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A Randomized Phase II Neoadjuvant Study of Cisplatin, Paclitaxel With or Without Everolimus in Patients with Stage II/III Triple-Negative Breast Cancer (TNBC): Responses and Long-term Outcome Correlated with Increased Frequency of DNA Damage Response Gene Mutations, TNBC Subtype, AR Status, and Ki67.
Jovanović B, Mayer IA, Mayer EL, Abramson VG, Bardia A, Sanders ME, Kuba MG, Estrada MV, Beeler JS, Shaver TM, Johnson KC, Sanchez V, Rosenbluth JM, Dillon PM, Forero-Torres A, Chang JC, Meszoely IM, Grau AM, Lehmann BD, Shyr Y, Sheng Q, Chen SC, Arteaga CL, Pietenpol JA
(2017) Clin Cancer Res 23: 4035-4045
MeSH Terms: Adult, Cisplatin, DNA Damage, Drug-Related Side Effects and Adverse Reactions, Everolimus, Female, High-Throughput Nucleotide Sequencing, Humans, Ki-67 Antigen, Lymphocytes, Tumor-Infiltrating, Middle Aged, Mutation, Neoplasm Staging, Paclitaxel, Receptors, Androgen, Treatment Outcome, Triple Negative Breast Neoplasms
Show Abstract · Added April 9, 2017
Because of inherent disease heterogeneity, targeted therapies have eluded triple-negative breast cancer (TNBC), and biomarkers predictive of treatment response have not yet been identified. This study was designed to determine whether the mTOR inhibitor everolimus with cisplatin and paclitaxel would provide synergistic antitumor effects in TNBC. Patients with stage II/III TNBC were enrolled in a randomized phase II trial of preoperative weekly cisplatin, paclitaxel and daily everolimus or placebo for 12 weeks, until definitive surgery. Tumor specimens were obtained at baseline, cycle 1, and surgery. Primary endpoint was pathologic complete response (pCR); secondary endpoints included clinical responses, breast conservation rate, safety, and discovery of molecular features associated with outcome. Between 2009 and 2013, 145 patients were accrued; 36% of patients in the everolimus arm and 49% of patients in the placebo arm achieved pCR; in each arm, 50% of patients achieved complete responses by imaging. Higher rates of neutropenia, mucositis, and transaminase elevation were seen with everolimus. Clinical response to therapy and long-term outcome correlated with increased frequency of DNA damage response (DDR) gene mutations, Basal-like1 and Mesenchymal TNBC-subtypes, AR-negative status, and high Ki67, but not with tumor-infiltrating lymphocytes. The paclitaxel/cisplatin combination was well tolerated and active, but addition of everolimus was associated with more adverse events without improvement in pCR or clinical response. However, discoveries made from correlative studies could lead to predictive TNBC biomarkers that may impact clinical decision-making and provide new avenues for mechanistic exploration that could lead to clinical utility. .
©2017 American Association for Cancer Research.
1 Communities
2 Members
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17 MeSH Terms
mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5 induction on 4E-BP1 dephosphorylation.
He K, Zheng X, Li M, Zhang L, Yu J
(2016) Oncogene 35: 148-57
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Antineoplastic Agents, Apoptosis, Cell Line, Tumor, Colonic Neoplasms, Everolimus, Female, Humans, Mice, Nude, Phosphoproteins, Phosphorylation, Protein Kinase Inhibitors, Receptors, TNF-Related Apoptosis-Inducing Ligand, Sirolimus, TOR Serine-Threonine Kinases, Transcription Factor CHOP, Xenograft Model Antitumor Assays
Show Abstract · Added July 28, 2015
The mammalian target of rapamycin (mTOR) is commonly activated in colon cancer. mTOR complex 1 (mTORC1) is a major downstream target of the PI3K/ATK pathway and activates protein synthesis by phosphorylating key regulators of messenger RNA translation and ribosome synthesis. Rapamycin analogs Everolimus and Temsirolimus are non-ATP-competitive mTORC1 inhibitors, and suppress proliferation and tumor angiogenesis and invasion. We now show that apoptosis plays a key role in their anti-tumor activities in colon cancer cells and xenografts through the DR5, FADD and caspase-8 axis, and is strongly enhanced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and 5-fluorouracil. The induction of DR5 by rapalogs is mediated by the ER stress regulator and transcription factor CHOP, but not the tumor suppressor p53, on rapid and sustained inhibition of 4E-BP1 phosphorylation, and attenuated by eIF4E expression. ATP-competitive mTOR/PI3K inhibitors also promote DR5 induction and FADD-dependent apoptosis in colon cancer cells. These results establish activation of ER stress and the death receptor pathway as a novel anticancer mechanism of mTOR inhibitors.
