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Sacituzumab Govitecan (also known by the brand name TRODELVY®) is a new and available treatment for metastatic triple-negative breast cancer, or mTNBC for short. Metastatic breast cancer means the breast cancer has spread to other parts of the body. Triple negative means the breast cancer does not have 3 common proteins on the cell surface called receptors. This is a summary of the ASCENT study, published in the New England Journal of Medicine in April 2021. This study compared Sacituzumab Govitecan with standard chemotherapy. Chemotherapy is a treatment that kills cancer cells or stops them from dividing. 529 people with mTNBC took part in the study across 7 countries. All who took part had already received 2 previous chemotherapies, which stopped working for their cancer. The study showed that patients who took Sacituzumab Govitecan lived longer than those who took a different chemotherapy while on the study. Tumors shrank in more patients who took Sacituzumab Govitecan than in patients who took chemotherapy. In general, patients who took Sacituzumab Govitecan experienced more side effects. This included low levels of a type of white blood cell known as neutrophils (neutropenia) and loose or watery stool (diarrhea). Use of supportive care lessened these side effects. This summary also includes insights and perspectives from 2 breast cancer patient advocates. ClinicalTrials.gov NCT number: NCT02574455. To read the full Plain Language Summary of this article, click on the View Article button above and download the PDF.Link to original article here. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer ( TNBC) accounts for 10-20% of all breast cancers ( BCs), and conventional chemotherapy is the only effective systemic treatment. Germline BRCA1/2 mutations are found in approximately 15% of TNBC patients. In the past, we have documented pathogenic mutations in BARD1, a BRCA1 interacting protein, in families at high risk for BC. In this study, we have analyzed germline DNA from 61 estrogen receptor negative patients (of which 42 were TNBC) for the presence of mutations in the BRCA1, BRCA2 and BARD1 gene. BRCA1/2 mutations were found in 8 out of 42 (19%) TNBC patients, but not in the ER−/ HER2+ cohort. We also found four good candidate pathogenic BARD1 mutations in the TNBC cohort, including two protein-truncating mutations (p. Gln564Ter and p. Arg641Ter). Our data suggest that TNBC patients are enriched for pathogenic BARD1 germline mutations as compared to control samples and high BC risk families. Ten of the 42 investigated TNBC patients carry a BRCA pathway mutation (in BRCA1, BRCA2 or BARD1) rendering them susceptible to homologous recombination deficiency. These patients should become eligible for exploring the efficacy of poly ( ADP-ribose) polymerase ( PARP) inhibitors. [ABSTRACT FROM AUTHOR]

Metastatic breast cancer is one of the leading causes of cancer-related mortality among women in the Western world. To date most research efforts have focused on the molecular analysis of the primary tumour to dissect the genotypes of the disease. However, accumulating evidence supports a molecular evolution of breast cancer during its life cycle, with metastatic lesions acquiring new molecular aberrations. Recognising this critical gap of knowledge, the Breast International Group is launching AURORA, a large, multinational, collaborative metastatic breast cancer molecular screening programme. Approximately 1300 patients with metastatic breast cancer who have received no more than one line of systemic treatment for advanced disease will, after giving informed consent, donate archived primary tumour tissue, as well as will donate tissue collected prospectively from the biopsy of metastatic lesions and blood. Both tumour tissue types, together with a blood sample, will then be subjected to next generation sequencing for a panel of cancer-related genes. The patients will be treated at the discretion of their treating physicians per standard local practice, and they will be followed for clinical outcome for 10 years. Alternatively, depending on the molecular profiles found, patients will be directed to innovative clinical trials assessing molecularly targeted agents. Samples of outlier patients considered as 'exceptional responders' or as 'rapid progressors' based on the clinical follow-up will be subjected to deeper molecular characterisation in order to identify new prognostic and predictive biomarkers. AURORA, through its innovative design, will shed light onto some of the unknown areas of metastatic breast cancer, helping to improve the clinical outcome of breast cancer patients. [ABSTRACT FROM AUTHOR]

