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de Azambuja E.,Institute Jules Bordet and Breast European Adjuvant Study Team | Holmes A.P.,Frontier Science Scotland Ltd | Piccart-Gebhart M.,Free University of Colombia | Holmes E.,Frontier Science Scotland Ltd | And 20 more authors.
The Lancet. Oncology

BACKGROUND: Findings from the randomised phase 3 NeoALTTO trial in women with HER2-positive early breast cancer showed that the combination of lapatinib and trastuzumab significantly improved rates of pathological complete response compared with either drug alone. Here, we report data for the prespecified secondary endpoints of event-free and overall survival, and assess the association between these outcomes and pathological complete response.METHODS: We enrolled women with HER2-positive early breast cancer and randomly assigned them to receive oral lapatinib (1500 mg), intravenous trastuzumab (4 mg/kg loading dose followed by 2 mg/kg), or lapatinib (1000 mg) plus trastuzumab (same dose as for single agent) in combination for 6 weeks, followed by an additional 12 weeks of the assigned anti-HER2 therapy in combination with weekly paclitaxel (80 mg/m(2)). Definitive surgery was done 4 weeks after the last dose of paclitaxel. After surgery, women received three cycles of FEC (fluorouracil 500 mg/m(2) plus epirubicin 100 mg/m(2) plus cyclophosphamide 500 mg/m(2)) given intravenously every 3 weeks, followed by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy. The primary endpoint was pathological complete response. Secondary endpoints included event-free and overall survival (intention-to-treat analysis), and the association between pathological complete response and event-free or overall survival (analysed by landmark analysis at 30 weeks after randomisation). Follow-up is ongoing, and the trial is registered with ClinicalTrials.gov, number NCT00553358.FINDINGS: 455 patients were enrolled: 154 (34%) were assigned to the lapatinib group, 149 (33%) to the trastuzumab group, and 152 (33%) to the lapatinib plus trastuzumab group. At an event follow-up of 3·77 years (IQR 3·50-4·22), 3-year event-free survival was 78% (95% CI 70-84) in the lapatinib group, 76% (68-82) in the trastuzumab group, and 84% (77-89) in the combination group. Event-free survival did not differ between the lapatinib and trastuzumab groups (HR 1·06, 95% CI 0·66-1·69, p=0·81), nor between the combination and trastuzumab groups (0·78, 0·47-1·28, p=0·33). Median survival follow-up was 3·84 years (IQR 3·60-4·24), and 3-year overall survival was 93% (95% CI 87-96) for lapatinib, 90% (84-94) for trastuzumab, and 95% (90-98) for combination therapy. Overall survival did not significantly differ between the lapatinib and trastuzumab groups (HR 0·86, 95% CI 0·45-1·63, p=0·65), nor between the combination and trastuzumab groups (0·62, 0·30-1·25, p=0·19). Landmark analyses showed that 3-year event-free survival was significantly improved for women who achieved pathological complete response compared with those who did not (HR 0·38, 95% CI 0·22-0·63, p=0·0003), as was 3-year overall survival (0·35, 0·15-0·70, p=0·005). Adverse events occurred in 149 (99%) patients receiving lapatinib, 142 (96%) patients receiving trastuzumab, and 147 (99%) patients receiving combination therapy. The most common adverse events were diarrhoea, rash or erythema, hepatic adverse events, and neutropenia (not related to FEC administration), and were consistent with known safety profiles of lapatinib and trastuzumab. Three primary and eight secondary cardiac events occurred, with no significant difference in incidence between treatment groups for primary or any cardiac events.INTERPRETATION: Although event-free survival or overall survival did not differ between treatment groups, findings from our study confirm that patients who achieve pathological complete response after neoadjuvant anti-HER2 therapy have longer event-free and overall survival than do patients without pathological complete response.FUNDING: GlaxoSmithKline. Copyright © 2014 Elsevier Ltd. All rights reserved. Source

Pileczki V.,Babes - Bolyai University | Braicu C.,Cancer Institute Prof Dr Ion Chiricuta | Balacescu O.,Cancer Institute Prof Dr Ion Chiricuta | Dragos N.,Babes - Bolyai University | And 2 more authors.
Annals of the Romanian Society for Cell Biology

Synthetic siRNA is used in mammalian cells for gene silencing. siRNA-induced RNAi is a key strategy for investigating gene function, a method that reduces the expression of individual genes in order to establish a link between gene identity and gene function. In our experiments we used siRNA VEGF to inhibit the main factor of angiogenesis that is considered to play an important role in tumor growth and metastasis. In this study a VEGF small interfering RNA (siRNA) was synthesized and through reverse-transfection technology was introduced in hepatocellular carcinoma cell line HepG2, using siPORT™ NeoFX Transfection Agent. VEGF expression was analysed by real time PCR, and the results were confirmed at protein levels by ELISA assay. MTT assay was used to detect cell viability. Apoptosis was analyzed using DAPI staining. The evaluation of real-time PCR gene expression showed a downregulation of VEGF at mRNA level in transfected cells compared to control group. These results were confirmed also at a protein level. VEGF-siRNA cell growth inhibition assessed by the MTT assay, showed that the transfection agent had no cytotoxic effect at 24 and 48 hours. An increased level of apoptotic processes was observed especially at 48 hours. MTT analysis shows that the transfection agent has no cytotoxic effect; the low cellular proliferation rate may be caused by the inhibition of VEGF gene and protein expression leading to the activation of apoptotic pathways. Source

Gherman C.,Cancer Institute Prof Dr Ion Chiricuta | Gherman C.,University of Agricultural Sciences and Veterinary Medicine, Iasi | Pileczki V.,Babes - Bolyai University | Petric R.C.,Babes - Bolyai University | And 4 more authors.
Annals of the Romanian Society for Cell Biology

In our study we investigated the contribution of oxaliplatin to mediated toxicity and transcription profile of genes involves in cancer in order to understand the mechanisms involved in tumor cell apoptosis and cancer disease progression. As colorectal cancer model we used the Colo320 cell line. We evaluated the oxaliplatin induced toxicity of a single dose of different concentrations at 24, 48 and 72 hours, and also multiple doses at different times, in order to establish the IC50 concentration. p53, NF B and PDGF gene expression levels were evaluated after treatment with a concentration close to the IC50 using the RT-PCR technique. The purpose of the study is to observe the changes in pharmacokinetic parameters after administration of a single dose in order to establish IC50, using the MTT cell proliferation assay on the line Colo320. We compared the parameters of cell proliferation observed after administration of a single dose and multiple doses, and tried to establish an optimal time and frequency of oxaliplatin treatment that induces the minimal cytotoxic effect. After evaluating the modulation of gene expression after treatment with oxaliplatin, we obtained a high gene expression of two major pro-apoptotic genes, p53 and NF B (nuclear factor-B) and the inhibition of a pro-angiogenic factor, the platelet-derived growth factor (PDGF). In conclusion, the frequency of drug administration is important, and may establish the minimum dose required and the frequency of administration, with maximum biological results and without adverse effect. Source

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