Smith, T.A.
West, C.M.
Joseph, N.
Lane, B.
Irlam-Jones, J.
More, E.
Mistry, H.
Reeves, K.J.
Song, Y.P.
Reardon, M.
Hoskin, P.J.
Hussain, S.A.
Denley, H.
Hall, E.
Porta, N.
Huddart, R.A.
James, N.D.
Choudhury, A.
(2024). A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial. Ebiomedicine,
Vol.101,
p. 105032.
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BACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. FUNDING: Cancer Research UK, NIHR, MRC..
Rescigno, P.
Porta, N.
Finneran, L.
Riisnaes, R.
Figueiredo, I.
Carreira, S.
Flohr, P.
Miranda, S.
Bertan, C.
Ferreira, A.
Crespo, M.
Rodrigues, D.N.
Gurel, B.
Nobes, J.
Crabb, S.
Malik, Z.
Ralph, C.
McGovern, U.
Hoskin, P.
Jones, R.J.
Birtle, A.
Gale, J.
Sankey, P.
Jain, S.
McLaren, D.
Chadwick, E.
Espinasse, A.
Hall, E.
de Bono, J.
(2024). Capivasertib in combination with enzalutamide for metastatic castration resistant prostate cancer after docetaxel and abiraterone: Results from the randomized phase II RE-AKT trial. Eur j cancer,
Vol.205,
p. 114103.
show abstract
BACKGROUND: PTEN loss and aberrations in PI3K/AKT signaling kinases associate with poorer response to abiraterone acetate (AA) in metastatic castration-resistant prostate cancer (mCRPC). In this study, we assessed antitumor activity of the AKT inhibitor capivasertib combined with enzalutamide in mCRPC with prior progression on AA and docetaxel. METHODS: This double-blind, placebo-controlled, randomized phase 2 trial, recruited men ≥ 18 years with progressing mCRPC and performance status 0-2 from 15 UK centers. Randomized participants (1:1) received enzalutamide (160 mg orally, once daily) with capivasertib (400 mg)/ placebo orally, twice daily on an intermittent (4 days on, 3 days off) schedule. Primary endpoint was composite response rate (RR): RECIST 1.1 objective response, ≥ 50 % PSA decrease from baseline, or circulating tumor cell count conversion (from ≥ 5 at baseline to < 5 cells/7.5 mL). Subgroup analyses by PTENIHC status were pre-planned. RESULTS: Overall, 100 participants were randomized (50:50); 95 were evaluable for primary endpoint (47:48); median follow-up was 43 months. RR were 9/47 (19.1 %) enzalutamide/capivasertib and 9/48 (18.8 %) enzalutamide/placebo (absolute difference 0.4 % 90 %CI -12.8 to 13.6, p = 0.58), with similar results in the PTENIHC loss subgroup. Irrespective of treatment, OS was significantly worse for PTENIHC loss (10.1 months [95 %CI: 4.6-13.9] vs 14.8 months [95 %CI: 10.8-18]; p = 0.02). Most common treatment-emergent grade ≥ 3 adverse events for the combination were diarrhea (13 % vs 2 %) and fatigue (10 % vs 6 %). CONCLUSIONS: Combined capivasertib/enzalutamide was well tolerated but didn't significantly improve outcomes from abiraterone pre-treated mCRPC..
Dubec, M.J.
Price, J.
Berks, M.
Gaffney, J.
Little, R.A.
Porta, N.
Sridharan, N.
Datta, A.
McHugh, D.J.
Hague, C.J.
Cheung, S.
Manoharan, P.
van Herk, M.
Choudhury, A.
Matthews, J.C.
Parker, G.J.
Buckley, D.L.
Harrington, K.J.
McPartlin, A.
O'Connor, J.P.
(2024). Oxygen-enhanced MRI detects incidence, onset and heterogeneity of radiation-induced hypoxia modification in HPV-associated oropharyngeal cancer. Clin cancer res,
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show abstract
PURPOSE: Hypoxia mediates treatment resistance in solid tumors. We evaluated if oxygen-enhanced (OE)-MRI-derived hypoxic volume (HVMRI) is repeatable and can detect radiotherapy-induced hypoxia modification in HPV-associated oropharyngeal head and neck squamous cell cancer (HNSCC). EXPERIMENTAL DESIGN: 27 patients were recruited prospectively between March 2021 and January 2024. HVMRI was measured in primary and nodal tumors prior to standard-of-care (chemo)radiotherapy then at weeks 2 and 4 (W2, W4) into therapy. Two pre-treatment scans assessed biomarker within-subject coefficient of variation (wCV) and repeatability coefficient (RC). Cohort treatment response was measured using mixed-effects modelling. Responding lesions were identified by comparing HVMRI change to RC limits of agreement (LOA). RESULTS: OE-MRI identified hypoxia in all lesions. HVMRI wCV was 24.6% and RC LOA were -45.7% to 84.1%. Cohort median pre-treatment HVMRI of 11.3 cm3 reduced to 6.9 cm3 at W2 and 5.9 cm3 at W4 (both p < 0.001). HVMRI was reduced in 54.5% of individual lesions by W2 and in 88.2% by W4. All lesions with W2 hypoxia reduction showed persistent modification at W4. HVMRI reduced in some lesions that showed no overall volume change. Hypoxia modification was discordant between primary and nodal tumors in 50.0% of patients. CONCLUSIONS: Radiation-induced hypoxia modification can occur as early as W2, but onset varies between patients and was not necessarily associated with overall size change. Half of all patients had discordant changes in primary and nodal tumors. These findings have implications for patient selection and timing of dose de-escalation strategies in HPV-associated oropharyngeal carcinoma..
Larkin, J.
Marais, R.
Porta, N.
Gonzalez de Castro, D.
Parsons, L.
Messiou, C.
Stamp, G.
Thompson, L.
Edmonds, K.
Sarker, S.
Banerji, J.
Lorigan, P.
Evans, T.R.
Corrie, P.
Marshall, E.
Middleton, M.R.
Nathan, P.
Nicholson, S.
Ottensmeier, C.
Plummer, R.
Bliss, J.
Valpione, S.
Turajlic, S.
(2024). Nilotinib in KIT-driven advanced melanoma: Results from the phase II single-arm NICAM trial. Cell rep med,
Vol.5
(3),
p. 101435.
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Mucosal (MM) and acral melanomas (AM) are rare melanoma subtypes of unmet clinical need; 15%-20% harbor KIT mutations potentially targeted by small-molecule inhibitors, but none yet approved in melanoma. This multicenter, single-arm Phase II trial (NICAM) investigates nilotinib safety and activity in KIT mutated metastatic MM and AM. KIT mutations are identified in 39/219 screened patients (18%); of 29/39 treated, 26 are evaluable for primary analysis. Six patients were alive and progression free at 6 months (local radiology review, 25%); 5/26 (19%) had objective response at 12 weeks; median OS was 7.7 months; ddPCR assay correctly identifies KIT alterations in circulating tumor DNA (ctDNA) in 16/17 patients. Nilotinib is active in KIT-mutant AM and MM, comparable to other KIT inhibitors, with demonstrable activity in nonhotspot KIT mutations, supporting broadening of KIT evaluation in AM and MM. Our results endorse further investigations of nilotinib for the treatment of KIT-mutated melanoma. This clinical trial was registered with ISRCTN (ISRCTN39058880) and EudraCT (2009-012945-49)..
Parr, H.
Porta, N.
Tree, A.C.
Dearnaley, D.
Hall, E.
(2023). A Personalized Clinical Dynamic Prediction Model to Characterize Prognosis for Patients With Localized Prostate Cancer: Analysis of the CHHiP Phase 3 Trial. Int j radiat oncol biol phys,
Vol.116
(5),
pp. 1055-1068.
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PURPOSE: The CHHiP trial assessed moderately hypofractionated radiation therapy in localized prostate cancer. We utilized longitudinal prostate-specific antigen (PSA) measurements collected over time to evaluate and characterize patient prognosis. METHODS AND MATERIALS: We developed a clinical dynamic prediction joint model to predict the risk of biochemical or clinical recurrence. Modeling included repeated PSA values and adjusted for baseline prognostic risk factors of age, tumor characteristics, and treatment received. We included 3071 trial participants for model development using a mixed-effect submodel for the longitudinal PSAs and a time-to-event hazard submodel for predicting recurrence of prostate cancer. We evaluated how baseline prognostic factor subgroups affected the nonlinear PSA levels over time and quantified the association of PSA on time to recurrence. We assessed bootstrapped optimism-adjusted predictive performance on calibration and discrimination. Additionally, we performed comparative dynamic predictions on patients with contrasting prognostic factors and investigated PSA thresholds over landmark times to correlate with prognosis. RESULTS: Patients who developed recurrence had generally higher baseline and overall PSA values during follow-up and had an exponentially rising PSA in the 2 years before recurrence. Additionally, most baseline risk factors were significant in the mixed-effect and relative-risk submodels. PSA value and rate of change were predictive of recurrence. Predictive performance of the model was good across different prediction times over an 8-year period, with an overall mean area under the curve of 0.70, mean Brier score of 0.10, and mean integrated calibration index of 0.048; these were further improved for predictions after 5 years of accrued longitudinal posttreatment PSA assessments. PSA thresholds <0.23 ng/mL after 3 years were indicative of a minimal risk of recurrence by 8 years. CONCLUSIONS: We successfully developed a joint statistical model to predict prostate cancer recurrence, evaluating prognostic factors and longitudinal PSA. We showed dynamically updated PSA information can improve prognostication, which can be used to guide follow-up and treatment management options..
Philipps, L.
Porta, N.
James, N.
Huddart, R.
Hafeez, S.
Hall, E.
(2023). Correlation of Clinician- and Patient-Reported Outcomes in the BC2001 Trial. Clin oncol (r coll radiol),
Vol.35
(5),
pp. 331-338.
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AIMS: To evaluate whether there is sufficient correlation between patient-reported outcomes (PROs) and clinician-reported outcomes (CROs) in bladder cancer follow-up post-radiotherapy to streamline data collection and to reduce trial follow-up burden on patients, clinicians and trial programmes. MATERIALS AND METHODS: PROs data were collected within the BC2001 trial using the Functional Assessment of Cancer Therapy specific to bladder cancer (FACT-BL) questionnaire. CROs data were collected by clinicians using Late Effects in Normal Tissues Subjective, Objective and Management (LENT/SOM). Data were collected at baseline, post-treatment, at 6 and 12 months post-randomisation and then annually to 5 years. The percentage agreement between CROs and PROs measures was evaluated at 2 and 5 years post-randomisation. Concordance was tested using the weighted Kappa statistic with 95% confidence intervals. RESULTS: Correlation was evaluated between six categories of the FACT-BL and LENT/SOM scores. At 2 years the percentage agreement across these domains ranged from 45 to 78%, with the weighted Kappa statistic between 0.07 and 0.35. Results were similar in year 5 with 48-83% agreement and kappa statistics between -0.02 and 0.21. CONCLUSION: The correlation between CROs and PROs in patients treated with radiotherapy for bladder cancer were generally poor. PROs appear to be more sensitive, with higher grade events reported. Further work is needed to evaluate whether PROs alone can be used to evaluate toxicity-related outcomes in randomised controlled trials..
Philipps, L.
Porta, N.
James, N.
Huddart, R.
Hafeez, S.
Ballas, L.
Hall, E.
(2023). Differences in Quality of Life and Toxicity for Male and Female Patients following Chemo(radiotherapy) for Bladder Cancer. Clin oncol (r coll radiol),
Vol.35
(5),
pp. e336-e343.
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AIMS: BC2001, a randomised trial of treatment for muscle-invasive bladder cancer, demonstrated no difference in health-related quality of life (HRQoL) or late toxicity between patients receiving radical radiotherapy with and without chemotherapy. This secondary analysis explored sex-based differences in HRQoL and toxicity. MATERIALS AND METHODS: Participants completed the Functional Assessment of Cancer Therapy Bladder (FACT-BL) HRQoL questionnaires at baseline, end of treatment, 6 months and annually until 5 years. Clinicians assessed toxicity with the Radiation Therapy Oncology Group (RTOG) and Late Effects in Normal Tissues Subjective, Objective and Management (LENT/SOM) scoring systems at the same timepoints. The impact of sex on patient-reported HRQoL was evaluated using multivariate analyses of change in FACT-BL subscores from baseline to the timepoints of interest. For clinician-reported toxicity, differences were compared by calculating the proportion of patients with grade 3-4 toxicities occurring over the follow-up period. RESULTS: For both males and females, all FACT-BL subscores had a reduction in HRQoL at the end of treatment. For males, the mean bladder cancer subscale (BLCS) score remained stable through to year 5. For females, there was a decline in BLCS from baseline at years 2 and 3 with a return to baseline at year 5. At year 3, females had a statistically significant and clinically meaningful worsening of mean BLCS score (-5.18; 95% confidence interval -8.37 to -1.99), which was not seen in males (0.24; -0.76 to 1.23). RTOG toxicity was more frequent in females than males (27% versus 16%, P = 0.027). CONCLUSION: Results suggest that female patients treated with radiotherapy ± chemotherapy for localised bladder cancer report worse treatment-related toxicity in post-treatment years 2 and 3 than males..
Dubec, M.J.
Buckley, D.L.
Berks, M.
Clough, A.
