The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Howard I Scher - One of the best experts on this subject based on the ideXlab platform.
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assessment of the validity of nuclear localized androgen receptor splice variant 7 in circulating tumor cells as a predictive biomarker for castration resistant prostate cancer
JAMA Oncology, 2018Co-Authors: Howard I Scher, Ryon P Graf, Nicole A Schreiber, Anuradha Jayaram, Eric Winquist, Brigit Mclaughlin, David S K LuAbstract:IMPORTANCE A blood test to determine whether to treat patients with metastatic castration-resistant prostate cancer (mCRPC) with an androgen receptor signaling (ARS) inhibitor or taxane is an unmet medical need. OBJECTIVE To determine whether a validated assay for the nuclear-localized androgen receptor splice variant 7 (AR-V7) protein in circulating tumor cells can determine differential overall survival among patients with mCRPC treated with Taxanes vs ARS inhibitors. DESIGN, SETTING, AND PARTICIPANTS This blinded correlative study conducted from December 31, 2012, to September 1, 2016, included 142 patients with histologically confirmed mCRPC and who were treated at Memorial Sloan Kettering Cancer Center, The Royal Marsden, or the London Health Sciences Centre. Blood samples were obtained prior to administration of ARS inhibitors or Taxanes as a second-line or greater systemic therapy for progressing mCRPC. MAIN OUTCOMES AND MEASURES Overall survival after treatment with an ARS inhibitor or taxane in relation to pretherapy AR-V7 status. RESULTS Among the 142 patients in the study (mean [SD] age, 69.5 [9.6] years), 70 were designated as high risk by conventional prognostic factors. In this high-risk group, patients positive for AR-V7 who were treated with Taxanes had superior overall survival relative to those treated with ARS inhibitors (median overall survival, 14.3 vs 7.3 months; hazard ratio, 0.62; 95% CI, 0.28-1.39; P = .25). Patients negative for AR-V7 who were treated with ARS inhibitors had superior overall survival relative to those treated with Taxanes (median overall survival, 19.8 vs 12.8 months; hazard ratio, 1.67; 95% CI, 1.00-2.81; P = .05). CONCLUSIONS AND RELEVANCE This study suggests that nuclear-localized AR-V7 protein in circulating tumor cells can identify patients who may live longer with taxane chemotherapy vs ARS inhibitor treatment.
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validation of nuclear localized ar v7 on circulating tumor cells ctc as a treatment selection biomarker for managing metastatic castration resistant prostate cancer mcrpc
Journal of Clinical Oncology, 2018Co-Authors: Howard I Scher, Ryon P Graf, Nicole A Schreiber, Eric Winquist, Brigit Mclaughlin, David S K Lu, Sarah Orr, Martin Fleisher, Lori E Lowes, Amanda K L AndersonAbstract:273Background: A previous analysis of 161 patients (pts) tested for nuclear-localized AR-V7(+) CTCs showed a therapy interaction between AR-V7 positivity and improved overall survival (OS) on taxane chemotherapy vs. androgen receptor signaling inhibitors (ARSI). To validate the use of the biomarker result for physician decision making, we prospectively analyzed an independent, multicenter, blinded, cross-sectional cohort (n = 225) to confirm a therapy interaction with AR-V7. We corrected for possible pt selection bias by the treating physician by analyzing the association of therapy to OS in low and high risk groups defined by the test cohort. Methods: Two analyses were performed: (1) the validation of a therapy interaction between AR-V7 positivity and superior OS benefit for pts treated with Taxanes in the context of use for 2nd+ line pts; and (2) as the choice between ARSI or Taxanes was at the discretion of the attending physician, pt risk was incorporated into the predictive biomarker assessment. A pt...
