Influence of CYP2D6-genotype on tamoxifen efficacy in advanced breast cancer.

The influence of CYP2D6 genotype on the efficacy of tamoxifen (Tam) has been extensively analyzed in early breast cancer with conflicting results. However, there is only scarce data regarding this potential influence in advanced breast cancer (ABC). We hypothesize that Tam is more effective in patients with a functional CYP2D6 allele than in patients with impaired CYP2D6 activity. ABC patients with prior or ongoing palliative Tam treatment (20 mg/d) were eligible. Genomic DNA was extracted from blood (n = 51) and formalin-fixed, paraffin-embedded tissue (n = 43). CYP2D6*2, *3, *4, *5, *6, *10, *17, *29, *41, CYP2D6 duplication and multiplication were determined in blood and CYP2D6*4 in tissue samples. Primary endpoint was progression free survival (PFS); secondary endpoints included clinical benefit (CB), and overall survival (OS). The clinical charts were retrospectively analyzed regarding survival and treatment effects. Genotyping was performed blinded and clinical data were analyzed separately. 94 patients were identified with a median age of 59 years (29-90 years). In 6 patients genotyping did not show conclusive results, therefore these patients were excluded from further analysis. Genotyping results were as follows: 1.1 % ultrarapid, 84.1 % extensive, 3.4 % intermediate, and 11.4 % poor metabolizers. Patients without any fully functional allele (IM/IM, IM/PM, PM/PM) had a significant shorter PFS and OS compared to patients with at least one functional allele (EM/EM, EM/IM, EM/PM) (PFS: p = 0.017; HR = 2.19; 95 % CI 1.15-4.18; OS: p = 0.028; HR = 2.79; 95 % CI 1.12-6.99). The CB rate was 73 % for EM-group and 38.5 % for IM + PM-group (p = 0.019). Our results show a significant influence of the CYP2D6 genotype on the efficacy of Tam in the treatment of ABC. In contrast to the adjuvant setting, the evidence in the palliative setting is congruent. CYP2D6 testing in ABC should be considered.

Treatment of primary breast cancer at the surgical unit of the Charité 1984-1998.

BACKGROUND: We have analyzed the patient population of one clinic (Charité) over a period of 15 years. Besides the changes in the technical facilities and therapeutical guidelines during these years, this period also reflects the changes in the health system attributable to the reunification of East and West Germany. Until now only few analyses for breast cancer patients from the German speaking area have been reported. PATIENTS AND METHODS: All 2,062 patients undergoing surgical treatment for breast cancer between 1984 and 1998 were documented and followed up until 2007. The analysis included 1,560 patients with a primary breast cancer who fulfilled certain inclusion criteria. The treatment strategies applied to this population are presented in 3 time periods (1984-1990, 1991-1993, and 1994-1998). The effects of prognostic factors on overall survival were investigated using univariate analyses. RESULTS: The percentage of pT1 tumors changed from 50.7% in the first period to 63.1% in the third period. The percentage of node-negative patients hardly changed with time (on average 61.6%). However, the percentage of patients with less than 10 assessed nodes decreased from 48.4% to 6.7% and 2.5% for the 3 periods, respectively. Therapeutic strategies changed drastically. Survival rate increased substantially, most likely due to improved therapeutic strategies, but also for other reasons not considered in the analysis.

A phase II trial to assess efficacy and safety of afatinib in extensively pretreated patients with HER2-negative metastatic breast cancer.