Gaffney, J.
Datta, A.
McHugh, D.J.
Porta, N.
Little, R.A.
Cheung, S.
Hague, C.
Eccles, C.L.
Hoskin, P.J.
Bristow, R.G.
Matthews, J.C.
van Herk, M.
Choudhury, A.
Parker, G.J.
McPartlin, A.
O'Connor, J.P.
(2023). First-in-human technique translation of oxygen-enhanced MRI to an MR Linac system in patients with head and neck cancer. Radiother oncol,
Vol.183,
p. 109592.
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BACKGROUND AND PURPOSE: Tumour hypoxia is prognostic in head and neck cancer (HNC), associated with poor loco-regional control, poor survival and treatment resistance. The advent of hybrid MRI - radiotherapy linear accelerator or 'MR Linac' systems - could permit imaging for treatment adaptation based on hypoxic status. We sought to develop oxygen-enhanced MRI (OE-MRI) in HNC and translate the technique onto an MR Linac system. MATERIALS AND METHODS: MRI sequences were developed in phantoms and 15 healthy participants. Next, 14 HNC patients (with 21 primary or local nodal tumours) were evaluated. Baseline tissue longitudinal relaxation time (T1) was measured alongside the change in 1/T1 (termed ΔR1) between air and oxygen gas breathing phases. We compared results from 1.5 T diagnostic MR and MR Linac systems. RESULTS: Baseline T1 had excellent repeatability in phantoms, healthy participants and patients on both systems. Cohort nasal concha oxygen-induced ΔR1 significantly increased (p < 0.0001) in healthy participants demonstrating OE-MRI feasibility. ΔR1 repeatability coefficients (RC) were 0.023-0.040 s-1 across both MR systems. The tumour ΔR1 RC was 0.013 s-1 and the within-subject coefficient of variation (wCV) was 25% on the diagnostic MR. Tumour ΔR1 RC was 0.020 s-1 and wCV was 33% on the MR Linac. ΔR1 magnitude and time-course trends were similar on both systems. CONCLUSION: We demonstrate first-in-human translation of volumetric, dynamic OE-MRI onto an MR Linac system, yielding repeatable hypoxia biomarkers. Data were equivalent on the diagnostic MR and MR Linac systems. OE-MRI has potential to guide future clinical trials of biology guided adaptive radiotherapy..
Ingles Garces, A.H.
Porta, N.
Graham, T.A.
Banerji, U.
(2023). Clinical trial designs for evaluating and exploiting cancer evolution. Cancer treat rev,
Vol.118,
p. 102583.
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The evolution of drug-resistant cell subpopulations causes cancer treatment failure. Current preclinical evidence shows that it is possible to model herding of clonal evolution and collateral sensitivity where an initial treatment could favourably influence the response to a subsequent one. Novel therapy strategies exploiting this understanding are being considered, and clinical trial designs for steering cancer evolution are needed. Furthermore, preclinical evidence suggests that different subsets of drug-sensitive and resistant clones could compete between themselves for nutrients/blood supply, and clones that populate a tumour do so at the expense of other clones. Treatment paradigms based on this clinical application of exploiting cell-cell competition include intermittent dosing regimens or cycling different treatments before progression. This will require clinical trial designs different from the conventional practice of evaluating responses to individual therapy regimens. Next-generation sequencing to assess clonal dynamics longitudinally will improve current radiological assessment of clinical response/resistance and be incorporated into trials exploiting evolution. Furthermore, if understood, clonal evolution can be used to therapeutic advantage, improving patient outcomes based on a new generation of clinical trials..
Keaveney, S.
Dragan, A.
Rata, M.
Blackledge, M.
Scurr, E.
Winfield, J.M.
Shur, J.
Koh, D.-.
Porta, N.
Candito, A.
King, A.
Rennie, W.
Gaba, S.
Suresh, P.
Malcolm, P.
Davis, A.
Nilak, A.
Shah, A.
Gandhi, S.
Albrizio, M.
Drury, A.
Pratt, G.
Cook, G.
Roberts, S.
Jenner, M.
Brown, S.
Kaiser, M.
Messiou, C.
(2023). Image quality in whole-body MRI using the MY-RADS protocol in a prospective multi-centre multiple myeloma study. Insights imaging,
Vol.14
(1),
p. 170.
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BACKGROUND: The Myeloma Response Assessment and Diagnosis System (MY-RADS) guidelines establish a standardised acquisition and analysis pipeline for whole-body MRI (WB-MRI) in patients with myeloma. This is the first study to assess image quality in a multi-centre prospective trial using MY-RADS. METHODS: The cohort consisted of 121 examinations acquired across ten sites with a range of prior WB-MRI experience, three scanner manufacturers and two field strengths. Image quality was evaluated qualitatively by a radiologist and quantitatively using a semi-automated pipeline to quantify common artefacts and image quality issues. The intra- and inter-rater repeatability of qualitative and quantitative scoring was also assessed. RESULTS: Qualitative radiological scoring found that the image quality was generally good, with 94% of examinations rated as good or excellent and only one examination rated as non-diagnostic. There was a significant correlation between radiological and quantitative scoring for most measures, and intra- and inter-rater repeatability were generally good. When the quality of an overall examination was low, this was often due to low quality diffusion-weighted imaging (DWI), where signal to noise ratio (SNR), anterior thoracic signal loss and brain geometric distortion were found as significant predictors of examination quality. CONCLUSIONS: It is possible to successfully deliver a multi-centre WB-MRI study using the MY-RADS protocol involving scanners with a range of manufacturers, models and field strengths. Quantitative measures of image quality were developed and shown to be significantly correlated with radiological assessment. The SNR of DW images was identified as a significant factor affecting overall examination quality. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03188172 , Registered on 15 June 2017. CRITICAL RELEVANCE STATEMENT: Good overall image quality, assessed both qualitatively and quantitatively, can be achieved in a multi-centre whole-body MRI study using the MY-RADS guidelines. KEY POINTS: • A prospective multi-centre WB-MRI study using MY-RADS can be successfully delivered. • Quantitative image quality metrics were developed and correlated with radiological assessment. • SNR in DWI was identified as a significant predictor of quality, allowing for rapid quality adjustment..
Bliss, J.
Porta, N.
Emson, M.
Miller, S.
Morden, J.
(2022). Combined Peri-operative Lapatinib and Trastuzumab in Early HER2 Positive Breast Cancer can Identify Early Responders: Results from the UK EPHOS-B Trial (CRUK/08/002. Clinical cancer research,
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full text
Bundred, N.
Porta, N.
Brunt, A.M.
Cramer, A.
Hanby, A.
Shaaban, A.M.
Rakha, E.A.
Armstrong, A.
Cutress, R.I.
Dodwell, D.
Emson, M.A.
Evans, A.
Hartup, S.M.
Horgan, K.
Miller, S.E.
McIntosh, S.A.
Morden, J.P.
Naik, J.
Narayanan, S.
Ooi, J.
Skene, A.I.
Cameron, D.A.
Bliss, J.M.
(2022). Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results. Clin cancer res,
Vol.28
(7),
pp. 1323-1334.
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PURPOSE: EPHOS-B aimed to determine whether perioperative anti-HER2 therapy inhibited proliferation and/or increased apoptosis in HER2-positive breast cancer. PATIENTS AND METHODS: This randomized phase II, two-part, multicenter trial included newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery. Patients were randomized to: part 1 (1:2:2), no treatment (control), trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. Treatment was given for 11 days presurgery. Coprimary endpoints were change in Ki67 and apoptosis between baseline and surgery tumor samples (biologic response: ≥30% change). Central pathology review scored residual cancer burden (RCB). Relapse-free survival (RFS) explored long-term effects. RESULTS: Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was evaluable for 223 patients: in part 1 Ki67 response occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P < 0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P = 0.02) and 2/28 (7%) control (P < 0.0001). No significant increase in apoptosis after 11 days was seen in treatment groups. Six patients achieved complete pathologic response (pCR, RCB0) and 13 RCB1, all but two in the combination group. After 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died. No recurrences or deaths were observed among patients who achieved a pCR. Ki67% falls ≥50% associated with fewer recurrences (P = 0.002). CONCLUSIONS: Early response after short duration anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway providing a strategy for exploring risk-adapted individualized treatment de-escalation..
Hall, E.
Hussain, S.A.
Porta, N.
Lewis, R.
Crundwell, M.
Jenkins, P.
Rawlings, C.
Tremlett, J.
Sreenivasan, T.
Wallace, J.
Syndikus, I.
Sheehan, D.
Lydon, A.
Huddart, R.
James, N.
BC2001 Investigators,
(2022). Chemoradiotherapy in Muscle-invasive Bladder Cancer: 10-yr Follow-up of the Phase 3 Randomised Controlled BC2001 Trial. Eur urol,
Vol.82
(3),
pp. 273-279.
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BACKGROUND: BC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer (MIBC), demonstrated improvement in locoregional control by adding fluorouracil and mitomycin C to radiotherapy (James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012;366:1477-88). There are limited data on long-term recurrence risk. OBJECTIVE: To determine whether benefit of adding chemotherapy to radiotherapy for MIBC is maintained in the long term. DESIGN, SETTING, AND PARTICIPANTS: A phase 3 randomised controlled 2 × 2 factorial trial was conducted. Between 2001 and 2008, 458 patients with T2-T4a N0M0 MIBC were enrolled; 360 were randomised to radiotherapy (178) or chemoradiotherapy (182), and 218 were randomised to standard whole-bladder radiotherapy (108) or reduced high-dose-volume radiotherapy (111). The median follow-up time was 9.9 yr. The trial is registered (ISRCTN68324339). INTERVENTION: Radiotherapy: 55 Gy in 20 fractions over 4 wk or 64 Gy in 32 fractions over 6.5 wk; concurrent chemotherapy: 5-fluorouracil and mitomycin C. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Locoregional control (primary endpoint), invasive locoregional control, toxicity, rate of salvage cystectomy, disease-free survival (DFS), metastasis-free survival (MFS), bladder cancer-specific survival (BCSS), and overall survival. Cox regression was used. The analysis of efficacy outcomes was by intention to treat. RESULTS AND LIMITATIONS: Chemoradiotherapy improved locoregional control (hazard ratio [HR] 0.61 [95% confidence interval {CI} 0.43-0.86], p = 0.004) and invasive locoregional control (HR 0.55 [95% CI 0.36-0.84], p = 0.006). This benefit translated, albeit nonsignificantly, for disease-related outcomes: DFS (HR 0.78 [95% CI 0.60-1.02], p = 0.069), MFS (HR 0.78, [95% CI 0.58-1.05], p = 0.089), overall survival (HR = 0.88 [95% CI 0.69-1.13], p = 0.3), and BCSS (HR 0.79 [95% CI 0.59-1.06], p = 0.11). The 5-yr cystectomy rate was 14% (95% CI 9-21%) with chemoradiotherapy versus 22% (95% CI 16-31%) with radiotherapy alone (HR 0.54, [95% CI 0.31-0.95], p = 0.034). No differences were seen between standard and reduced high-dose-volume radiotherapy. CONCLUSIONS: Long-term findings confirm the benefit of adding concomitant 5-fluorouracil and mitomycin C to radiotherapy for MIBC. PATIENT SUMMARY: We looked at long-term outcomes of a phase 3 clinical trial testing radiotherapy with or without chemotherapy for patients with invasive bladder cancer. We concluded that the benefit of adding chemotherapy to radiotherapy was maintained over 10 yr..
Parr, H.
Hall, E.
Porta, N.
(2022). Joint models for dynamic prediction in localised prostate cancer: a literature review. Bmc med res methodol,
Vol.22
(1),
p. 245.
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BACKGROUND: Prostate cancer is a very prevalent disease in men. Patients are monitored regularly during and after treatment with repeated assessment of prostate-specific antigen (PSA) levels. Prognosis of localised prostate cancer is generally good after treatment, and the risk of having a recurrence is usually estimated based on factors measured at diagnosis. Incorporating PSA measurements over time in a dynamic prediction joint model enables updates of patients' risk as new information becomes available. We review joint model strategies that have been applied to model time-dependent PSA trajectories to predict time-to-event outcomes in localised prostate cancer. METHODS: We identify articles that developed joint models for prediction of localised prostate cancer recurrence over the last two decades. We report, compare, and summarise the methodological approaches and applications that use joint modelling accounting for two processes: the longitudinal model (PSA), and the time-to-event process (clinical failure). The methods explored differ in how they specify the association between these two processes. RESULTS: Twelve relevant articles were identified. A range of methodological frameworks were found, and we describe in detail shared-parameter joint models (9 of 12, 75%) and joint latent class models (3 of 12, 25%). Within each framework, these articles presented model development, estimation of dynamic predictions and model validations. CONCLUSIONS: Each framework has its unique principles with corresponding advantages and differing interpretations. Regardless of the framework used, dynamic prediction models enable real-time prediction of individual patient prognosis. They utilise all available longitudinal information, in addition to baseline prognostic risk factors, and are superior to traditional baseline-only prediction models..
Hussain, S.A.
Porta, N.
Hall, E.
Salawu, A.
Lewis, R.
Sreenivasan, T.
Wallace, J.
Crundwell, M.
Jenkins, P.
Tremlett, J.
Huddart, R.
James, N.D.