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association of ar v7 on circulating tumor cells as a treatment specific biomarker with outcomes and survival in castration resistant prostate cancer
JAMA Oncology, 2016Co-Authors: Howard I Scher, Ryon P Graf, Nicole A Schreiber, Jessica Louw, Hebert Alberto Vargas, Ann Johnson, Adam Jendrisak, Richard Martin BamburyAbstract:Importance A critical decision in the management of metastatic castration-resistant prostate cancer (mCRPC) is when to administer an androgen receptor signaling (ARS) inhibitor or a taxane. Objective To determine if pretherapy nuclear androgen-receptor splice variant 7 (AR-V7) protein expression and localization on circulating tumor cells (CTCs) is a treatment-specific marker for response and outcomes between ARS inhibitors and Taxanes. Design, Setting, and Participants For this cross-sectional cohort study at Memorial Sloan Kettering Cancer Center, 265 men with progressive mCRPC undergoing a change in treatment were considered; 86 were excluded because they were not initiating ARS or taxane therapy; and 18 were excluded for processing time constraints, leaving 161 patients for analysis. Between December 2012 and March 2015, blood was collected and processed from patients with progressive mCRPC immediately prior to new line of systemic therapy. Patients were followed up to 3 years. Main Outcomes and Measures Prostate-specific antigen (PSA) response, time receiving therapy, radiographic progression-free survival (rPFS), and overall survival (OS). Results Overall, of 193 prospectively collected blood samples from 161 men with mCRPC, 191 were evaluable (128 pre-ARS inhibitor and 63 pretaxane). AR-V7–positive CTCs were found in 34 samples (18%), including 3% of first-line, 18% of second-line, and 31% of third- or greater line samples. Patients whose samples had AR-V7–positive CTCs before ARS inhibition had resistant posttherapy PSA changes (PTPC), shorter rPFS, shorter time on therapy, and shorter OS than those without AR-V7–positive CTCs. Overall, resistant PTPC were seen in 65 of 112 samples (58%) without detectable AR-V7–positive CTCs prior to ARS inhibition. There were statistically significant differences in OS but not in PTPC, time on therapy, or rPFS for patients with or without pretherapy AR-V7–positive CTCs treated with a taxane. A multivariable model adjusting for baseline factors associated with survival showed superior OS with Taxanes relative to ARS inhibitors when AR-V7–positive CTCs were detected pretherapy (hazard ratio, 0.24; 95% CI, 0.10-0.57; P = .035). Conclusions and Relevance The results validate CTC nuclear expression of AR-V7 protein in men with mCRPC as a treatment-specific biomarker that is associated with superior survival on taxane therapy over ARS-directed therapy in a clinical practice setting. Continued examination of this biomarker in prospective studies will further aid clinical utility.
Scott T Tagawa - One of the best experts on this subject based on the ideXlab platform.
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taxane induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer
Cancer Research, 2011Co-Authors: Medha S Darshan, Matthew S Loftus, Maria Thadanimulero, Ben P Levy, Daniel Escuin, Xi Kathy Zhou, Ada Gjyrezi, Chantal Chanelvos, Ruoqian Shen, Scott T TagawaAbstract:Prostate cancer progression requires active androgen receptor (AR) signaling which occurs following translocation of AR from the cytoplasm to the nucleus. Chemotherapy with Taxanes improves survival in patients with castrate resistant prostate cancer (CRPC). Taxanes induce microtubule stabilization, mitotic arrest, and apoptotic cell death, but recent data suggest that Taxanes can also affect AR signaling. Here, we report that Taxanes inhibit ligand-induced AR nuclear translocation and downstream transcriptional activation of AR target genes such as prostate-specific antigen. AR nuclear translocation was not inhibited in cells with acquired β-tubulin mutations that prevent taxane-induced microtubule stabilization, confirming a role for microtubules in AR trafficking. Upon ligand activation, AR associated with the minus-end-microtubule motor dynein, thereby trafficking on microtubules to translocate to the nucleus. Analysis of circulating tumor cells (CTC) isolated from the peripheral blood of CRPC patients receiving taxane chemotherapy revealed a significant correlation between AR cytoplasmic sequestration and clinical response to therapy. These results indicate that Taxanes act in CRPC patients at least in part by inhibiting AR nuclear transport and signaling. Further, they suggest that monitoring AR subcellular localization in the CTCs of CRPC patients might predict clinical responses to taxane chemotherapy.
