epothilone-a and Endometrial-Neoplasms

Endometrial cancer (EC) is the most common gynaecological cancer. Despite significant progress in the multimodality treatment approach, the prognosis remains poor for patients with advanced disease. Thus, there is the necessity of more effective strategies. The microtubule-stabilizing agent ixabepilone is the first drug in this new class of agents that has been approved for metastatic breast cancer treatment. Based on empiric data and on the clinical efficacy demonstrated in breast cancer, several clinical trials were proposed to define its role in EC. The aim of this review is to determine whether ixabepilone improved the clinical outcome in patients with locally advanced, recurrent or metastatic EC.. Preclinical and clinical studies of ixabepilone in endometrial cancer were analyzed and discussed. Data were obtained by searching for English peer-reviewed articles on PubMed, phase I and II studies registered on clincaltrials.gov, and related abstracts recently presented at major international congresses.. Advanced or recurrent EC still represents a challenge and an unmet need in the panorama of gynaecological malignancies. Ixabepilone's future therapeutic role in EC remains ill defined. Nevertheless, despite its limited efficacy in EC, clinicians treating gynaecological tumours should be aware of its main aspects.

Topics: Animals; Antineoplastic Agents; Endometrial Neoplasms; Epothilones; Female; Humans

Uterine serous carcinoma (USC) is a rare but aggressive subtype of endometrial cancer. Although it represents only 10% of all endometrial cancer cases, USC accounts for up to 40% of all endometrial cancer-related recurrences and subsequent deaths. With such a dismal prognosis, there is an expanding role for novel targeted approaches in the treatment of USC. Recent whole-exome sequencing studies have demonstrated gain of function of the HER2/NEU gene, as well as driver mutations in the PIK3CA/AKT/mTOR and cyclin E/FBXW7 oncogenic pathways in a large number of USCs. The results emphasize the relevance of these novel therapeutic targets for biologic therapy of USC, which will be reviewed in this article.

Topics: Antibodies, Monoclonal; Antineoplastic Agents; Class I Phosphatidylinositol 3-Kinases; Cyclin E; Cystadenocarcinoma, Serous; Endometrial Neoplasms; Epothilones; Exome; Female; Humans; Molecular Targeted Therapy; Mutation; Neoplasm Recurrence, Local; Oncogene Proteins; Prognosis; Protein Kinase Inhibitors; Protein Phosphatase 2; Radioimmunotherapy; Receptor, ErbB-2; Sequence Analysis, DNA; Signal Transduction; TOR Serine-Threonine Kinases; Tubulin Modulators; Tumor Suppressor Protein p53; Uterine Neoplasms; Vascular Endothelial Growth Factor A

While early-stage endometrial cancer is often successfully treated with surgical intervention, treatment of advanced endometrial carcinoma can be difficult and prognosis poor, particularly in the context of metastatic or recurrent disease. Standard chemotherapy agents for both adjuvant first-line treatment (for selected patients deemed at high risk of relapse) and recurrent endometrial cancer include doxorubicin, platinum agents and paclitaxel. Investigational options currently being studied in phase II trials include both combined regimens of standard chemotherapeutic agents versus radiation as well as targeted treatments such as epothilones, mammalian target of rapamycin (mTOR) inhibitors and anti-angiogenic agents. Recent interest in the molecular pathways of carcinogenesis have lead to increased investigation of these novel agents and the hope that they will impact positively on the overall survival of women with endometrial cancer.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Endometrial Neoplasms; Epothilones; Female; Humans; Randomized Controlled Trials as Topic; TOR Serine-Threonine Kinases; Tubulin Modulators

Paclitaxel and carboplatin (PC) is a standard initial therapy for advanced endometrial cancer. We evaluated the efficacy and tolerability of incorporating three novel agents into initial therapy.. In this randomized phase II trial, patients with chemotherapy-naïve stage III/IVA (with measurable disease) and stage IVB or recurrent (with or without measurable disease) endometrial cancer were randomly assigned to treatment with PC plus bevacizumab (Arm 1), PC plus temsirolimus (Arm 2) or ixabepilone and carboplatin (IC) plus bevacizumab (Arm 3). The primary endpoint was progression-free survival (PFS). Comparable patients on the PC Arm of trial GOG209 were used as historical controls. Secondary endpoints were response rate, overall survival (OS), and safety.. Overall, 349 patients were randomized. PFS duration was not significantly increased in any experimental arm compared with historical controls (p > 0.039). Treatment HRs (92% CI) for Arms 1, 2, and 3 relative to controls were 0.81 (0.63-1.02), 1.22 (0.96-1.55) and 0.87 (0.68-1.11), respectively. Response rates were similar across arms (60%, 55% and 53%, respectively). Relative to controls, OS duration (with censoring at 36 months), was significantly increased in Arm 1 (p < 0.039) but not in Arms 2 and 3; the HRs (92% CIs) were 0.71 (0.55-0.91), 0.99 (0.78-1.26), and 0.97 (0.77-1.23), respectively. No new safety signals were identified. Common mutations and rates of mismatch repair protein loss are described by histotype. Potential predictive biomarkers for temsirolimus and bevacizumab were identified.. PFS was not significantly increased in any experimental arm compared to historical controls. NRG Oncology/Gynecologic Oncology Group Study GOG-86P.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Endometrial Neoplasms; Epothilones; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Sirolimus