BC2001 Investigators,
(2021). Outcomes in Patients with Muscle-invasive Bladder Cancer Treated with Neoadjuvant Chemotherapy Followed by (Chemo)radiotherapy in the BC2001 Trial. Eur urol,
Vol.79
(2),
pp. 307-315.
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BACKGROUND: BC2001 demonstrated improved local control with the addition of chemotherapy to radiotherapy in 360 patients with muscle-invasive bladder cancer. OBJECTIVE: To establish whether such benefit remained in BC2001 patients who received prior neoadjuvant chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: A total of 117 patients (33%) received neoadjuvant chemotherapy and were randomised to radiotherapy with (48%) or without (52%) concomitant chemotherapy. Patients were recruited between August 2001 and April 2008 from 28 UK centres. INTERVENTION: Platinum-based neoadjuvant chemotherapy, followed by radiotherapy with (cRT) or without (RT) synchronous 5-fluorouracil and mitomycin-C. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Toxicity, locoregional control (LRC), overall survival (OS), and quality of life (QoL) were measured. RESULTS AND LIMITATIONS: Of the patients, 74% received gemcitabine plus cisplatin or carboplatin. Compliance rates with full-dose radiotherapy were cRT 93% and RT 92%. An excess of grade ≥3 toxicities while on (chemo)radiation occurred for cRT 33% versus RT 22%, although nonstatistically significant (p = 0.16). With 110 mo median follow-up for survival (interquartile range 96-123), cRT showed improved LRC though not statistically significant (adjusted hazard ratio [aHR] = 0.64, 95% confidence interval [CI] 0.33-1.23, p = 0.18). No differences in OS (aHR = 0.95, 95% CI 0.57-1.57, p = 0.8) were observed. No significant detriment in QoL was observed between cRT and RT in this subgroup of patients. CONCLUSIONS: Neoadjuvant chemotherapy does not compromise the delivery of radical curative treatment. Although underpowered due to a small sample size, the benefit of chemoradiotherapy to improve local control in this group of patients receiving neoadjuvant chemotherapy is consistent with that observed in the main trial. Although a nonsignificant excess of toxicity was observed, there was no evidence of impaired QoL. PATIENT SUMMARY: Chemotherapy before radical chemo(radiotherapy) is feasible and well tolerated..
Choudhury, A.
Porta, N.
Hall, E.
Song, Y.P.
Owen, R.
MacKay, R.
West, C.M.
Lewis, R.
Hussain, S.A.
James, N.D.
Huddart, R.
Hoskin, P.
BC2001 and BCON investigators,
(2021). Hypofractionated radiotherapy in locally advanced bladder cancer: an individual patient data meta-analysis of the BC2001 and BCON trials. Lancet oncol,
Vol.22
(2),
pp. 246-255.
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BACKGROUND: Two radiotherapy fractionation schedules are used to treat locally advanced bladder cancer: 64 Gy in 32 fractions over 6·5 weeks and a hypofractionated schedule of 55 Gy in 20 fractions over 4 weeks. Long-term outcomes of these schedules in several cohort studies and case series suggest that response, survival, and toxicity are similar, but no direct comparison has been published. The present study aimed to assess the non-inferiority of 55 Gy in 20 fractions to 64 Gy in 32 fractions in terms of invasive locoregional control and late toxicity in patients with locally advanced bladder cancer. METHODS: We did a meta-analysis of individual patient data from patients (age ≥18 years) with locally advanced bladder cancer (T1G3 [high-grade non-muscle invasive] or T2-T4, N0M0) enrolled in two multicentre, randomised, controlled, phase 3 trials done in the UK: BC2001 (NCT00024349; assessing addition of chemotherapy to radiotherapy) and BCON (NCT00033436; assessing hypoxia-modifying therapy combined with radiotherapy). In each trial, the fractionation schedule was chosen according to local standard practice. Co-primary endpoints were invasive locoregional control (non-inferiority margin hazard ratio [HR]=1·25); and late bladder or rectum toxicity, assessed with the Late Effects Normal Tissue Task Force-Subjective, Objective, Management, Analytic tool (non-inferiority margin for absolute risk difference [RD]=10%). If non-inferiority was met for invasive locoregional control, superiority could be considered if the 95% CI for the treatment effect excluded the null effect (HR=1). One-stage individual patient data meta-analysis models for the time-to-event and binary outcomes were used, accounting for trial differences, within-centre correlation, randomised treatment received, baseline variable imbalances, and potential confounding from relevant prognostic factors. FINDINGS: 782 patients with known fractionation schedules (456 from the BC2001 trial and 326 from the BCON trial; 376 (48%) received 64 Gy in 32 fractions and 406 (52%) received 55 Gy in 20 fractions) were included in our meta-analysis. Median follow-up was 120 months (IQR 99-159). Patients who received 55 Gy in 20 fractions had a lower risk of invasive locoregional recurrence than those who received 64 Gy in 32 fractions (adjusted HR 0·71 [95% CI 0·52-0·96]). Both schedules had similar toxicity profiles (adjusted RD -3·37% [95% CI -11·85 to 5·10]). INTERPRETATION: A hypofractionated schedule of 55 Gy in 20 fractions is non-inferior to 64 Gy in 32 fractions with regard to both invasive locoregional control and toxicity, and is superior with regard to invasive locoregional control. 55 Gy in 20 fractions should be adopted as a standard of care for bladder preservation in patients with locally advanced bladder cancer. FUNDING: Cancer Research UK..
Winfield, J.M.
Wakefield, J.C.
Brenton, J.D.
AbdulJabbar, K.
Savio, A.
Freeman, S.
Pace, E.
Lutchman-Singh, K.
Vroobel, K.M.
Yuan, Y.
Banerjee, S.
Porta, N.
Ahmed Raza, S.E.
deSouza, N.M.
(2021). Biomarkers for site-specific response to neoadjuvant chemotherapy in epithelial ovarian cancer: relating MRI changes to tumour cell load and necrosis. Br j cancer,
Vol.124
(6),
pp. 1130-1137.
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BACKGROUND: Diffusion-weighted magnetic resonance imaging (DW-MRI) potentially interrogates site-specific response to neoadjuvant chemotherapy (NAC) in epithelial ovarian cancer (EOC). METHODS: Participants with newly diagnosed EOC due for platinum-based chemotherapy and interval debulking surgery were recruited prospectively in a multicentre study (n = 47 participants). Apparent diffusion coefficient (ADC) and solid tumour volume (up to 10 lesions per participant) were obtained from DW-MRI before and after NAC (including double-baseline for repeatability assessment in n = 19). Anatomically matched lesions were analysed after surgical excision (65 lesions obtained from 25 participants). A trained algorithm determined tumour cell fraction, percentage tumour and percentage necrosis on histology. Whole-lesion post-NAC ADC and pre/post-NAC ADC changes were compared with histological metrics (residual tumour/necrosis) for each tumour site (ovarian, omental, peritoneal, lymph node). RESULTS: Tumour volume reduced at all sites after NAC. ADC increased between pre- and post-NAC measurements. Post-NAC ADC correlated negatively with tumour cell fraction. Pre/post-NAC changes in ADC correlated positively with percentage necrosis. Significant correlations were driven by peritoneal lesions. CONCLUSIONS: Following NAC in EOC, the ADC (measured using DW-MRI) increases differentially at disease sites despite similar tumour shrinkage, making its utility site-specific. After NAC, ADC correlates negatively with tumour cell fraction; change in ADC correlates positively with percentage necrosis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01505829..
Messiou, C.
Porta, N.
Sharma, B.
Levine, D.
Koh, D.-.
Boyd, K.
Pawlyn, C.
Riddell, A.
Downey, K.
Croft, J.
Morgan, V.
Stern, S.
Cheung, B.
Kyriakou, C.
Kaczmarek, P.
Winfield, J.
Blackledge, M.
Oyen, W.J.
Kaiser, M.F.
(2021). Prospective Evaluation of Whole-Body MRI versus FDG PET/CT for Lesion Detection in Participants with Myeloma. Radiol imaging cancer,
Vol.3
(5),
p. e210048.
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Purpose To compare disease detection of myeloma using contemporary whole-body (WB) MRI and fluorine 18 (18F) fluorodeoxyglucose (FDG) PET/CT protocols and to correlate imaging with laboratory estimates of disease burden, including molecular characteristics. Materials and Methods In this observational, prospective study, participants were recruited from November 2015 to March 2018 who had a diagnosis of myeloma, who were planned to undergo chemotherapy and autologous stem cell transplantation, and who underwent baseline WB-MRI and FDG PET/CT (ClinicalTrials.gov identifier NCT02403102). Baseline clinical data, including genetics, were collected. Paired methods were used to compare burden and patterns of disease. Results Sixty participants (mean age, 60 years ± 9 [standard deviation]; 35 men) underwent baseline WB-MRI and FDG PET/CT. WB-MRI showed significantly higher detection for focal lesions at all anatomic sites (except ribs, scapulae, and clavicles) and for diffuse disease at all sites. Two participants presented with two or more focal lesions smaller than 5 mm only at WB-MRI but not FDG PET/CT. Participants with diffuse disease at MRI had higher plasma cell infiltration (percentage of nucleated cells: median, 60% [interquartile range {IQR}, 50%-61%] vs 15% [IQR, 4%-50%]; P = .03) and paraprotein levels (median, 32.0 g/L [IQR, 24.0-48.0 g/L] vs 20.0 g/L [IQR, 12.0-22.6 g/L]; P = .02) compared with those without diffuse disease. All genetically high-risk tumors showed diffuse infiltration at WB-MRI. Conclusion WB-MRI helped detect a higher number of myeloma lesions than FDG PET/CT, and diffuse disease detected at WB-MRI correlated with laboratory measures of disease burden and molecular markers of risk. Keywords: MR-Imaging, Skeletal-Appendicular, Skeletal-Axial, Bone Marrow, Hematologic Diseases, Oncology Clinical trial registration no. NCT02403102. Supplemental material is available for this article. © RSNA, 2021..
McHugh, D.J.
Porta, N.
Little, R.A.
Cheung, S.
Watson, Y.
Parker, G.J.
Jayson, G.C.
O'Connor, J.P.
(2021). Image Contrast, Image Pre-Processing, and T1 Mapping Affect MRI Radiomic Feature Repeatability in Patients with Colorectal Cancer Liver Metastases. Cancers (basel),
Vol.13
(2).
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Imaging biomarkers require technical, biological, and clinical validation to be translated into robust tools in research or clinical settings. This study contributes to the technical validation of radiomic features from magnetic resonance imaging (MRI) by evaluating the repeatability of features from four MR sequences: pre-contrast T1- and T2-weighted images, pre-contrast quantitative T1 maps (qT1), and contrast-enhanced T1-weighted images. Fifty-one patients with colorectal cancer liver metastases were scanned twice, up to 7 days apart. Repeatability was quantified using the intraclass correlation coefficient (ICC) and repeatability coefficient (RC), and the impact of non-Gaussian feature distributions and image normalisation was evaluated. Most radiomic features had non-Gaussian distributions, but Box-Cox transformations enabled ICCs and RCs to be calculated appropriately for an average of 97% of features across sequences. ICCs ranged from 0.30 to 0.99, with volume and other shape features tending to be most repeatable; volume ICC > 0.98 for all sequences. 19% of features from non-normalised images exhibited significantly different ICCs in pair-wise sequence comparisons. Normalisation tended to increase ICCs for pre-contrast T1- and T2-weighted images, and decrease ICCs for qT1 maps. RCs tended to vary more between sequences than ICCs, showing that evaluations of feature performance depend on the chosen metric. This work suggests that feature-specific repeatability, from specific combinations of MR sequence and pre-processing steps, should be evaluated to select robust radiomic features as biomarkers in specific studies. In addition, as different repeatability metrics can provide different insights into a specific feature, consideration of the appropriate metric should be taken in a study-specific context..
Carreira, S.
Porta, N.
Arce-Gallego, S.
Seed, G.
Llop-Guevara, A.
Bianchini, D.
Rescigno, P.
Paschalis, A.
Bertan, C.
Baker, C.
Goodall, J.
Miranda, S.
Riisnaes, R.
Figueiredo, I.
Ferreira, A.
Pereira, R.
Crespo, M.
Gurel, B.
Nava Rodrigues, D.
Pettitt, S.J.
Yuan, W.
Serra, V.
Rekowski, J.
Lord, C.J.
Hall, E.
Mateo, J.
de Bono, J.S.
(2021). Biomarkers Associating with PARP Inhibitor Benefit in Prostate Cancer in the TOPARP-B Trial. Cancer discov,
Vol.11
(11),
pp. 2812-2827.
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PARP inhibitors are approved for treating advanced prostate cancers (APC) with various defective DNA repair genes; however, further studies to clinically qualify predictive biomarkers are warranted. Herein we analyzed TOPARP-B phase II clinical trial samples, evaluating whole-exome and low-pass whole-genome sequencing and IHC and IF assays evaluating ATM and RAD51 foci (testing homologous recombination repair function). BRCA1/2 germline and somatic pathogenic mutations associated with similar benefit from olaparib; greater benefit was observed with homozygous BRCA2 deletion. Biallelic, but not monoallelic, PALB2 deleterious alterations were associated with clinical benefit. In the ATM cohort, loss of ATM protein by IHC was associated with a better outcome. RAD51 foci loss identified tumors with biallelic BRCA and PALB2 alterations while most ATM- and CDK12-altered APCs had higher RAD51 foci levels. Overall, APCs with homozygous BRCA2 deletion are exceptional responders; PALB2 biallelic loss and loss of ATM IHC expression associated with clinical benefit. SIGNIFICANCE: Not all APCs with DNA repair defects derive similar benefit from PARP inhibition. Most benefit was seen among patients with BRCA2 homozygous deletions, biallelic loss of PALB2, and loss of ATM protein. Loss of RAD51 foci, evaluating homologous recombination repair function, was found primarily in tumors with biallelic BRCA1/2 and PALB2 alterations.This article is highlighted in the In This Issue feature, p. 2659..
