Regional Histopathology and Prostate MRI Positivity: A Secondary Analysis of the PROMIS Trial.

Background The effects of regional histopathologic changes on prostate MRI scans have not been accurately quantified in men with an elevated prostate-specific antigen (PSA) level and no previous biopsy. Purpose To assess how Gleason grade, maximum cancer core length (MCCL), inflammation, prostatic intraepithelial neoplasia (PIN), or atypical small acinar proliferation within a Barzell zone affects the odds of MRI visibility. Materials and Methods In this secondary analysis of the Prostate MRI Imaging Study (PROMIS; May 2012 to November 2015), consecutive participants who underwent multiparametric MRI followed by a combined biopsy, including 5-mm transperineal mapping (TPM), were evaluated. TPM pathologic findings were reported at the whole-prostate level and for each of 20 Barzell zones per prostate. An expert panel blinded to the pathologic findings reviewed MRI scans and declared which Barzell areas spanned Likert score 3-5 lesions. The relationship of Gleason grade and MCCL to zonal MRI outcome (visible vs nonvisible) was assessed using generalized linear mixed-effects models with random intercepts for individual participants. Inflammation, PIN, and atypical small acinar proliferation were similarly assessed in men who had negative TPM results. Results Overall, 161 men (median age, 62 years [IQR, 11 years]) were evaluated and 3179 Barzell zones were assigned MRI status. Compared with benign areas, the odds of MRI visibility were higher when a zone contained cancer with a Gleason score of 3+4 (odds ratio [OR], 3.1; 95% CI: 1.9, 4.9; P < .001) or Gleason score greater than or equal to 4+3 (OR, 8.7; 95% CI: 4.5, 17.0; P < .001). MCCL also determined visibility (OR, 1.24 per millimeter increase; 95% CI: 1.15, 1.33; P < .001), but odds were lower with each prostate volume doubling (OR, 0.7; 95% CI: 0.5, 0.9). In men who were TPM-negative, the presence of PIN increased the odds of zonal visibility (OR, 3.7; 95% CI: 1.5, 9.1; P = .004). Conclusion An incremental relationship between cancer burden and prostate MRI visibility was observed. Prostatic intraepithelial neoplasia contributed to false-positive MRI findings. ClinicalTrials.gov registration no. NCT01292291 © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Harmath in this issue.

Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal cancer treatment (ICON8): overall survival results from an open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Standard-of-care first-line chemotherapy for epithelial ovarian cancer is carboplatin and paclitaxel administered once every 3 weeks. The JGOG 3016 trial reported significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly (ie, once every 3 weeks) carboplatin. However, this benefit was not observed in the previously reported progression-free survival results of ICON8. Here, we present the final coprimary outcomes of overall survival and updated progression-free survival analyses of ICON8. METHODS: In this open-label, randomised, controlled, phase 3 trial (ICON8), women aged 18 years or older with newly diagnosed stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma (here collectively termed ovarian cancer, as defined by International Federation of Gynecology and Obstetrics [FIGO] 1988 criteria) and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 117 hospitals with oncology departments in the UK, Australia and New Zealand, Mexico, South Korea, and Ireland. Patients could enter the trial after immediate primary surgery (IPS) or with planned delayed primary surgery (DPS) during chemotherapy, or could have no planned surgery. Participants were randomly assigned (1:1:1), using the Medical Research Council Clinical Trials Unit at University College London randomisation line with stratification by Gynecologic Cancer Intergroup group, FIGO disease stage, and outcome and timing of surgery, to either 3-weekly carboplatin area under the curve (AUC)5 or AUC6 and 3-weekly paclitaxel 175 mg/m2 (control; group 1), 3-weekly carboplatin AUC5 or AUC6 and weekly paclitaxel 80 mg/m2 (group 2), or weekly carboplatin AUC2 and weekly paclitaxel 80 mg/m2 (group 3), all administered via intravenous infusion for a total of six 21-day cycles. Coprimary outcomes were progression-free survival and overall survival, with comparisons done between group 2 and group 1, and group 3 and group 1, in the intention-to-treat population. Safety was assessed in all patients who started at least one chemotherapy cycle. The trial is registered on ClinicalTrials.gov, NCT01654146, and ISRCTN registry, ISRCTN10356387, and is closed to accrual. FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 patients were randomly assigned to group 1 (n=522), group 2 (n=523), or group 3 (n=521). The median age was 62 years (IQR 54-68), 1073 (69%) of 1566 patients had high-grade serous carcinoma, 1119 (71%) had stage IIIC-IV disease, and 745 (48%) had IPS. As of data cutoff (March 31, 2020), with a median follow-up of 69 months (IQR 61-75), no significant difference in overall survival was observed in either comparison: median overall survival of 47·4 months (95% CI 43·1-54·8) in group 1, 54·8 months (46·6-61·6) in group 2, and 53·4 months (49·2-59·6) in group 3 (group 2 vs group 1: hazard ratio 0·87 [97·5% CI 0·73-1·05]; group 3 vs group 1: 0·91 [0·76-1·09]). No significant difference was observed for progression-free survival in either comparison and evidence of non-proportional hazards was seen (p=0·037), with restricted mean survival time of 23·9 months (97·5% CI 22·1-25·6) in group 1, 25·3 months (23·6-27·1) in group 2, and 24·8 months (23·0-26·5) in group 3. The most common grade 3-4 adverse events were reduced neutrophil count (78 [15%] of 511 patients in group 1, 183 [36%] of 514 in group 2, and 154 [30%] of 513 in group 3), reduced white blood cell count (22 [4%] in group 1, 80 [16%] in group 2, and 71 [14%] in group 3), and anaemia (26 [5%] in group 1, 66 [13%] in group 2, and 24 [5%] in group 3). No new serious adverse events were reported. Seven treatment-related deaths were reported (two in group 1, four in group 2, and one in group 3). INTERPRETATION: In our cohort of predominantly European women with epithelial ovarian cancer, we found that first-line weekly dose-dense chemotherapy did not improve overall or progression-free survival compared with standard 3-weekly chemotherapy and should not be used as part of standard multimodality front-line therapy in this patient group. FUNDING: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.

