225 results on '"Niven Mehra"'
Search Results
202. Abstract 4976: Monitoring CHD1 during prostate cancer progression
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Juan M. Mosquera, Daniel Nava Rodrigues, Adam Sharp, Mark A. Rubin, Sara Aziz, Niven Mehra, Joaquin Mateo, Theresa Y. MacDonald, Veronica Gil, Christopher E. Barbieri, Ruth Riisnaes, Rossitza Christova, Mateus Crespo, Susana Miranda, Gunther Boysen, Ines Figueiredo, Pasquale Rescigno, and Johann S. de Bono
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Oncology ,Cancer Research ,medicine.medical_specialty ,biology ,medicine.diagnostic_test ,business.industry ,Cancer ,medicine.disease ,Androgen receptor ,Prostate cancer ,medicine.anatomical_structure ,Docetaxel ,Prostate ,Internal medicine ,biology.protein ,Medicine ,PTEN ,Immunohistochemistry ,business ,medicine.drug ,Fluorescence in situ hybridization - Abstract
Adenocarcinomas of the prostate consist of a collection of malignancies with distinct molecular underpinnings. Linking molecular background to clinical behaviour, i.e. tumour progression and response to therapy has not yet been fully established. This is in large measure due to a paucity of well-annotated patient cohorts, which cover the evolution from localized, hormone naïve to metastatic castration resistant prostate cancer. Deletions in the gene Chromodomain Helicase DNA Binding Protein 1 (CHD1) are among the most frequent genomic alterations in prostate cancer. CHD1 is a ATPase-dependent helicase mediating a variety of biological processes by modifying chromatin structure. In hormone sensitive prostate cancer, loss of CHD1 has been associated with increased genomic instability and aggressiveness. Here we monitor CHD1 status during the progression from hormone sensitive (HSPC) to castration resistant prostate cancer (CRPC). To molecularly stratify this patient subgroup we correlate CHD1 status with markers of prostate cancer including AR, ERG, PTEN and Ki67. Finally, we analyze the impact of alterations in CHD1 on outcome and response to therapy of CRPC patients. We retrospectively identified 52 patients of whom HSPC and CRPC tissue was available for immunohistochemical analysis of CHD1, ERG, PTEN, AR and Ki67 as well as for CHD1 fluorescence in situ hybridization. Relationship with outcome was analyzed using univariate Cox regression and log-rank analyses. By using Fluorescence In Situ Hybridization (FISH) and immunohistochemistry (IHC) in a cohort of 52 men who developed CRPC, we show that the frequency of loss of CHD1 does not change during disease progression (7.7% in HSPC vs 9.6% in CRPC). Homozygously deleted tumors demonstrate a tendency towards poorer prognosis but this observation lacks statistical power in our cohort. Interestingly, in patients that show CHD1 protein expression in their hormone naïve sample, a decrease of expression in the matched CRPC sample correlates with poorer overall survival (OS) (p = 0.03). Although preclinical data suggest a role for CHD1 in androgen receptor (AR) activity, CHD1 expression did not correlate with AR protein level. Additionally, Ki67 expression did not show correlation with CHD1 levels of expression. Further molecular stratification confirms a known mutual exclusive relationship with the expression of the ERG transcription factor (p = 0.048). Clinically, although decreased CHD1 protein expression during disease progression correlated with worse outcome (overall survival (p = 0.03) and survival from diagnosis of CRPC (p = 0.02)), no significant impact on survival after docetaxel or abiraterone treatment was measured.Here we monitor CHD1 deletion during prostate cancer progression. Our results show that this genomic marker defines a distinct molecular subgroup of prostate cancer. In addition, loss of CHD1 protein expression during disease progression is associated with poorer clinical outcome. Citation Format: Gunther Boysen, Daniel Nava Rodrigues, Joaquin Mateo, Rossitza Christova, Ruth Riisnaes, Mateus Crespo, Theresa MacDonald, Susana Miranda, Ines Figueiredo, Veronica Gil, Sara Aziz, Adam Sharp, Niven Mehra, Pasquale Rescigno, Juan M. Mosquera, Christopher E. Barbieri, Mark A. Rubin, Johann S. de Bono. Monitoring CHD1 during prostate cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4976.
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- 2016
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203. Association of plasma cell-free DNA concentration [cfDNA] with outcome from taxane therapy (TT) for castration resistant prostate cancer (CRPC)
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Stéphane Oudard, David Lorente, Gunther Boysen, Rossitza Christova, Mustapha Chadjaa, Niven Mehra, Lorna Pope, Sandrine Macé, Karim Fizazi, Oliver Sartor, Jane Goodall, Nuria Porta, Emma Hall, Johann S. de Bono, Penelope Flohr, Suzanne Carreira, Mario A. Eisenberger, and Diletta Bianchini
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Oncology ,Cancer Research ,medicine.medical_specialty ,Taxane ,business.industry ,030232 urology & nephrology ,Plasma cell ,Castration resistant ,urologic and male genital diseases ,medicine.disease ,Free dna ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Internal medicine ,Medicine ,business - Abstract
5014Background: Biomarkers are needed to guide CRPC treatment; we evaluated [cfDNA] pre- and post-TT, associating this with outcome. Methods: cfDNA was isolated and quantified from 1 mL of plasma, ...
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- 2016
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204. Clinical and radiological characteristics of metastatic prostate cancer (mPCa) patients (pts) with liver metastases (LM) and association with overall survival (OS)
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Roberta Ferraldeschi, Daniel Nava Rodrigues, Nina Tunariu, Raquel Perez, Joaquin Mateo, A. Jayaram, Zafeiris Zafeiriou, Gerhardt Attard, Johann S. de Bono, Spyridon Sideris, Suzanne Carreira, Nuria Porta, Semini Sumanasuriya, Niven Mehra, Diletta Bianchini, Pasquale Rescigno, David Lorente, Gunther Boysen, Adam Sharp, and Michael Kolinsky
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Oncology ,Cancer Research ,medicine.medical_specialty ,Poor prognosis ,business.industry ,Incidence (epidemiology) ,medicine.disease ,humanities ,Prostate cancer ,Radiological weapon ,Internal medicine ,medicine ,Retrospective analysis ,Overall survival ,business - Abstract
5043Background: The diagnosis (Dx) of LM in PCa pts carries a poor prognosis and its incidence is increasing. We conducted a retrospective analysis to identify clinical and radiological factors ass...