Banerjee, S.
Stewart, J.
Porta, N.
Toms, C.
Leary, A.
Lheureux, S.
Khalique, S.
Tai, J.
Attygalle, A.
Vroobel, K.
Lord, C.J.
Natrajan, R.
Bliss, J.
(2021). ATARI trial: ATR inhibitor in combination with olaparib in gynecological cancers with ARID1A loss or no loss (ENGOT/GYN1/NCRI). Int j gynecol cancer,
Vol.31
(11),
pp. 1471-1475.
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BACKGROUND: ARID1A (AT-rich interactive domain containing protein 1A) loss-of-function mutations have been reported in gynecological cancers, including rarer subtypes such as clear cell carcinoma. Preclinical studies indicate that ARID1A mutant cancers display sensitivity to ATR inhibition while tumors without ARID1A mutations may be sensitive to Ataxia telangiectasia and Rad3 related (ATR) inhibitors in combination with poly-ADP ribose polymerase (PARP) inhibitors. PRIMARY OBJECTIVE: To determine whether the ATR inhibitor, ceralasertib, has clinical activity as a single agent and in combination with the PARP inhibitor, olaparib, in patients with ARID1A 'loss' and 'no loss' clear cell carcinomas and other relapsed gynecological cancers. STUDY HYPOTHESIS: ARID1A deficient clear cell carcinoma of the ovary or endometrium is sensitive to ATR inhibition, while the combination of ATR and PARP inhibition has activity in other gynecological tumors, irrespective of ARID1A status. TRIAL DESIGN: ATARI (ENGOT/GYN1/NCRI) is a multicenter, international, proof-of-concept, phase II, parallel cohort trial assessing ceralasertib activity as a single agent and in combination with olaparib in ARID1A stratified gynecological cancers. Patients with relapsed ovarian/endometrial clear cell carcinoma with ARID1A loss will receive ceralasertib monotherapy (cohort 1A). Relapsed ovarian/endometrial clear cell carcinoma patients with no ARID1A loss (cohort 2) or patients with other histological subtypes (endometrioid, carcinosarcoma, cervical) (cohort 3) will receive combination therapy (olaparib/ceralasertib). Treatment will continue until disease progression. MAJOR INCLUSION/EXCLUSION CRITERIA: Patients with histologically confirmed recurrent clear cell (ovarian, endometrial, or endometriosis related), endometrioid (ovarian, endometrial, or endometriosis related), cervical (adenocarcinomas or squamous), or carcinosarcomas (ovarian or endometrial) are eligible. Patients progressing after ≥1 prior platinum with evidence of measurable (RECIST v1.1) radiological disease progression since last systemic anticancer therapy and prior to trial entry are eligible. Previous ATR or PARP inhibitor treatment is not permissible. PRIMARY ENDPOINT: Best overall objective response rate (RECIST v1.1). SAMPLE SIZE: A minimum of 40 and a maximum of 116. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Accrual is anticipated to be complete by the second quarter of 2022, with reporting of results by the fourth quarter of 2022. Overall accrual targets and reporting timelines are dependent on individual cohort progression to stage 2. TRIAL REGISTRATION NUMBER: NCT0405269..
Rescigno, P.
Gurel, B.
Pereira, R.
Crespo, M.
Rekowski, J.
Rediti, M.
Barrero, M.
Mateo, J.
Bianchini, D.
Messina, C.
Fenor de la Maza, M.D.
Chandran, K.
Carmichael, J.
Guo, C.
Paschalis, A.
Sharp, A.
Seed, G.
Figueiredo, I.
Lambros, M.
Miranda, S.
Ferreira, A.
Bertan, C.
Riisnaes, R.
Porta, N.
Yuan, W.
Carreira, S.
de Bono, J.S.
(2021). Characterizing CDK12-Mutated Prostate Cancers. Clin cancer res,
Vol.27
(2),
pp. 566-574.
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PURPOSE: Cyclin-dependent kinase 12 (CDK12) aberrations have been reported as a biomarker of response to immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). Herein, we characterize CDK12-mutated mCRPC, presenting clinical, genomic, and tumor-infiltrating lymphocyte (TIL) data. EXPERIMENTAL DESIGN: Patients with mCRPC consented to the molecular analyses of diagnostic and mCRPC biopsies. Genomic analyses involved targeted next-generation (MiSeq; Illumina) and exome sequencing (NovaSeq; Illumina). TILs were assessed by validated immunocytochemistry coupled with deep learning-based artificial intelligence analyses including multiplex immunofluorescence assays for CD4, CD8, and FOXP3 evaluating TIL subsets. The control group comprised a randomly selected mCRPC cohort with sequencing and clinical data available. RESULTS: Biopsies from 913 patients underwent targeted sequencing between February 2015 and October 2019. Forty-three patients (4.7%) had tumors with CDK12 alterations. CDK12-altered cancers had distinctive features, with some revealing high chromosomal break numbers in exome sequencing. Biallelic CDK12-aberrant mCRPCs had shorter overall survival from diagnosis than controls [5.1 years (95% confidence interval (CI), 4.0-7.9) vs. 6.4 years (95% CI, 5.7-7.8); hazard ratio (HR), 1.65 (95% CI, 1.07-2.53); P = 0.02]. Median intratumoral CD3+ cell density was higher in CDK12 cancers, although this was not statistically significant (203.7 vs. 86.7 cells/mm2; P = 0.07). This infiltrate primarily comprised of CD4+FOXP3- cells (50.5 vs. 6.2 cells/mm2; P < 0.0001), where high counts tended to be associated with worse survival from diagnosis (HR, 1.64; 95% CI, 0.95-2.84; P = 0.077) in the overall population. CONCLUSIONS: CDK12-altered mCRPCs have worse prognosis, with these tumors surprisingly being primarily enriched for CD4+FOXP3- cells that seem to associate with worse outcome and may be immunosuppressive.See related commentary by Lotan and Antonarakis, p. 380..
Mariam, N.B.
Song, Y.P.
Joseph, N.
Hoskin, P.
Reeves, K.
Porta, N.
James, N.
Choudhury, A.
(2021). Hypofractionation: less is more?. Oncotarget,
Vol.12
(17),
pp. 1729-1733.
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One third of patients with bladder cancer present with muscle invasive bladder cancer (MIBC) which has a poor prognosis. International guidelines for the management of MIBC recommend radical cystectomy or bladder-preserving treatment based on radical radiotherapy with a form of radiosensitisation. In the UK, both conventional fractionation with 64 Gy in 32 fractions and hypofractionation with 55 Gy in 20 fractions are standard of care options with the choice varying between centres. A meta-analysis of individual patients with locally advanced bladder cancer from two UK multicentre phase 3 trials was published recently. This study evaluated the non-inferiority of a hypofractionated schedule compared to a conventional regime. This analysis confirmed the non-inferiority of the hypofractionated regimen, and noted superior locoregional control. We discuss the relevance of these findings to current practice while considering the radiobiology of hypofractionation, the role of systemic therapies and radiosensitisation, as well as the socioeconomic benefits..
Mateo, J.
Seed, G.
Bertan, C.
Rescigno, P.
Dolling, D.
Figueiredo, I.
Miranda, S.
Nava Rodrigues, D.
Gurel, B.
Clarke, M.
Atkin, M.
Chandler, R.
Messina, C.
Sumanasuriya, S.
Bianchini, D.
Barrero, M.
Petermolo, A.
Zafeiriou, Z.
Fontes, M.
Perez-Lopez, R.
Tunariu, N.
Fulton, B.
Jones, R.
McGovern, U.
Ralph, C.
Varughese, M.
Parikh, O.
Jain, S.
Elliott, T.
Sandhu, S.
Porta, N.
Hall, E.
Yuan, W.
Carreira, S.
de Bono, J.S.
(2020). Genomics of lethal prostate cancer at diagnosis and castration resistance. J clin invest,
Vol.130
(4),
pp. 1743-1751.
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The genomics of primary prostate cancer differ from those of metastatic castration-resistant prostate cancer (mCRPC). We studied genomic aberrations in primary prostate cancer biopsies from patients who developed mCRPC, also studying matching, same-patient, diagnostic, and mCRPC biopsies following treatment. We profiled 470 treatment-naive prostate cancer diagnostic biopsies and, for 61 cases, mCRPC biopsies, using targeted and low-pass whole-genome sequencing (n = 52). Descriptive statistics were used to summarize mutation and copy number profile. Prevalence was compared using Fisher's exact test. Survival correlations were studied using log-rank test. TP53 (27%) and PTEN (12%) and DDR gene defects (BRCA2 7%; CDK12 5%; ATM 4%) were commonly detected. TP53, BRCA2, and CDK12 mutations were markedly more common than described in the TCGA cohort. Patients with RB1 loss in the primary tumor had a worse prognosis. Among 61 men with matched hormone-naive and mCRPC biopsies, differences were identified in AR, TP53, RB1, and PI3K/AKT mutational status between same-patient samples. In conclusion, the genomics of diagnostic prostatic biopsies acquired from men who develop mCRPC differ from those of the nonlethal primary prostatic cancers. RB1/TP53/AR aberrations are enriched in later stages, but the prevalence of DDR defects in diagnostic samples is similar to mCRPC..
Mateo, J.
Porta, N.
Bianchini, D.
McGovern, U.
Elliott, T.
Jones, R.
Syndikus, I.
Ralph, C.
Jain, S.
Varughese, M.
Parikh, O.
Crabb, S.
Robinson, A.
McLaren, D.
Birtle, A.
Tanguay, J.
Miranda, S.
Figueiredo, I.
Seed, G.
Bertan, C.
Flohr, P.
Ebbs, B.
Rescigno, P.
Fowler, G.
Ferreira, A.
Riisnaes, R.
Pereira, R.
Curcean, A.
Chandler, R.
Clarke, M.
Gurel, B.
Crespo, M.
Nava Rodrigues, D.
Sandhu, S.
Espinasse, A.
Chatfield, P.
Tunariu, N.
Yuan, W.
Hall, E.
Carreira, S.
de Bono, J.S.
(2020). Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet oncol,
Vol.21
(1),
pp. 162-174.
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BACKGROUND: Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer. METHODS: In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to <5 cells per 7·5 mL blood). A confirmed response in a consecutive assessment after at least 4 weeks was required for each component. The primary analysis was done in the evaluable population. If at least 19 (43%) of 44 evaluable patients in a dose cohort responded, then the dose cohort would be considered successful. Safety was assessed in all patients who received at least one dose of olaparib. This trial is registered at ClinicalTrials.gov, NCT01682772. Recruitment for the trial has completed and follow-up is ongoing. FINDINGS: 711 patients consented for targeted screening between April 1, 2015, and Aug 30, 2018. 161 patients had DDR gene aberrations, 98 of whom were randomly assigned and treated (49 patients for each olaparib dose), with 92 evaluable for the primary endpoint (46 patients for each olaparib dose). Median follow-up was 24·8 months (IQR 16·7-35·9). Confirmed composite response was achieved in 25 (54·3%; 95% CI 39·0-69·1) of 46 evaluable patients in the 400 mg cohort, and 18 (39·1%; 25·1-54·6) of 46 evaluable patients in the 300 mg cohort. Radiological response was achieved in eight (24·2%; 11·1-42·3) of 33 evaluable patients in the 400 mg cohort and six (16·2%; 6·2-32·0) of 37 in the 300 mg cohort; PSA50 response was achieved in 17 (37·0%; 23·2-52·5) of 46 and 13 (30·2%; 17·2-46·1) of 43; and circulating tumour cell count conversion was achieved in 15 (53·6%; 33·9-72·5) of 28 and 13 (48·1%; 28·7-68·1) of 27. The most common grade 3-4 adverse event in both cohorts was anaemia (15 [31%] of 49 patients in the 300 mg cohort and 18 [37%] of 49 in the 400 mg cohort). 19 serious adverse reactions were reported in 13 patients. One death possibly related to treatment (myocardial infarction) occurred after 11 days of treatment in the 300 mg cohort. INTERPRETATION: Olaparib has antitumour activity against metastatic castration-resistant prostate cancer with DDR gene aberrations, supporting the implementation of genomic stratification of metastatic castration-resistant prostate cancer in clinical practice. FUNDING: Cancer Research UK, AstraZeneca, Prostate Cancer UK, the Prostate Cancer Foundation, the Experimental Cancer Medicine Centres Network, and the National Institute for Health Research Biomedical Research Centres..
Huddart, R.A.
Hall, E.
Lewis, R.
Porta, N.
Crundwell, M.
Jenkins, P.J.
Rawlings, C.
Tremlett, J.
Campani, L.
Hendron, C.
Hussain, S.A.
James, N.D.