The HER2/neu oncogene encodes a receptor-like tyrosine kinase whose overexpression in breast cancer predicts poor prognosis and resistance to conventional therapies. However, the mechanisms underlying aggressiveness of HER2 (human epidermal growth factor receptor 2)-overexpressing tumors remain incompletely understood. Because it assists epidermal growth factor (EGF) and neuregulin receptors, we overexpressed HER2 in MCF10A mammary cells and applied growth factors. HER2-overexpressing cells grown in extracellular matrix formed filled spheroids, which protruded outgrowths upon growth factor stimulation. Our transcriptome analyses imply a two-hit model for invasive growth: HER2-induced proliferation and evasion from anoikis generate filled structures, which are morphologically and transcriptionally analogous to preinvasive patients' lesions. In the second hit, EGF escalates signaling and transcriptional responses leading to invasive growth. Consistent with clinical relevance, a gene expression signature based on the HER2/EGF-activated transcriptional program can predict poorer prognosis of a subgroup of HER2-overexpressing patients. In conclusion, the integration of a three-dimensional cellular model and clinical data attributes progression of HER2-overexpressing lesions to EGF-like growth factors acting in the context of the tumor's microenvironment. [ABSTRACT FROM AUTHOR]

Environ 70 à 80 % des cancers mammaires expriment des récepteurs aux estrogènes (RO). L’hormonothérapie est le pilier du traitement des cancers du sein RO+. Depuis son utilisation, le traitement endocrinien a bouleversé le devenir du cancer du sein RO+ avec une amélioration importante de la survie sans récidive et de la survie globale. Néanmoins, le bénéfice de l’hormonothérapie se heurte au développement de la résistance. Des données expérimentales concluent que la résistance au traitement hormonal serait due, au moins en partie, à l’activation de différentes voies de transduction du signal de la prolifération cellulaire. Cela a incité un nombre d’essais cliniques de phases II/III évaluant les différentes approches d’utilisation des inhibiteurs de transduction du signal (ITS) en combinaison avec un traitement hormonal. Ces essais ont testé la faisabilité et le bénéfice de cette combinaison à retarder ou à prévenir l’hormonorésistance et font l’objet de cette revue. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of bortezomib plus docetaxel in patients with anthracycline-pretreated advanced/metastatic breast cancer. Forty-eight patients received up to eight 21-day cycles of docetaxel (60-100 mg m(-2) on day 1) plus bortezomib (1.0-1.5 mg m(-2) on days 1, 4, 8, and 11). Pharmacodynamic and pharmacokinetic analyses were performed in a subset of patients. Five patients experienced DLTs: grade 3 bone pain (n=1) and febrile neutropenia (n=4). The MTD was bortezomib 1.5 mg m(-2) plus docetaxel 75 mg m(-2). All 48 patients were assessable for safety and efficacy. The most common adverse events were diarrhoea, nausea, alopecia, asthenia, and vomiting. The most common grade 3/4 toxicities were neutropenia (44%), and febrile neutropenia and diarrhoea (each 19%). Overall patient response rate was 29%. Median time to progression was 5.4 months. In patients with confirmed response, median time to response was 1.3 months and median duration of response was 3.2 months. At the MTD, response rate was 38%. Pharmacokinetic characteristics of bortezomib/docetaxel were comparable with single-agent data. Addition of docetaxel appeared not to affect bortezomib inhibition of 20S proteasome activity. Mean alpha-1 acid glycoprotein concentrations increased from baseline at nearly all time points across different bortezomib dose levels. Bortezomib plus docetaxel is an active combination for anthracycline-pretreated advanced/metastatic breast cancer. The safety profile is manageable and consistent with the side effects of the individual agents. [ABSTRACT FROM AUTHOR]