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- 2016
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205. High neutrophil-to-lymphocyte ratio (NLR), myeloid-derived suppressor cells (MDSCs) and resistance to corticosteroid therapy (CST) in castration-resistant prostate cancer (CRPC)
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Adam Sharp, Daniel Nava Rodrigues, Penelope Flohr, Johann S. de Bono, Chris Parker, Mateus Crespo, Karen Thomas, Diletta Bianchini, Alison Morilla, Maryou B. Lambros, David P. Dearnaley, Niven Mehra, and Ricardo Morilla
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Cancer Research ,Poor prognosis ,business.industry ,fungi ,Inflammation ,Castration resistant ,medicine.disease ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Oncology ,Corticosteroid therapy ,030220 oncology & carcinogenesis ,Myeloid-derived Suppressor Cell ,Cancer research ,Medicine ,030211 gastroenterology & hepatology ,Treatment resistance ,medicine.symptom ,Neutrophil to lymphocyte ratio ,business - Abstract
5076Background: Cancer-secreted cytokines drive inflammation, supporting tumour growth and increasing the NLR. A high NLR associates with poor prognosis and treatment resistance (TXR). MDSCs are ar...
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- 2016
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206. Interrogating metastatic prostate cancer treatment switch decisions
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Heather Payne, Leon W.M.M. Terstappen, Emma Hall, Maarten Joost IJzerman, Miguel Miranda, Johann S. de Bono, Aurelius Omlin, Praful Ravi, Niven Mehra, Carmel Pezaro, and David Lorente
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Cancer Research ,medicine.medical_specialty ,business.industry ,Treatment switch ,Treatment options ,Disease ,Computer-assisted web interviewing ,medicine.disease ,Response to treatment ,Clinical Practice ,Prostate cancer ,Oncology ,Radiological weapon ,Physical therapy ,Medicine ,business ,Intensive care medicine - Abstract
296 Background: Increased availability of treatment options in CRPC requires improved biomarkers to optimize decision making for therapeutic sequencing. Despite evidence for the value of CTCs in assessing prognosis and response to treatment, their use in clinical practice is not widely implemented. Clinicians rely on PCWG2 criteria based on PSA, clinical and radiological criteria although these are only inconsistently used in clinical practice. We evaluated the trends for clinical decision-making by physicians treating CRPC. Methods: An online questionnaire was distributed to physicians treating PC from the UK, Switzerland and Australia. Questions on clinical practice, familiarity with progression criteria, use of CTCs and clinical-decision making were formulated. Results: 111 participants replied. Most (84.7%) were oncologists treating ≥ 50 patients per year (65.3%). Although only 39.6% usually used PCWG2 in clinical practice, 74.5% considered PSA, bone scans and CT to be useful for monitoring disease. 55.6% considered PSA to be an important biomarker. A minority were able to identify PSA (41.4%) and bone scan (39.4%) progression criteria by PCWG2. On average, more physicians discontinued cabazitaxel (28%) than docetaxel (10.4%) before cycle 4. Similar number of cycles were given to bone only disease compared to RECIST evaluable patients. Clinical progression was most important for switching treatment for most physicians (90.5%), followed by RECIST (71.6%), bone scan (47.7%), CTC (23.2%) and PSA (21.1%). The main challenge associated with the use of CTCs was the access to technology (84.7%). Most respondents (92%) would not stop therapy with rising PSA but falling CTC counts; most (88.8%) would not stop with declining PSA but rising CTCs. Although 50% acknowledged the prognostic value of CTCs, only 33% would use them to guide decision-making. Conclusions: A significant number of physicians discontinue treatment before 12 weeks. Most physicians rely on clinical progression for decision-making. Knowledge of PCWG2 response and progression criteria is generally suboptimal. Greater physician awareness, access to technology and further evidence and will be required for the implementation of CTCs as a routine biomarker in CRPC.
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- 2016
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207. Loco-regional treatment (LRT) for M1 at diagnosis prostate cancer (PCa) patients (pts) and impact on overall survival (OS): A retrospective analysis
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Zafeiris Zafeiriou, Rosalind A. Eeles, Raquel Perez, Johann S. de Bono, A. Jayaram, Gerhardt Attard, Hazel 'O Sullivan, Diletta Bianchini, David P. Dearnaley, Michael Kolinsky, Vincent Khoo, Chris Parker, David Lorente Estelles, Nicholas van As, Nina Tunariu, Joaquin Mateo, Alison Tree, Pasquale Rescigno, Semini Sumanasuriya, and Niven Mehra
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Prostatectomy ,Proportional hazards model ,medicine.medical_treatment ,medicine.disease ,Optimal management ,Surgery ,Radiation therapy ,Prostate cancer ,Median time ,Internal medicine ,medicine ,Retrospective analysis ,Overall survival ,business - Abstract
280 Background: The optimal management of the primary tumour in pts with M1 at diagnosis PCa is not established. We aimed to evaluate the impact on OS of LRT (surgery or radiotherapy to the primary tumour) in de novo metastatic disease. Methods: PCa pts with M1 disease at diagnosis treated at the Royal Marsden between June 2003 and December 2011 were evaluated. LRT+ patients were defined as those that had received surgery or radiotherapy for the primary. Covariates analysed included age, diagnostic Gleason score, lines of CRPC treatment, PSA, burden of bone metastases ( ≥ 4 vs < 4 bone metastases) and ECOG PS. Kaplan-Meier analyses generated OS data. The association between LRT and OS was evaluated in univariate (UV) and multivariate (MV) Cox regression models. Results: Overall 234 pts with M1 at diagnosis were identified; 27 (11.53%) received LRT (25 XRT; 2 prostatectomy). Median time interval between diagnosis and LRT was 782 days (range 0-4130). Patients receiving LRT were younger (49 vs 61 yrs, p = 0.042), had lower baseline PSA values (68 vs 148; p < 0.001), and were more likely to have lymph node only disease (26% vs 10%; p = 0.029) and a lower burden of bone metastases with < 4 metastases (85% vs 34%;p < 0.001). Patients receiving LRT had a significantly longer survival (74.2 vs 55.1 months; HR 0.39; p < 0.001) in UV and MV cox-regression analysis (table). LRT+ remained highly prognostic, independently of disease volume at diagnosis and baseline PSA. Conclusions: LRT was associated with increased survival in patients with de novo metastatic disease, and in these analyses the prognostic utility of this LRT prognostic biomarker was independent of volume of metastatic disease at baseline and I'd baseline PSA. Other possible confounder factors may need to be taken into account when interpreting these results which require prospective validation from clinical trials such as STAMPEDE . [Table: see text]