BC2001 Investigators,
(2020). Patient-reported Quality of Life Outcomes in Patients Treated for Muscle-invasive Bladder Cancer with Radiotherapy ± Chemotherapy in the BC2001 Phase III Randomised Controlled Trial. Eur urol,
Vol.77
(2),
pp. 260-268.
show abstract
full text
BACKGROUND: BC2001, the largest randomised trial of bladder-sparing treatment for muscle-invasive bladder cancer, demonstrated improvement of local control and bladder cancer-specific survival from the addition of concomitant 5-fluorouracil and mitomycin C to radiotherapy. OBJECTIVE: To determine the impact of treatment on the health-related quality of life (HRQoL) of BC2001 participants. DESIGN, SETTING, AND PARTICIPANTS: 458 UK patients with T2-T4a N0 M0 transitional cell carcinoma of the bladder. INTERVENTION: Patients were randomised to the chemotherapy comparison (radiotherapy, 178, or chemoradiotherapy, 182); and/or to the radiotherapy comparison (standard, 108, or reduced high-dose volume radiotherapy, 111). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients completed Functional Assessment of Cancer Therapy-Bladder (FACT-BL) questionnaires at baseline, end of treatment (EoT), and 6, 12, 24, 36, 48, and 60 months after radiotherapy. The primary endpoint was change from baseline in the bladder cancer subscale (BLCS) at 12 months. RESULTS AND LIMITATIONS: Data were available for 331 (92%) and 204 (93%) participants at baseline and for 192 (54%) and 114 (52%) at 12 months for the chemotherapy and radiotherapy comparisons, respectively. HRQoL declined at EoT (BLCS -5.06 [99% confidence interval: -6.12 to -4.00, p< 0.001]; overall FACT-B TOTAL score -8.22 [-10.76 to -5.68, p< 0.01]), recovering to baseline at 6 months and remaining similar to baseline subsequently. There was no significant difference between randomised groups at any time point. CONCLUSIONS: Immediately following (chemo)radiotherapy, a significant proportion of patients report declines in HRQoL, which improve to baseline after 6 months. Two-thirds of patients report stable or improved HRQoL on long-term follow-up. There is no evidence of impairment in HRQoL resulting from the addition of chemotherapy. PATIENT SUMMARY: Quality of life of bladder cancer patients treated with radiotherapy±chemotherapy deteriorates during treatment, but improves to at least pretreatment levels within 6 months. Addition of chemotherapy to radiotherapy does not affect patient-reported quality of life..
Cullen, M.
Huddart, R.
Joffe, J.
Gardiner, D.
Maynard, L.
Hutton, P.
Mazhar, D.
Shamash, J.
Wheater, M.
White, J.
Goubar, A.
Porta, N.
Witts, S.
Lewis, R.
Hall, E.
111 Trial Management Group,
(2020). The 111 Study: A Single-arm, Phase 3 Trial Evaluating One Cycle of Bleomycin, Etoposide, and Cisplatin as Adjuvant Chemotherapy in High-risk, Stage 1 Nonseminomatous or Combined Germ Cell Tumours of the Testis. Eur urol,
Vol.77
(3),
pp. 344-351.
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BACKGROUND: Standard management in the UK for high-risk stage 1 nonseminoma germ cell tumours of the testis (NSGCTT) is two cycles of adjuvant bleomycin, etoposide (360 mg/m2), and cisplatin (BE360P) chemotherapy, or surveillance. OBJECTIVE: To test whether one cycle of BE500P achieves similar recurrence rates to two cycles of BE360P. DESIGN, SETTING, AND PARTICIPANTS: A total of 246 patients with vascular invasion-positive stage 1 NSGCTT or combined seminoma + NSGCTT were centrally registered in a single-arm prospective study. INTERVENTION: One cycle comprising bleomycin 30000 IU on days 1, 8, and 15, etoposide 165 mg/m2 on days 1-3, and cisplatin 50 mg/m2 on days 1-2, plus antibacterial and granulocyte colony stimulating factor prophylaxis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was 2-yr malignant recurrence (MR); the aim was to exclude a rate of ≥5%. Participants had regular imaging and tumour marker (TM) assessment for 5 yr. RESULTS AND LIMITATIONS: The median follow-up was 49 mo (interquartile range 37-60). Ten patients with rising TMs at baseline were excluded. Four patients had MR at 6, 7, 13, and 27 mo; all received second-line chemotherapy and surgery and three remained recurrence-free at 5 yr. The 2-yr MR rate was 1.3% (95% confidence interval 0.3-3.7%). Three patients developed nonmalignant recurrences with localised teratoma differentiated, rendered disease-free after surgery. Grade 3-4 febrile neutropenia occurred in 6.8% of participants. CONCLUSIONS: BE500P is safe and the 2-yr MR rate is consistent with that seen following two BE360P cycles. The 111 study is the largest prospective trial investigating one cycle of adjuvant BE500P in high-risk stage 1 NSGCTT. Adoption of one cycle of BE500P as standard would reduce overall exposure to chemotherapy in this young population. PATIENT SUMMARY: Removing the testicle fails to cure many patients with high-risk primary testicular cancer since undetectable cancers are often present elsewhere. A standard additional treatment in Europe is two cycles of chemotherapy to eradicate these. This trial shows one cycle has few adverse effects and comparable outcomes to those seen with two cycles..
Kolinsky, M.P.
Rescigno, P.
Bianchini, D.
Zafeiriou, Z.
Mehra, N.
Mateo, J.
Michalarea, V.
Riisnaes, R.
Crespo, M.
Figueiredo, I.
Miranda, S.
Nava Rodrigues, D.
Flohr, P.
Tunariu, N.
Banerji, U.
Ruddle, R.
Sharp, A.
Welti, J.
Lambros, M.
Carreira, S.
Raynaud, F.I.
Swales, K.E.
Plymate, S.
Luo, J.
Tovey, H.
Porta, N.
Slade, R.
Leonard, L.
Hall, E.
de Bono, J.S.
(2020). A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer. Ann oncol,
Vol.31
(5),
pp. 619-625.
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BACKGROUND: Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss. PATIENTS AND METHODS: mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated. RESULTS: Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline ≥50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples. CONCLUSIONS: The combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway. CLINICAL TRIAL NUMBER: NCT02525068..
Mostafid, A.H.
Porta, N.
Cresswell, J.
Griffiths, T.R.
Kelly, J.D.
Penegar, S.R.
Davenport, K.
McGrath, J.S.
Campain, N.
Cooke, P.
Masood, S.
Knowles, M.A.
Feber, A.
Knight, A.
Catto, J.W.
Lewis, R.
Hall, E.
(2020). CALIBER: a phase II randomized feasibility trial of chemoablation with mitomycin-C vs surgical management in low-risk non-muscle-invasive bladder cancer. Bju int,
Vol.125
(6),
pp. 817-826.
show abstract
OBJECTIVES: To evaluate the activity of intravesical mitomycin-C (MMC) to ablate recurrent low-risk non-muscle-invasive bladder cancer (NMIBC) and assess whether it may enable patients to avoid surgical intervention for treatment of recurrence. PATIENTS AND METHODS: CALIBER is a phase II feasibility study. Participants were randomized (2:1) to treatment with four once-weekly MMC 40-mg intravesical instillations (chemoablation arm) or to surgical management. The surgical group was included to assess the feasibility of randomization. The primary endpoint was complete response to intravesical MMC in the chemoablation arm at 3 months, reported with exact 95% confidence intervals (CIs). Secondary endpoints included time to subsequent recurrence, summarized by Kaplan-Meier methods. RESULTS: Between February 2015 and August 2017, 82 patients with visual diagnosis of recurrent low-risk NMIBC were enrolled from 24 UK hospitals (chemoablation, n = 54; surgical management, n =28). The median follow-up was 24 months. Complete response at 3 months was 37.0% (20/54; 95% CI 24.3-51.3) with chemoablation and 80.8% (21/26; 95% CI 60.6-93.4) with surgical management. Amongst patients with complete response at 3 months, a similar proportion was recurrence-free by 12 months in both groups (84%). Amongst those with residual disease at 3 months, the 12-month recurrence-free proportion was lower in the surgical management group (40.0%) than in the chemoablation group (84%). Recruitment stopped early as chemoablation did not meet the prespecified threshold of 45% complete responses at 3 months. CONCLUSION: Intravesical chemoablation in low-risk NMIBC is feasible and safe, but did not demonstrate sufficient response in the present trial. After chemoablation there may be a reduction in recurrence rate, even in non-responders, that is greater than with surgery alone. Further research is required to investigate the role and optimal schedule of neoadjuvant intravesical chemotherapy prior to surgery for NMIBC..
Cox, E.
Saramago, P.
Kelly, J.
Porta, N.
Hall, E.
Tan, W.S.
Sculpher, M.
Soares, M.
(2020). Effects of Bladder Cancer on UK Healthcare Costs and Patient Health-Related Quality of Life: Evidence From the BOXIT Trial. Clin genitourin cancer,
Vol.18
(4),
pp. e418-e442.
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BACKGROUND: Limited evidence exists regarding the cost and health-related quality of life (HRQoL) effects of non-muscle-invasive bladder cancer (NMIBC) recurrence and progression to muscle-invasive bladder cancer (MIBC). We examined these effects using evidence from a recent randomized control trial. MATERIAL AND METHODS: The costs and HRQoL associated with bladder cancer were assessed using data from the BOXIT trial (bladder COX-2 inhibition trial; n = 472). The cost and HRQoL effects from clinical events were estimated using generalized estimating equations. The costs were derived from the recorded resource usage and UK unit costs. HRQoL was assessed using the EQ-5D-3L and reported UK preference tariffs. The events were categorized using the TMN classification. RESULTS: Cases of grade 3 recurrence and progression were associated with statistically significant HRQoL decrements (-0.08; 95% confidence interval [CI], -0.13 to -0.03; and -0.10; 95% CI, -0.17 to -0.03, respectively). The 3-year average cost per NMIBC patient was estimated at £8735 (95% CI, 8325-9145). Cases of grade 1, 2, and 3 recurrence were associated with annual cost effects of £1218 (95% CI, 403-2033), £1677 (95% CI, 920-2433), and £3957 (95% CI, 2332-5583), respectively. Progression to MIBC was associated with an average increase in costs of £5407 (95% CI, 2663-8152). CONCLUSION: Evidence from the BOXIT trial suggests that patients with NMIBC will both experience decrements in HRQoL and incur significant costs, especially in the event of a grade 3 recurrence or a progression to MIBC..
Syndikus, I.
Cruickshank, C.
Staffurth, J.
Tree, A.
Henry, A.
Naismith, O.
Mayles, H.
Snelson, N.
Hassan, S.
Brown, S.
Porta, N.
Griffin, C.
Hall, E.
(2020). PIVOTALboost: A phase III randomised controlled trial of prostate and pelvis versus prostate alone radiotherapy with or without prostate boost (CRUK/16/018). Clin transl radiat oncol,
Vol.25,
pp. 22-28.
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•PIVOTALboost evaluates benefits/toxicity of pelvic node RT and focal boost dose escalation.•Unfavourable intermediate/high risk and bulky local disease are most likely to benefit.•Functional MRI imaging is used to select patients for different types of dose escalation.•HDR brachytherapy or focal dose escalation with IMRT are used as options.•Training and support is provided to reduce variations of contouring and radiotherapy planning.•The trial is recruiting patients in 38 radiotherapy centres through the UK..
Kelly, J.D.
Tan, W.S.
Porta, N.
Mostafid, H.
Huddart, R.
Protheroe, A.
Bogle, R.
Blazeby, J.
Palmer, A.
Cresswell, J.
Johnson, M.
Brough, R.
Madaan, S.
Andrews, S.
Cruickshank, C.
Burnett, S.
Maynard, L.
Hall, E.
BOXIT Investigators,
(2019). BOXIT-A Randomised Phase III Placebo-controlled Trial Evaluating the Addition of Celecoxib to Standard Treatment of Transitional Cell Carcinoma of the Bladder (CRUK/07/004). Eur urol,
Vol.75
(4),
pp. 593-601.
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BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) has a significant risk of recurrence despite adjuvant intravesical therapy. OBJECTIVE: To determine whether celecoxib, a cyclo-oxygenase 2 inhibitor, reduces the risk of recurrence in NMIBC patients receiving standard treatment. DESIGN, SETTING, AND PARTICIPANTS: BOXIT (CRUK/07/004, ISRCTN84681538) is a double-blinded, phase III, randomised controlled trial. Patients aged ≥18 yr with intermediate- or high-risk NMIBC were accrued across 51 UK centres between 1 November 2007 and 23 July 2012. INTERVENTION: Patients were randomised (1:1) to celecoxib 200mg twice daily or placebo for 2 yr. Patients with intermediate-risk NMIBC were recommended to receive six weekly mitomycin C instillations; high-risk NMIBC cases received six weekly bacillus Calmette-Guérin and maintenance therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was time to disease recurrence. Analysis was by intention to treat. RESULTS AND LIMITATIONS: A total of 472 patients were randomised (236:236). With median follow-up of 44 mo (interquartile range: 36-57), 3-yr recurrence-free rate (95% confidence interval) was as follows: celecoxib 68% (61-74%) versus placebo 64% (57-70%; hazard ratio [HR] 0.82 [0.60-1.12], p=0.2). There was no difference in high-risk (HR 0.77 [0.52-1.15], p=0.2) or intermediate-risk (HR 0.90 [0.55-1.48], p=0.7) NMIBC. Subgroup analysis suggested that time to recurrence was longer in pT1 NMIBC patients treated with celecoxib compared with those receiving placebo (HR 0.53 [0.30-0.94], interaction test p=0.04). The 3-yr progression rates in high-risk patients were low: 10% (6.5-17%) and 9.7% (6.0-15%) in celecoxib and placebo arms, respectively. Incidence of serious cardiovascular events was higher in celecoxib (5.2%) than in placebo (1.7%) group (difference +3.4% [-0.3% to 7.2%], p=0.07). CONCLUSIONS: BOXIT did not show that celecoxib reduces the risk of recurrence in intermediate- or high-risk NMIBC, although celecoxib was associated with delayed time to recurrence in pT1 NMIBC patients. The increased risk of cardiovascular events does not support the use of celecoxib. PATIENT SUMMARY: Celecoxib was not shown to reduce the risk of recurrence in intermediate- or high-risk non-muscle-invasive bladder cancer (NMIBC), although celecoxib was associated with delayed time to recurrence in pT1 NMIBC patients. The increased risk of cardiovascular events does not support the use of celecoxib..