BAY 43-9006 is a novel dual-action Raf kinase and vascular endothelial growth factor receptor (VEGFR) inhibitor that targets tumour cell proliferation and tumour angiogenesis. This Phase I study was undertaken to determine the safety profile, maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics, and tumour response profile of oral BAY 43-9006 in patients with advanced, refractory solid tumours. BAY 43-9006 was administered daily for repeated cycles of 21 days on/7 days off. A total of 44 patients were enrolled at doses from 50 to 800?mg b.i.d. Pharmacokinetic profiles of BAY 43-9006 in plasma were determined during the first treatment cycle. The most frequently reported adverse events over multiple cycles were gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%), or hepatic (61%) related. A MTD of 400?mg b.i.d. BAY 43-9006 was defined. BAY 43-9006 was absorbed rapidly; steady-state conditions were reached within 7 days. BAY 43-9006 exposure increased nonproportionally with increasing dose. In all, 32 patients were evaluated for tumour response: 15 patients showed tumour progression, 16 patients experienced stable disease (>6 months in eight patients), and one patient with renal cell carcinoma achieved a partial response. BAY 43-9006 given for 21 days with 7 days off treatment was safe, well tolerated, and showed antitumour activity.British Journal of Cancer (2005) 92, 1855-1861. doi:10.1038/sj.bjc.6602584 www.bjcancer.com Published online 3 May 2005 [ABSTRACT FROM AUTHOR]

In the present article, an extensive review of the current knowledge regarding predictive molecular markers in breast cancer is presented. The main emphasis has been given to the adjuvant therapy setting, because of the lack of well-designed studies evaluating predictive markers in the metastatic setting. In the first part of the article some general concepts have been summarized, mainly to emphasize the difference between prognostic and predictive markers. In the second part of the article, studies evaluating molecular markers with predictive value for the most commonly used drugs or regimens (i.e., cyclophosphamide, methotrexate, 5-fluorouracil [CMF], anthracyclines, taxanes, and herceptin) have been reviewed and discussed. An attempt has been made to provide for each single predictive marker the currently available level of evidence, to allow the reader to have immediate information regarding the impact of the evaluated marker in daily clinical practice. In the last part of the article, the most important findings have been summarized and future avenues of research have been outlined. [ABSTRACT FROM AUTHOR]

Objective: To assess the economic impact of two polychemotherapy regimens for patients with advanced ovarian cancer from the perspective of the Belgian health insurance and financing system.Design: An economic evaluation was integrated in an intergroup randomised controlled trial (EORTC 55931) in which patients were randomised to receive the new treatment of paclitaxel and cisplatin or the standard therapy of cyclophosphamide and cisplatin. Data on the use of medical resources were collected prospectively for the 231 European Organization for Research and Treatment of Cancer (EORTC) patients in the trial and costs were valued by using unit prices. The outcome for the economic evaluation was mean survival time as determined by the so-called restricted means method, with the time point of restriction fixed by statistical criteria. A correction of censoring of the cost data collected in the trial was also performed.Main Outcome Measures and Results: The paclitaxel and cisplatin group experienced a statistically significant improvement in mean survival time of 4 months, which was associated with an increase in the average total cost per patient of 6795 euros (EUR; 1998 values), when costs were assessed over the same period as the gain in mean survival time. This corresponds to a point estimate of the incremental cost-effectiveness ratio of EUR20 385 per life-year gained. The impact of uncertainty was assessed by using a bias-corrected and accelerated bootstrap method with 5000 resamples, and the final results of the analysis are expressed in terms of a cost-effectiveness acceptability curve.Conclusions: The present economic evaluation has shown that the substitution of paclitaxel for cyclophosphamide in the chemotherapy regimen for women with advanced ovarian cancer leads to a significant improvement in patient survival, which is associated with an increase in costs for the Belgian health insurance system. [ABSTRACT FROM AUTHOR]