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- 2016
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208. Two-protein signature of novel serological markers apolipoprotein-A2 and serum amyloid alpha predicts prognosis in patients with metastatic renal cell cancer and improves the currently used prognostic survival models
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Wim H. J. Kruit, Stefan Sleijfer, Jan H.M. Schellens, Jeanine M.L. Roodhart, Rachel H. Giles, Judith Y. M. N. Engwegen, Catharina M. Korse, John B. A. G. Haanen, Gerard Groenewegen, Emile E. Voest, Joost S.P. Vermaat, Marlies H.G. Langenberg, Niven Mehra, Jos H. Beijnen, I. van der Tweel, Medical Oncology, and Hematology
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Oncology ,Male ,Proteomics ,medicine.medical_specialty ,Pathology ,Enzyme-Linked Immunosorbent Assay ,Cohort Studies ,SDG 3 - Good Health and Well-being ,Internal medicine ,Medicine ,Humans ,Risk factor ,Neoplasm Metastasis ,Survival rate ,Carcinoma, Renal Cell ,Survival analysis ,Aged ,Retrospective Studies ,Serum Amyloid A Protein ,Performance status ,business.industry ,Proportional hazards model ,Cancer ,Hematology ,Middle Aged ,medicine.disease ,Kidney Neoplasms ,Survival Rate ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Apolipoprotein A2 ,Female ,business ,Kidney cancer ,Apolipoprotein A-II ,Biomarkers - Abstract
Background: In metastatic renal cell cancer (mRCC), the Memorial Sloan-Kettering Cancer Center (MSKCC) risk model is widely used for clinical trial design and patient management. To improve prognostication, we applied proteomics to identify novel serological proteins associated with overall survival (OS). Patients and methods: Sera from 114 mRCC patients were screened by surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS). Identified proteins were related to OS. Three proteins were subsequently validated with enzyme-linked immunosorbent assays and immunoturbidimetry. Prognostic models were statistically bootstrapped to correct for overestimation. Results: SELDI-TOF MS detected 10 proteins associated with OS. Of these, apolipoprotein A2 (ApoA2), serum amyloid alpha (SAA) and transthyretin were validated for their association with OS (P = 5.5×10-9, P = 1.1×0-7 and P = 0.0004, respectively). Combining ApoA2 and SAA yielded a prognostic two-protein signature [Akaike's Information Criteria (AIC) = 732, P = 5.2×10-7]. Including previously identified prognostic factors, multivariable Cox regression analysis revealed ApoA2, SAA, lactate dehydrogenase, performance status and number of metastasis sites as independent factors for survival. Using these five factors, categorization of patients into three risk groups generated a novel protein-based model predicting patient prognosis (AIC = 713, P = 4.3×10-11) more robustly than the MSKCC model (AIC = 729, P = 1.3×10-7). Applying this protein-based model instead of the MSKCC model would have changed the risk group in 38% of the patients. Conclusions: Proteomics and subsequent validation yielded two novel prognostic markers and survival models which improved prediction of OS in mRCC patients over commonly used risk models. Implementation of these models has the potential to improve current risk stratification, although prospective validation will still be necessary.
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- 2009
209. Identification of two new serum protein profiles for renal cell carcinoma
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Judith Y M N, Engwegen, Niven, Mehra, John B A G, Haanen, Jan H M, Schellens, Emile E, Voest, and Jos H, Beijnen
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Adult ,Male ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Molecular Sequence Data ,Biomarkers, Tumor ,Humans ,Female ,Amino Acid Sequence ,Blood Proteins ,Middle Aged ,Carcinoma, Renal Cell ,Kidney Neoplasms ,Aged - Abstract
Renal cell carcinoma (RCC) is the most lethal urological cancer, and survival greatly depends on early diagnosis. Therefore, reliable, new biomarkers for detection of RCC are required. We assessed serum protein profiles of samples from two institutes with SELDI-TOF MS in duplicate on CM10 chips at pH 6.0 (set 1: 37 RCC + 32 healthy controls (HC), set 2: 20 RCC + 25 HC). Mean peak intensities of detected proteins were compared between RCC and HC with non-parametric testing. Classification trees were built with discriminating peaks using one sample set as training set and the other as independent validation set. We found 15 peaks significantly different (p0.01) between RCC and HC. Two classification trees could be built with these peaks. Tree A achieved 75% sensitivity and 85% specificity for cross-validation and 76 and 65% for independent validation. Tree B had 71 and 62% sensitivity and specificity for cross-validation and 83 and 82% for independent validation. Although two serum protein profiles comprising 5 protein peaks were found that could separate RCC from HC, the sensitivity and specificity is not sufficient to recommend large scale use. Upon structural identification and quantitative validation, however, these proteins might prove suitable markers in the follow up of RCC patients.
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- 2009
210. Identification of two new serum protein profiles for renal cell carcinoma
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Emile E. Voest, Jan H.M. Schellens, John B. A. G. Haanen, Jos H. Beijnen, Niven Mehra, and Judith Y. M. N. Engwegen
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Cancer Research ,medicine.medical_specialty ,Pathology ,Oncogene ,business.industry ,Urology ,Cancer ,General Medicine ,Cell cycle ,urologic and male genital diseases ,medicine.disease ,Proteomics ,Molecular medicine ,female genital diseases and pregnancy complications ,Oncology ,Renal cell carcinoma ,Carcinoma ,medicine ,business ,Kidney cancer - Abstract
Renal cell carcinoma (RCC) is the most lethal urological cancer, and survival greatly depends on early diagnosis. Therefore, reliable, new biomarkers for detection of RCC are required. We assessed serum protein profiles of samples from two institutes with SELDI-TOF MS in duplicate on CM10 chips at pH 6.0 (set 1: 37 RCC + 32 healthy controls (HC), set 2: 20 RCC + 25 HC). Mean peak intensities of detected proteins were compared between RCC and HC with non-parametric testing. Classification trees were built with discriminating peaks using one sample set as training set and the other as independent validation set. We found 15 peaks significantly different (p
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- 2009
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211. 2558 Impact of PTEN protein loss on response to docetaxel and overall survival (OS) in metastatic castration resistant prostate cancer (mCRPC) patients