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18 MeSH Terms
FDG-PET as a predictive biomarker for therapy with everolimus in metastatic renal cell cancer.
Chen JL, Appelbaum DE, Kocherginsky M, Cowey CL, Rathmell WK, McDermott DF, Stadler WM
(2013) Cancer Med 2: 545-52
MeSH Terms: Adult, Aged, Antineoplastic Agents, Biomarkers, Carcinoma, Renal Cell, Everolimus, Female, Fluorodeoxyglucose F18, Humans, Kidney Neoplasms, Male, Middle Aged, Neoplasm Metastasis, Positron-Emission Tomography, Sirolimus, Treatment Outcome, Tumor Burden
Show Abstract · Added October 17, 2015
The mTOR (mammalian target of rapamycin) inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and delays renal cell carcinoma (RCC) progression. Preclinical evidence suggests that baseline elevated tumor glucose metabolism as quantified by FDG-PET ([(18)F] fluorodeoxy-glucose positron emission tomography) may predict antitumor activity. Metastatic RCC (mRCC) patients refractory to vascular endothelial growth factor (VEGF) pathway inhibition were treated with standard dose everolimus. FDG-PET scans were obtained at baseline and 2 weeks; serial computed tomography (CT) scans were obtained at baseline and every 8 weeks. Maximum standardized uptake value (SUVmax) of the most FDG avid lesion, average SUVmax of all measured lesions and their corresponding 2-week relative changes were examined for association with 8-week change in tumor size. A total of 63 patients were enrolled; 50 were evaluable for the primary endpoint of which 48 had both PET scans. Patient characteristics included the following: 36 (72%) clear cell histology and median age 59 (range: 37-80). Median pre- and 2-week treatment average SUVmax were 6.6 (1-17.9) and 4.2 (1-13.9), respectively. Response evaluation criteria in solid tumors (RECIST)-based measurements demonstrated an average change in tumor burden of 0.2% (-32.7% to 35.9%) at 8 weeks. Relative change in average SUVmax was the best predictor of change in tumor burden (all evaluable P = 0.01; clear cell subtype P = 0.02), with modest correlation. Baseline average SUVmax was correlated with overall survival and progression-free survival (PFS) (P = 0.023; 0.020), but not with change in tumor burden. Everolimus therapy decreased SUVs on follow-up PET scans in mRCC patients, but changes were only modestly correlated with changes in tumor size. Thus, clinical use of FDG-PET-based biomarkers is challenged by high variability.
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17 MeSH Terms
Role of inhibitors of mammalian target of rapamycin in the treatment of luminal breast cancer.
Ciruelos E, Cortes-Funes H, Ghanem I, Manso L, Arteaga C
(2013) Anticancer Drugs 24: 769-80
MeSH Terms: Androstadienes, Animals, Antineoplastic Combined Chemotherapy Protocols, Aromatase Inhibitors, Biomarkers, Tumor, Breast Neoplasms, Disease-Free Survival, Everolimus, Female, Humans, Molecular Targeted Therapy, Protein Kinase Inhibitors, Signal Transduction, Sirolimus, TOR Serine-Threonine Kinases, Treatment Outcome
Show Abstract · Added March 7, 2014
Approximately 75% of patients with breast cancer present hormone receptor-positive tumors. This subtype of breast cancer initially shows a high overall response rate to hormonal treatments. However, resistance eventually develops, resulting in tumor progression. The PI3K/Akt/mTOR pathway regulates several cellular functions in cancer such as cell growth, survival, and proliferation. In addition, a high activation level of the PI3K/Akt/mTOR pathway is related to resistance to conventional chemotherapy and hormone therapy. The mTOR inhibitor everolimus, in combination with hormonal treatments, has led to excellent results in progression-free survival in patients with metastatic breast cancer resistant to hormone therapies. Therefore, everolimus has entered the National Comprehensive Cancer Network (NCCN) guidelines 2012 and its combination with exemestane was approved recently by the US Food and Drug Administration and the European Medicines Agency. This is the first time that a drug will have been approved for the restoration of hormone sensitivity in breast cancer.
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16 MeSH Terms
New therapies for tuber-less sclerosis: white matter matters?
