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Human breast cancer (BC) is characterized by a considerable clinical heterogeneity. Steroid hormone receptor expression and growth factor receptor expression have been considered suitable diagnostic and prognostic markers, whereas mutations of oncosuppressor and gatekeeper genes have been found associated with an increased risk for this malignancy. To evaluate the role that polymorphisms of genes involved in the regulation of inflammatory response might play in BC susceptibility, we investigated associations between cytokine functionally relevant polymorphisms in 84 BC patients compared to 110 age- and sex-matched controls. TNF-alpha (-308G/A), TGF-beta1 (+869C/T), IL-10 (-1117G/A; -854C/T; -627C/A), and IFN-gamma (874T/A) single nucleotide polymorphisms (SNPs) were identified by sequence-specific primers (SSP)-PCR or restriction fragment length polymorphism (RFLP)-PCR. Genotype or haplotype distributions for each polymorphisms were consistent with the HWE in these populations. We were unable to demonstrate differences in genotype or allele frequencies between patient and control groups. Data obtained in this study indicate that none of the cytokine SNPs studied is likely to have predisposing or protective effects on BC susceptibility. On the other hand, both positive and negative association with BC have been reported for some of the studied genotypes by different research groups. In conclusion, further studies involving larger numbers of subjects are required.

It is well established that cancer arises in chronically inflamed tissue, and this is particularly notable in the gastrointestinal tract. Classic examples include Helicobacter pylori-associated gastric cancer, hepatocellular carcinoma, and inflammatory bowel disease-associated colorectal cancer. Growing evidence suggests that these associations might be not casual findings. Focusing on individual cytokines has generated evidence that anti-inflammatory cytokine interleukin (IL)-10 and transforming growth factor-beta1 (TGF-beta1) may have a complex role in gastrointestinal carcinogenesis. As an example, IL-10-deficient mice develop severe atrophic gastritis and a chronic enterocolitis, developing colorectal cancer similar to human inflammatory bowel disease-associated neoplasia. TGF-beta1 is a multifunctional signaling molecule with a wide array of roles. Animal experiments suggest that TGF-beta1 plays a biphasic role in carcinogenesis by protecting against the early formation of benign epithelial growths, but promoting a significant stimulation of tumor growth invasion and metastasis during tumor progression. We assessed association of functional polymorphisms (-1082G/A; -592C/A) and TGF-beta1 (-509C/T; +869C/T) influencing the IL-10 production to colorectal cancer risk in a case-control study of 62 patients and 124 matched controls. No significant differences were observed among cancer patients and controls for IL-10 -1082G/A; -592C/A genotype frequencies. Evaluation of odds ratios (OR) for the TGF-beta1 +869C/T genotypes showed a significant increased risk for individuals bearing +869CC genotype compared to +869CT- and +869TT-positive individuals. These results suggest that the +869C allele, responsible for a Leu-->Pro substitution in the signal peptide sequence of the TGF-beta1 protein, may have a predisposing role in the development of colorectal cancer.

Objectives: We conducted a multicenter phase II study to evaluate the clinical efficacy, toxicity, and dose intensity of a new weekly schedule of docetaxel and gemcitabine as first-line treatment of metastatic breast cancer patients. Methods: We enrolled 58 patients, 52% of whom had received a previous anthracycline-containing chemotherapy. The treatment schedule was: docetaxel 35 mg/m2 and gemcitabine 800 mg/m2 i.v. on days 1, 8, 15 every 28 days. Results: All patients were assessable for toxicity and 56 for efficacy. Overall response rate was 64.3% with 16.1% of complete responses and 48.2% of partial responses. Median survival was 22.10 months (95% CI: 15.53–28.67) and median time to tumor progression was 13.6 months (95% CI: 10.71–16.49). The most common hematological toxicity was neutropenia (no febrile neutropenia), which occurred in 28 patients (48.3%) but grade 3–4 in only 8 patients (14%). Alopecia, the most common nonhematological toxicity, occurred in 20 (34.5%) patients, but only 5 patients (8.6%) experienced grade 3 alopecia. Conclusion: The activity of docetaxel and gemcitabine in metastatic breast cancer is confirmed. The promising results of the employed schedule, in agreement with other published studies, need to be further confirmed within a phase III study.

Metastatic breast cancer is still considered an incurable and difficult to treat disease, even if several classes of antineoplastic agents have shown various levels of activity in these patients. Taxanes are the most effective drugs in breast cancer, together with the anthracyclines, but they have several important side-effects with standard administration schedules. The weekly administration of both paclitaxel and docetaxel, respectively at 80-100 mg/m 2 /week and 35-40 mg/m 2 /week, is feasible and it has an efficacy level at least comparable with the standard 21-day administration. These schedules can also be administered at an increased dose-intensity with a better toxicity profile. Even if most of the data available today come from small phase I and/or II trials, the weekly schedules of taxanes administration are an attractive therapeutic chance, especially (but not only) in the elderly patients. Moreover the minimal side-effects make this approach very interesting for combination therapy with other drugs as well as with new biological agents such as anti-HER-2 and anti-EGF molecules. Ongoing phase III trials will clarify the efficacy of the weekly administration schedules and will define their role in the treatment of the metastatic breast cancer.

20092 Background: Circulating serum levels of the extracellular domain of the HER-2/neu receptor have been described in up to 15–30% of pre-surgical BC pts and 45% of metastatic BC (MBC) pts. S-HER2 has been reported to have a potential prognostic and predictive role in BC pts. Methods: We conducted a prospective evaluation of the S-HER2 levels in BC pts with the aim of studying its prognostic role and correlation with the clinical situation.The S-HER-2 levels were measured by an ELISA immunometric test (cut-off 13 ng/ml) at the first visit and then every 3 months.All pts gave a written informed consent. Results: From Jan ‘05 97 consecutive BC pts [68 st I-III; 29 (1 male) st.IV; median age at entry: 60y (28–83)] have been accrued and a total of 196 serum samples have been tested for S-HER2 (mean = 2/pt).Preliminary results are reported.Elevated S-HER2 levels at the first dosage (bS-HER2) were present in 25% of primary and 52% of MBC pts.In 68 primary BC pts the tumor HER2 status was 0/1+ in 54% (bS-HER2 >13 ng/ml = 22%) and 2+/3+ in 22% (bS-HER2 >13 ng/ml = 27%); there was no correlation between bS-HER2 with tumor HER2 status, size,axillary nodes, ER status, grading according to the Fisher’s exact test. In 29 MBC pts the tumor HER2 status was 0/1+ in 24% (bS-HER2 >13 ng/ml = 24%) and 2+/3+ in 48% (bS-HER2 >13 ng/ml = 21%); there was no correlation between S-HER2 and sites of metastases/n.of sites even if the S-HER2 median value was 18 and 12.5 ng/ml in visceral vs no visceral metastases.We also observed in 35% of MBC pts experiencing progression of disease that S-HER2 sequential values increased from baseline;in 21% of MBC pts that experienced complete remission the S-HER2 values decreased No significant financial relationships to disclose.

9656 Background:the anti-inflammatory IL-10 -1082 (G/A) SNP might be associated with different risk for breast tumor development. The -1082GG homozygous genotype is associated with an higher IL-10 ...