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Pasquale Rescigno, Michael Paul Kolinsky, Federica Recine, D. Nava Rodrigues, A. Reid, Raquel Perez-Lopez, N. Tunariu, A. Jayaram, Ruth Riisnaes, Diletta Bianchini, Mateus Crespo, J.S. de Bono, Ines Figueiredo, Susana Miranda, Zafeiris Zafeiriou, Niven Mehra, G. Attard, David Lorente, Roberta Ferraldeschi, and Joaquin Mateo
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Castration resistant ,medicine.disease ,PTEN Protein ,Prostate cancer ,Docetaxel ,Internal medicine ,Overall survival ,Medicine ,business ,medicine.drug - Published
- 2015
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212. 2578 Neutrophil-to-lymphocyte ratio (NLR) in relation to outcome of castration-resistant prostate cancer (CRPC) patients treated with corticosteroids (CS)
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Karen Thomas, Pasquale Rescigno, Michael Paul Kolinsky, Niven Mehra, Chris Parker, Diletta Bianchini, A. Jayaram, Joaquin Mateo, Zafeiris Zafeiriou, David Lorente, David P. Dearnaley, and J.S. de Bono
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Oncology ,Cancer Research ,medicine.medical_specialty ,Prostate cancer ,business.industry ,Internal medicine ,medicine ,Neutrophil to lymphocyte ratio ,Castration resistant ,medicine.disease ,business - Published
- 2015
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213. 2579 Evaluation of clinical decision-making and the use of circulating tumor cells (CTCs) by physicians treating castration-resistant prostate cancer (CRPC)
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Alexa Gillman, A. Jayaram, Nuria Porta, Pasquale Rescigno, Michael Paul Kolinsky, Praful Ravi, Diletta Bianchini, Maarten Joost IJzerman, David Lorente, Emma Hall, Carmel Jo Pezaro, J.S. de Bono, Niven Mehra, Aurelius Omlin, Joaquin Mateo, and Miguel Miranda
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Oncology ,Cancer Research ,medicine.medical_specialty ,Prostate cancer ,Circulating tumor cell ,Clinical decision making ,business.industry ,Internal medicine ,medicine ,Castration resistant ,business ,medicine.disease - Published
- 2015
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214. Phase 1/2 trial of cabazitaxel with abiraterone acetate in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone acetate: Phase 2 results
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Charles J. Ryan, Liji Shen, Diletta Bianchini, Karim Fizazi, Carmel Pezaro, Yohann Loriot, Niven Mehra, Gerhardt Attard, Andrea Varga, Joaquin Mateo, Christophe Massard, Daniel P. Petrylak, Jenny Zhang, Johann S. de Bono, and Laurence Albiges
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Cancer Research ,medicine.medical_specialty ,Mitoxantrone ,business.industry ,Urology ,Abiraterone acetate ,Pharmacology ,medicine.disease ,Prostate cancer ,chemistry.chemical_compound ,Oncology ,Tolerability ,chemistry ,Docetaxel ,Cabazitaxel ,medicine ,Prednisolone ,Clinical endpoint ,business ,medicine.drug - Abstract
268 Background:Abiraterone acetate (A) and cabazitaxel (C) improve survival for patients with mCRPC. We conducted an open-label trial of A+C to assess the antitumor activity and tolerability of the combination in patients (pts) previously treated with docetaxel (D) and A (NCT01511536). Here, we report results for the phase 2 part of the study, after the combination MTD was established (Massard C, et al. ASCO 2013). Methods: Pts received A (1,000 mg QD) and C (25 mg/m2 every 3 weeks) with prednisone/ prednisolone (5 mg BID). Eligibility criteria included prior D and prior A for at least 3 months, disease progression by rising PSA, ECOG PS 0–1 and no prior C or mitoxantrone. The primary endpoint was PSA response rate (PSA-RR: ≥50% decrease confirmed ≥3 weeks later). A 1-sided exact test was planned to test a null hypothesis of PSA-RR 25%, with a type 1 error of 0.05. With a sample size of 26, this test would have a power of 83% under the alternative hypothesis of PSA-RR 50%. Secondary endpoints included progression-free survival (PFS), duration of response, radiological-RR, overall survival and safety. Results: Twenty-seven pts were treated in this phase 2 part of the study. The median time on A prior to A+C was 8.3 months (range 3.1–29.8). All pts previously received D and A; 4 pts (15%) had also received prior treatment with enzalutamide. The median number of C cycles administered was 7 (range 1–21). Main treatment-emergent adverse events (AE) Grade≥3 were neutropenia (15 pts; 55%; 1 pt [3.7%] had febrile neutropenia), fatigue (4 pts; 15%) and sepsis (3 pts; 11%). Seven pts (25.9%) required a dose reduction of C due to AE, but all patients received ≥80% of the planned dose intensity. Of 26 pts evaluable for the primary endpoint, 12 achieved a PSA response (PSA-RR 46.2%; 95% CI 26.6–66.4%), and therefore the null hypothesis was rejected (p
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- 2015
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215. The von Hippel-Lindau tumor suppressor protein influences microtubule dynamics at the cell periphery
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Emile E. Voest, Niven Mehra, Martijn P. Lolkema, Anita S. Jorna, Moniek van Beest, and Rachel H. Giles
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endocrine system diseases ,Ubiquitin-Protein Ligases ,Cell ,macromolecular substances ,Biology ,urologic and male genital diseases ,Microtubules ,chemistry.chemical_compound ,Microtubule ,Cell Line, Tumor ,medicine ,Humans ,Cytoskeleton ,Carcinoma, Renal Cell ,neoplasms ,Centrosome ,Photobleaching ,Tumor Suppressor Proteins ,Fluorescence recovery after photobleaching ,Cell Biology ,Exons ,Subcellular localization ,female genital diseases and pregnancy complications ,Cell biology ,Renal disorders [UMCN 5.4] ,Nocodazole ,Kinetics ,medicine.anatomical_structure ,Tubulin ,chemistry ,Gene Expression Regulation ,Microscopy, Fluorescence ,Von Hippel-Lindau Tumor Suppressor Protein ,biology.protein - Abstract
Item does not contain fulltext The von Hippel-Lindau (VHL) protein protects microtubules (MTs) from destabilization by nocodazole treatment. Based on this fixed-cell assay with static end points, VHL has been reported to directly stabilize the MT cytoskeleton. To investigate the dynamic changes in MTs induced by VHL in living cells, we measured the influence of VHL on tubulin turnover using fluorescence recovery after photobleaching (FRAP). To this end, we engineered VHL-deficient renal cell carcinoma cells to constitutively incorporate fluorescently labeled tubulin and to inducibly express VHL. Induction of VHL in these cells resulted in a decrease of tubulin turnover as measured by FRAP at the cell periphery, while minimally influencing MT dynamics around the centrosome. Our data indicates that VHL changes the behavior of MTs dependent on their subcellular localization implying a role for VHL in cellular processes such as migration, polarization, and cell-cell interactions. Here we propose a complementary method to directly measure VHL-induced subcellular changes in microtubule dynamics, which may serve as a tool to study the effect of MT binding proteins such as VHL.