Genetic variation in ST6GAL1 is a determinant of capecitabine and oxaliplatin induced hand-foot syndrome.

Cancer patients treated with capecitabine and oxaliplatin (XELOX) often develop hand-foot syndrome (HFS) or palmar-plantar erythrodysesthesia. Genetic variation in ST6GAL1 is a risk factor for type-2 diabetes (T2D), a disease also associated with HFS. We analysed genome-wide association data for 10 toxicities in advanced colorectal cancer (CRC) patients from the COIN and COIN-B trials. One thousand and fifty-five patients were treated with XELOX ± cetuximab and 745 with folinic acid, fluorouracil and oxaliplatin ± cetuximab. We also analysed rs6783836 in ST6GAL1 with HFS in CRC patients from QUASAR2. Using UK Biobank data, we sought to confirm an association between ST6GAL1 and T2D (17 384 cases, 317 887 controls) and analysed rs6783836 against markers of diabetes, inflammation and psoriasis. We found that 68% of patients from COIN and COIN-B with grade 2-3 HFS responded to treatment as compared to 58% with grade 0-1 HFS (odds ratio [OR] = 1.1, 95% confidence interval [CI] = 1.02-1.2, P = 2.0 × 10-4 ). HFS was also associated with improved overall survival (hazard ratio = 0.92, 95% CI = 0.84-0.99, P = 4.6 × 10-2 ). rs6783836 at ST6GAL1 was associated with HFS in patients treated with XELOX (OR = 3.1, 95% CI = 2.1-4.6, P = 4.3 × 10-8 ) and was borderline significant in patients receiving capecitabine from QUASAR2, but with an opposite allele effect (OR = 0.66, 95% CI = 0.42-1.03, P = .05). ST6GAL1 was associated with T2D (lead SNP rs3887925, OR = 0.94, 95% CI = 0.92-0.96, P = 1.2 × 10-8 ) and the rs6783836-T allele was associated with lowered HbA1c levels (P = 5.9 × 10-3 ) and lymphocyte count (P = 2.7 × 10-3 ), and psoriasis (P = 7.5 × 10-3 ) beyond thresholds for multiple testing. In conclusion, HFS is a biomarker of treatment outcome and rs6783836 in ST6GAL1 is a potential biomarker for HFS with links to T2D and inflammation.

Experiences of running a stratified medicine adaptive platform trial: Challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal cancer.

