Sorafenib in combination with docetaxel as first-line therapy for HER2-negative metastatic breast cancer: Final results of the randomized, double-blind, placebo-controlled phase II MADONNA study.

BACKGROUND: This multicenter, double-blind phase II study assessed the antitumor activity and toxicity profile of docetaxel with the antiangiogenic multikinase inhibitor sorafenib or matching placebo as a first-line treatment in patients with metastatic or locally advanced HER2-negative breast cancer. PATIENTS AND METHODS: Patients were randomized 1:1 to receive docetaxel 100 mg/m2 on day 1 every 3 weeks in combination with sorafenib 400 mg bid or placebo on days 2-18 of each cycle until tumor progression, or unacceptable toxicity. Sorafenib/placebo could be continued at the investigator's discretion if docetaxel was stopped due to toxicity. Primary endpoint was progression free survival (PFS). RESULTS: From October 2008 to December 2013, 102 patients were randomized; 98 patients were evaluable. The trial was prematurely terminated due to slow accrual. Due to increased toxicity the dose of docetaxel was reduced to 75 mg/m2 and an increasing sorafenib dosing schedule was implemented as part of a protocol amendment. The addition of sorafenib to docetaxel did not improve PFS (8.2 vs. 7.3 months for docetaxel/placebo; HR 0.84, log rank p = 0.43), but led to higher rates of early treatment discontinuation. There were no statistically significant differences between sorafenib dosing schedules. CONCLUSIONS: Addition of sorafenib to taxane-based first-line chemotherapy in patients with metastatic breast cancer failed to improve PFS and resulted in increased toxicity.

Dose tailoring of adjuvant chemotherapy for breast cancer based on hematologic toxicities: further results from the prospective PANTHER study with focus on obese patients.

Background: Adjuvant chemotherapy (ACT) for breast cancer improves relapse-free survival (BCRFS) and overall survival. Differences in terms of efficacy and toxicity could partly be explained by the significant interpatient variability in pharmacokinetics which cannot be captured by dosing according to body surface area. Consequently, tailored dosing was prospectively evaluated in the PANTHER trial. Patients and methods: PANTHER is a multicenter, open-label, randomized phase III trial which compared tailored, dose-dense (DD) epirubicin/cyclophosphamide (E/C) and tailored docetaxel (D) (tDD) with standard interval 5-fluorouracil/E/C and D. The primary end point was BCRFS and the primary efficacy analysis has been previously published. In this secondary analysis, we aimed to retrospectively explore the concept of dose tailoring. Our two hypotheses were that BCRFS would not vary depending on the cumulative administered epirubicin dose; and that dose tailoring would lead to appropriate dosing and improved outcomes for obese patients, who are known to have worse prognosis and increased toxicity after DD ACT. Results: Patients treated with tDD had similar BCRFS regardless of the cumulative epirubicin dose (P = 0.495), while obese patients in this group [body mass index (BMI) ≥30] had improved BCRFS compared with nonobese ones (BMI <30) [hazard ratio (HR) = 0.51, 95% confidence interval (CI) 0.30-0.89, P = 0.02]. Moreover, tDD was associated with improved BCRFS compared with standard treatment only in obese patients (HR = 0.49, 95% CI 0.26-0.90, P = 0.022) but not in nonobese ones (HR = 0.79, 95% CI 0.60-1.04, P = 0.089). The differences were not formally statistically significant (P for interaction 0.175). There were no differences in terms of toxicity across the epirubicin dose levels or the BMI groups. Conclusions: Dose tailoring is a feasible strategy that can potentially improve outcomes in obese patients without increasing toxicity and should be pursued in further clinical studies. ClinicalTrials.gov identifier: NCT00798070.

Safety and efficacy outcomes with erythropoiesis-stimulating agents in patients with breast cancer: a meta-analysis.