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- 2004
216. Sequencing of Docetaxel (D) and Abiraterone Acetate (Aa) for Metastatic Castration-Resistant Prostate Cancer (Mcrpc)
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Pasquale Rescigno, Aurelius Omlin, Nina Tunariu, Diletta Bianchini, David Lorente, Amelia Altavilla, Carmel Pezaro, Zafeiris Zafeiriou, Niven Mehra, J.S. de Bono, Praful Ravi, Gerhardt Attard, R. Perez Lopez, Spyridon Sideris, Alan D. Smith, Deborah Mukherji, Emily Grist, Roberta Ferraldeschi, and Joaquin Mateo
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Oncology ,medicine.medical_specialty ,business.industry ,Abiraterone acetate ,Hematology ,medicine.disease ,Gastroenterology ,Prostate cancer ,Prostate-specific antigen ,Abiraterone ,chemistry.chemical_compound ,Docetaxel ,chemistry ,Cabazitaxel ,Internal medicine ,medicine ,Enzalutamide ,business ,Prospective cohort study ,medicine.drug - Abstract
Aim: D and AA are approved as front-line treatments for mCRPC. Their optimal sequencing is as yet undefined. We retrospectively evaluated whether sequencing of AA and D has an effect on survival in mCRPC. Methods: We retrospectively identified mCRPC patients (pts) who received both D and AA at the Royal Marsden Hospital. Pts were divided into two groups, the first having received D followed by AA (D- > AA) and the second AA followed by D(AA- > D). Pts who received D in the non-castrate setting or enzalutamide prior to D or AA were excluded. Hormonal treatments or phase I/II investigational agents were allowed between D and AA. Cabazitaxel(C) was allowed either before or after the second part of treatment. Overall survival (OS) was defined as time from initiation of first treatment, D or AA, to death or last follow-up (LFU). Log-Rank testing was used to compare OS between the two groups and two-sided Pearson's Chi-Square and Student's t-test to compare categorical and continuous variables respectively. Results: Time between treatment stages in months. Mean; Median (Min;Max) Diagnosis to CRes CRes to D End of D to AA End of AA to C End of AA to LFU D- > AA 50.0;33.8 (2.4;190.1) 15.0;10.3 (0.0;122.1) 11.5;9.2 (0.0;47.8) -1.5;1.0 (-17.0;9.1) 9.7;6.8 (0.0;57.0) Diagnosis to CRes Cres to AA End of AA to D End of D to C End of D to LFU AA- > D 54.4;35.8 (4.8;210.7) 14.9;13.7 (0.2;71.5) 7.5; 4.0 (0.9; 28.5) 14.7;9.2 (1.6;38.8) 12.5;8.2 (0.4;51.0) CRes: Castration Resistance. Between 10/2004 and 06/2012 161 and 37 mCRPC pts were identified who received D- > AA and AA- > D respectively. Baseline mean values of prognostic parameters were comparable in the two groups: Hg was 11.9g/dl and 12.7g/dl (p = 0.04), LDH 195.2u/l and 203.6u/l(p = 0.5), ALP 252.1u/l and 156u/l(p = 0.1), albumin 35.2g/l and 36.9g/l(p = 0.06), PSA 786.3ng/ml and 118.7ng/ml (p = 0.7) –median(m)PSA 131ng/ml and 72ng/ml- in D- > AA and AA- > D group respectively. Similar proportion of pts received C in the two groups: 36 pts (22.4%) in D- > AA and 4 (10.8%) in AA- > D (p = 0.1). After a mFU of 2.7 years 18 pts (11.2%) in the D- > AA group were alive and 2 (5.4%) in the AA- > D group; mOS was 31.4 months (95%CI: 28.3-34.4) in D- > AA and 38.6months (95% CI:30.3-46.9) in AA- > D (p = 0.6). The difference was not statistically significant. Conclusions: This retrospective analysis did not identify a statistically significant difference in mOS between pts treated with D- > AA or AA- > D. Prospective studies to evaluate optimal treatment sequencing for mCRPC are warranted. Disclosure: Z. Zafeiriou: Employee at the time of manuscript preparation of the Institute of Cancer Research, Sutton, Surrey, UK, that has commercial interest in abiraterone. Z.Z has received grants from Hellenic Society of Medical Oncology; R. Ferraldeschi, A. Altavilla, S. Sideris, P. Rescigno, D. Bianchini, A. Smith, R. Perez Lopez, N. Mehra, P. Ravi, E. Grist and N. Tunariu: Employee at the time of manuscript preparation of the Institute of Cancer research, Sutton, Surrey, UK, that has commercial interest in abiraterone; A. Omlin: Employee at the time of manuscript preparation of the Institute of Cancer research, Sutton, Surrey, UK, that has commercial interest in abiraterone. Advisory role: Janssen as COI; C. Pezaro and D. Mukherji: Employee at the time of manuscript preparation of the Institute of Cancer research, Sutton, Surrey, UK, that has commercial interest in abiraterone. Has has received honoraria from Sanofi-Aventis and Janssen-Cilag; D. Lorente: Employed at the Institute of Cancer Research, which has a commercial interest in the development of abiraterone; J. Mateo: Employed at the Institute of Cancer Research when the abstract was created, which has a commercial interest in the development of this agent; G. Attard: GA is listed in the ICR co-inventors reward scheme for abiraterone acetate; J.S. de Bono: JSB has a consultant role with Johnson & Johnson, and received honoraria from Johnson & Johnson. Consultant and Chief Investigator of the Abiraterone Trial.
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- 2014
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217. P13 Elevated, cell-free mitochondrial RNA in plasma identifies a poorprognosis in prostate, head and neck, kidney and colorectal cancerpatients
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Niven Mehra, Jolanda Maas, Maarten Penning, J. Roodhart, Emile E. Voest, and N. van Daal
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Oncology ,Cancer Research ,Kidney ,medicine.medical_specialty ,business.industry ,Cell free ,medicine.anatomical_structure ,Mitochondrial RNA ,Prostate ,Internal medicine ,medicine ,Cancer research ,Head and neck ,business - Published
- 2007
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218. Use of serum proteins identified by proteomics to predict prognosis in patients with metastatic renal cell cancer (mRCC) and comparison to the currently used MSKCC survival model
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J. H. Beijnen, J.H.M. Schellens, I. van der Tweel, J.B.A.G. Haanen, Judith Y. M. N. Engwegen, Stefan Sleijfer, Catharina M. Korse, E. E. Voest, Niven Mehra, and Joost S.P. Vermaat
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Proportional hazards model ,Clinical study design ,Cancer ,medicine.disease ,Bioinformatics ,Proteomics ,Blood proteins ,Internal medicine ,Medicine ,Akaike information criterion ,business ,Survival analysis ,Immunoturbidimetry - Abstract
11078 Background: In mRCC the Memorial Sloan-Kettering Cancer Center (MSKCC) risk model (Motzer et al.,JCO2002) is widely used for clinical trial design and patient management. To improve this model, we searched for serum proteins associated with overall survival (OS) using proteomics and determined their potential contribution to the composition of better prognostic models. Methods: Sera from 125 mRCC patients, mostly interferon-treated, collected between 2001–2006 in three Dutch Cancer Centers, were screened by SELDI-TOF mass spectrometry (MS). Identified proteins were analyzed for their association with OS by Cox regression analysis and Kaplan-Meier curves. Three proteins were subsequently validated with conventional ELISAs and immunoturbidimetry. Computed Cox PH regression models were individually compared with the Akaike's Information Criteria (AIC). The final model was statistically bootstrapped to strengthen its validity. Results: SELDI-TOF MS successfully detected eleven prognostic proteins associated with OS. The strongest prognostic proteins, apolipoprotein A-II (ApoA2), serum amyloid alpha (SAA), and transthyretin were validated by alternative methods and confirmed for their association with OS (p=7.4×10-9, p=3.2×10-8 and p=0.0002, respectively). Stepwise multivariable Cox regression analysis provided an optimal combination of prognostic factors; ApoA2, SAA, LDH, performance status and number of metastasis sites. Subsequent categorization of patients into three risk groups generated a novel survival model that robustly predicts patient prognosis (AIC=684 and p=5.8×10-15) with increased accuracy compared to the MSKCC model (AIC=719, p=2.0×10-7). Bootstrapping our model resulted in an optimism correction of 0.04 (R2=0.45). Initiating systemic therapy according to novel proposed model instead of the MSKCC model would result in a change of treatment in 14% of the patients. Conclusions: Using proteomics, serum proteins associated with OS in mRCC patients can be identified. Incorporating some of these factors together with traditional risk factors yields a prognostic model outperforming the MSKCC risk model thereby further improving patients’ management. No significant financial relationships to disclose.