Purpose. The association of continuous infusion 5-fluorouracil, epirubicin (50mg/m2 q 3weeks) and a platinum compound (cisplatin or carboplatin) was found to be very active in patients with either locally advanced/inflammatory (LA/I) [1, 2] or large operable (LO) breast cancer (BC) [3]. The same rate of activity in terms of response rate (RR) and response duration was observed in LA/I BC patients when cisplatin was replaced by cyclophosphamide [4]. The dose of epirubicin was either 50mg/m2 [1, 2, 3] or 60mg/m2/cycle [4]. The main objective of this study was to determine the maximum tolerated dose (MTD) of epirubicin when given in combination with fixed doses of cyclophosphamide and infusional 5-fluorouracil (CEF-infu) as neoadjuvant therapy in patients with LO or LA/I BC for a maximum of 6 cycles. Patients and methods. Eligible patients had LO or LA/I BC, a performance status 0–1, adequate organ function and were ≤65 years old. Cyclophosphamide was administered at the dose of 400mg/m2 day 1 & 8, q 4weeks and infusional 5-fluorouracil 200mg/m2/day was given day 1–28, q 4weeks. Epirubicin was escalated from 30 to 45 and to 60mg/m2 day 1&8; dose escalation was permitted if 0/3 or 1/6 patients experienced dose limiting toxicity (DLT) during the first 2 cycles of therapy. DLT for epirubicin was defined as febrile neutropenia, grade 4 neutropenia lasting for ≥7 days, grade 4 thrombocytopenia, or any non-haematological toxicity of CTC grade ≥3, excluding alopecia and plantar-palmar erythrodysesthesia (this toxicity was attributable to infusional 5-fluorouracil and was not considered a DLT of epirubicin). Results. A total of 21 patients, median age 44 years (range 29–63) have been treated. 107 courses have been delivered, with a median number of 5 cycles per patient (range 4–6). DLTs on cycles 1 and 2 on level 1, 2, 3: grade 3 (G3) mucositis occurred in 1/10 patients treated at the third dose level. An interim analysis showed that G3 PPE occurred in 5/16 pts treated with the 28-day infusional 5-FU schedule at the 3 dose levels. The protocol was subsequently amended to limit the duration of infusional 5-fluorouracil infusion from 4 to 3 weeks. No G3 PPE was detected in 5 patients treated with this new schedule. Conclusions. This study establishes that epirubicin 60mg/m2 day 1&8, cyclophosphamide 400mg/m2 day 1&8 and infusional 5-fluorouracil 200mg/m2/day day 1-21, q 4 weeks is the recommended dose level. Given the encouraging activity of this regimen (15/21 clinical responses) we have replaced infusional 5-fluorouracil by oral capecitabine in a recently activated study. [ABSTRACT FROM AUTHOR]

Background: Surgical or medical castration and antiestrogenic treatment with tamoxifen are common endocrine treatments for premenopausal women with breast cancer. However, tamoxifen therapy induces high levels of plasma estradiol, with unknown long-term effects. In this study, we investigated the effect of combining estrogen suppression with the luteinizing hormone-releasing hormone agonist buserelin and estradiol receptor blockade with tamoxifen to determine whether the high estradiol levels induced by tamoxifen could be reduced and whether the antitumor effects would be better.Methods: In a three-arm, randomized, prospective trial, from 1988 through 1995, a total of 161 premenopausal patients with advanced breast cancer were randomly assigned to treatment with buserelin, tamoxifen, or both. Patients with steroid receptor-negative tumors or with tumors of unknown receptor status who had a disease-free interval of less than 2 years were excluded. The median follow-up was 7.3 years, during which 76% of the patients died, all of breast cancer. Patient and tumor characteristics were well balanced among treatment groups. All P values are from two-sided tests.Results: Combined treatment with buserelin and tamoxifen was superior to treatment with buserelin or tamoxifen alone by objective response rate (48%, 34%, and 28% of patients who could be evaluated, respectively; P =.11 [chi(2) test]), median progression-free survival (9.7 months, 6.3 months, and 5.6 months; P =.03), and overall survival (3.7 years, 2.5 years, and 2.9 years; P =.01). Actuarial 5-year survival percentages were 34.2% (95% confidence interval [CI] = 20.4%-48.0%), 14.9% (95% CI = 3.9%-25.9%), and 18.4% (95% CI = 7.0%-29.8%), respectively. No differences in antitumor effects were observed between single-agent treatment groups. During combined treatment or treatment with buserelin alone, plasma estradiol levels were suppressed equally; in contrast, during treatment with tamoxifen alone, plasma estradiol levels increased threefold to fourfold over pretreatment levels.Conclusion: Combined treatment with buserelin and tamoxifen was more effective and resulted in longer overall survival than treatment with either drug alone. [ABSTRACT FROM AUTHOR]