BACKGROUND: Complex innovative design trials are becoming increasingly common and offer potential for improving patient outcomes in a faster time frame. FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and it remains one of the first umbrella trial designs to be launched globally. Here, we aim to describe lessons learned from delivery of the trial over the last 10 years. METHODS: FOCUS4 was a Phase II/III molecularly stratified umbrella trial testing the safety and efficacy of targeted therapies in metastatic colorectal cancer. It used adaptive statistical methodology to decide which sub-trial should close early, and new therapies were added as protocol amendments. Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified sub-trial (FOCUS4-B, C or D) or non-stratified FOCUS4-N. The primary outcome for all studies was progression-free survival comparing the intervention with active monitoring/placebo. At the close of the trial, feedback was elicited from all investigators through surveys and interviews and consolidated into a series of recommendations and lessons learned for the delivery of similar future trials. RESULTS: Between January 2014 and October 2020, 1434 patients were registered from 88 UK hospitals. Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted sub-trials were activated: FOCUS4-D (February 2014-March 2016) evaluated AZD8931 in the BRAF-PIK3CA-RAS wildtype subgroup; FOCUS4-B (February 2016-July 2018) evaluated aspirin in the PIK3CA mutant subgroup and FOCUS4-C (June 2017-October 2020) evaluated adavosertib in the RAS+TP53 double mutant subgroup. FOCUS4-N was active throughout and evaluated capecitabine monotherapy versus a treatment break. A total of 361 (25%) registered patients were randomised into a sub-trial. Feedback on the experiences of delivery of FOCUS4 could be grouped into three main areas of challenge: funding/infrastructure, biomarker testing procedures and trial design efficiencies within which 20 recommendations are summarised. CONCLUSION: Adaptive stratified medicine platform studies are feasible in common cancers but present challenges. Our stakeholder feedback has helped to inform how these trial designs can succeed and answer multiple questions efficiently, providing resource is adequate.

Genome-wide association studies of toxicity to oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab in 1800 patients with advanced colorectal cancer.

Chemotherapies administered at normal therapeutic dosages can cause significant side-effects and may result in early treatment discontinuation. Inter-individual variation in toxicity highlights the need for biomarkers to personalise treatment. We sought to identify such biomarkers by conducting 40 genome-wide association studies, together with gene and gene set analyses, for any toxicity and 10 individual toxicities in 1800 patients with advanced colorectal cancer treated with oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab from the MRC COIN and COIN-B trials (385 patients received FOLFOX, 360 FOLFOX + cetuximab, 707 XELOX and 348 XELOX + cetuximab). Single nucleotide polymorphisms (SNPs), genes and gene sets that reached genome-wide or suggestive significance were validated in independent patient groups. We found that MROH5 was significantly associated with neutropenia in MAGMA gene analyses in patients treated with XELOX (P = 6.6 × 10-7 ) and was independently validated in those receiving XELOX + cetuximab; pooled P = 3.7 × 10-7 . rs13260246 at 8q21.13 was significantly associated with vomiting in patients treated with XELOX (odds ratio = 5.0, 95% confidence interval = 3.0-8.3, P = 9.8 × 10-10 ) but was not independently replicated. SNPs at 139 loci had suggestive associations for toxicities and lead SNPs at five of these were independently validated (rs6030266 with diarrhoea, rs1546161 with hand-foot syndrome, rs9601722 with neutropenia, rs13413764 with lethargy and rs4600090 with nausea; all with pooled P's < 5.0 × 10-6 ). In conclusion, the association of MROH5 with neutropenia and five other putative biomarkers warrant further investigation for their potential clinical utility. Despite our comprehensive genome-wide analyses of large, well-characterised, clinical trials, we found a lack of common variants with modest effect sizes associated with toxicities.

Weekly platinum-based chemotherapy versus 3-weekly platinum-based chemotherapy for newly diagnosed ovarian cancer (ICON8): quality-of-life results of a phase 3, randomised, controlled trial.