Ess KC, Roach ES
(2012) Neurology 78: 520-1
MeSH Terms: Corpus Callosum, Diffusion Tensor Imaging, Everolimus, Female, Humans, Immunosuppressive Agents, Male, Nerve Fibers, Myelinated, Sirolimus, Tuberous Sclerosis
Added August 25, 2013
1 Communities
1 Members
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10 MeSH Terms
Integration of diffusion-weighted MRI data and a simple mathematical model to predict breast tumor cellularity during neoadjuvant chemotherapy.
Atuegwu NC, Arlinghaus LR, Li X, Welch EB, Chakravarthy BA, Gore JC, Yankeelov TE
(2011) Magn Reson Med 66: 1689-96
MeSH Terms: Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Cell Survival, Chemotherapy, Adjuvant, Cisplatin, Computer Simulation, Diffusion Magnetic Resonance Imaging, Drug Therapy, Computer-Assisted, Everolimus, Female, Humans, Image Enhancement, Image Interpretation, Computer-Assisted, Middle Aged, Models, Biological, Paclitaxel, Prognosis, Reproducibility of Results, Sensitivity and Specificity, Sirolimus, Systems Integration, Treatment Outcome
Show Abstract · Added November 13, 2013
Diffusion-weighted magnetic resonance imaging data obtained early in the course of therapy can be used to estimate tumor proliferation rates, and the estimated rates can be used to predict tumor cellularity at the conclusion of therapy. Six patients underwent diffusion-weighted magnetic resonance imaging immediately before, after one cycle, and after all cycles of neoadjuvant chemotherapy. Apparent diffusion coefficient values were calculated for each voxel and for a whole tumor region of interest. Proliferation rates were estimated using the apparent diffusion coefficient data from the first two time points and then used with the logistic model of tumor growth to predict cellularity after therapy. The predicted number of tumor cells was then correlated to the corresponding experimental data. Pearson's correlation coefficient for the region of interest analysis yielded 0.95 (P = 0.004), and, after applying a 3 × 3 mean filter to the apparent diffusion coefficient data, the voxel-by-voxel analysis yielded a Pearson correlation coefficient of 0.70 ± 0.10 (P < 0.05).
Copyright © 2011 Wiley Periodicals, Inc.
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4 Members
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24 MeSH Terms
Phase II trial of gefitinib and everolimus in advanced non-small cell lung cancer.
Price KA, Azzoli CG, Krug LM, Pietanza MC, Rizvi NA, Pao W, Kris MG, Riely GJ, Heelan RT, Arcila ME, Miller VA
(2010) J Thorac Oncol 5: 1623-9
MeSH Terms: Adenocarcinoma, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Clinical Trials, Phase I as Topic, Cohort Studies, ErbB Receptors, Everolimus, Female, Gefitinib, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Neoplasm Staging, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Quinazolines, Salvage Therapy, Sirolimus, Survival Rate, Treatment Outcome, ras Proteins
Show Abstract · Added March 24, 2014
INTRODUCTION - Concurrent signal transduction inhibition with the epidermal growth factor receptor (EGFR) inhibitor gefitinib and the mammalian target-of-rapamycin inhibitor everolimus has been hypothesized to result in enhanced antitumor activity in patients with non-small cell lung cancer (NSCLC). This phase II trial assessed the efficacy of the combination of gefitinib and everolimus in patients with advanced NSCLC.
METHODS - Two cohorts of 31 patients with measurable stage IIIB/IV NSCLC were enrolled: (1) no prior chemotherapy and (2) previously treated with cisplatin or carboplatin and docetaxel or pemetrexed. All patients received daily everolimus 5 mg and gefitinib 250 mg. Response was assessed after 1 month and then every 2 months. Pretreatment tumor specimens were collected for mutation testing.
RESULTS - Sixty-two patients were enrolled (median age: 66 years, 50% women, 98% stage IV, all current/former smokers, and 85% adenocarcinoma). Partial responses were seen in 8 of 62 patients (response rate: 13%; 95% confidence interval: 5-21%); five responders had received no prior chemotherapy. Three partial responders had an EGFR mutation. Both patients with a KRAS (G12F) mutation responded. The median time to progression was 4 months. Median overall survival was 12 months, 27 months for no prior chemotherapy patients, and 11 months for patients previously treated with chemotherapy.
CONCLUSIONS - The 13% partial response rate observed did not meet the prespecified response threshold to pursue further study of the combination of gefitinib and everolimus. The response rate in patients with non-EGFR mutant tumors was 8%, likely reflecting activity of everolimus. Further investigation of mammalian target-of-rapamycin inhibitors in patients with NSCLC with KRAS G12F-mutated tumors is warranted.