Background: A randomized trial conducted by the Gynecologic Oncology Group (GOG, study #111) in the United States showed a better outcome for patients with advanced ovarian cancer on the paclitaxel-cisplatin regimen than for those on a standard cyclophosphamide-cisplatin regimen. Before considering the paclitaxel-cisplatin regimen as the new "standard," a group of European and Canadian investigators planned a confirmatory phase III trial.Methods: This intergroup trial recruited 680 patients with broader selection criteria than the GOG #111 study and administered paclitaxel as a 3-hour instead of a 24-hour infusion; progression-free survival was the primary end point. Patient survival was analyzed by use of the Kaplan-Meier technique. Treatment effects on patient survival were estimated by Cox proportional hazards regression models. All statistical tests were two-sided.Results: The overall clinical response rate was 59% in the paclitaxel group and 45% in the cyclophosphamide group; the complete clinical remission rates were 41% and 27%, respectively; both differences were statistically significant (P =.01 for both). At a median follow-up of 38.5 months and despite a high rate of crossover (48%) from the cyclophosphamide arm to the paclitaxel arm at first detection of progression of disease, a longer progression-free survival (log-rank P =.0005; median of 15.5 months versus 11.5 months) and a longer overall survival (log-rank P =. 0016; median of 35.6 months versus 25.8 months) were seen in the paclitaxel regimen compared with the cyclophosphamide regimen.Conclusions: There is strong and confirmatory evidence from two large randomized phase III trials to support paclitaxel-cisplatin as the new standard regimen for treatment of patients with advanced ovarian cancer. [ABSTRACT FROM AUTHOR]

Liarozole is an imidazole compound that inhibits enzymes involved in steroid hormone aromatisation and retinoid metabolism. The IDBBC branch of the EORTC has performed a series of phase II studies of the agent in four groups of postmenopausal women with metastatic breast cancer. This paper reports the results of the first two groups: ‘Chemotherapy Resistant’ (unrestricted ER status, 1 or 2 prior chemotherapy regimens, 0–2 prior hormonal therapies) and ‘Potentially Hormone Sensitive’ (ER positive or unknown, 1 or 2 prior hormonal therapies with a substantial disease free interval or progression free survival, and no history of chemotherapy for metastatic disease). Liarozole was administered at 150–300 mg orally bid. The objective response rate was 12% in the ‘Chemotherapy Resistant’ group ( n=34), and 22% in the ‘Potentially Hormone Sensitive’ group ( n=37), with median response durations of 9 and 14 months, respectively. Median time to treatment failure was only 2 months in both groups, due largely to the significant percentage (24%) of patients who ceased treatment following excessive mucocutaneous and gastrointestinal toxicity. This adverse event profile will limit its use in breast cancer. Results of the ‘ER negative’ and ‘Tamoxifen Refractory’ groups will be reported in a future paper. [ABSTRACT FROM AUTHOR]