Afatinib (BIBW 2992) is an ErbB-family blocker that irreversibly inhibits signaling from all relevant ErbB-family dimers. Afatinib has demonstrated preclinical activity in human epidermal growth factor receptor HER2 (ErbB2)-positive and triple-negative xenograft models of breast cancer, and clinical activity in phase I studies. This was a multicenter phase II study enrolling patients with HER2-negative metastatic breast cancer progressing following no more than three lines of chemotherapy. No prior epidermal growth factor receptor-targeted therapy was allowed. Patients received 50-mg afatinib once daily until disease progression. Tumor assessment was performed at every other 28-day treatment course. The primary endpoint was clinical benefit (CB) for ≥4 treatment courses in triple-negative (Cohort A) metastatic breast cancer (TNBC) and objective responses measured by Response Evaluation Criteria in Solid Tumors in patients with HER2-negative, estrogen receptor-positive, and/or progesterone receptor-positive breast cancer (Cohort B). Fifty patients received treatment, including 29 patients in Cohort A and 21 patients in Cohort B. No objective responses were observed in either cohort. Median progression-free survival was 7.4 and 7.7 weeks in Cohorts A and B, respectively. Three patients with TNBC had stable disease for ≥4 treatment courses, one of them for 12 courses (median 26.3 weeks; range 18.9-47.9 weeks). The most frequently observed afatinib-associated adverse events (AEs) were gastrointestinal and skin-related side effects, which were manageable by symptomatic treatment and dose reductions. Afatinib pharmacokinetics were comparable to those observed in previously reported phase I trials. In conclusion, afatinib had limited activity in HER2-negative breast cancer. AEs were generally manageable and mainly affected the skin and the gastrointestinal tract.

Effect of the tyrosine kinase inhibitor lapatinib on CUB-domain containing protein (CDCP1)-mediated breast cancer cell survival and migration.

The surface receptor CUB domain-containing protein 1 (CDCP1) is highly expressed in several adenocarcinomas and speculated to participate in anchorage-independent cell survival and cell motility. Tyrosine kinase phosphorylation seems to be crucial for intracellular signaling of CDCP1. Lapatinib, a tyrosine kinase inhibitor (TKI), is approved for treatment of HER-2/neu overexpressing metastatic breast cancer and functions by preventing autophosphorylation following HER-2/neu receptor activation. This study aimed to investigate the effect of CDCP1 expression on anchorage-independent growth and cell motility of breast cancer cells. Moreover, studies were performed to examine if lapatinib provided any beneficial effect on HER-2/neu((+)/-)/CDCP1(+) breast cancer cell lines. In our studies, we affirmed that CDCP1 prevents cells from undergoing apoptosis when cultured in the absence of cell-substratum anchorage and that migratory and invasive properties of these cells were decreased when CDCP1 was down-regulated. However, only HER-2/neu(+), but not HER-2/neu((+)/-) cells showed decreased proliferation and invasion and an enhanced level of apoptosis towards loss of anchorage when treated with lapatinib. Therefore, we conclude that CDCP1 might be involved in regulating adhesion and motility of breast cancer cells but that lapatinib has no effect on tyrosine kinases regulating CDCP1. Nonetheless, other TKIs might offer therapeutic approaches for CDCP1-targeted breast cancer therapy and should be studied considering this aspect.

Primary tumor excision in stage IV breast cancer at diagnosis without influence on survival: a retrospective analysis and review of the literature.

BACKGROUND: Patients with synchronous metastastic breast cancer and intact primary tumor traditionally undergo systemic treatment. Surgical intervention at the primary site is typically reserved for palliation and often replaceable by radiation. Nevertheless, local surgery in metastatic breast cancer has become an issue of great controversy since retrospective studies published during the recent years suggested a slight benefit from an operative procedure. We evaluated the effect of surgery on long-term survival and progression-free survival in synchronous stage IV breast cancer. METHODS: We retrospectively reviewed the records of all breast cancer patients treated at our institution between 1986 and 2007. Information recorded for each patient included age, tumor characteristics, metastasis characteristics, therapy, progression-free survival, and overall survival. Survival data were compared between surgical and nonsurgical patients. RESULTS: 61 patients with synchronous metastastic breast cancer and intact primary tumor were analyzed. 26 patients (43%) received no primary site surgery and 35 (57%) patients had surgery. Overall survival and progression-free survival determined via the Kaplan-Meier method showed no significant difference between the surgery and the non-surgery group. CONCLUSION: In patients with metastatic breast cancer, the operation of the primary tumor did not influence overall survival or progression-free survival.