BACKGROUND: The ICON8 study reported no significant improvement in progression-free survival (a primary endpoint) with weekly chemotherapy compared with standard 3-weekly treatment among patients with epithelial ovarian cancer. All ICON8 patients were eligible to take part in the accompanying health-related quality-of-life study, which measured the effect of treatment on self-reported wellbeing, reported here. METHODS: In this open-label, randomised, controlled, phase 3, three-arm, Gynecologic Cancer Intergroup (GCIG) trial done at 117 hospital sites in the UK, Australia, New Zealand, Mexico, South Korea, and Republic of Ireland, women (aged at least 18 years) with newly diagnosed, histologically confirmed International Federation of Gynecology and Obstetrics stage IC-IV ovarian cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were randomly assigned (1:1:1) centrally using minimisation to group 1 (intravenous carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 intravenous paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 weekly and 80 mg/m2 paclitaxel weekly). Randomisation was stratified by GCIG group, disease stage, and outcome and timing of surgery. Patients and clinicians were not masked to treatment assignment. Patients underwent immediate or delayed primary surgery according to clinicians' choice. Patients were asked to complete European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 questionnaires at enrolment, before each chemotherapy cycle, then 6-weekly up to 9 months, 3-monthly up to 2 years, and 6-monthly up to 5 years. Quality of life was a prespecified secondary outcome of the ICON8 study. Within the quality-of-life study, the co-primary endpoints were QLQ-C30 global health score at 9 months (cross-sectional analysis) and mean QLQ-C30 global health score from randomisation to 9 months (longitudinal analysis). Data analyses were done on an intention-to-treat basis. The trial is registered on ClinicalTrials.gov, NCT01654146 and ISRCTN Registry, ISRCTN10356387, and is currently in long-term follow up. FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 patients were recruited into ICON8 (522 were included in group 1, 523 in group 2, and 521 in group 3). Baseline quality-of-life questionnaires were completed by 1438 (92%) of 1566 patients and 9-month questionnaires by 882 (69%) of 1280 patients. We observed no significant difference in global health score at 9 months (cross-sectional analysis) between study groups (group 2 vs group 1, difference in mean score 2·3, 95% CI -0·4 to 4·9, p=0·095; group 3 vs group 1, -0·8, -3·8 to 2·2, p=0·61). Using longitudinal analysis, we found lower global health scores for those receiving weekly paclitaxel than for those receiving 3-weekly chemotherapy (group 2 vs group 1, mean difference -1·8, 95% CI -3·6 to -0·1, p=0·043; group 3 vs group 1, -2·9, -4·7 to -1·1, p=0·0018). INTERPRETATION: We found no evidence of a difference in global quality of life between treatment groups at 9 months; however, patients receiving weekly treatment reported lower mean quality of life across the 9-month period after randomisation. Taken together with the lack of progression-free survival benefit, these findings do not support routine use of weekly paclitaxel-containing regimens in the management of newly diagnosed ovarian cancer. FUNDING: Cancer Research UK, Medical Research Council, Health Research Board Ireland, Irish Cancer Society, and Cancer Australia.

Effects of Intensive Versus Standard Ambulatory Blood Pressure Control on Cerebrovascular Outcomes in Older People (INFINITY).

BACKGROUND: Subcortical microvascular disease represented by brain white matter hyperintensity on magnetic resonance imaging is associated with functional decline in older people with hypertension. The effects of 2 levels of 24-hour average systolic blood pressure (BP) on mobility, white matter disease progression, and cognitive function over 3 years were studied. METHODS: This trial was a prospective, randomized, blinded end-points study in patients ≥75 years of age with systolic hypertension and magnetic resonance imaging evidence of white matter hyperintensity lesions. Patients were randomized to a 24-hour mean systolic BP of ≤130 mm Hg (intensive treatment) versus ≤145 mm Hg (standard treatment) with antihypertensive therapies. Primary study outcomes were changes in mobility (gait speed) and accrual of white matter hyperintensity volume after 3 years. Changes in cognitive function (executive processing) and adverse events were also evaluated. RESULTS: In 199 randomized patients, the mean age of the cohort was 80.5 years, and 54% were women; the average 24-hour systolic BP was 149 mm Hg. Goal BPs were achieved after a median treatment period of 3 to 4 months; at that time, the mean 24-hour systolic BP was 127.7 mm Hg in the intensive treatment group and 144.0 mm Hg in the standard treatment group for an average difference of 16.3 mm Hg. Changes in gait speed were not different between treatment groups (0.40±2.0 versus 0.42±2.7 s in the intensive treatment and standard treatment groups, respectively; P=0.91), whereas changes from baseline in white matter hyperintensity volumes were smaller (0.29%) in the intensive treatment group compared with the standard treatment group (0.48%; P=0.03). Cognitive outcomes also were not different between the treatment groups. Major adverse cardiovascular events were higher in the standard treatment group compared with the intensive treatment group (17 versus 4 patients; P=0.01). Falls, with or without injury, and syncope were comparable in the treatment groups. CONCLUSIONS: Intensive lowering of ambulatory BP reduction in older patients with hypertension did not result in differences in mobility outcomes but was associated with a reduction in accrual of subcortical white matter disease. Over periods >3 years, a reduction in the accumulation of white matter disease may be a factor in conserving function. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01650402.

Dolutegravir-based Antiretroviral Therapy for Patients Coinfected With Tuberculosis and Human Immunodeficiency Virus: A Multicenter, Noncomparative, Open-label, Randomized Trial.