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- 2009
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219. P12 SELDI-TOF MS serum protein profiling predicts poor prognosis renal cancer patients
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J. H. Beijnen, J. Engwegen, John B. A. G. Haanen, Johannes M.G. Bonfrer, J.H.M. Schellens, C. van Gils, Niven Mehra, and Emile E. Voest
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Oncology ,Sorafenib ,Cancer Research ,medicine.medical_specialty ,education.field_of_study ,Bevacizumab ,Sunitinib ,business.industry ,Population ,Disease ,medicine.disease ,Internal medicine ,medicine ,Erlotinib ,education ,business ,Kidney cancer ,Survival rate ,medicine.drug - Abstract
Background: Approximately 30% of patients present with metastasized disease and only 15-25% of patients respond to anti-tumor treatment. Surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF MS) may identify protein signatures in the serum proteome of RCC patients that discriminate between poor and good prognosis patients. Methods: In this study we analyze protein profiles in the serum of 57 renal cancer patients (2% stage I, 12% stage II, 7% stage III and 79% stage IV patients according to the American Joint Committee on Cancer) and 59 healthy controls. Denatured serum samples were incubated on CM10 ProteinChip arrays and analyzed using the PBS-IIC ProteinChip Reader. Clinical data was collected and the extended Memorial Sloan-Kettering Prognostic Factors Model for survival was calculated. Ratios discriminating between RCC cases and controls were selected to generate a predictive multiprotein model. Univariate and multivariate Cox Proportional Hazard analyses were performed. Protein masses were identified. Results: In RCC serum samples we identified ion masses predictive for patient survival, and built a protein-model consisting of five signature peaks with m/z ratios of 2944, 3331, 6457, 6654, and 9201 Da, that could correctly identify poor prognosis patients with sensitivity and specificity of 80% and 76% for 1-year survival. Cumulative 1-year survival was 93% for low-risk patients, compared to 48% for high-risk patients (P=0.0001, Log-rank test). Multivariate analysis indicated that our model was an independent predictor of survival. Conclusion: SELDI-TOF MS can be used to assess the prognosis of RCC patients independent of present prognostic factor models. Introduction Kidney cancer accounts for approximately 3% of all adult malignancies. Peak incidence of renal cell cancer (RCC) is from 50-70 years, with a male to female ratio of 6:1 (1). Kidney cancer can grow to very large sizes without causing any complaints, and when symptoms such as hematuria, abdominal pain or discomfort occur it is commonly associated with an advanced stage of the disease (2). Response rates in patients with metastatic RCC remain at 15-25% for immune based therapies, and approximately 2-40% for small molecules or antibodies, such as sorafenib, sunitinib, erlotinib and bevacizumab (3). RCC is currently the most lethal of all urological cancers with a corresponding 5-year survival rate of 9% in metastatic disease (4). Although treatment outcome is improving due to the development of various targeted therapies, adequate selection of patients for these treatment approaches is important. SELDI-based protein MS has mostly been limited to diagnostics (5-9), while many other potential implementations of SELDITOF MS in the oncology field are practically untried. Gene expression profiles of tumor tissues allow the possibility to select patients on a particular gene expression signature out of a homogenous population of cancer patients, whom would benefit from adjuvant treatment to gain complete remission or increase disease free survival (10;11). Subsequently, proteomic-based research evaluating protein expression in high-throughput tissue arrays originating from RCC tumor biopsies or resection material have identified new protein markers as independent predictors of survival 170 | NOVEL BIOMARKERS FOR CANCER DETECTION AND PROGNOSTICATION CHAPTER 13
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- 2007
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220. Endothelial progenitor marker CD133 mRNA expression in peripheral blood mononuclear cells predicts outcome of cancer patients
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Niven Mehra, Jolanda Maas, Maarten Penning, N. van Daal, and Emile E. Voest
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Cancer Research ,business.industry ,Mrna expression ,Cancer ,medicine.disease ,Peripheral blood mononuclear cell ,Peripheral blood ,Haematopoiesis ,Oncology ,Cancer research ,Medicine ,Progenitor cell ,business ,Progenitor - Abstract
10087 Background: We examined whether expression of CD133, a surface molecule expressed on progenitors of hematopoietic and endothelial lineages, is increased in the peripheral blood mononuclear cells (PBMC’s) of cancer patients. Furthermore we correlated CD133 mRNA expression with tumor prognostication factors and overall survival. Methods: PBMC’s were isolated from the blood of 130 advanced cancer patients (43 renal cell carcinoma, 27 colorectal cancer, 34 prostate cancer, 27 head and neck cancer). Clinicopathological parameters were obtained. Median follow-up time was 16 months after inclusion (range 3–33 months). For the quantification of CD133 mRNA we used a real-time detection and quantification method based on nucleic acid sequence-based amplification (NASBA). Also U1A DNA was quantified as internal control for input and isolation. CD133 mRNA copy numbers were expressed as copies per 10.000 cells, as determined by U1A DNA. Results: Patients with metastasized disease have a significant increase in CD133 mRNA as compared to patients without metastasis. This increase is strongest in patients with bone metastasis. Subgroup analysis in patients with bone involvement show that CD133 mRNA also correlates with PSA (n=34)and inversely with hemoglobin (n=50). CD133 mRNA expression is an independent predictor for overall survival in Cox’s multivariate analysis (variables in the model included age, hemoglobin, metastasis, previous treatment and CD133 as categorical variable). A CD133 mRNA cut-off value was established by Receiver Operating Characteristic analysis of CD133 expression in relationship to survival (sensitivity 64% and specificity 71%). Cancer patients with more than 200 copies of CD133 mRNA, demonstrate a decreased survival compared to patients with lower CD133 expression (median survival 8 and 15.4 months, respectively). In patients with bone metastasis the median survival of high and low expressers is 6.3 months and 21.9 months, respectively. Conclusions: mRNA expression of stem-cell marker CD133 is increased in cancer patients with metastasized disease and an independent prognostic factor for overall survival. Increased CD133 mRNA expression may reflect an activated angiogenic state in these cancer patients. [Table: see text]
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- 2006
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221. PROfound: Efficacy of olaparib (ola) by prior taxane use in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) gene alterations