5FU continuous infusion in heavily pretreated advanced breast cancer patients.

BACKGROUND: Despite advances in the first- and secondline treatment of advanced breast cancer, optimal therapy thereafter remains controversial. Treatment of heavily pretreated patients is not standardized, often of low efficacy, and limited by comorbidity. In these patients, an effective treatment with low toxicity is needed. PATIENTS AND METHODS: We retrospectively analyzed all metastatic breast cancer patients treated with 5-fluorouracil as continuous infusion (CI-5FU) with daily doses of 150-300 mg/m(2). RESULTS: 43 patients were treated with CI-5FU until disease progression. The median number of metastatic sites was 3. Most patients were heavily pretreated with a median of 3 palliative chemotherapies (range 1-11). 42 patients were evaluable for objective response; among them 5 (12%) showed a partial response (PR) and 6 (15%) showed stable disease (SD) lasting at least 6 months, leading to a clinical benefit (CB) rate (complete response + PR + SD ≥ 6 months) of 27%. The median time to progression of patients with CB was 10 months (range 3-22). Overall survival of all patients from the start of CI-5FU was 8 months (range 1-75) and from the time of first metastases 42 months (range 9-281). Toxicity was low even in patients with hepatic insufficiency. CONCLUSION: CI-5FU showed a positive efficacy/toxicity ratio. Taking into account the high number of previous treatments, it results in a remarkable CB rate of 27%.

Cost-effectiveness analysis of anastrozole versus tamoxifen in adjuvant therapy for early-stage breast cancer - a health-economic analysis based on the 100-month analysis of the ATAC trial and the German health system.

BACKGROUND: In the 'Arimidex', Tamoxifen Alone or in Combination (ATAC) trial, the aromatase inhibitor (AI) anastrozole had a significantly better efficacy and safety profile than tamoxifen as initial adjuvant therapy for hormone receptor-positive (HR+) early breast cancer (EBC) in postmenopausal patients. To compare the combined long-term clinical and economic benefits, we carried out a cost-effectiveness analysis (CEA) of anastrozole versus tamoxifen based on the data of the 100month analysis of the ATAC trial from the perspective of the German public health insurance. PATIENTS AND METHODS: A Markov model with a 25-year time horizon was developed using the 100-month analysis of the ATAC trial as well as data obtained from published literature and expert opinion. RESULTS: Adjuvant treatment of EBC with anastrozole achieved an additional 0.32 quality-adjusted life-years (QALYs) gained per patient compared with tamoxifen, at an additional cost of D 6819 per patient. Thus, the incremental cost effectiveness of anastrozole versus tamoxifen at 25 years was D 21,069 ($30,717) per QALY gained. CONCLUSIONS: This is the first CEA of an AI that is based on extended follow-up data, taking into account the carryover effect of anastrozole, which maintains the efficacy benefits beyond therapy completion after 5 years. Adjuvant treatment with anastrozole for postmenopausal women with HR+ EBC is a cost-effective alternative to tamoxifen.

Therapeutic implication of BAL in patients with neutropenia.

Bronchoalveolar lavage (BAL) is a practicable procedure establishing the etiology of pneumonia. In patients with neutropenia, empirical antimicrobial treatment is mandatory immediately after diagnosis of infection, usually before results of BAL are available. We evaluated the impact of BAL on treatment and outcome of pneumonia in immunocompromised patients with a special regard to neutropenia. Bronchoscopy with BAL was performed in 58 episodes of clinical documented pneumonia in patients with hematological malignancies (88%) or solid tumors (12%), in 30 cases patients had neutropenia, in 28 cases patients had no neutropenia. In 93% of cases, BAL was performed under empirical antimicrobial treatment. BAL fluid was cultivated for bacteria, fungi, and tested for Pneumocystis jirovecii and cytomegalovirus (CMV). BAL revealed positive bacterial results in 67% of cases. Gram-positive microorganisms were detected in 95% of positive BAL results, gram-negative microorganisms in 23%, mixed bacterial cultures occurred in 41%. Positive fungi cultures were found in 59%. P. jirovecii was detected in 5% of cases tested and CMV in 8%. There was no significant difference between neutropenic and non-neutropenic patients. BAL results directed a change of therapy in only six of 58 episodes (5%). Overall mortality related to pneumonia was 16%. In this patient setting, the yield of BAL rarely has a significant influence on treatment and outcome of pneumonia. The early beginning of antimicrobial treatment reduces the diagnostic yield of BAL. In patients with pneumonia during neutropenia, its use should be well considered.