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taxane induced blockade to nuclear accumulation of the androgen receptor predicts clinical responses in metastatic prostate cancer
Cancer Research, 2011Co-Authors: Medha S Darshan, Matthew S Loftus, Maria Thadanimulero, Ben P Levy, Daniel Escuin, Xi Kathy Zhou, Ada Gjyrezi, Chantal Chanelvos, Ruoqian Shen, Scott T TagawaAbstract:Prostate cancer progression requires active androgen receptor (AR) signaling which occurs following translocation of AR from the cytoplasm to the nucleus. Chemotherapy with Taxanes improves survival in patients with castrate resistant prostate cancer (CRPC). Taxanes induce microtubule stabilization, mitotic arrest, and apoptotic cell death, but recent data suggest that Taxanes can also affect AR signaling. Here, we report that Taxanes inhibit ligand-induced AR nuclear translocation and downstream transcriptional activation of AR target genes such as prostate-specific antigen. AR nuclear translocation was not inhibited in cells with acquired β-tubulin mutations that prevent taxane-induced microtubule stabilization, confirming a role for microtubules in AR trafficking. Upon ligand activation, AR associated with the minus-end-microtubule motor dynein, thereby trafficking on microtubules to translocate to the nucleus. Analysis of circulating tumor cells (CTC) isolated from the peripheral blood of CRPC patients receiving taxane chemotherapy revealed a significant correlation between AR cytoplasmic sequestration and clinical response to therapy. These results indicate that Taxanes act in CRPC patients at least in part by inhibiting AR nuclear transport and signaling. Further, they suggest that monitoring AR subcellular localization in the CTCs of CRPC patients might predict clinical responses to taxane chemotherapy. Cancer Res; 71(18); 6019–29. ©2011 AACR.
Richard Martin Bambury - One of the best experts on this subject based on the ideXlab platform.
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association of ar v7 on circulating tumor cells as a treatment specific biomarker with outcomes and survival in castration resistant prostate cancer
JAMA Oncology, 2016Co-Authors: Howard I Scher, Ryon P Graf, Nicole A Schreiber, Jessica Louw, Hebert Alberto Vargas, Ann Johnson, Adam Jendrisak, Richard Martin BamburyAbstract:Importance A critical decision in the management of metastatic castration-resistant prostate cancer (mCRPC) is when to administer an androgen receptor signaling (ARS) inhibitor or a taxane. Objective To determine if pretherapy nuclear androgen-receptor splice variant 7 (AR-V7) protein expression and localization on circulating tumor cells (CTCs) is a treatment-specific marker for response and outcomes between ARS inhibitors and Taxanes. Design, Setting, and Participants For this cross-sectional cohort study at Memorial Sloan Kettering Cancer Center, 265 men with progressive mCRPC undergoing a change in treatment were considered; 86 were excluded because they were not initiating ARS or taxane therapy; and 18 were excluded for processing time constraints, leaving 161 patients for analysis. Between December 2012 and March 2015, blood was collected and processed from patients with progressive mCRPC immediately prior to new line of systemic therapy. Patients were followed up to 3 years. Main Outcomes and Measures Prostate-specific antigen (PSA) response, time receiving therapy, radiographic progression-free survival (rPFS), and overall survival (OS). Results Overall, of 193 prospectively collected blood samples from 161 men with mCRPC, 191 were evaluable (128 pre-ARS inhibitor and 63 pretaxane). AR-V7–positive CTCs were found in 34 samples (18%), including 3% of first-line, 18% of second-line, and 31% of third- or greater line samples. Patients whose samples had AR-V7–positive CTCs before ARS inhibition had resistant posttherapy PSA changes (PTPC), shorter rPFS, shorter time on therapy, and shorter OS than those without AR-V7–positive CTCs. Overall, resistant PTPC were seen in 65 of 112 samples (58%) without detectable AR-V7–positive CTCs prior to ARS inhibition. There were statistically significant differences in OS but not in PTPC, time on therapy, or rPFS for patients with or without pretherapy AR-V7–positive CTCs treated with a taxane. A multivariable model adjusting for baseline factors associated with survival showed superior OS with Taxanes relative to ARS inhibitors when AR-V7–positive CTCs were detected pretherapy (hazard ratio, 0.24; 95% CI, 0.10-0.57; P = .035). Conclusions and Relevance The results validate CTC nuclear expression of AR-V7 protein in men with mCRPC as a treatment-specific biomarker that is associated with superior survival on taxane therapy over ARS-directed therapy in a clinical practice setting. Continued examination of this biomarker in prospective studies will further aid clinical utility.
Andrea Necchi - One of the best experts on this subject based on the ideXlab platform.