Haviland, J.S.
Mannino, M.
Griffin, C.
Porta, N.
Sydenham, M.
Bliss, J.M.
Yarnold, J.R.
START Trialists' Group,
(2018). Late normal tissue effects in the arm and shoulder following lymphatic radiotherapy: Results from the UK START (Standardisation of Breast Radiotherapy) trials. Radiother oncol,
Vol.126
(1),
pp. 155-162.
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full text
BACKGROUND AND PURPOSE: Adjuvant lymphatic radiotherapy (LNRT) is recommended for selected axillary node positive women with early breast cancer. We investigated whether hypofractionated LNRT is safe combined with similarly-hypofractionated breast/chest wall radiotherapy (RT). MATERIAL AND METHODS: The Standardisation of Breast Radiotherapy (START) pilot, A and B trials randomised women with early breast cancer to schedules of 2.67-3.3 Gy versus 2.0 Gy fractions (control). RT adverse effects were assessed by patients using the EORTC QLQ-BR23 and protocol-specific questions, and by physicians. Rates of arm/shoulder effects were compared between schedules for patients given LNRT. RESULTS: 864/5861 (14.7%) patients received LNRT (385 START-pilot, 318 START-A, 161 START-B). Prevalences of moderate/marked arm/shoulder effects were low up to 10 years. There were no significant differences between the hypofractionated and control groups for patient- and physician-assessed symptoms in START-A or START-B. In START-pilot, adverse effect rates were higher after 13 fractions of 3.3 Gy, consistent with effects reported in the breast/chest wall (significant for shoulder stiffness, HR 3.07, 95%CI 1.62-5.83, p = 0.001). CONCLUSIONS: The START trial results suggest that appropriately-dosed hypofractionated LNRT is safe in the long-term, according to patient and physician-assessed arm and shoulder symptoms. These findings are consistent with those reported after the same schedules delivered to the breast/chest wall..
Cheang, M.C.
Bliss, J.M.
Viale, G.
Speirs, V.
Palmieri, C.
Shaaban, A.
Lønning, P.E.
Morden, J.
Porta, N.
Jassem, J.
van De Velde, C.J.
Rasmussen, B.B.
Verhoeven, D.
Bartlett, J.M.
Coombes, R.C.
PathIES Sub-Committee,
(2018). Evaluation of applying IHC4 as a prognostic model in the translational study of Intergroup Exemestane Study (IES): PathIES. Breast cancer res treat,
Vol.168
(1),
pp. 169-178.
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BACKGROUND: Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to exemestane. This PathIES aimed to assess the role of immunohistochemical (IHC)4 score in determining the relative sensitivity to either tamoxifen or sequential treatment with tamoxifen and exemestane. PATIENTS AND METHODS: Primary tumour samples were available for 1274 patients (27% of IES population). Only patients for whom the IHC4 score could be calculated (based on oestrogen receptor, progesterone receptor, HER2 and Ki67) were included in this analysis (N = 430 patients). The clinical score (C) was based on age, grade, tumour size and nodal status. The association of clinicopathological parameters, IHC4(+C) scores and treatment effect with time to distant recurrence-free survival (TTDR) was assessed in univariable and multivariable Cox regression analyses. A modified clinical score (PathIEscore) (N = 350) was also estimated. RESULTS: Our results confirm the prognostic importance of the original IHC4, alone and in conjunction with clinical scores, but no significant difference with treatment effects was observed. The combined IHC4 + Clinical PathIES score was prognostic for TTDR (P < 0.001) with a hazard ratio (HR) of 5.54 (95% CI 1.29-23.70) for a change from 1st quartile (Q1) to Q1-Q3 and HR of 15.54 (95% CI 3.70-65.24) for a change from Q1 to Q4. CONCLUSION: In the PathIES population, the IHC4 score is useful in predicting long-term relapse in patients who remain disease-free after 2-3 years. This is a first trial to suggest the extending use of IHC4+C score for prognostic indication for patients who have switched endocrine therapies at 2-3 years and who remain disease-free after 2-3 years..
Lorente, D.
Ravi, P.
Mehra, N.
Pezaro, C.
Omlin, A.
Gilman, A.
Miranda, M.
Rescigno, P.
Kolinsky, M.
Porta, N.
Bianchini, D.
Tunariu, N.
Perez, R.
Mateo, J.
Payne, H.
Terstappen, L.
IJzerman, M.
Hall, E.
de Bono, J.
(2018). Interrogating Metastatic Prostate Cancer Treatment Switch Decisions: A Multi-institutional Survey. Eur urol focus,
Vol.4
(2),
pp. 235-244.
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BACKGROUND: Evaluation of responses to treatment for metastatic castration-resistant prostate cancer (mCRPC) remains challenging. Consensus criteria based on prostate-specific antigen (PSA) and clinical and radiologic biomarkers are inconsistently utilized. Circulating tumor cell (CTC) counts can inform prognosis and response, but are not routinely used. OBJECTIVE: To evaluate the use of biomarkers and trends in clinical decision-making in current mCRPC treatment. DESIGN, SETTING, AND PARTICIPANTS: A 23-part online questionnaire was completed by physicians treating mCRPC. OUTCOME MEASURES AND STATISTICAL ANALYSIS: Results are presented as the proportion (%) of physicians responding to each of the options. We used χ2 and Fisher's tests to compare differences. RESULTS AND LIMITATIONS: A total of 118 physicians (22.1%) responded. Of these, 69.4% treated ≥50 mCRPC patients/year. More physicians administered four or fewer courses of cabazitaxel (27.9%) than for docetaxel (10.4%), with no significant difference in the number of courses between bone-only disease and Response Evaluation Criteria in Solid Tumours (RECIST)-evaluable disease. Some 74.5% of respondents considered current biomarkers useful for monitoring disease, but only 39.6% used the Prostate Cancer Working Group (PCWG2) criteria in clinical practice. PSA was considered an important biomarker by 55.7%, but only 41.4% discarded changes in PSA before 12 wk, and only 39.4% were able to identify bone-scan progression according to PCWG2. The vast majority of physicians (90.5%) considered clinical progression to be important for switching treatment. The proportion considering biomarkers important was 71.6% for RECIST, 47.4% for bone scans, 23.2% for CTCs, and 21.1% for PSA. Although 53.1% acknowledged that baseline CTC counts are prognostic, only 33.7% would use CTC changes alone to switch treatment in patients with bone-only disease. The main challenges in using CTC counts were access to CTC technology (84.7%), cost (74.5%), and uncertainty over utility as a response indicator (58.2%). CONCLUSIONS: A significant proportion of physicians discontinue treatment for mCRPC before 12 wk, raising concerns about inadequate response assessment. Many physicians find current biomarkers useful, but most rely on symptoms to drive treatment switch decisions, suggesting there is a need for more precise biomarkers. PATIENT SUMMARY: In this report we analyse the results of a questionnaire evaluating tools for clinical decision-making completed by 118 prostate cancer specialists. We found that most physicians favour clinical progression over prostate-specific antigen or imaging, and that criteria established by the Prostate Cancer Working Group are not widely used..
Franco, P.
Porta, N.
Holliday, J.D.
Willett, P.
(2017). Molecular similarity considerations in the licensing of orphan drugs. Drug discov today,
Vol.22
(2),
pp. 377-381.
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The large costs associated with modern drug discovery mean that governments and regulatory bodies need to provide economic incentives to promote the development of orphan drugs (i.e., medicinal products that are designed to treat rare disease that affect only small numbers of patients). Under European Union (EU) legislation, a medicine can only be authorised for treating a specific rare disease if it is not similar to other orphan drugs already authorised for that particular disease. Here, we discuss the use of 2D fingerprints to calculate the Tanimoto similarity between potential and existing orphan drugs for the same disease, and present logistic regression models correlating these computed similarities with the judgements of human experts..
Perez-Lopez, R.
Mateo, J.
Mossop, H.
Blackledge, M.D.
Collins, D.J.
Rata, M.
Morgan, V.A.
Macdonald, A.
Sandhu, S.
Lorente, D.
Rescigno, P.
Zafeiriou, Z.
Bianchini, D.
Porta, N.
Hall, E.
Leach, M.O.
de Bono, J.S.
Koh, D.-.
Tunariu, N.
(2017). Diffusion-weighted Imaging as a Treatment Response Biomarker for Evaluating Bone Metastases in Prostate Cancer: A Pilot Study. Radiology,
Vol.283
(1),
pp. 168-177.
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full text
Purpose To determine the usefulness of whole-body diffusion-weighted imaging (DWI) to assess the response of bone metastases to treatment in patients with metastatic castration-resistant prostate cancer (mCRPC). Materials and Methods A phase II prospective clinical trial of the poly-(adenosine diphosphate-ribose) polymerase inhibitor olaparib in mCRPC included a prospective magnetic resonance (MR) imaging substudy; the study was approved by the institutional research board, and written informed consent was obtained. Whole-body DWI was performed at baseline and after 12 weeks of olaparib administration by using 1.5-T MR imaging. Areas of abnormal signal intensity on DWI images in keeping with bone metastases were delineated to derive total diffusion volume (tDV); five target lesions were also evaluated. Associations of changes in volume of bone metastases and median apparent diffusion coefficient (ADC) with response to treatment were assessed by using the Mann-Whitney test and logistic regression; correlation with prostate-specific antigen level and circulating tumor cell count were assessed by using Spearman correlation (r). Results Twenty-one patients were included. All six responders to olaparib showed a decrease in tDV, while no decrease was observed in all nonresponders; this difference between responders and nonresponders was significant (P = .001). Increases in median ADC were associated with increased odds of response (odds ratio, 1.08; 95% confidence interval [CI]: 1.00, 1.15; P = .04). A positive association was detected between changes in tDV and best percentage change in prostate-specific antigen level and circulating tumor cell count (r = 0.63 [95% CI: 0.27, 0.83] and r = 0.77 [95% CI: 0.51, 0.90], respectively). When assessing five target lesions, decreases in volume were associated with response (odds ratio for volume increase, 0.89; 95% CI: 0.80, 0.99; P = .037). Conclusion This pilot study showed that decreases in volume and increases in median ADC of bone metastases assessed with whole-body DWI can potentially be used as indicators of response to olaparib in mCRPC. Online supplemental material is available for this article..
Goodall, J.
Mateo, J.
Yuan, W.
Mossop, H.
Porta, N.
Miranda, S.
Perez-Lopez, R.
Dolling, D.
Robinson, D.R.
Sandhu, S.
Fowler, G.
Ebbs, B.
Flohr, P.
Seed, G.
Rodrigues, D.N.
Boysen, G.
Bertan, C.
Atkin, M.
Clarke, M.
Crespo, M.
Figueiredo, I.
Riisnaes, R.
Sumanasuriya, S.
Rescigno, P.
Zafeiriou, Z.
Sharp, A.
Tunariu, N.
Bianchini, D.
Gillman, A.
Lord, C.J.
Hall, E.
Chinnaiyan, A.M.
Carreira, S.
de Bono, J.S.
TOPARP-A investigators,
(2017). Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition. Cancer discov,
Vol.7
(9),
pp. 1006-1017.
show abstract
full text
Biomarkers for more precise patient care are needed in metastatic prostate cancer. We have reported a phase II trial (TOPARP-A) of the PARP inhibitor olaparib in metastatic prostate cancer, demonstrating antitumor activity associating with homologous recombination DNA repair defects. We now report targeted and whole-exome sequencing of serial circulating cell-free DNA (cfDNA) samples collected during this trial. Decreases in cfDNA concentration independently associated with outcome in multivariable analyses (HR for overall survival at week 8: 0.19; 95% CI, 0.06-0.56; P = 0.003). All tumor tissue somatic DNA repair mutations were detectable in cfDNA; allele frequency of somatic mutations decreased selectively in responding patients (χ2P < 0.001). At disease progression, following response to olaparib, multiple subclonal aberrations reverting germline and somatic DNA repair mutations (BRCA2, PALB2) back in frame emerged as mechanisms of resistance. These data support the role of liquid biopsies as a predictive, prognostic, response, and resistance biomarker in metastatic prostate cancer.Significance: We report prospectively planned, serial, cfDNA analyses from patients with metastatic prostate cancer treated on an investigator-initiated phase II trial of olaparib. These analyses provide predictive, prognostic, response, and resistance data with "second hit" mutations first detectable at disease progression, suggesting clonal evolution from treatment-selective pressure and platinum resistance. Cancer Discov; 7(9); 1006-17. ©2017 AACR.See related commentary by Domchek, p. 937See related article by Kondrashova et al., p. 984See related article by Quigley et al., p. 999This article is highlighted in the In This Issue feature, p. 920..