0 Communities
1 Members
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27 MeSH Terms
Prospective assessment of discontinuation and reinitiation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of everolimus.
Riely GJ, Kris MG, Zhao B, Akhurst T, Milton DT, Moore E, Tyson L, Pao W, Rizvi NA, Schwartz LH, Miller VA
(2007) Clin Cancer Res 13: 5150-5
MeSH Terms: Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Drug Resistance, Neoplasm, Erlotinib Hydrochloride, Everolimus, Female, Fluorodeoxyglucose F18, Gefitinib, Humans, Lung Neoplasms, Male, Middle Aged, Positron-Emission Tomography, Prospective Studies, Protein Kinase Inhibitors, Quinazolines, Sirolimus, Tomography, X-Ray Computed
Show Abstract · Added March 24, 2014
PURPOSE - Ten percent of U.S. patients with non-small cell lung cancer experience partial radiographic responses to erlotinib or gefitinib. Despite initial regressions, these patients develop acquired resistance to erlotinib or gefitinib. In these patients, we sought to assess changes in tumor metabolism and size after stopping and restarting erlotinib or gefitinib and to determine the effect of adding everolimus.
EXPERIMENTAL DESIGN - Patients with non-small cell lung cancer and acquired resistance to erlotinib or gefitinib were eligible. Patients had 18-fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography and computed tomography scans at baseline, 3 weeks after stopping erlotinib or gefitinib, and 3 weeks after restarting erlotinib or gefitinib. Three weeks after restarting erlotinib or gefitinib, everolimus was added to treatment.
RESULTS - Ten patients completed all four planned studies. Three weeks after stopping erlotinib or gefitinib, there was a median 18% increase in SUV(max) and 9% increase in tumor diameter. Three weeks after restarting erlotinib or gefitinib, there was a median 4% decrease in SUV(max) and 1% decrease in tumor diameter. No partial responses (0 of 10; 95% confidence interval, 0-31%) were seen with the addition of everolimus to erlotinib or gefitinib.
CONCLUSIONS - In patients who develop acquired resistance, stopping erlotinib or gefitinib results in symptomatic progression, increase in SUV(max), and increase in tumor size. Symptoms improve and SUV(max) decreases after restarting erlotinib or gefitinib, suggesting that some tumor cells remain sensitive to epidermal growth factor receptor blockade. No responses were observed with combined everolimus and erlotinib or gefitinib. We recommend a randomized trial to assess the value of continuing erlotinib or gefitinib after development of acquired resistance.
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22 MeSH Terms
Phase 1 trial of everolimus and gefitinib in patients with advanced nonsmall-cell lung cancer.
Milton DT, Riely GJ, Azzoli CG, Gomez JE, Heelan RT, Kris MG, Krug LM, Pao W, Pizzo B, Rizvi NA, Miller VA
(2007) Cancer 110: 599-605
MeSH Terms: Adenocarcinoma, Aged, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Dose-Response Relationship, Drug, Everolimus, Female, Gefitinib, Humans, Lung Neoplasms, Male, Middle Aged, Quinazolines, Sirolimus, Survival Rate, United States
Show Abstract · Added March 24, 2014
BACKGROUND - Preclinical studies have demonstrated that the inhibition of the PI3K/Akt/mTOR pathway restores gefitinib sensitivity in resistant cancer cell lines. A phase 1 study was conducted of the combination of everolimus, an mTOR inhibitor, and gefitinib to determine a daily dose of everolimus with gefitinib in patients with advanced nonsmall-cell lung cancer (NSCLC).
METHODS - Oral everolimus and gefitinib were both administered daily to patients with progressive NSCLC. Patients were enrolled in 3-patient cohorts at everolimus dose levels of 5 and 10 mg daily. All patients received gefitinib 250 mg daily.
RESULTS - Ten patients were enrolled. The maximum tolerated dose of everolimus was 5 mg when administered daily with gefitinib 250 mg. Two patients who were treated at the 10 mg dose level of everolimus experienced dose-limiting toxicity, including grade 5 hypotension and grade 3 stomatitis. Pharmacokinetic studies demonstrated no consistent, significant interaction on the t(max), C(max), and AUC(0-8h) of either agent. Two partial radiographic responses were identified among the 8 response-evaluable patients.
CONCLUSIONS - For further study, everolimus at a dose of 5 mg daily in combination with daily gefitinib 250 mg is recommended. The 2 radiographic responses identified are encouraging. A phase 2 trial in patients with NSCLC is under way.
(c) 2007 American Cancer Society.
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17 MeSH Terms