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the impact of adding Taxanes to gemcitabine and platinum chemotherapy for the first line therapy of advanced or metastatic urothelial cancer a systematic review and meta analysis
European Urology, 2016Co-Authors: Patrizia Giannatempo, Matthew D Galsky, Gregory R Pond, Guru Sonpavde, Daniele Raggi, Gurudatta Naik, Joaquim Bellmunt, Andrea NecchiAbstract:Abstract Context Gemcitabine/platinum chemotherapy is the most widely used first-line regimen for metastatic urothelial carcinoma, and the potential improvement of adding Taxanes needs to be clarified. Objective To study the survival impact of taxane plus gemcitabine/platinum compared with gemcitabine/platinum alone as upfront therapy. Evidence acquisition Literature was searched for studies including gemcitabine/platinum ± Taxanes (paclitaxel or docetaxel only). We pooled trial level data including the median, proportions, and confidence intervals on response-rate, progression-free survival, overall survival (OS), and side effects. Univariable and multivariable regression models evaluated the prognostic role of addition of Taxanes after adjusting for platinum type, performance status 2, and the presence of visceral metastases. Data were weighted by the logarithm of the trial sample size. Evidence synthesis Thirty-five arms of trials including 2,365 patients were selected (seven with Taxanes [ n =617], and 28 arms without Taxanes [ n =1,748]). Median OS was univariably significantly different ( p =0.019) between trials with and without Taxanes. Across trials, the median ‘median OS' amongst trials containing Taxanes was 15.5 mo, compared with 12.5 mo in trials which did not. Multivariably, visceral disease and performance status were significantly associated with OS, and the addition of Taxanes trended toward significantly better OS ( p =0.056) and increase in grade ≥ 3 neurotoxicity ( p =0.051), regardless of specific platinum agent used. Conclusions In this meta-analysis, adding Taxanes to gemcitabine and platinum showed a trend for improved OS and higher grade ≥ 3 neurotoxicity. Improvements in patient selection and the evaluation of a more potent and tolerable tubulin inhibitor in combination with gemcitabine/platinum in a well-powered trial are the critical next steps. Patient summary In this report, a trend for improved overall survival and worse neurotoxicity was observed for adding a taxane to first-line gemcitabine/platinum chemotherapy for metastatic urothelial carcinoma. More effective Taxanes should be investigated further in urothelial carcinoma in combination with gemcitabine/platinum.
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incomplete cross resistance between Taxanes for advanced urothelial carcinoma implications for clinical practice and trial design
Clinical Genitourinary Cancer, 2015Co-Authors: Guru Sonpavde, Jonathan E Rosenberg, Gregory R Pond, Joaquim Bellmunt, Andrea Necchi, Stephanie A Mullane, Giuseppe Di Lorenzo, Piera Federico, Toni K ChoueiriAbstract:Abstract Background Taxanes such as paclitaxel and docetaxel are commonly used for second- or third-line salvage systemic therapy for metastatic UC. Although trials have generally excluded previous exposure to Taxanes when using a taxane in a salvage therapy trial, Taxanes might not be completely cross-resistant. Hence, we aimed to study outcomes with docetaxel after previous paclitaxel and the reverse sequence, to identify the level of cross-resistance between these Taxanes. Patients and Methods Data from a randomized phase II trial that compared salvage therapy with docetaxel combined with either placebo or vandetanib for advanced UC were analyzed. Both arms were combined for analysis because no differences in any outcomes were observed. Data were also requested from institutions for patients who received paclitaxel after previous docetaxel treatment. Descriptive statistics were used to summarize patient and treatment characteristics and outcomes. The primary clinical end point of interest was overall survival (OS). Results Of 148 patients who received docetaxel with either vandetanib or placebo, 21 had received previous paclitaxel treatment. No difference in OS, progression-free survival, or response rate was observed with docetaxel based on previous paclitaxel treatment after adjusting for known prognostic factors. Among the 8 patients who received paclitaxel after previous docetaxel treatment, partial response was observed in 1 patient (12.5%) and stable disease in 2 patients (25%). Conclusion Docetaxel treatment after previous paclitaxel treatment and the reverse sequence demonstrates activity in advanced UC. There is no strong evidence to disallow patients with previous exposure to a taxane to enroll in a clinical trial involving another taxane.