Choudhury, A.
West, C.M.
Porta, N.
Hall, E.
Denley, H.
Hendron, C.
Lewis, R.
Hussain, S.A.
Huddart, R.
James, N.
(2017). The predictive and prognostic value of tumour necrosis in muscle invasive bladder cancer patients receiving radiotherapy with or without chemotherapy in the BC2001 trial (CRUK/01/004). Br j cancer,
Vol.116
(5),
pp. 649-657.
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full text
BACKGROUND: Severe chronic hypoxia is associated with tumour necrosis. In patients with muscle invasive bladder cancer (MIBC), necrosis is prognostic for survival following surgery or radiotherapy and predicts benefit from hypoxia modification of radiotherapy. Adding mitomycin C (MMC) and 5-fluorouracil (5-FU) chemotherapy to radiotherapy improved locoregional control (LRC) compared to radiotherapy alone in the BC2001 trial. We hypothesised that tumour necrosis would not predict benefit for the addition of MMC and 5-FU to radiotherapy, but would be prognostic. METHODS: Diagnostic tumour samples were available from 230 BC2001 patients. Tumour necrosis was scored on whole-tissue sections as absent or present, and its predictive and prognostic significance explored using Cox proportional hazards models. Survival estimates were obtained by Kaplan-Meier methods. RESULTS: Tumour necrosis was present in 88/230 (38%) samples. Two-year LRC estimates were 71% (95% CI 61-79%) for the MMC/5-FU chemoradiotherapy group and 49% (95% CI 38-59%) for the radiotherapy alone group. When analysed by tumour necrosis status, the adjusted hazard ratios (HR) for MMC/5-FU vs. no chemotherapy were 0.46 (95% CI: 0.12-0.99; P=0.05, necrosis present) and 0.55 (95% CI: 0.31-0.98; P=0.04, necrosis absent). Multivariable analysis of prognosis for LRC by the presence vs. absence of necrosis yielded a HR=0.89 (95% CI 0.55-1.44, P=0.65). There was no significant association for necrosis as a predictive or prognostic factor with respect to overall survival. CONCLUSIONS: Tumour necrosis was neither predictive nor prognostic, and therefore MMC/5-FU is an appropriate radiotherapy-sensitising treatment in MIBC independent of necrosis status..
Martínez-Momblán, M.A.
Gómez, C.
Santos, A.
Porta, N.
Esteve, J.
Úbeda, I.
Halperin, I.
Campillo, B.
Guillaumet, M.
Webb, S.M.
Resmini, E.
(2016). A specific nursing educational program in patients with Cushing's syndrome. Endocrine,
Vol.53
(1),
pp. 199-209.
show abstract
Cushing's syndrome (CS) is a rare endocrine disease, due to cortisol hypersecretion. CS patients have comorbidities, often still present after biochemical cure. Specific nursing healthcare programs to address this disease and achieve improved health related quality of life (HRQoL) are lacking. Thus, an educational nursing intervention, through the development and promotion of specific educational tools, appears to be justified. The objective of this study is to assess the effectiveness of an educational nursing program in CS patients on HRQoL, clinical parameters, level of pain and physical activity, patterns of rest, and use of health resources. A prospective, randomized study was conducted in two reference hospitals for CS. Sixty-one patients (mean age 47 ± 12.7 years, 83.6 % females) were enrolled and divided into 2 groups: an "intervention" group where educational sessions were performed over 9 months and a "control" group, without these sessions. Specific questionnaires were used at the beginning and end of the study. After educational sessions, the intervention group had a better score in the CushingQoL questionnaire (p < 0.01), reduced level of pain (p < 0.05), improved physical activity (p < 0.01) and healthy lifestyle (p < 0.001) compared to the control group. A correlation between the CushingQoL score and reduced pain (r = 0.46, p < 0.05), improved physical activity (r = 0.89, p < 0.01), and sleep (r = 0.53, p = 0.01) was observed. This educational nursing program improved physical activity, healthy lifestyle, better sleep patterns, and reduced pain in CS patients, influencing HRQoL and reducing consumption of health resources. Moreover, the brief nature of the program suggests it as a good candidate to be used in CS patients..
Wilkins, A.
Furness, A.
Corbett, R.W.
Bloomfield, A.
Porta, N.
Morris, S.
Ali, Z.
Larkin, J.
Harrington, K.
(2015). The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma. Br j cancer,
Vol.113
(9),
pp. 1275-1281.
show abstract
full text
BACKGROUND: The melanoma-specific graded prognostic assessment (msGPA) assigns patients with brain metastases from malignant melanoma to 1 of 4 prognostic groups. It was largely derived using clinical data from patients treated in the era that preceded the development of newer therapies such as BRAF, MEK and immune checkpoint inhibitors. Therefore, its current relevance to patients diagnosed with brain metastases from malignant melanoma is unclear. This study is an external validation of the msGPA in two temporally distinct British populations. METHODS: Performance of the msGPA was assessed in Cohort I (1997-2008, n=231) and Cohort II (2008-2013, n=162) using Kaplan-Meier methods and Harrell's c-index of concordance. Cox regression was used to explore additional factors that may have prognostic relevance. RESULTS: The msGPA does not perform well as a prognostic score outside of the derivation cohort, with suboptimal statistical calibration and discrimination, particularly in those patients with an intermediate prognosis. Extra-cerebral metastases, leptomeningeal disease, age and potential use of novel targeted agents after brain metastases are diagnosed, should be incorporated into future prognostic models. CONCLUSIONS: An improved prognostic score is required to underpin high-quality randomised controlled trials in an area with a wide disparity in clinical care..
Mateo, J.
Carreira, S.
Sandhu, S.
Miranda, S.
Mossop, H.
Perez-Lopez, R.
Nava Rodrigues, D.
Robinson, D.
Omlin, A.
Tunariu, N.
Boysen, G.
Porta, N.
Flohr, P.
Gillman, A.
Figueiredo, I.
Paulding, C.
Seed, G.
Jain, S.
Ralph, C.
Protheroe, A.
Hussain, S.
Jones, R.
Elliott, T.
McGovern, U.
Bianchini, D.
Goodall, J.
Zafeiriou, Z.
Williamson, C.T.
Ferraldeschi, R.
Riisnaes, R.
Ebbs, B.
Fowler, G.
Roda, D.
Yuan, W.
Wu, Y.-.
Cao, X.
Brough, R.
Pemberton, H.
A'Hern, R.
Swain, A.
Kunju, L.P.
Eeles, R.
Attard, G.
Lord, C.J.
Ashworth, A.
Rubin, M.A.
Knudsen, K.E.
Feng, F.Y.
Chinnaiyan, A.M.
Hall, E.
de Bono, J.S.
(2015). DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. N engl j med,
Vol.373
(18),
pp. 1697-1708.
show abstract
full text
BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib. METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies. RESULTS: Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib. CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.)..
Franco, P.
Porta, N.
Holliday, J.D.
Willett, P.
(2014). The use of 2D fingerprint methods to support the assessment of structural similarity in orphan drug legislation. J cheminform,
Vol.6
(1),
p. 5.
show abstract
BACKGROUND: In the European Union, medicines are authorised for some rare disease only if they are judged to be dissimilar to authorised orphan drugs for that disease. This paper describes the use of 2D fingerprints to show the extent of the relationship between computed levels of structural similarity for pairs of molecules and expert judgments of the similarities of those pairs. The resulting relationship can be used to provide input to the assessment of new active compounds for which orphan drug authorisation is being sought. RESULTS: 143 experts provided judgments of the similarity or dissimilarity of 100 pairs of drug-like molecules from the DrugBank 3.0 database. The similarities of these pairs were also computed using BCI, Daylight, ECFC4, ECFP4, MDL and Unity 2D fingerprints. Logistic regression analyses demonstrated a strong relationship between the human and computed similarity assessments, with the resulting regression models having significant predictive power in experiments using data from submissions of orphan drug medicines to the European Medicines Agency. The BCI fingerprints performed best overall on the DrugBank dataset while the BCI, Daylight, ECFP4 and Unity fingerprints performed comparably on the European Medicines Agency dataset. CONCLUSIONS: Measures of structural similarity based on 2D fingerprints can provide a useful source of information for the assessment of orphan drug status by regulatory authorities..
Lincker, H.
Ziogas, C.
Carr, M.
Porta, N.
Eichler, H.-.
(2014). Regulatory watch: Where do new medicines originate from in the EU?. Nat rev drug discov,
Vol.13
(2),
pp. 92-93.
Pedrós, C.
Quintana, B.
Rebolledo, M.
Porta, N.
Vallano, A.
Arnau, J.M.
(2014). Prevalence, risk factors and main features of adverse drug reactions leading to hospital admission. Eur j clin pharmacol,
Vol.70
(3),
pp. 361-367.
show abstract
PURPOSE: To assess the prevalence of hospital admission related to adverse drug reactions (ADRs) in a third-level hospital, to analyse the associated factors, and to describe the reactions and the drugs involved. METHODS: A cross-sectional study was conducted for a 120-day period. Patients that were urgently hospitalized entered the study. The primary endpoint was the ADR-related urgent admission. A descriptive analysis of demographic, clinical, and drug-related variables was performed. The association between the likelihood of urgent admission due to ADRs and age, gender, and number of drugs used was analysed. A descriptive analysis of the suspected drugs and the reactions in ADR-related admissions was performed. RESULTS: Overall, 186 out of 4,403 hospital admissions were due to ADRs (prevalence: 4.2 % [95 % CI 3.7-4.8 %]). Age (≥65 years: OR 1.59 [95 % CI 1.10-2.29]) and number of drugs used at the time of admission (3-5 drugs: OR 5.07 [95 % CI 2.71-9.59]; 6-9 drugs: OR 5.90 [95 % CI 3.16-11.0]; ≥10 drugs: OR 8.94 [95 % CI 4.73-16.89]), but not gender, were identified as independent factors associated with ADR-related hospitalization. The overall in-hospital stay for patients admitted with ADRs amounted to 1,785 days. The ADRs were mainly type A reactions (92 %). Acute renal failure related to renin-angiotensin system inhibitors, haemorrhage due to anticoagulants, and upper gastrointestinal bleeding related to antiplatelet drugs and/or non-steroidal anti-inflammatory drugs were the most frequent. CONCLUSION: Over 4 % of urgent hospitalizations are caused by ADRs, which are dose-related and predictable in more than 90 % of cases. The main risk factors are advanced age and polypharmacy..
Coelho, S.
Ortíz, F.
Gelpi, R.
Koskinen, P.
Porta, N.
Bestard, O.
Melilli, E.
Taco, O.
Torras, J.
Honkanen, E.
Grinyó, J.M.
Cruzado, J.M.
(2014). Sterile leukocyturia is associated with interstitial fibrosis and tubular atrophy in kidney allograft protocol biopsies. Am j transplant,
Vol.14
(4),
pp. 908-915.
show abstract
Kidney allograft interstitial fibrosis and tubular atrophy (IF/TA) is associated with a poorer renal function and outcome. In the current clinical practice, an early diagnosis can only be provided by invasive tests. We aimed to investigate the association of sterile leukocyturia with Banff criteria histological findings in kidney allograft protocol biopsies. We studied 348 allograft biopsies from two different European countries performed at 8.5 + 3.5 months after transplantation. In these cases, the presence of sterile leukocyturia (Leuc+, n = 70) or no leukocyturia (Leuc-, n = 278) was analyzed and related to Banff elementary lesions. Only IF/TA was significantly different between Leuc+ and Leuc- groups. IF/TA was present in 85.7% of Leuc+ and 27.7% of Leuc- patients (p < 0.001). IF/TA patients had higher serum creatinine and presence of proteinuria (p < 0.05). Independent predictors of IF/TA were donor age, donor male sex, serum creatinine and Leuc+ (hazard ratio 18.2; 95% confidence interval, 8.1-40.7). The positive predictive value of leukocyturia for predicting IF/TA was 85.7% whereas the negative predictive value was 72.3%. These studies suggest that leukocyturia is a noninvasive and low-cost test to identify IF/TA. An early diagnosis may allow timely interventional measures directed to minimize its impact and improve graft outcome..
Yildirim, T.
Yilmaz, R.
Altindal, M.
Turkmen, E.
Arici, M.
Altun, B.
Erdem, Y.
Guliyev, O.
Erkmen Uyar, M.
Tutal, E.
Bal, Z.
Sezer, S.
Erkmen Uyar, M.
Bal, U.
Bal, Z.
Tutal, E.
Say n, B.
Guliyev, O.
Erdemir, B.
Sezer, S.
O'Rourke-Potowki, A.
Gauge, N.
Penny, H.
Cronin, A.
Frame, S.
Goldsmith, D.J.
Yagan, J.A.
Chandraker, A.
Velickovic Radovanovic, R.M.