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Niven Mehra, Susan Feyerabend, Nobuaki Matsubara, Michael Paul Kolinsky, Guilhem Roubaud, Nicolas Penel, Michael A. Carducci, Kazuo Nishimura, Christian Heinrich Poehlein, Nicholas J. Vogelzang, Giuseppe Procopio, Jinyu Kang, Neal D. Shore, Jae Young Joung, Fred Saad, Maha Hussain, Karim Fizazi, Mustafa Ozguroglu, W. Wu, and Johann S. de Bono
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Cancer Research ,Taxane ,business.industry ,Castration resistant ,medicine.disease ,Olaparib ,03 medical and health sciences ,Prostate cancer ,chemistry.chemical_compound ,0302 clinical medicine ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,In patient ,business ,Homologous recombination ,Gene ,030215 immunology - Abstract
134 Background: Optimal sequencing of therapies for mCRPC is not established. In the Phase III PROfound study (NCT02987543), ola significantly prolonged radiographic progression-free survival (rPFS) vs physician’s choice of new hormonal agent (pcNHA) in pts with mCRPC and an alteration in genes with a direct or indirect role in HRR. We report exploratory subgroup analyses by prior taxane (yes vs no). Methods: Men with mCRPC that had progressed on prior NHA were randomized to ola (tablets; 300 mg bid) or pcNHA (enzalutamide or abiraterone). Pts had alterations in BRCA1, BRCA2 or ATM (Cohort A) or ≥1 of 12 other prespecified genes with a direct or indirect role in HRR (Cohort B). Stratification factors were prior taxane use and measurable disease. rPFS was assessed by blinded independent central review with RECIST v1.1 + PCWG3. Results: Subgroup analyses of rPFS and overall survival (OS) favored ola vs pcNHA irrespective of prior taxane in Cohort A, Cohorts A+B and pts with a BRCA1 and/or BRCA2 or CDK12 alteration (Table). In the ATM subgroup hazard ratio (HR) point estimates for rPFS and OS were lower in pts who had received prior taxane vs pts who had not, but 95% CIs overlapped and pt numbers were small so data should be interpreted with caution. Conclusions: The benefit of ola over pcNHA in pts with mCRPC and HRR gene alterations was generally independent of prior taxane status in the overall study population. Clinical trial information: NCT02987543. [Table: see text]
222. Association between PSA declines at 4 weeks and OS in patients treated with abiraterone acetate (AA) for metastatic castration resistant prostate cancer (mCRPC) after docetaxel
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Raquel Perez Lopez, Chris Parker, Zafeiris Zafeiriou, Spyridon Sideris, Alan D. Smith, Nina Tunariu, Gerhardt Attard, Johann S. de Bono, David Lorente, Emily Grist, Roberta Ferraldeschi, Joaquin Mateo, David P. Dearnaley, Anuradha Jayaram, Michael Kolinsky, Emma Hall, Niven Mehra, Diletta Bianchini, and Pasquale Rescigno
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Oncology ,Gynecology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Proportional hazards model ,Abiraterone acetate ,Castration resistant ,medicine.disease ,chemistry.chemical_compound ,Prostate-specific antigen ,Prostate cancer ,chemistry ,Docetaxel ,Internal medicine ,Prednisolone ,medicine ,In patient ,business ,medicine.drug - Abstract
215 Background: Falls in prostate specific antigen (PSA) levels by 50% from the baseline at 12 weeks are currently used to assess response to treatment for mCRPC (Scher et al, 2008). However PSA decline algorithms do not provide robust intermediate endpoints of overall survival (OS) benefit in mCRPC. We evaluated the association between PSA decline at 4 weeks and OS. Methods: We identified mCRPC patients who had received treatment with abiraterone acetate (AA) plus prednisolone post-docetaxel at the Royal Marsden (London, UK) between 01.01.2006 and 30.04.14. Patients were eligible for this analysis if they had PSA levels assessed at baseline, after 4 weeks and 12 weeks of treatment. PSA response at 4 weeks was defined as a ≥30% (PSA4w30) and ≥50% (PSA4w50) decline from baseline (PSABL). Association with outcome was analyzed using multivariate Cox regression and log-rank analyses. A significant p-value of 0.0167 was pre-specified to account for multiple testing. Demographics and clinical data were retrospectively collected from the hospital electronic patient record system (EPR). Results: We identified 124 patients who had received AA post-docetaxel and were eligible for this analysis. PSA4w30 was associated with longer OS (median OS 11.1 vs. 6.8 months; HR 0.50; 95% CI 0.32-0.80; p=.004). PSA4w50 was not associated with OS. A ≥50% PSA decline at 12 weeks (PSA12w50), the standard response measure, was also associated with OS (median OS 9.3 vs. 8.2; HR 0.49; 95% CI 0.29-0.80; p=.005). PSA4w30 was significantly associated with PSA12w50 (p
223. Activity of Platinum-Based Chemotherapy in Patients With Advanced Prostate Cancer With and Without DNA Repair Gene Aberrations
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Daniel Vargas Pivato de Almeida, Sabine Schmid, Hiroyoshi Suzuki, Celestia S. Higano, Rafael Morales-Barrera, Elisa Ledet, Kostas Karalis, Ursina Zürrer-Härdi, Aurelius Omlin, Andries M. Bergman, Aaron R. Hansen, Elena Castro, Dirk Klingbiel, Pernelle Lavaud, William Oh, Nieves Martinez Chanza, Steven Yip, Malou C.P. Kuppen, Tomasz M. Beer, Silke Gillessen, Himisha Beltran, Che-Kai Tsao, Fernando C. Maluf, Ugo De Giorgi, Christopher Sweeney, Carmel Pezaro, Oliver Sartor, Giuseppe Di Lorenzo, Vincenza Conteduca, Marcello Tucci, Niven Mehra, Andrea Zivi, Kim N. Chi, Mo Linh Le, Diletta Bianchini, Sämi Schär, Institut Català de la Salut, [Schmid S] Department of Medical Oncology and Haematology, Cantonal Hospital of St Gallen, St Gallen, Switzerland. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada. [Omlin A] Department of Medical Oncology and Haematology, Cantonal Hospital of St Gallen, St Gallen, Switzerland. [Higano C] Seattle Cancer Care Alliance, University of Washington, Seattle. [Sweeney C, Martinez Chanza N] Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts. [Mehra N] Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands. [Morales-Barrera R] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus, and Health Technology Assessment (HTA)
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Pròstata - Càncer - Quimioteràpia ,Oncology ,ADN - Reparació ,medicine.medical_specialty ,Neoplasms::Neoplasms by Site::Urogenital Neoplasms::Genital Neoplasms, Male::Prostatic Neoplasms [DISEASES] ,Combination therapy ,Population ,Otros calificadores::Otros calificadores::/farmacoterapia [Otros calificadores] ,Other subheadings::Other subheadings::/drug therapy [Other subheadings] ,Prostate cancer ,SDG 3 - Good Health and Well-being ,Nutritional and Metabolic Diseases::Metabolic Diseases::DNA Repair-Deficiency Disorders [DISEASES] ,Internal medicine ,Medicine ,education ,Original Investigation ,education.field_of_study ,business.industry ,Research ,enfermedades nutricionales y metabólicas::enfermedades metabólicas::trastornos por deficiencias en la reparación del ADN [ENFERMEDADES] ,Retrospective cohort study ,General Medicine ,Evaluable Disease ,medicine.disease ,neoplasias::neoplasias por localización::neoplasias urogenitales::neoplasias de los genitales masculinos::neoplasias de la próstata [ENFERMEDADES] ,Online Only ,Prostate-specific antigen ,Docetaxel ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Cohort ,business ,medicine.drug - Abstract