ACT-FASTER, a Prospective Cohort Study Exploring Treatment Patterns with Fulvestrant and Exemestane in Postmenopausal Patients with Advanced Hormone Receptor-Positive Breast Cancer under Real-Life Conditions in Germany.

BACKGROUND: Endocrine therapy is recommended for the treatment of postmenopausal women with hormone receptor-positive (HR+) advanced breast cancer (ABC). METHODS: ACT-FASTER was a German prospective non-interventional cohort study in postmenopausal women with HR+ ABC receiving fulvestrant 500 mg as first line (1 L), second line (2 L) or third line (3 L), or exemestane (any line) in the real-world palliative setting. Primary study objectives included the effectiveness of fulvestrant according to line of palliative treatment measured by time to progression (TTP), and real-life data on the epidemiology and management of these patients. RESULTS: Of 498 evaluable patients (mean age 67.5 years), 99% were estrogen receptor-positive. On study, 86.7% of patients received fulvestrant 500 mg and 13.3% exemestane. Median TTP was 9.7 months in patients receiving fulvestrant 1 L; 6.8 months for 2 L; and 6.7 months for 3 L. The comparison between fulvestrant 1 L palliative treatment and 2 L or 3 L showed that early initiation of treatment prolonged TTP (hazard ratio 1.26; 95% confidence interval 1.08-1.48). Treatments were well tolerated. CONCLUSION: Fulvestrant 500 mg was administered successfully to patients under daily practice conditions, and both medications were well tolerated. TTP was longest in patients treated with fulvestrant 500 mg 1 L compared with 2 L and 3 L in the palliative care setting.

Anti-tumor effect of honokiol alone and in combination with other anti-cancer agents in breast cancer.

Honokiol, an active component isolated and purified from Chinese traditional herb magnolia, was demonstrated to inhibit growth and induce apoptosis of different cancer cell lines such as human leukaemia, colon, and lung cancer cell lines; to attenuate the angiogenic activities of human endothelial cells in vitro; and to efficiently suppress the growth of angiosarcoma in nude mice. In this study, we have demonstrated that treatment of different human breast cancer cell lines with honokiol resulted in a time- and concentration-dependent growth inhibition in both estrogen receptor-positive and -negative breast cancer cell lines, as well as in drug-resistant breast cancer cell lines such as adriamycin-resistant and tamoxifen-resistant cell lines. The inhibition of growth was associated with a G1-phase cell cycle arrest and induction of caspase-dependent apoptosis. The effects of honokiol might be reversely related to the expression level of human epidermal growth receptor 2, (HER-2, also known as erbB2, c-erbB2) since knockdown of her-2 expression by siRNA significantly enhanced the sensitivity of the her-2 over-expressed BT-474 cells to the honokiol-induced apoptosis. Furthermore, inhibition of HER-2 signalling by specific human epidermal growth receptor 1/HER-2 (EGFR/HER-2) kinase inhibitor lapatinib synergistically enhanced the anti-cancer effects of honokiol in her-2 over-expressed breast cancer cells. Finally, we showed that honokiol was able to attenuate the PI3K/Akt/mTOR (Phosphoinositide 3-kinases/Akt/mammalian target of rapamycin) signalling by down-regulation of Akt phosphorylation and upregulation of PTEN (Phosphatase and Tensin homolog deleted on chromosome Ten) expression. Combination of honokiol with the mTOR inhibitor rapamycin presented synergistic effects on induction of apoptosis of breast cancer cells. In conclusion, honokiol, either alone or in combination with other therapeutics, could serve as a new, promising approach for breast cancer treatment.