We performed a phase I-II trial of escalating doses of cisplatin (CDDP: 50–100 mg/m per course) plus carboplatin (CBDCA: 300–400 mg/m per course) as a potential way in which to maximize platinum doses without causing excessive toxic effects in patients with advanced ovarian cancer. Thirty-three patients with nonoptimally debulked disease of FIGO (International Federation of Gynecology and Obstetrics) stages IIc-IV [median age: 60 yr; median WHO (World Health Organization) performance status: 2; no prior chemotherapy] received a median of six courses of therapy. CBDCA was infused on day 1 and CDDP on day 2 with an aggressive 48-hour hydration regimen. Myelosuppression was dose-limiting: at the highest dose levels, WHO grade 4 neutropenia and thrombocytopenia led to dose reduction and/or treatment delay in 45% of the patients. Nonhematologic toxic effects included acute nausea and vomiting (97% of the patients), mild alopecia (45%), ototoxic effects (39%), neurotoxic effects (21%), and renal toxic effects (serum creatinine >1.5 mg/dL: 12.5%). The pathologic complete response rate was 22%. We conclude that CBDCA and CDDP can be given safely in combination at reasonably high doses (CBDCA at 300 mg/ m per course and CDDP at 100 mg/m per course) over a 6-month period, provided a close hematologic follow-up is conducted. Randomized clinical trials are needed to define whether this regimen is any better than standard combination chemotherapy. [J Natl Cancer Inst 82:703–707,1990] [ABSTRACT FROM PUBLISHER]

We investigated the pharmacokinetic behavior of carzelesin in 31 patients receiving this drug by 10-min intravenous infusion in a Phase I clinical trial, which was conducted at institutions in Nijmegen (institution 1) and Brussels (institution 2). The dose steps were 24, 48, 96, 130, 150, 170, 210, 250, and 300 μg/m2. Carzelesin is a cyclopropylpyrroloindole prodrug that requires metabolic activation via U-76,073 to U-76,074. The lower limit of quantitation (LLQ) of the high-performance liquid chromatography (HPLC) method used in this study was 1 ng/ml for the parent drug and its metabolic products. Carzelesin was rapidly eliminated from plasma (elimination half-life 23 ± 9 min; mean value ± SD). At all dose levels, U-76,073 was found as early as in the first samples taken after the start of the infusion. However, the concentration of U-76,074 exceeded the LLQ for only short periods and only at the higher dose levels. Although the plasma levels of all three compounds were well above the respective IC50 values obtained by in vitro clonogenic assays, they were much lower than those observed in a preclinical study in mice. There was a substantial discrepancy in the mean plasma clearance␣observed between patients from institution 1 (7.9 ± 2.1 l h−1 m−2) and those from institution 2 (18.4 ± 13.6 l h−1 m−2; P = 0.038), probably reflecting problems with drug administration in the latter institution. The results recorded for patients in institution 1 indicated that the AUC increased proportionately with increasing doses. There was a good correlation between the maximal plasma concentration and the AUC, enabling future monitoring of drug exposure from one timed blood sample. Urinary excretion of carzelesin was below 1% of the delivered dose. [ABSTRACT FROM AUTHOR]

Mitomycin C (MMC)-vinblastine (VBL) is a regimen that has commonly been used as salvage therapy for advanced breast cancer for many years. The hematologic toxicity of this combination is one aspect that limits its usefulness. Amifostine, an organic thiophosphate, has been developed as a selective chemoprotective agent. In this pilot study, we tested the feasibility of MMC/VBL administration in combination with amifostine and we monitored the hematologic toxicity closely. Patients having failed one or two chemotherapy regimens for advanced breast cancer, with a good performance status scored at 2 or better and measurable or evaluable lesion(s), were eligible. They were treated according to the following schedule: mitomycin C 10 mg/m2 i.v. day 1, vinblastine 5 mg/m2 i.v. day 1 and 15, amifostine 910 mg/m2 in short i.v. infusion prior to MMC. Premedication consisted of dexamethasone 3 x 20 mg, haloperidol 2 x 0.5 mg p.o., hydration with 11 of normal saline, metoclopramide 1.5 mg/kg in short infusion and procyclide HCl 10 mg i.v. Cycles were repeated every 4 weeks. In all, 14 cycles were administrated to six heavily pretreated patients. Following the first cycle, five of the six patients experienced grade 3 or 4 neutropenia on day 15, and consequently did not receive the second vinblastine administration as planned. Three out of four patients receiving two or more cycles had moderate thrombocytopenia. There were no patients with neutropenic fever or major bleeding problems. The MMC/VBL+amifostine regimen was well tolerated regarding other toxicities. Neither amifostine-related acute vomiting nor any significant decrease in blood pressure was observed. Administration of amifostine in combination with MMC/VBL was feasible but in this group of heavily pretreated patients there were no hints of a protective effect of amifostine on the hematologic toxicity profile of this chemotherapy regimen. [ABSTRACT FROM AUTHOR]

