VEGFC and VEGFR1 mRNA Expression According to HER2 Status in Breast Cancer: A Study of Primary Tumors from Patients with High-risk Early Breast Cancer Participating in a Randomized Hellenic Cooperative Oncology Group Trial.

BACKGROUND: Vascular endothelial growth factor C (VEGFC) and vascular endothelial growth factor receptor 1 (VEGFR1) mRNA overexpression has recently been shown to have strong predictive and prognostic value in patients with high-risk early breast cancer undergoing adjuvant chemotherapy. The present study evaluated associations of VEGFC and VEGFR1 with human epidermal growth factor receptor 2 (HER2) and their prognostic value dependent on HER2 status. PATIENTS AND METHODS: RNA was isolated from 298 formalin-fixed paraffin-embedded tumor tissue samples from the HeCOG 10/97 (HE10/97) trial, evaluating adjuvant dose-dense sequential chemotherapy with epirubicin followed by cyclophosphamide, methotrexate and 5-fluorouracil therapy with or without paclitaxel (E-T-CMF vs. E-CMF). A fully-automated method based on magnetic beads was applied for RNA extraction, followed by one-step quantitative reverse transcription-polymerase chain reaction. RESULTS: At 13.3 years of median follow-up, 116 patients (38.9%) had experienced relapse and 115 (38.6%) had died. There were strong associations between VEGFC/VEGFR1 mRNA expression and HER2 and estrogen receptor/progesterone receptor status. In multivariate analysis, both VEGFC and VEGFR1 were found to be associated with risk for death or relapse, but such associations depended on HER2 status and treatment group. High VEGFC was a negative prognostic factor for disease-free survival [hazard ratio (HR)=1.79, 95% confidence interval (CI)=1.05-3.05, Wald's p=0.032], with a trend for overall survival (HR=1.80, 95% CI=0.94-3.47, p=0.078) in patients treated with E-CMF adjusted for clinicopathological characteristics, while high VEGFR1 was associated with increased risk for death, yet non significantly in patients with HER2-negative disease (HR=1.51, 95% CI=0.82-2.77, p=0.18), regardless of treatment. CONCLUSION: VEGFC and VEGFR1 mRNA overexpression is of prognostic value, dependent on HER2 status, in patients with high-risk early breast cancer undergoing adjuvant treatment. Among HER2-negative cases, these angiogenic markers could identify more aggressive tumors with worse prognosis. Further studies are warranted to validate VEGFC and VEGFR1 as potential biomarkers in adjuvant therapy and their use in identifying sub-groups that could benefit from anti-VEGF strategies.

In vitro and in vivo activities of Chios mastic gum extracts and constituents against Helicobacter pylori.

The extracts and pure major constituents of Chios mastic gum (resin of Pistacia lentiscus var. chia) were tested for their activities against Helicobacter pylori. A total mastic extract without polymer (TMEWP) was prepared after removal of the contained insoluble polymer in order to ameliorate solubility and enhance in vivo activity. Administration of TMEWP to H. pylori SS1-infected mice over the period of 3 months with an average dose of 0.75 mg/day led to an approximately 30-fold reduction in the H. pylori colonization (1.5 log CFU/g of tissue). However, no attenuation in the H. pylori-associated chronic inflammatory infiltration and the activity of chronic gastritis was observed. To further characterize potential active mastic constituents, the TMEWP was separated into an acidic and a neutral fraction. Both were extensively characterized by nuclear magnetic resonance and mass spectroscopy to elucidate the structure of the components contained within each fraction. After chromatographic separation, the acid fraction gave the major triterpenic acids, while the neutral fraction gave several triterpenic alcohols and aldehydes. Mastic extracts and isolated pure triterpenic acids were tested for in vitro activity against a panel of 11 H. pylori clinical strains. The acid fraction was found to be the most active extract (minimum bactericidal concentration [MBC], 0.139 mg/ml), and the most active pure compound was isomasticadienolic acid (MBC, 0.202 mg/ml [0.443 mM]). Our results show that administration of TMEWP may be effective in reducing H. pylori colonization and that the major triterpenic acids in the acid extract may be responsible for such an activity.