BACKGROUND: New data on erythropoiesis-stimulating agents (ESAs) regarding overall survival and disease progression-related outcomes in patients with breast cancer receiving chemotherapy are presented in a meta-analysis of controlled trials of ESA use (epoetin α, epoetin ß, darbepoetin α, biosimilars). PATIENTS AND METHODS: A literature search identified reports from January 1997 through March 2014. We used company databases for Amgen, Inc., or Janssen studies and published data for other studies. Random-effects odds ratios (ORs) were calculated to compare results for patients randomized to ESA with those randomized to control. RESULTS: Deaths were reported for 571 of 2346 patients (24%) in the ESA groups and 523 of 2367 patients (22%) in the control groups [OR, 1.20; 95% confidence interval (CI) 1.03-1.40]. Sensitivity analyses were conducted to explore the effects of individual studies and exclusion of one study (BEST) resulted in an OR for death of 1.12 (95% CI 0.94-1.34). In seven studies reporting progression-related end points (N = 4197; ESA n = 2088; control n = 2109), the OR was 1.01 (95% CI 0.87-1.16) for ESA compared with control. CONCLUSIONS: After incorporating recent results of ESA use in patients with breast cancer, risks of survival and progression-free survival remain consistent with previously published data.

Chemotherapy versus hormonal treatment in platinum- and paclitaxel-refractory ovarian cancer: a randomised trial of the German Arbeitsgemeinschaft Gynaekologische Onkologie (AGO) Study Group Ovarian Cancer.

BACKGROUND: The majority of patients with ovarian cancer are not cured by first-line treatment. Until now, no study could demonstrate any substantial benefit when exposing ovarian cancer patients to second-line chemotherapy. However, most treatment regimens induce toxicity, thus negatively influencing the quality of rather limited life spans. Here we evaluate whether a second-line chemotherapy can offer any benefit compared with a less toxic hormonal treatment. PATIENTS AND METHODS: Patients with ovarian cancer progressing during platinum-paclitaxel containing first-line therapy or experiencing relapse within 6 months were eligible. Patients were stratified for response to primary treatment (progression versus no change/response), and measurable versus non-measurable disease. Treatment consisted of either treosulfan 7 g/m5 infused over 30 min or leuprorelin 3.75 mg injected subcutaneously or intramuscularly. Both regimens were repeated every 4 weeks. RESULTS: This study began in late 1996, and after 2.5 years accrual an interim analysis was performed when several investigators reported their concern about a suspected lack of efficacy. Following this analysis the recruitment was stopped early and the 78 patients already enrolled were followed up. The majority of patients received treatment until progressive disease was diagnosed or death occurred. Treatment delay was observed rarely and dose reduction was performed only in the treosulfan arm in 5% of 150 courses. Overall, both treatment arms were well tolerated. No objective responses were observed. The median survival time was 36 and 30 weeks in the treosulfan and leuprorelin arms, respectively. Overall survival did not differ between patients with relapse 3-6 months after first-line chemotherapy compared with patients with progressive disease within 3 months. CONCLUSIONS: The selected patient population represents a subgroup with extremely poor prognosis. Accordingly, results were not impressive. Both treatment arms showed favourable toxicity data, but failed to show remarkable activity, thus adding only limited evidence to the issue of whether patients with refractory ovarian cancer might benefit from second-line chemotherapy. Even stratified analysis did not identify any subgroup of patients in whom the administration of second-line chemotherapy could demonstrate a clinically relevant survival benefit.

Second-line carboplatin and gemcitabine in platinum sensitive ovarian cancer--a dose-finding study by the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) Ovarian Cancer Study Group.