Key Points Question Is there a role for platinum-based treatment in molecularly selected patients with advanced prostate cancer? Findings In a case series of 508 patients, platinum-based therapy was associated with antitumor activity, especially among patients with known DNA repair gene aberrations. In patients with DNA repair gene aberrations, nearly half had a decrease in prostate-specific antigen levels of at least 50% and experienced soft tissue responses. Meaning In patients with prostate cancer and DNA repair gene aberrations, platinum-based therapy may be considered a treatment option., This case series characterizes the antitumor activity of platinum-based therapies in men with castration-resistant prostate cancer with or without DNA repair gene alterations., Importance DNA repair gene aberrations occur in 20% to 30% of patients with castration-resistant prostate cancer (CRPC), and some of these aberrations have been associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition platinum-based treatments. However, previous trials assessing platinum-based treatments in patients with CRPC have mostly included a biomarker-unselected population; therefore, efficacy in these patients is unknown. Objective To characterize the antitumor activity of platinum-based therapies in men with CRPC with or without DNA repair gene alterations. Design, Setting, and Participants In this case series, data from 508 patients with CRPC treated with platinum-based therapy were collected from 25 academic centers from 12 countries worldwide. Patients were grouped by status of DNA repair gene aberrations (ie, cohort 1, present; cohort 2, not detected; and cohort 3, not tested). Data were collected from January 1986 to December 2018. Data analysis was performed in 2019, with data closure in April 2019. Exposure Treatment with platinum-based compounds either as monotherapy or combination therapy. Main Outcomes and Measures The primary end points were as follows: (1) antitumor activity of platinum-based therapy, defined as a decrease in prostate-specific antigen (PSA) level of at least 50% and/or radiological soft tissue response in patients with measurable disease and (2) the association of response with the presence or absence of DNA repair gene aberrations. Results A total of 508 men with a median (range) age of 61 (27-88) years were included in this analysis. DNA repair gene aberrations were present in 80 patients (14.7%; cohort 1), absent in 98 (19.3%; cohort 2), and not tested in 330 (65.0%; cohort 3). Of 408 patients who received platinum-based combination therapy, 338 patients (82.8%) received docetaxel, paclitaxel, or etoposide, and 70 (17.2%) received platinum-based combination treatment with another partner. A PSA level decrease of at least 50% was seen in 33 patients (47.1%) in cohort 1 and 26 (36.1%) in cohort 2 (P = .20). In evaluable patients, soft tissue responses were documented in 28 of 58 patients (48.3%) in cohort 1 and 21 of 67 (31.3%) in cohort 2 (P = .07). In the subgroup of 44 patients with BRCA2 gene alterations, PSA level decreases of at least 50% were documented in 23 patients (63.9%) and soft tissue responses in 17 of 34 patients (50.0%) with evaluable disease. In cohort 3, PSA level decreases of at least 50% and soft tissue responses were documented in 81 of 284 patients (28.5%) and 38 of 185 patients (20.5%) with evaluable disease, respectively. Conclusions and Relevance In this study, platinum-based treatment was associated with relevant antitumor activity in a biomarker-positive population of patients with advanced prostate cancer with DNA repair gene aberrations. The findings of this study suggest that platinum-based treatment may be considered an option for these patients.
224. PSA levels after dexamethasone withdrawal (DW) in castration resistant prostate cancer (CRPC)
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Johann S. de Bono, Adam Sharp, Sophia Wong, Joaquin Mateo, Semini Sumanasuriya, Raquel Perez Lopez, A. Jayaram, Diletta Bianchini, Michael Kolinsky, Pasquale Rescigno, Nina Tunariu, Gerhardt Attard, Zafeiris Zafeiriou, David Lorente, Federica Recine, Spyridon Sideris, and Niven Mehra
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Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Urology ,PSA PROGRESSION ,Castration resistant ,medicine.disease ,Confidence interval ,Surgery ,Radiation therapy ,Prostate cancer ,Oncology ,Medicine ,business ,Dexamethasone ,medicine.drug - Abstract
278 Background: PSA decline (PSAD) in CRPC after withdrawal of antiandrogens and steroid related drugs is well established. DW responses have been anecdotal and not well characterized. In this study we investigated the frequency and magnitude of PSA changes after DW. Methods: We retrospectively identified patients treated in the Royal Marsden for CRPC with D monotherapy. Patients were considered evaluable if they had between DW and their next treatment or radiotherapy an interval of at least 7 days, no other intervention and at least one PSA reading. Patients who received radiotherapy during treatment with D or received D for palliation of symptoms were excluded. The number of patients showing PSAD was recorded together with its percentage change from baseline. Chi-square test was used to compare response rates between different groups and 95% confidence intervals (CI) for the description of frequencies. PSA progression (PSAP) was defined according to Prostate Cancer Working Group 2 criteria. Results: 200 patients were identified who had received D of which 50 were evaluable. During D treatment PSA responses were not available for 5 patients, while 16 (35%, 95%CI [20%-50%]) had a ≥ 50% PSAD which was confirmed a month later with a second reading. For the responders, the median duration of PSA response from initiation of treatment to PSAP was 293 days (range: 219 to 1063). After DW, PSAD was observed in 12 patients (24%, 95% CI [12%,36%]). PSAD ≥ 25%, ≥ 30% and ≥ 50% was observed in 6, 3 and 2 patients respectively (12%, 6% and 4%) and in only one could the ≥ 30% PSAD be confirmed with a second reading a month later. In 5 cases of ≥ 25% PSAD, next treatment was initiated despite a dropping PSA, after 8 to 43 days. In one case only was PSAP reached during DW with a response duration of 53 days from DW to PSAP. The frequency of ≥ 25% PSAW responses was not significantly different between patients with and without prior response to dexamethasone: 6% and 17% respectively, Chi-square test p = 0.29. One patient reported improvement of his urinary symptoms after DW. Conclusions: DW responses are observed in a minority of patients. This phenomenon merits further prospective characterization and needs to be considered in the design of clinical trials.
225. MOESM8 of Blood-derived dendritic cell vaccinations induce immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer
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Westdorp, Harm, Creemers, Jeroen, Oort, Inge, Schreibelt, Gerty, Gorris, Mark, Niven Mehra, Simons, Michiel, Goede, Anna, Rossum, Michelle, Croockewit, Alexandra, Figdor, Carl, J. Witjes, Aarntzen, Erik, Mus, Roel, Brüning, Mareke, Petry, Katja, Gotthardt, Martin, Barentsz, Jelle, I. Vries, and Winald Gerritsen
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3. Good health - Abstract
Additional file 8: Table S1. Immunological, immunohistochemical and whole genome sequencing data.
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