Prescription pattern of aromatase inhibitors for the adjuvant therapy of breast cancer in Germany - results of the second survey among gynaecologists and medical oncologists.

INTRODUCTION: In sequence to our first survey in 2004 on antihormonal therapy with aromatase inhibitors (AIs), we conducted a second survey on the prescription practice in 2005. MATERIAL AND METHODS: We distributed the anonymous questionnaires amongst the participants of the 2005 congresses of the German Society of Senology and German Society of Haematology and Oncology. RESULTS: The surveys were mostly completed by gynaecologists (46%) and medical oncologists (46%). According to the responses given, over 31,000 breast cancer patients were treated in these institutions in 2004, over 18,000 of whom received AIs. 37/30% of doctors prescribed AIs for national/private health insurance patients depending on the known risks of tamoxifen treatment (> 50% of cases). Whilst only 6/10% of doctors prescribed AIs for more than 50% of patients with either national/private health insurance in 2004, this figure reached 49% in 2005, independent of the type of medical insurance. Assuming unrestricted approval, 68/65% of doctors would treat over 50% of their patients with an AI. CONCLUSION: The rate of treatment with AIs has increased dramatically. The previous gold standard, tamoxifen, was by and large replaced by AIs in 2004/2005. We may assume that almost all receptor- positive breast cancer patients will receive an AI in the course of their adjuvant therapy in the very near future.

Tumor Cell-selective Synergism of TRAIL- and ATRA-induced Cytotoxicity in Breast Cancer Cells.

BACKGROUND/AIM: One of the major problems in breast cancer treatment is pharmacoresistance. Therefore, exploration of treatment alternatives is of clinical relevance. The present work focused on tumor cell-inhibiting effects of a combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and all trans retinoic acid (ATRA) in breast cancer cells. MATERIALS AND METHODS: Breast cancer cell lines (BT-20, BT-474, MDA-MB-231, MDA-MB-436, MDA-MB-453, MCF-7, SKBR3, T47D, ZR-75-1) and the mammary epithelial cell line MCF-10A were treated with TRAIL and ATRA alone and in combination. Cell viability was assessed via 3-(4,5)-dimethylthiahiazo(-z-yl)-3,5-di-phenytetrazoliumromide (MTT) assay, the potential of cell colony formation via clonogenic assay, cell death induction via cell-cycle analysis by fluorescence-activated cell sorting (FACS), terminal deoxynucleotidyltransferase-mediated UTP nick end labeling (TUNEL) assay and Cell death detection ELISAPLUS, expression of apoptosis and TRAIL pathway proteins via western blot and cell surface expression of TRAIL receptor 1 (DR4) via FACS analysis. RESULTS: TRAIL and ATRA evoked synergistic inhibition of breast cancer cell viability based on cytostatic and cytotoxic mechanisms. This correlated with augmented fragmentation of nuclear DNA, up-regulation of TRAIL receptor, down-regulation of cyclin D1 and enhancement of caspase activity. MCF-10A cells were merely slightly susceptible to TRAIL and ATRA. CONCLUSION: The cytostatic and cytotoxic effects of the combination of TRAIL and ATRA are tumor cell-selective.

The effect of induced hyperthermia on the immune system.

Therapeutical hyperthermia has been considered for cancer therapy since William Coley observed tumour remission after induction of fever by bacterial toxins at the end of the 19th century. Because fever is associated with a variety of immunological reactions, it has been suspected, that therapeutical hyperthermia might also activate the immune system in a reproducible manner and thereby positively influence the course of the disease. During the last decade, new insight has been gained regarding the immunological changes taking place during therapeutic hyperthermia. In this chapter, we review the most relevant data known about the effect of hyperthermia on the immune system with special focus on alterations induced by therapeutical whole-body hyperthermia (WBH) in cancer patients.