The purpose of this multicenter, open label, randomized phase III study was to determine whether ixabepilone resulted in improved overall survival (OS) compared with commonly used single-agent chemotherapy (doxorubicin or paclitaxel) in women with locally advanced, recurrent, or metastatic endometrial cancer with at least one failed prior platinum-based chemotherapeutic regimen.. Patients were randomized 1:1 to ixabepilone (40mg/m(2)), or either paclitaxel (175mg/m(2)) or doxorubicin (60mg/m(2)), every 21days. Patients that had previously received an anthracycline were randomized to ixabepilone or paclitaxel; all other patients were randomized to ixabepilone or doxorubicin. An interim analysis of futility for OS was planned.. At the time of database lock, 496 patients were randomized to receive ixabepilone (n=248) or control (n=248); nine patients in the control arm were not treated. The interim analysis of futility for OS (219 events) favored the control chemotherapy arm (hazard ratio=1.3 [95% confidence interval: 1.0-1.7], stratified log rank test P=0.0397), indicating that the study would not meet its primary objective. The study was discontinued based on the interim OS results. The frequency of adverse events was comparable between the treatment arms.. The study did not meet its primary objective of improving OS in the ixabepilone arm compared to the control chemotherapy arm. A favorable risk/benefit ratio was not observed for ixabepilone versus control at the time of the interim analysis. The safety results were consistent with the known safety profiles of ixabepilone and control.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Doxorubicin; Endometrial Neoplasms; Epothilones; Female; Humans; Middle Aged; Paclitaxel; Survival Rate

PURPOSE A phase II study was conducted to determine the response rate of ixabepilone (BMS-247550, National Cancer Institute (NCI)-supplied agent investigational new drug No. 59,699) in patients with persistent or recurrent endometrial cancer who have progressed despite standard therapy. PATIENTS AND METHODS Eligible patients had recurrent or persistent endometrial cancer and measurable disease. One prior chemotherapeutic regimen, which could have included either paclitaxel or docetaxel, was allowed. Patients received ixabepilone 40 mg/m(2) as a 3-hour infusion on day 1 of a 21-day cycle. Treatment was continued until disease progression or until unacceptable toxicity occurred. Results Fifty-two patients were entered on the study, and 50 of these were eligible. The median age was 64 years (range, 40 to 83 years). Prior treatment included radiation in 21 patients (42%) and hormonal therapy in eight patients (16%). All patients had prior chemotherapy, and 47 (94%) received prior paclitaxel therapy. The overall response rate was 12%; one patient achieved a complete remission (2%), and five achieved partial remission (10%). Stable disease for at least 8 weeks was noted in 30 patients (60%). The median progression-free survival (PFS) was 2.9 months, and the 6-month PFS was 20%. Major grade 3 toxicities were neutropenia (52%), leukopenia (48%), gastrointestinal (24%), neurologic (18%), constitutional (20%), infection (16%), and anemia (14%). CONCLUSION In a cohort of women with advanced or recurrent endometrial cancer who were previously treated with paclitaxel, ixabepilone showed modest activity of limited duration as a second-line agent.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Disease-Free Survival; Endometrial Neoplasms; Epothilones; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Treatment Outcome

Successfully combining targeted agents with chemotherapy is an important future goal for cancer therapy. However, an improvement in patient outcomes requires an enhanced understanding of the tumor biomarkers that predict for drug sensitivity. NRG Oncology/Gynecologic Oncology Group (GOG) Study GOG-86P was one of the first attempts to combine targeted agents (bevacizumab or temsirolimus) with chemotherapy in patients with advanced endometrial cancer. Herein we performed exploratory analyses to examine the relationship between mutations in TP53, the most commonly mutated gene in cancer, with outcomes on GOG-86P.. TP53 mutational status was determined and correlated with progression-free survival (PFS) and overall survival (OS) on GOG-86P.. Mutations in TP53 were associated with improved PFS and OS for patients that received bevacizumab as compared to temsirolimus (PFS: HR 0.48, 95% CI 0.31, 0.75; OS: HR: 0.61, 95% CI 0.38, 0.98). By contrast, there was no statistically significant difference in PFS or OS between arms for cases with WT TP53.. This exploratory study suggests that combining chemotherapy with bevacizumab, but not temsirolimus, may enhance PFS and OS for patients whose tumors harbor mutant p53. These data set the stage for larger clinical studies evaluating the potential of TP53 mutational status as a biomarker to guide choice of treatment for endometrial cancer patients. Clintrials.gov: NCT00977574.

Topics: Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carboplatin; Clinical Trials, Phase II as Topic; Endometrial Neoplasms; Epothilones; Female; Genes, p53; Humans; Mutation; Neoplasm Recurrence, Local; Neoplasm Staging; Paclitaxel; Progression-Free Survival; Randomized Controlled Trials as Topic; Sirolimus; Survival Rate; Treatment Outcome; Tumor Suppressor Protein p53