BACKGROUND: Despite the progress that has been achieved in the last years, recurrence rates in ovarian cancer patients are still considerably high and the majority of patients ultimately become candidates for second-line treatment. Carboplatin reinduction is a broadly adopted regimen in patients with recurrences occurring six months or later after first-line treatment. Gemcitabine is among the candidates as combination partner in second-line regimens. PATIENTS AND METHODS: We performed a study with escalating doses of gemcitabine combined with carboplatin in 26 platinum-pretreated patients with recurrent ovarian cancer and a treatment-free interval of 6+ months. Dose-limiting toxicity (DLT) and a maximum tolerable dose (MTD) recommendable for further trials was evaluated. RESULTS: The DLT was myelosuppression, mainly thrombocytopenia. No dose limiting non-hematological toxicities were observed. The MTD of gemcitabine was 1,000 mg/m2 given on days 1 + 8 of a three-week schedule combined with carboplatin AUC 4 given on day 1. The majority of evaluable patients showed an objective response (62.5%), and median progression-free and overall survival were 10 and 18+ months, respectively. CONCLUSION: Gemcitabine-carboplatin given according to the MTD is well tolerated and active against recurrent platinum-sensitive disease. A randomized trial comparing carboplatin with or without gemcitabine in platinum-sensitive ovarian cancer has already been initiated.

Modulation of soluble CD44 concentrations by hormone and anti-hormone treatment in gynecological tumor cell lines.

Serum levels of CD44 (sCD44) are increased in a variety of human diseases including gynecological malignancies showing hormone-dependent growth and proliferation. Very little is known about the mechanisms underlying the processing of soluble CD44 and influencing its release. Due to their major impact on gene transcription and cell proliferation steroid hormones or their antagonists might influence sCD44 processing. We investigated the effects of different hormonal conditions on overall soluble CD44 (sCD44std) concentrations in a subset of gynecological tumor cell lines. Established human breast and endometrium cancer cell lines were characterized for their membrane-bound CD44 protein, CD44 mRNA expression and steroid receptor status prior and after incubation with 17beta estradiol (E2), medroxyprogesterone acetate (MPA), 4-hydroxy-tamoxifen (4-OH-Tam) and the gonadotropin releasing hormone (GnRH) agonist busereline. An enzyme linked immuno-sorbent assay (ELISA) using a monoclonal antibody directed against an epitope common to all CD44 isoforms was used to determine sCD44 levels in the supernatants of the tested cell lines. Interestingly, a strong correlation between sCD44 levels and the receptor status of the cells was seen. However, membrane-bound CD44 expression was not influenced by the hormonal environment. Our results indicate that distinct steroid hormones can specifically influence concentrations of soluble CD44. How this effect is involved in the tumorigenesis of gynecological malignancies and whether it might contribute to the biological behavior of special tumors should be investigated in further studies.

Adenoviral transduction efficiency of ovarian cancer cells can be limited by loss of integrin beta3 subunit expression and increased by reconstitution of integrin alphavbeta3.

Recombinant adenoviruses expressing a therapeutic gene are currently used in clinical studies for treatment of advanced ovarian cancer. We therefore tested whether the expression level of primary (CAR) and secondary adenovirus receptors (integrins) was predictive of the efficacy of adenoviral gene transfer in ovarian cancer cells. Adenoviral transduction efficiency (ATE) was determined with an E1-deleted adenovirus type 5 expressing beta-galactosidase under a CMV promoter (AdGal). ATE was studied in relationship to the expression level of both CAR (coxsackie and adenovirus receptor) and integrins. A representative sample of 25 permanent human cell lines established from advanced ovarian cancer in our laboratory and the OV-2774 cell line were tested. Overall, ATE increased with increasing titers of AdGal. At a given titer of 50 infectious units per cell, transduction efficiency varied from 6 to 94% among the individual cell lines. All cell lines expressed CAR and integrin alpha(v)beta(5), but no relation between ATE and expression level of CAR or alpha(v)beta(5) integrin was observed. In contrast, cell lines with poor ATE, despite expressing high levels of CAR, lacked expression of integrins alpha(v)beta(3) and alpha(5)beta(1). Reconstitution of alpha(v)beta(3) integrin by reexpressing the beta(3) subunit significantly enhanced ATE of ovarian cancer cells. In ovarian cancer, neither integrins nor CAR alone appear to be potentially useful predictive markers for ATE by serotype 5 adenovirus in clinical gene therapy. A minimum level of CAR necessary for binding of adenoviruses was observed in all tested ovarian cancer cell lines. Loss of alpha(v)beta(3) integrin is frequently associated with advanced stages of ovarian cancer and can significantly reduce ATE.