Up-front tandem high-dose chemotherapy compared with standard chemotherapy with doxorubicin and paclitaxel in metastatic breast cancer: results of a randomized trial.

PURPOSE: The role of high-dose chemotherapy (HDCT) in metastatic breast cancer remains controversial. Trials with late intensification HDCT have failed to show an advantage in overall survival. This study was initiated to compare up-front tandem HDCT and standard combination therapy in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients without prior chemotherapy for metastatic disease were randomly assigned to standard combination therapy with doxorubicin and paclitaxel (AT) or double HDCT with cyclophosphamide, mitoxantrone, and etoposide followed by peripheral-blood stem-cell transplantation. HDCT was repeated after 6 weeks. Patients were stratified by menopausal and hormone-receptor status. The primary objective was to compare complete response (CR) rates. RESULTS: A total of 93 patients were enrolled onto the trial. Intent-to-treat CR rates for patients randomized to HDCT and AT were 12.5% and 11.1%, respectively (P = .84). Objective response rates were 66.7% for patients in the high-dose group and 64.4% for patients in the AT arm (P = .82). In an intent-to-treat analysis, there were no significant differences between the two treatments in median time to progression (HDCT, 11.1 months; AT, 10.6 months; P = .67), duration of response (HDCT, 13.9 months; AT, 14.3 months; P = .98), and overall survival (HDCT, 26.9 months; AT, 23.4 months; P = .60). HDCT was associated with significantly more myelosuppression, infection, diarrhea, stomatitis, and nausea and vomiting, whereas patients treated with AT developed more neurotoxicity. CONCLUSION: This trial failed to show a benefit for up-front tandem HDCT compared with standard combination therapy. HDCT was associated with more acute adverse effects.

Pretreatment of BMSCs with TZD solution decreases the proliferation rate of MCF­7 cells by reducing FGF4 protein expression.

The present study aimed to investigate the effects of bone marrow­derived mesenchymal stem cells (BMSCs) that had been pretreated with pioglitazone and/or rosiglitazone on the growth and proliferation rate of MCF­7 cells. The adhesive interaction between the BMSCs and the MCF­7 cancer cells revealed that the pretreatment of BMSCs with a combination of two types of thiazolidinedione drug reduced the growth and proliferation rate of the MCF­7 cells. The proliferation rate of the MCF­7 cells could also be reduced by the non­adhesive interaction of the cancer cells with BMSCs pretreated with pioglitazone and/or rosiglitazone. The growth and proliferation rate reduction effects on the MCF­7 cells may be attributed to the reduction in the protein level of fibroblast growth factor 4 (FGF4) in the conditioned medium of the pretreated BMSCs. The evidence that the low protein level of FGF4 in the conditioned medium of the pretreated BMSCs perturbed the proliferation rate of the MCF­7 cells by reducing the levels of Ki­67 and proliferating cell nuclear antigen transcripts in the cancer cells was also demonstrated in the present study using a FGF4­neutralizing antibody. All the above findings demonstrate that future studies on the correlation between FGF4 and pretreated BMSCs would be beneficial.

Variations in the 5-hydroxytryptamine type 3B receptor gene as predictors of the efficacy of antiemetic treatment in cancer patients.