Catic Djordjevic, A.
Mitic, B.
Stefanovic, N.
Cvetkovic, T.
Serpieri, N.
Grosjean, F.
Sileno, G.
Torreggiani, M.
Esposito, V.
Mangione, F.
Abelli, M.
Castoldi, F.
Catucci, D.
Esposito, C.
Dal Canton, A.
Vatazin, A.V.
Zulkarnaev, A.B.
Borst, C.
Liu, Y.
Thoning, J.
Tepel, M.
Libetta, C.
Margiotta, E.
Borettaz, I.
Canevari, M.
Martinelli, C.
Lainu, E.
Abelli, M.
Meloni, F.
Sepe, V.
Dal Canton, A.
Miguel Costa, R.
Vasquez Martul, E.
Reboredo, J.
Rivera, C.
Simonato, F.
Tognarelli, G.
Daidola, G.
Gallo, E.
Burdese, M.
Cantaluppi, V.
Biancone, L.
Segoloni, G.P.
Burdese, M.
Priora, M.
Messina, M.
Tamagnone, M.
Daidola, G.
Linsalata, A.
Lavacca, A.
Biancone, L.
Segoloni, G.
Zuidema, W.
Erdman, R.
van de Wetering, J.
Dor, F.
Roodnat, J.
Massey, E.
Timmerman, L.
IJzermans, J.
Weimar, W.
Goldsmith, D.J.
Sibley-Allen, C.
Hilton, R.
Moghul, M.
Burnapp, L.
Blake, G.
Koo, T.Y.
Park, J.-.
Park, H.C.
Kim, G.-.
Lee, C.H.
Oh, I.H.
Kang, C.M.
Hwang, J.K.
Park, S.C.
Choi, B.S.
Chun, H.J.
Kim, J.I.
Yang, C.W.
Moon, I.S.
Van Laecke, S.
Van Biesen, W.
Nagler, E.V.
Taes, Y.
Peeters, P.
Vanholder, R.
Pruthi, R.
Ravanan, R.
Casula, A.
Harber, M.
Roderick, P.
Fogarty, D.
Cho, A.
Shin, J.-.
Jang, H.R.
Lee, J.E.
Huh, W.
Kim, D.J.
Oh, H.Y.
Kim, Y.-.
Sancho Calabuig, A.
Gavela Martinez, E.
Kanter Berga, J.
Beltran Catalan, S.
Avila Bernabeu, A.I.
Pallardo Mateu, L.M.
Gonzalez, E.
Polanco, N.
Molina, M.
Gutierrez, E.
Garcia Puente, L.
Sevillano, A.
Morales, E.
Praga, M.
Andres, A.
Banasik, M.
Boratynska, M.
Koscielska-Kasprzak, K.
Bartoszek, D.
Myszka, M.
Zmonarski, S.
Nowakowska, B.
Wawrzyniak, E.
Halon, A.
Chudoba, P.
Klinger, M.
Rojas-Rivera, J.
Gonzalez, E.
Polanco, N.
Morales, E.
Andres, A.
Morales, J.M.
Egido, J.
Praga, M.
Kopecky, C.M.
Haidinger, M.
Kaltenecker, C.
Antlanger, M.
Marsche, G.
Holzer, M.
Kovarik, J.
Werzowa, J.
Hecking, M.
Saemann, M.D.
Hwang, J.K.
Kim, J.M.
Koh, E.S.
Chung, B.H.
Park, S.C.
Choi, B.S.
Kim, J.I.
Yang, C.W.
Kim, Y.S.
Moon, I.S.
Banasik, M.
Boratynska, M.
Koscielska-Kasprzak, K.
Krajewska, M.
Mazanowska, O.
Kaminska, D.
Bartoszek, D.
Zabinska, M.
Halon, A.
Malkiewicz, B.
Patrzalek, D.
Klinger, M.
Sulowicz, J.
Szostek, S.
Wojas-Pelc, A.
Ignacak, E.
Sulowicz, W.
Bellizzi, V.
Calella, P.
Cupisti, A.
Capitanini, A.
D'Alessandro, C.
Giannese, D.
Camocardi, A.
Conte, G.
Barsotti, M.
Bilancio, G.
Luciani, R.
Locsey, L.
Seres, I.
Kovacs, D.
Asztalos, L.
Paragh, G.
Wohlfahrtova, M.
Balaz, P.
Rokosny, S.
Wohlfahrt, P.
Bartonova, A.
Viklicky, O.
Kers, J.
Geskus, R.B.
Meijer, L.J.
Bemelman, F.
ten Berge, I.J.
Florquin, S.
Hwang, J.-.
Jiang, M.-.
Lu, Y.-.
Weng, S.-.
Testa, A.
Porto, G.
Sanguedolce, M.
Spoto, B.
Parlongo, R.
Pisano, A.
Enia, G.
Tripepi, G.
Zoccali, C.
Zuidema, W.
Mamode, N.
Lennerling, A.
Citterio, F.
Massey, E.
Van Assche, K.
Sterckx, S.
Frunza, M.
Jung, H.
Pascalev, A.
Johnson, R.
Loven, C.
Weimar, W.
Dor, F.
Soleymanian, T.
Keyvani, H.
Jazayeri, S.M.
Fazeli, Z.
Ghamari, S.
Mahabadi, M.
Chegeni, V.
Najafi, I.
Ganji, M.R.
Meys, K.M.
Groothoff, J.W.
Jager, K.
Schaefer, F.
Tonshoff, B.
Mota, C.
Cransberg, K.
van Stralen, K.
Gurluler, E.
Gures, N.
Alim, A.
Gurkan, A.
Cakir, U.
Berber, I.
Van Laecke, S.
Caluwe, R.
Nagler, E.
Van Biesen, W.
Peeters, P.
Van Vlem, B.
Vanholder, R.
Sulowicz, J.
Wojas-Pelc, A.
Ignacak, E.
Betkowska-Prokop, A.
Kuzniewski, M.
Krzanowski, M.
Sulowicz, W.
Masson, I.
Flamant, M.
Maillard, N.
Cavalier, E.
Moranne, O.
Alamartine, E.
Mariat, C.
Delanaye, P.
Canas Sole, L.L.
Iglesias Alvarez, E.
Pastor, M.C.
Moreno Flores, F.F.
Abujder, V.V.
Graterol, F.F.
Bonet Sol, J.J.
Lauzurica Valdemoros, R.R.
Yoshikawa, M.
Kitamura, K.
Nakai, K.
Goto, S.
Fujii, H.
Ishimura, T.
Takeda, M.
Fujisawa, M.
Nishi, S.
Prasad, N.
Gurjer, D.
Bhadauria, D.
Gupta, A.
Sharma, R.
Kaul, A.
Cybulla, M.
West, M.
Nicholls, K.
Torras, J.
Sunder-Plassmann, G.
Feriozzi, S.
Lo, S.
Wong, P.Y.
Ip, D.
Wong, C.K.
Chow, V.C.
Mo, S.K.
Molnar, M.
Ujszaszi, A.
Czira, M.E.
Novak, M.
Mucsi, I.
Cruzado, J.M.
Coelho, S.
Porta, N.
Bestard, O.
Melilli, E.
Taco, O.
Rivas, I.
Grinyo, J.
Pouteau, L.-.
N'Guyen, J.-.
Hami, A.
Hourmant, M.
Ghahramani, N.
Karparvar, Z.
Shadrou, S.
Ghahramani, M.
Fauvel, J.P.
Hadj-Aissa, A.
Buron, F.
Morelon, E.
Ducher, M.
Heine, C.
Glander, P.
Neumayer, H.-.
Budde, K.
Liefeldt, L.
Montero, N.
Webster, A.C.
Royuela, A.
Zamora, J.
Crespo, M.
Pascual, J.
Adema, A.Y.
van Dorp, W.T.
Mallat, M.J.
de Fijter, H.W.
Kim, Y.S.
Hong, Y.A.
Chung, B.H.
Park, C.W.
Yang, C.W.
Kim, Y.-.
Choi, B.S.
Suleymanlar, G.
Uzundurukan, Z.
Kapuagas, A.
Sencan, I.
Akdag, R.
Pascual, J.
Torio, A.
Mas, V.
Perez-Saez, M.J.
Mir, M.
Faura, A.
Montes-Ares, O.
Checa, M.D.
Crespo, M.
Sawinski, D.
Trofe-Clark, J.
Sparkes, T.
Patel, P.
Goral, S.
Bloom, R.
Kim, H.J.
Park, S.J.
Kim, T.H.
Kim, Y.W.
Kim, Y.H.
Kang, S.W.
Abdel Halim, M.
Gheith, O.
Al-Otaibi, T.
Mosaad, A.
Awadeen, W.
Said, T.
Nair, P.
Nampoory, M.R.
(2013). Transplantation: clinical studies - A. Nephrology dialysis transplantation,
Vol.28
(suppl 1),
pp. i275-i292.
Muñoz, L.
Moure, R.
Porta, N.
Gonzalez, L.
Guerra, R.
Alcaide, F.
Santin, M.
(2013). GeneXpert® for smear-negative pulmonary tuberculosis: does it play a role in low-burden countries?. Diagn microbiol infect dis,
Vol.75
(3),
pp. 325-326.
show abstract
We performed a retrospective analysis of costs and time to treatment (TT) of 150 culture-confirmed TB cases: 100 sputum smear (SS) (+) and 50 SS(-). This group underwent GeneXpert® (GX) assay. Expenditures and TT of SS(-)/GX(+) cases were inferred from the SS(+) group. GX detected 68% of SS(-) cases..
Fernández-Lorente, L.
Riera, L.
Bestard, O.
Carrera, M.
Gomà, M.
Porta, N.
Torras, J.
Melilli, E.
Gil-Vernet, S.
Grinyó, J.M.
Cruzado, J.M.
(2012). Long-term results of biopsy-guided selection and allocation of kidneys from older donors in older recipients. Am j transplant,
Vol.12
(10),
pp. 2781-2788.
show abstract
In our old-for-old program, we discard or allocate older extended criteria donor kidneys to single (SKT) or dual kidney transplantation (DKT) depending on histological Remuzzi's score in recipients older than 60 years. Here, we analyze the long-term results of this program and try to identify independent predictors of patient and graft survival. Between December 1996 and January 2008, we performed 115 SKT and 88 DKT. Discard rate was 15%. Acute rejection incidence was higher in SKT than in DKT (22.6% vs. 11.4%, p = 0.04). Renal function was better in DKT than in SKT up to 5 years after transplantation. Surgical complications were frequent in DKT. Ten-year cumulative graft survival was significantly lower in the SKT group (31% vs. 53%, p = 0.03). In SKT, histological score 4 provided similar graft survival than 3 or less, whereas in DKT score 4, 5 or 6 displayed similar outcome. Finally, independent predictors of graft survival were history of major adverse cardiac event and 1-year serum creatinine, rather than SKT or DKT. In conclusion, this biopsy-guided old-for-old strategy resulted in acceptable long-term graft survival. Our results suggest that DKT should be considered for scores of 5 or 6 only..
Porta, N.
Calle, M.L.
Malats, N.
Gómez, G.
(2012). A dynamic model for the risk of bladder cancer progression. Stat med,
Vol.31
(3),
pp. 287-300.
show abstract
We propose a multistate modeling approach to describe the observed evolution of patients diagnosed with non-muscle-invasive bladder cancer. On the basis of data from the Spanish Bladder Cancer/EPICURO study, we adjust a multistate model taking into account the disease-related events of interest (recurrence, progression, and disease-related deaths) as well as competing deaths due to other causes. We then develop a dynamic predictive process for bladder cancer progression, which allows the risk of a patient to be updated whenever new information of his or her evolution is available. By using specific measures of prospective accuracy in the presence of competing risks, the proposed dynamic model has shown to improve prediction accuracy and provides a more personalized management of bladder patients..
Porta, N.
Bonet, C.
Cobo, E.
(2007). Discordance between reported intention-to-treat and per protocol analyses. J clin epidemiol,
Vol.60
(7),
pp. 663-669.
show abstract
OBJECTIVE: To quantify the degree of disagreement between the two most popular methods for dealing with missing data: intention to treat (ITT) and per protocol (PP). STUDY DESIGN AND SETTING: We performed a systematic review of randomized two-armed clinical trials (CTs) published between 2001 and 2003, abstracted in PubMed and reporting both the ITT and PP analyses on a primary binary endpoint, out of which 74 papers were finally selected. The treatment effect of each CT was measured by the odds ratio, and the disagreement between them was quantified by the Bland-Altman method. RESULTS: On average, the PP estimator provides greater values Log(e)ORPP=1 x 25.Log(e)ORITT, (95% CI: 1.15, 1.35) than the corresponding ITT estimator, although the limits of concordance showed that the ratio between the two estimators varies greatly from 0.39 up to 2.53. CONCLUSION: These results confirm that missing values may cause both systematic and unpredictable bias in CTs. Further efforts should be made to minimize protocol deviations and to use better statistical methods to highlight the drawbacks of missing information. In the presence of protocol deviations, the conclusion of a CT cannot rest on the single reporting of either the ITT or the PP approach alone..
Bliss, J.
Porta, N.
Banerji, J.
Larkin, J.
A Phase II Trial of Nilotinib in KIT-driven Advanced Melanoma (NICAM). Cell reports medicine,
.
full text