Antitumor activity of new organometallic compounds in human ovarian cancer cell lines and comparison to platin derivatives.

Cisplatin, Carboplatin and new compounds such as Paclitaxel and Docetaxel are effective drugs in the treatment of ovarian cancer. Multidrug resistance however remains an issue in ovarian cancer. The search for new effective drugs will remain of the highest priority in the field of cancer research. The in vitro and in vivo growth inhibiting potencies of two new metallocene dichlorides, Titanocendichloride and Vanadocendichloride, were compared to Cisplatin and Carboplatin using 20 permanent human ovarian cancer cell lines. Under in vivo and in vitro conditions Cisplatin was more effective than Carboplatin. Under in vitro conditions a Vanadocendichloride concentration of as low as 1.5 x 10(-7) mol/l resulted in a 50% decrease in the cell proliferation. Titanocendichloride inhibited cellular growth only at concentrations of 10(-4) mol/l. In contrast, Titanocendichloride was more effective in inhibiting growth of xenotransplanted ovarian cancer cell lines in nude mice. The clinically supposed equipotentiality of Carboplatin should be handled cautiously. The new organometallic substances clearly exhibit antiproliferative properties in ovarian cancer cells and are considered for clinical phase I trials.

Multiplex PCR screening detects small p53 deletions and insertions in human ovarian cancer cell lines.

Mutations at the p53 tumor suppressor gene locus are a frequent genetic alteration associated with human ovarian carcinoma. Little information exists regarding whether mutational events occur other than point mutations and large deletions, causing loss of heterozygosity. Small intragenic deletions and insertions in the p53 gene have been observed in various human neoplasias. We developed a multiplex polymerase chain reaction (MPCR) screening assay to amplify the complete p53 coding region from genomic DNA in a single step. Deletions and/or insertions were found in six out of 11 newly established ovarian carcinoma cell lines. MPCR detected deletions as small as 2 bp, as confirmed by nucleotide sequence analysis. Most of the observed alterations (6/7) were homozygous or hemizygous. Structural aberrations of the p53 gene possibly leading to loss of p53 cell cycle control may be a consequence of a slipped-mispairing mechanism in rapid DNA replication during repetitious ovulation and wound repair of ovarian epithelial cells. MPCR may be a valuable tool for screening for possible p53 deletion and insertion mutations not only in ovarian cancer but also in other malignancies.

Chicken ovalbumin upstream promoter transcription factor (COUP-TF): an orphan steroid receptor with a specific pattern of differential expression in human ovarian cancer cell lines.

The possible role of a novel steroid receptor in ovarian malignancy was investigated. The evolutionarily conserved orphan steroid receptor COUP-TF (chicken ovalbumin upstream promoter transcription factor) was originally identified as a protein interacting with an upstream promoter element of the chicken ovalbumin gene. The human receptor protein was purified from a cervical cancer cell line. An immunocytochemical technique for the visualization of COUP-TF was developed using a specific polyclonal rabbit antibody. Four established ovarian cancer cell lines were evaluated. The patterns of COUP-TF expression were compared to the staining intensities of immunocytochemical assays for estrogen receptor (ER), androgen receptor (AR), aromatase, and HER2/neu. A comparison of the ovarian cancer cell lines showed differential expression of COUP-TF in the nucleus. The pattern of COUP-TF expression did not follow the profile of any of the other four variables. In agreement with transfection experiments showing reduction of activity of other steroid receptors by elevated COUP-TF levels, high COUP-TF expression correlated with low ER activity also in native ovarian cancer cells. These data represent the first reported evidence that COUP-TF-like proteins may play a role in the metabolism and possibly in the process of dedifferentiation of human ovarian cancer.