PURPOSE: Serotonin (5-hydroxytryptamine type 3 [5-HT3]) receptor antagonists have substantially reduced but not eliminated nausea and vomiting in patients undergoing cancer chemotherapy. They act through specific binding to the 5-HT3A, 5-HT3B receptor complex. The 5-HT3B subunit seems to be most important for its functionality. We hypothesized that patients with genetic variations in the 5-HT3B receptor gene might respond differently to antiemetic treatment. PATIENTS AND METHODS: We included 242 cancer patients on their first day of chemotherapy. Nausea and vomiting were documented before and twice during the chemotherapy using standardized interviews and visual analog scales. We sequenced the entire 5-HT3B receptor gene, including the 5' flanking region and at least a 20-base pair intronic sequence of each intron-exon splice site of all patients. RESULTS: Approximately 30% of all patients suffered from nausea or vomiting. Sequencing of the 5-HT3B receptor gene revealed 13 polymorphisms: two of them were amino acid exchanges (Tyr129Ser, Ala223Thr) and two were deletion variants. In both observation periods, patients homozygous for the -100_-102delAAG deletion variant of the promotor region experienced vomiting more frequently than did all the other patients. CONCLUSION: A more efficient antiemetic treatment with 5-HT3 receptor antagonists might be possible on a pharmacogenetic basis. However, only a small fraction of the therapeutic failure is explained by the -AAG deletion variant of the 5-HT3B receptor gene. Additional clinical and biochemical studies are needed to confirm the association.

Patient-tailored antiemetic treatment with 5-hydroxytryptamine type 3 receptor antagonists according to cytochrome P-450 2D6 genotypes.

PURPOSE: The use of serotonin 5-hydroxytryptamine type 3 receptor antagonists has substantially reduced, but not eliminated, nausea and vomiting in cancer chemotherapy. This study sought to investigate whether efficacy of antiemetic treatment with ondansetron and tropisetron depends on cytochrome P-450 2D6 (CYP2D6) genotype, hypothesizing that the rapid and particularly the ultrarapid metabolizers of these drugs are at risk of being undertreated. PATIENTS AND METHODS: Included in the study were 270 cancer patients receiving their first day of chemotherapy. Nausea and vomiting were documented using standardized interviews. The intensity of nausea was measured with visual analog scales before and twice during the chemotherapy. The relationship between the CYP2D6 genotypes and the tropisetron serum concentrations 3 and 6 hours after drug administration was analyzed in a subgroup of 42 patients. CYP2D6 genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Genetically defined poor metabolizers had higher serum concentrations of tropisetron than all other patients (P <.03). Approximately 30% of all patients receiving chemotherapy experienced nausea and vomiting. Genetically defined ultrarapid meta-bolizers of CYP2D6 substrates had higher frequency of vomiting within the first 4 hours (P <.001) and within the period 5 to 24 hours (P <.03) after treatment than all the other patients; the tendency for nausea was similar. This difference was more pronounced in patients treated with tropisetron than in those treated with ondansetron. CONCLUSION: Antiemetic treatment with tropisetron or ondansetron could be improved by adjustment for the CYP2D6 genotype; approximately 50 subjects would have to be genotyped to protect one patient from severe emesis.

Gemcitabine as prolonged infusion and vinorelbine in anthracycline and/or taxane pretreated metastatic breast cancer: a phase II study.

BACKGROUND: Gemcitabine and vinorelbine are active agents for the treatment of metastatic breast cancer. Prolonged infusion of gemcitabine can result in higher levels of active metabolites compared to shorter administration. This phase II trial was initiated to evaluate the efficacy and tolerability of gemcitabine as prolonged infusion in combination with vinorelbine in anthracycline and/or taxane pretreated patients with metastatic breast cancer. PATIENTS AND METHODS: Patients who had received one prior line of chemotherapy for metastatic disease were treated with gemcitabine (350 mg/m2 as 4 h infusion) and vinorelbine (25 mg/m2 on days 1 and 8. Treatment was repeated every 3 weeks for a maximum of six cycles. RESULTS: Of 26 patients enrolled, 84% had received prior anthracycline treatment and 50% prior taxane therapy. In total, one complete and six partial responses were achieved, accounting for an overall response rate of 30.4%. The clinical benefit rate was 47.8%. Median duration of response and median time to progression were 7.3 months and 4.6 months, respectively. Median overall survival was 14.5 months. Although the predominant toxicity was myelosuppression with grade 3/4 neutropenia in 42% of patients, few neutropenic complications resulted. Non-hematological toxicity was generally moderate. Most common non-hematologic toxicities were nausea, vomiting, alopecia, peripheral neuropathy and elevation of liver enzymes. CONCLUSION: Gemcitabine as prolonged infusion and vinorelbine are a safe and effective combination treatment in anthracycline and/or taxane pretreated patients. Approximately 47.8% of patients derived clinical benefit from treatment. This regimen represents a therapeutic option for patients receiving second-line therapy for metastatic breast cancer.

