Vinorelbine Sequential Or Combined With Capecitabine Treatment For Breast Cancer Clinical And Molecular Markers

Part I Randomized phase II study of sequential versus simultaneous use of vinorelbine and capecitabine as first line chemotherapy for patients with metastatic breast cancerPurposeIt remains unclear whether simultaneous use of two chemotherapeutic drugs is better than sequential use due to selection of a lower dose in the simultaneous arm. This trial was designed to compare efficacy and safety of sequential versus simultaneous use of vinorelbine and capecitabine at the same dosage as first-line therapy in metastatic breast cancer (MBC).Patients and MethodsThis was a unicenter, randomized, open-label phaseⅡtrial. Patients who were randomized into the simultaneous arm were simultaneously administered with vinorelbine (VNB) and capecitabine (Xe) (VNB 25 mg/m2 days 1 and 8; Xe 1,000 mg/m2 twice daily days 1 through 14; repeated every 21 days), until disease progression or unacceptable toxicity occurred. Patients who were randomized into the sequential arm (arm B) were sequentially administered with the two drugs at the same dosage, VNB should be used until disease progression or unacceptable toxicity occurred, then switched to Xe, until disease progression or unacceptable toxicity occurred. Medical history, physical examinations, ECOG performance status evaluations, laboratory examinations and image examinations were all performed at baseline and after every 2 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints contained overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR), time-to-treatment failure (TTF) and safety.ResultsFrom April 2008 to June 2009,66 patients were enrolled and 60 of them were randomly assigned to simultaneous arm or sequential arm. Patient characteristics were balanced between arms, and all the enrolled patients were assessable for both efficacy and safety. There were substantial but not statistically significant difference in overall response rates (ORR) of 53.3% in arm A and 33.3% in arm B (P=0.118), however, the difference in the clinical benefit rate (CBR) reached statistical significance with 80.0% for arm A and 53.3% for arm B (P=0.028). With a median follow up time of 13.5 months, median PFS was 7.70 months [95% confidence interval (CI),6.59 to 8.81 months] for the simultaneous arm and 7.23 months (95% CI,4.36 to 10.10 months) for the sequential arm (P=0.436) and overall survival (OS) was not different between arms and the median OS was not reached for either arm since too few events occurred. Time to treatment failure (TTF; defined as all discontinuations for any cause) didn't show significant difference between arms (P= 0.121). Both arms were safe during treatment. GradeⅢorⅣneutropenia (83.3% in the simultaneous arm vs. 50.0% in the sequential arm, P=0.006), all grades of fatigue (56.7% in the simultaneous arm vs.30.0% in the sequential arm, P= 0.037) and all grades of anorexia (53.3% in the simultaneous arm vs.23.3% in the sequential arm, P= 0.017) were significantly more frequent in the simultaneous arm. Fewer patients in the sequential arm experienced dose reductions due to drug-related adverse events (13.3% vs.46.7%, P=0.005).ConclusionsBoth simultaneous and sequential administration showed promising efficacy and acceptable toxicities. Simultaneous administration of VNB and Xe can bring about improvements in CBR in MBC patients, but cannot translate into long-term benefits, such as PFS or OS. These findings, combined with a relatively better tolerability in the sequential arm, suggested that both simultaneous and sequential administration are reasonable options for patients with MBC,. PartⅡBiomarkers predictive for clinical efficacy of vinorelbine-based chemotherapy and prognosis in metastatic breast cancer PurposeTo explore the relationship betweenβ-Ⅲ-tubulin expression and efficacy of vinorelbine-based chemotherapy and the value ofβ-Ⅲ-tubulin in predicting the prognosis of metastatic breast cancer (MBC) patients.Materials and methodsParaffin embedded tumor tissues and patient's data were collected from 42 of the 60 patients in the phaseⅡclinical trial. Monoclonal antibody specific for theβ-Ⅲ-tubulin isotype was obtained from abcam company and immunohistochemistry was performed according to EnVision two steps methods, including deparaffinization, antigen retrieval, antibody dilution, washing, immunostaining, double staining, read and analyze the expression of each slide, negative control to verify the results and photographing. All the immunohistochemical slides were analysed at optical microscope by two independent observers. A numerical score was assigned for each specimen, incorporating quantitative assessment of malignant cell cytoplasmic staining intensity and the proportions of tumor cell stained. Intensity scoring (Ⅰ)forβ-Ⅲ-tubulin was scored as'0'with samples with no stained tumor cells above background, a score'1'was assigned to samples with low levels of staining, and a score of'2'was given to samples with strong staining. The H score was calculated using the following formula:H score= A (1+I)*PC, where PC represents the percentage of malignant cells that stained at each intensity, respectively. The H scores of the two observers were said to agree when they differed by<10%. Discrepant scores of>10% were resolved by reassessment and consensus between the two observers. All the H scores were ranked and those above the median were classified as high expression while those below the median were classified as low expression. The staining of mesenchymal cells and para-malignant tissues were internal negative control. Statistical analysis were performed by SPSS 15.0 software package. Time-to-event end points were evaluated by Kaplan-Meier estimates and were compared by the log-rank test at a two-sided 5% significance level (ie, P value less than 0.05 to demonstrate statistical significance). Comparisons of rates were conducted with Pearson's x2 test and a Cox regression model was accessed to analyze the independent value ofβ-Ⅲ-tubulin expression in predicting the efficacy of vinorelbine-based chemotherapy and the prognostic factors of metastatic breast cancer(MBC) patients.ResultsAll the specimens were successfully stained. There's no mesenchymal cells or para-malignant tissues strongly stained, and 34 of the 42 patients (81.0%) were demonstrated a positive staining ofβ-Ⅲ-tubulin in the malignant cells, there're significant differences between malignant cells and mesenchymal cells or para-malignant tissues as to positive rates ofβ-Ⅲ-tubulin expression (P=0.001). The range of Hscore was 100-295, with a median score of 202.5 and a mean of 201. Theβ-Ⅲ-tubulin expression between arms were well balanced (P=0.757).Univariant analysis showed that theβ-Ⅲ-tubulin expression status was not significantly related with the ORR of VNB (P=0.355) or the CBR of VNB (P=0.707). PFS and OS were not significantly affected byβ-Ⅲ-tubulin expression status (P=0.794 for PFS and P=0.772 for OS). Correlation analysis of theβ-Ⅲ-tubulin expression status and clinical-pathological factors showed that only HER2 over-expression was strongly correlated withβ-Ⅲ-tubulin high expression (P=0.050). Cox regression model showed that only PR status and lymph node status significantly affected PFS (P=0.033 for lymph node status and P=0.004 PR status). Took H score as a continuous variable to perform the analysis, the results also showed that HER2 status was significantly correlated withβ-Ⅲ-tubulin expression status (P=0.009)ConclusionsThere're significant differences between malignant cells and mesenchymal cells or para-malignant tissues as to positive rates ofβ-Ⅲ-tubulin expression (P=0.001) Patients with lymph node positive or HER2 overexpression showed higher positive rates ofβ-Ⅲ-tubulin expression. HER2 status was significantly correlated withβ-Ⅲ-tubulin expression status. The ORR of VNB, PFS and OS were not significantly affected byβ-Ⅲ-tubulin expression status.