FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG).

A randomized multicenter phase III study was conducted to compare the sequential docetaxel followed by epirubicin/cyclophosphamide combination with that of FEC regimen as adjuvant chemotherapy in women with axillary node-positive early breast cancer. Seven hundred and fifty-six women with axillary lymph node-positive breast cancer were randomized to receive either 4 cycles of docetaxel (100 mg/m(2)) followed by 4 cycles of epirubicin (75 mg/m(2)) plus cyclophosphamide (700 mg/m(2)) (experimental arm) or 6 cycles of FEC (epirubicin 75 mg/m(2), cyclophosphamide 700 mg/m(2), and 5-fluorouracil 700 mg/m(2); control arm). All regimes were administered every 3 weeks. The primary end point was five-year disease-free survival (DFS). After a median follow-up period of 5 years, 233 (30.8%) relapses had occurred (108 and 125 in the experimental and control arms, respectively; P = 0.181). The five-year DFS was 72.6% (95% CI 63.8-81.3%) and 67.2% (95% CI 58.0-76.4%) for women randomized in the experimental and control arms, respectively (P = 0.041; log rank test). There was no difference in the overall survival between the two arms (83.8 and 81.4% in the experimental and control arms, respectively; P = 0.533). The experimental arm was associated with increased neutropenia requiring administration of granulocyte colony-stimulating factor in 90.5% of the patients as compared with 74.1% in the control arm (P = 0.0001). The sequential docetaxel followed by epirubicin/cyclophosphamide adjuvant chemotherapy regimen resulted in improved five-year DFS in women with axillary node-positive early breast cancer at the expense of increased but manageable myelotoxicity.

Expression of p27KIP1, p21WAF1 and p53 does not correlate with prognosis in node-negative invasive ductal carcinoma of the breast.

The expressions ofp27Kip1 (p27) and p21waf1 (p21) cyclin-dependent kinase inhibitors and p53 were examined in a series of 170 node-negative breast carcinomas (NNBCs) to evaluate their prognostic significance. Low nuclear (p27TN) and cytoplasmic (p27TC) p27 expressions were noted in 66% and 81% of NNBCs, respectively. p21 and p53 overexpressions were detected in 56% and 26%, respectively. Low p27TN was significantly associated with high grade (p=0.001), age < or = 50 years (p=0.01), negative hormone receptors (p<0.001), low p27TC (p<0.001) and p53 overexpression (p=0.02). Low p27TC was associated with negative hormone receptors (p<0.001). p53 overexpression was associated with high grade (p<0.001) and negative hormone receptors (p<0.001). p21 overexpression, although not correlated with the examined parameters, was associated with increased disease-free survival in univariate analysis. In multivariate analysis, p27TN, p27TC, p21 and p53 were not associated with disease-free survival or overall survival. These findings argue against the prognostic value of p27, p21 and p53 in NNBC.

The combination of estramustine, vinorelbine, and mitoxantrone in hormone-refractory prostate cancer: a Phase II feasibility study conducted by the Hellenic Cooperative Oncology Group.

OBJECTIVES: To evaluate the safety profile and therapeutic value of the combination of estramustine, mitoxantrone, and vinorelbine in the treatment of hormone-refractory prostate cancer. METHODS: Fifty-two patients with hormone-refractory prostate cancer were included in the study. Median age was 70 years (range, 49 to 100 years), World Health Organization performance status ranged from 0 to 2. The treatment schedule consisted of estramustine capsules (140 mg 3 times daily on days 1 to 3 and days 8 to 10 per os), intravenous mitoxantrone (12 mg/m2 on day 2), and intravenous vinorelbine (25 mg/m2 on day 2 and day 9), given in a 3-week cycle. RESULTS: Thirty-one percent of patients with measurable soft-tissue disease demonstrated an objective response, which included six complete and ten partial responses in all involved organs (bone responses not included). Twenty-nine patients (56%) had a greater than 50% reduction in serum prostate-specific antigen level. The median duration of response was 6.9 months, and the median survival for all patients was 14.5 months. CONCLUSIONS: The combination of estramustine, vinorelbine, and mitoxantrone is safe, well tolerated, and relatively active in patients with hormone-refractory prostate cancer.

Hereditary breast and ovarian cancer in Cyprus: identification of a founder BRCA2 mutation.

The entire coding regions of the two breast cancer susceptibility genes BRCA1 and BRCA2 from breast cancer patients from 40 Cypriot families with multiple cases of breast and ovarian cancer were sequenced. A total of four protein-truncating mutations were found in six families. In BRCA1, a novel truncating mutation 5429delG was found in exon 21. In BRCA2, three truncating mutations were detected: a frameshift 8984delG in exon 22 and two nonsense mutations C1913X in exon 11 and K3326X in exon 27. It is noted that mutation 8984delG was found in three separate families, and haplotype analysis showed that this may be a founder mutation in the Cypriot population. In addition, a pair of rare variants, Q356R and S1512I, was detected in BRCA1 in patients belonging to two Cypriot families. The simultaneous presence of this pair of missense mutations may be associated with the breast cancer phenotype in the Cypriot population. We conclude that the BRCA2 gene appears to play a more important role in familial breast cancer in the Cypriot population than BRCA1.

BRCA2 germline mutations in Cypriot patients with familial breast/ovarian cancer.

Germline mutations in the BRCA2 gene have been shown to be associated with familial female and male breast cancer. Mutations occur throughout the entire coding region of the gene, and there is considerable ethnic and geographical diversity in the deleterious mutations detected in different populations. No data exist on the role of the BRCA2 gene in the Cypriot population. In this study we present the results of characterizing mutations in the BRCA2 gene, in 26 Cypriot families with multiple cases of breast/ovarian cancer. The entire coding region, including splice sites, of BRCA2 were sequenced using cycle sequencing. In total 29 BRCA2 variants were detected which include 3 truncating mutations, 8 missense mutations, 6 polymorphisms and 12 intronic variants. The 3 truncating mutations are frameshift mutation 8984delG (exon 22), and two nonsense mutations, namely C1913X (exon 11) which is a novel mutation, and K3326X (exon 27). It is of interest that frameshift mutation 8984delG was the most frequent, since it was detected in 5 patients from three different families. Among the 6 polymorphisms detected, polymorphism T77T is novel and similarly 4 of the 12 intronic variants were also novel, namely IVS1+8G>A, IVS1-96insA, IVS4+36A>G and IVS11-51G>T. These results show that deleterious BRCA2 mutations, occur at the same frequency, about 20%, in Cypriot families, as that recorded in other European populations. We conclude that the BRCA2 gene plays a significant role in the familial breast cancer phenotype in the Cypriot population.

Q356R and S1512I are BRCA1 variants that may be associated with breast cancer in a Cypriot family.

A molecular study was performed on BRCA1 and BRCA2 genes in a Cypriot family, with a history of both male and female breast cancers. Three variants were detected in the BRCA1 gene, two of which are missense mutations at nucleotide positions 1186 in exon 11 (Q356R), and 4654 in exon 15 (S1512I). The third variant is a polymorphism at position 2430 in exon 11 (771L). Similarly in the BRCA2 gene two variants were detected: a missense mutation at position 1342, exon 10 (H372N), and a polymorphism at position 3624 in exon 11 (1132K). Since these BRCA2 variants appear to be polymorphisms in the Cypriot population, we suggest that the two BRCA1 mutations, Q356R and S1512I, may be related to the breast cancer phenotype.