PURPOSE::Tamoxifen undergoes bioactivation to its active metabolite (Z)-endoxifen, which blocks estrogen-dependent breast tumor growth at high potency. We tested the feasibility and safety of supplementing standard tamoxifen therapy with low-dose (Z)-endoxifen in patients with breast cancer with compromised tamoxifen bioactivation. PATIENTS AND METHODS::We conducted a prospective, interventional, three group randomized trial including 235 patients with hormone receptor-positive breast cancer who received standard tamoxifen therapy (20 mg/day). Patients were stratified by CYP2D6 genotype (n = 78), defining poor, intermediate, and normal metabolizers, or by baseline (Z)-endoxifen plasma concentration (n = 78), defining ≤15, 15 to 25, and ≥25 nmol/L. Co-treatment with (Z)-endoxifen 3 and 1.5 mg/day or placebo was performed, respectively. A control group (n = 79) received placebo regardless of metabolizer phenotype. The primary endpoint was the number of patients with (Z)-endoxifen levels >32 nmol/L after 6 weeks of treatment. Adverse events were continuously monitored. RESULTS:A higher proportion of patients in both intervention groups achieved target concentrations >32 nmol/L compared with control (P < 0.0001). At 3 mg (Z)-endoxifen supplementation, 92.3% of CYP2D6 poor metabolizer patients and all patients with baseline (Z)-endoxifen ≤15 nmol/L achieved the target concentration. At 1.5 mg (Z)-endoxifen supplementation, 88% of CYP2D6 intermediate metabolizer patients and 95% of patients with 15 to 25 nmol/L baseline (Z)-endoxifen levels achieved the target concentration. Similar proportions of patients receiving (Z)-endoxifen (6/80, 7.5%) or placebo (8/155, 5.2%) experienced grade 3 adverse events. CONCLUSIONS:Adding low-dose (Z)-endoxifen to standard tamoxifen is safe and provides a new approach to personalized antiestrogen treatment for patients with low endoxifen plasma levels.

BACKGROUND/AIM:In this retrospective study, we compared breast cancer patients treated with and without mistletoe lectin I (ML-I) in addition to standard breast cancer treatment in order to determine a possible effect of this complementary treatment.PATIENTS AND METHODS:This study included 18,528 patients with invasive breast cancer. Data on additional ML-I treatments were reported for 164 patients. We developed a "similar case" method with a distance measure retrieved from the beta variable in Cox regression to compare these patients, after stage adjustment, with their non-ML-1 treated counterparts in order to answer three hypotheses concerning overall survival, recurrence free survival and life quality.RESULTS:Raw data analysis of an additional ML-I treatment yielded a worse outcome (p=0.02) for patients with ML treatment, possibly due to a bias inherent in the ML-I-treated patients. Using the "similar case" method (a case-based reasoning approach) we could not confirm this harm for patients using ML-I. Analysis of life quality data did not demonstrate reliable differences between patients treated with ML-I treatment and those without proven ML-I treatment.CONCLUSION:Based on a "similar case" model we did not observe any differences in the overall survival (OS), recurrence-free survival (RFS), and quality of life data between breast cancer patients with standard treatment and those who in addition to standard treatment received ML-I treatment.

Background: The well-characterized tubular-type of breast tumors is classified as low-risk breast cancer. Patients and Methods: We report on the results of a retrospective analysis on clinical and biological features of 248 tubular breast tumors including follow-up and treatment data from two German series of 21,065 breast cancer cases. The majority of tumors were stage I or stage II, ER- and PR-positive and c-erbB2-negative with a 5-year survival-rate of 96.3%. 51.3% of patients received hormonal treatment, 75.5% had postoperative radiotherapy and 11.8% were treated with a chemotherapeutical regimen. Conclusion: Our retrospective analysis showed no treatment benefit for either anti-hormonal or chemotherapeutical regimens. Post-operative radiotherapy, however, improved the survival rate of patients with tubular carcinoma (log-rank=5, p=0.025). Our data suggest that post-operative radiotherapy is an important treatment to prolong survival for patients suffering from tubular breast cancer.

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 3147 Model systems which allow studying drug effects on primary tumour cells within different compartments of an individual tumour ex vivo provide a great advance for research on both response prediction and investigation of efficacy of novel treatment strategies. We recently established a tumor tissue model that allows short term culture of freshly excised breast cancer tissues. This model system allows the determination of cell viability, cell death, proliferation, and expression of surface molecules in different compartments of cancer tissues over a time period of at least 4 days (van der Kuip et al., BMC Cancer, 2006). We now expanded this system on other tumor entities such as colon carcinoma, lung carcinoma, ovary carcinoma, and lung metastasis. In total we cultivated tissue slices from 78 tumors (breast: 37; colon: 9; lung: 19; ovary: 4; lung metastasis: 9). With the exception of tissues from 2 ovaries and 2 mucinous breast carcinomas, which turned out to be too soft to cut, and tissues from 1 colon, 2 breast, and 2 ovary cancers, which were contaminated with bacteria, all tissue types were successfully cultivated: cells remained viable for at least 4 days within their tissue environment. By treating different tissue slices with different drugs/drug combinations, this model system allows a rapid assessment of drug efficacy in different tumor entities. For the identification of potential predicitive markers for treatment response, we started to investigate the influence of erlotinib in tissues from primary lung cancers and metastasis on protein expression by 2D gel electrophoresis and mass spectrometry. In lung metastases treated with 2µM erlotinib for 72 hours proliferation was significantly inhibited and initially 30 proteins were found to be changed including proliferation and tumour associated factors. In conclusion, we describe a tissue culture method which allows the assessment of drug efficacy and proteomic analysis within individual cancer tissues from different origin. This method has significant advantages for the identification of potential predictive markers for efficacy of clinically significant drugs in tissues from individual tumors.

BACKGROUND:Sensitivity of breast tumors to anticancer drugs depends upon dynamic interactions between epithelial tumor cells and their microenvironment including stromal cells and extracellular matrix. To study drug-sensitivity within different compartments of an individual tumor ex vivo, culture models directly established from fresh tumor tissues are absolutely essential.METHODS:We prepared 0.2 mm thick tissue slices from freshly excised tumor samples and cultivated them individually in the presence or absence of taxol for 4 days. To visualize viability, cell death, and expression of surface molecules in different compartments of non-fixed primary breast cancer tissues we established a method based on confocal imaging using mitochondria- and DNA-selective dyes and fluorescent-conjugated antibodies. Proliferation and apoptosis was assessed by immunohistochemistry in sections from paraffin-embedded slices. Overall viability was also analyzed in homogenized tissue slices by a combined ATP/DNA quantification assay.RESULTS:We obtained a mean of 49 tissue slices from 22 breast cancer specimens allowing a wide range of experiments in each individual tumor. In our culture system, cells remained viable and proliferated for at least 4 days within their tissue environment. Viability of tissue slices decreased significantly in the presence of taxol in a dose-dependent manner. A three-color fluorescence viability assay enabled a rapid and authentic estimation of cell viability in the different tumor compartments within non-fixed tissue slices.CONCLUSION:We describe a tissue culture method combined with a novel read out system for both tissue cultivation and rapid assessment of drug efficacy together with the simultaneous identification of different cell types within non-fixed breast cancer tissues. This method has potential significance for studying tumor responses to anticancer drugs in the complex environment of a primary cancer tissue.

c-erbB2 (also known as HER-2/neu) and topoisomerase IIα are frequently overexpressed in breast cancer. The aim of the study was to analyze retrospectively whether the expression of c-erbB2 and topoisomerase IIα protein influences the long-term outcome of patients with primary breast cancer.