In an ongoing phase II trial conducted in advanced breast cancer, we tested a therapy schedule consisting of continuous, 24-h infusion of 5 g/m ifosfamide (IFO) in 3 l dextrose saline with mesna (MSN), repeated every 3 weeks until disease progression. Since September 1988, 16 heavily pretreated patients with advanced disease (11 with visceral lesions) considered refractory to standard chemotherapy (regimens always including cyclophosphamide) have been included. Objective partial remissions were observed in two cases (one in liver and one in soft-tissue and pleural lesions), and disease stabilization for at least 3 months occurred in four cases. No treatment-related death was recorded and tolerance was judged to be excellent (six cases) or acceptable in all instances. The haematological toxicity consisted mainly of transient leucopenia (nadirs evaluated by WHO scale as grade 3 in 43% and grade 4 in 29%), sometimes associated with thrombocytopenia (grade 3 in 7% and grade 4 in 7%). Other side effects included nausea and/or vomiting (grade 3-4 in 33%); worsening of preexisting alopecia (five cases); haemorrhagic cystitis (one case); mild, transient somnolence (two cases); and moderate fluid retention (two cases). We concluded that infusion of 5 g/m IFO over 24 h with MSN rescue might represent an acceptable second-or third-line salvage regimen. Close monitoring of haematological and renal function parameters is recommended. A larger number of patients will be treated in a continuation of this study to evaluate the true response rate within narrower confidence limits. [ABSTRACT FROM AUTHOR]

Background: The proto-oncogene Src is an important non-receptor protein tyrosine kinase involved in signaling pathways that control cell adhesion, growth, migration and differentiation. It negatively regulates osteoblast activity, and, as such, its inhibition is a potential means to prevent bone loss. Dasatinib is a new dual Src/Bcr-Abl tyrosine kinase inhibitor initially developed for the treatment of chronic myeloid leukemia. It has also shown promising results in preclinical studies in various solid tumors. However, its effects on the differentiation of human osteoblasts have never been examined.Methods: We evaluated the effects of dasatinib on bone marrow-derived mesenchymal stromal cells (MSC) differentiation into osteoblasts, in the presence or absence of a mixture of dexamethasone, ascorbic acid and beta-glycerophosphate (DAG) for up to 21 days. The differentiation kinetics was assessed by evaluating mineralization of the extracellular matrix, alkaline phosphatase (ALP) activity, and expression of osteoblastic markers (receptor activator of nuclear factor kappa B ligand [RANKL], bone sialoprotein [BSP], osteopontin [OPN]).Results: Dasatinib significantly increased the activity of ALP and the level of calcium deposition in MSC cultured with DAG after, respectively, 7 and 14 days; it upregulated the expression of BSP and OPN genes independently of DAG; and it markedly downregulated the expression of RANKL gene and protein (decrease in RANKL/OPG ratio), the key factor that stimulates osteoclast differentiation and activity.Conclusions: Our results suggest a dual role for dasatinib in both (i) stimulating osteoblast differentiation leading to a direct increase in bone formation, and (ii) downregulating RANKL synthesis by osteoblasts leading to an indirect inhibition of osteoclastogenesis. Thus, dasatinib is a potentially interesting candidate drug for the treatment of osteolysis through its dual effect on bone metabolism. [ABSTRACT FROM AUTHOR]