William J Gradishar - One of the best experts on this subject based on the ideXlab platform.
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Taxanes for the treatment of metastatic breast cancer
Breast Cancer: Basic and Clinical Research, 2012Co-Authors: William J GradisharAbstract:Taxanes have remained a cornerstone of breast cancer treatment over the past three decades, improving the lives of patients with both early- and late-stage disease. The purpose of this review is to summarize the current role of Taxanes, including an albumin-bound formulation that enhances delivery of paclitaxel to tumors, in the management of metastatic breast cancer (MBC). Since the introduction of Cremophor EL-paclitaxel to the clinic in the mid-1990s, a substantial amount of investigation has gone into subjects such as formulation, dose, schedule, and taxane resistance, allowing physicians greater flexibility in treating patients with MBC. This review will also examine how the shrinking pool of taxane-naive patients, a result of the expansion of Taxanes into the neoadjuvant and adjuvant settings, will respond to taxane retreatment for metastatic disease. Taxane treatment seems likely to continue to play an important role in the treatment of MBC.
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management of advanced breast cancer with the epothilone b analog ixabepilone
Drug Design Development and Therapy, 2009Co-Authors: William J GradisharAbstract:Despite the activity of standard chemotherapies in advanced breast cancer, disease progression remains inevitable. Most patients exposed to anthracyclines and Taxanes develop resistance and a significant subset shows primary resistance. The increasing use of these agents as adjuvant therapy may result in more anthracycline- and taxane-resistant patients in the metastatic setting; few treatment options are available for patients with metastatic breast cancer (MBC) resistant to multiple chemotherapies. The heterogeneity of breast cancer represents another therapeutic challenge. Breast cancers may be classified as luminal, human epidermal growth factor 2 (HER2)-positive, or estrogen receptor-, progesterone receptor-, and human epidermal growth factor 2-negative (ER/PR/HER2-negative, triple negative). HER2-positive and ER/PR/HER2-negative tumors are associated with poor prognosis owing to aggressive disease and poor long-term response to therapy. The epothilone B analog ixabepilone has low susceptibility to multiple mechanisms of resistance and has demonstrated activity in patients with MBC resistant to anthracyclines, Taxanes, and/or capecitabine. Ixabepilone is the first epothilone to be approved, as monotherapy or in combination with capecitabine, for treatment of resistant/refractory MBC or locally advanced breast cancer. Treatment with ixabepilone is an option for patients with ER/PR/HER2-negative or HER2-positive disease and/or primary resistance to Taxanes.
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evidence based use of neoadjuvant taxane in operable and inoperable breast cancer
Clinical Cancer Research, 2004Co-Authors: Laura G Estevez, William J GradisharAbstract:Neoadjuvant chemotherapy (NC) is standard therapy for patients with locally advanced breast cancer and is increasingly used for early-stage operable disease. The aim of NC is a pathological complete response (pCR) in the breast and axillary lymph nodes, which is the best predictor of improved outcome and prolonged survival. The Taxanes docetaxel and paclitaxel are potent agents in breast cancer management, with promising single-agent activity and acceptable tolerability in the neoadjuvant setting. In this review of the Taxanes as NC for operable and inoperable breast cancer, we include all fully published Phase II-III studies enrolling ≥30 patients. Current evidence suggests that the sequential administration of taxane- and anthracycline-based therapy may be superior to concomitant administration. Indeed, until the recent Phase III Aberdeen study (n = 162), it was uncertain whether NC could prolong survival. In this study, sequential docetaxel after anthracycline-based NC significantly enhanced the clinical response rate and pathological complete response, and yielded a significant 3-year survival advantage, versus anthracycline-based NC alone. Recently, the Phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B27 trial (n = 2411) showed that sequential docetaxel after doxorubicin-cyclophosphamide significantly increased both clinical and pathological response rates for operable breast cancer, with the benefit evident in both estrogen receptor-positive and estrogen receptor-negative patients. This apparent superiority of a sequential anthracycline-taxane regimen is limited to docetaxel, with no similar Phase III trials of paclitaxel versus a non-taxane-based comparator having been conducted to date. In conclusion, current evidence supports the inclusion of a taxane in NC schedules for patients with large and locally advanced breast cancer.