Serum levels of carboxy-terminal telopeptide of type-I collagen are elevated in patients with multiple myeloma showing skeletal manifestations in magnetic resonance imaging but lacking lytic bone lesions in conventional radiography.

PURPOSE: Skeletal involvement is a hallmark of multiple myeloma. Increased bone resorption can even be present in patients lacking osteolyses in conventional radiography. Magnetic resonance imaging (MRI) of the spine was established as a more sensitive technique to depict bone abnormalities. Type-I collagen degradation product carboxyterminal telopeptide of type-I collagen (ICTP) was introduced as a novel biochemical parameter reflecting the bone resorption activity in myeloma. The aim of this study was to evaluate whether increased ICTP serum levels predict abnormal MRI patterns in myeloma patients. EXPERIMENTAL DESIGN: MRI of the spine was performed in 32 untreated patients with multiple myeloma, who had no skeletal abnormalities in conventional radiographies. Simultaneously, ICTP was measured in serum by a competitive radioimmunoassay at corresponding time points. RESULTS: Serum ICTP was significantly (P = 0.002) elevated in patients with abnormal bone MRI compared with those patients with normal MRI findings. The sensitivity of ICTP for depiction of MRI abnormalities was 79%; the positive and negative predictive values were 85 and 84%, respectively. Compared with ICTP, the parameters of disease activity, beta2-microglobulin and C-reactive protein, had a much lower sensitivity for abnormal MRI (29 and 64%, respectively). CONCLUSIONS: In myeloma patients without osteolytic lesions in conventional radiography, abnormal skeletal MRI is accompanied by an increase in serum levels of ICTP. Our data show that ICTP can be used as an inexpensive parameter to identify myeloma patients with normal skeletal survey who have a high probability of skeletal involvement and deserve more accurate diagnostic evaluation using MRI.

Expression of receptor activator of nuclear factor kappaB ligand on bone marrow plasma cells correlates with osteolytic bone disease in patients with multiple myeloma.

PURPOSE: Increased bone resorption is a hallmark of multiple myeloma and is attributable to osteoclast activation. Recent studies showed that the receptor activator of nuclear factor kappaB ligand (RANKL) is the key mediator of osteoclastogenesis and plays a crucial role in bone destruction in malignant bone disease. We found that human myeloma cells express RANKL and analyzed the association of the RANKL expression with the presence of osteolytic bone disease in patients with multiple myeloma. EXPERIMENTAL DESIGN: Flow cytometry was performed on bone marrow samples derived from controls and multiple myeloma patients with or without osteolytic bone lesions on conventional radiography. Plasma cells were identified as CD38++/CD138+ cells. The level of RANKL expression on the surface of bone marrow plasma cells was correlated with the bone status of the patients. RESULTS: The bone marrow plasma cells from controls showed no or only a weak surface expression of RANKL, and the median mean fluorescence index (MFI) was 6. In contrast, expression of RANKL could be detected on bone marrow plasma cells from all of the patients with multiple myeloma, and median MFI was 47. The difference in MFI for RANKL expression of bone marrow plasma cells from controls and myeloma patients was highly significant (P < 0.0005). Myeloma patients with osteolytic bone lesions showed a significantly higher expression of RANKL (median MFI = 60; range, 16-2494) compared with patients without osteolysis (median MFI = 16; range, 6-229; P < 0.0005). CONCLUSIONS: These results show for the first time that the level of RANKL expression by myeloma cells correlates significantly with osteolytic bone disease.