BACKGROUND: The concurrent treatment of tuberculosis and human immunodeficiency virus (HIV) is challenging, owing to drug interactions, overlapping toxicities, and immune reconstitution inflammatory syndrome (IRIS). The efficacy and safety of dolutegravir (DTG) were assessed in adults with HIV and drug-susceptible tuberculosis. METHODS: International Study of Patients with HIV on Rifampicin ING is a noncomparative, active-control, randomized, open-label study in HIV-1-infected antiretroviral therapy-naive adults (CD4+ ≥50 cells/mm3). Participants on rifampicin-based tuberculosis treatment ≤8 weeks were randomized (3:2) to receive DTG (50 mg twice daily both during and 2 weeks after tuberculosis therapy, then 50 mg once daily) or efavirenz (EFV; 600 mg daily) with 2 nucleoside reverse transcriptase inhibitors for 52 weeks. The primary endpoint was the proportion of DTG-arm participants with plasma HIV-1-RNA <50 copies/mL (responders) by the Food and Drug Administration Snapshot algorithm (intent-to-treat exposed population) at Week 48. The study was not powered to compare arms. RESULTS: For DTG (n = 69), the baseline HIV-1 RNA was >100 000 copies/mL in 64% of participants, with a median CD4+ count of 208 cells/mm3; for EFV (n = 44), 55% of participants had HIV-1 RNA >100 000 copies/mL, with a median CD4+ count of 202 cells/mm3. The Week 48 response rates were 75% (52/69, 95% confidence interval [CI] 65-86%) for DTG and 82% (36/44, 95% CI 70-93%) for EFV. The DTG nonresponses were driven by non-treatment related discontinuations (n = 10 lost to follow-up). There were no deaths or study drug switches. There were 2 discontinuations for toxicity (EFV). There were 3 protocol-defined virological failures (2 DTG, no acquired resistance; 1 EFV, emergent resistance to nucleoside reverse transcriptase inhibitors and nonnucleoside reverse transcriptase inhibitors). The tuberculosis treatment success rate was high. Tuberculosis-associated IRIS was uncommon (4/arm), with no discontinuations for IRIS. CONCLUSIONS: Among adults with HIV receiving rifampicin-based tuberculosis treatment, twice-daily DTG was effective and well tolerated. CLINICAL TRIALS REGISTRATION: NCT02178592.

Weekly dose-dense chemotherapy in first-line epithelial ovarian, fallopian tube, or primary peritoneal carcinoma treatment (ICON8): primary progression free survival analysis results from a GCIG phase 3 randomised controlled trial.

BACKGROUND: Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer. METHODS: In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3). FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24·4 months [97·5% CI 23·0-26·0] in group 1, 24·9 months [24·0-25·9] in group 2, 25·3 months [23·9-26·9] in group 3; median progression-free survival 17·7 months [IQR 10·6-not reached] in group 1, 20·8 months [11·9-59·0] in group 2, 21·0 months [12·0-54·0] in group 3; log-rank p=0·35 for group 2 vs group 1; group 3 vs 1 p=0·51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups. INTERPRETATION: Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations. FUNDING: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia.

Comparison of Transrectal Ultrasound Biopsy to Transperineal Template Mapping Biopsies Stratified by Multiparametric Magnetic Resonance Imaging Score in the PROMIS Trial.

PURPOSE: We evaluated the performance of transrectal ultrasound guided systematic and transperineal template mapping biopsies with a 5 mm sampling frame stratified by the multiparametric magnetic resonance imaging Likert score in the PROMIS (Prostate MR Imaging Study). MATERIALS AND METHODS: Biopsy naïve men due to undergo prostate biopsy for elevated prostate specific antigen and/or abnormal digital rectal examination underwent multiparametric magnetic resonance imaging, and transperineal template mapping and transrectal ultrasound guided systematic biopsies, which were performed and reported while blinded to other test results. Clinically significant prostate cancer was primarily defined as Gleason 4 + 3 or greater, or a maximum cancer core length of 6 mm or more of any grade. It was secondarily defined as Gleason 3 + 4 or greater, or a maximum cancer core length of 4 mm or more of any grade. RESULTS: In 41 months 740 men were recruited at a total of 11 centers, of whom 576 underwent all 3 tests. Eight of the 150 men (5.1%) with a multiparametric magnetic resonance imaging score of 1-2 had any Gleason 3 + 4 or greater disease on transrectal ultrasound guided systematic biopsy. Of the 75 men in whom transrectal ultrasound guided systematic biopsy showed Gleason 3 + 3 of any maximum cancer core length 61 (81%) had Gleason 3 + 4, 8 (11%) had Gleason 4 + 3 and 0 (0%) had Gleason 4 + 5 or greater disease. For definition 1 (clinically significant prostate cancer) transrectal ultrasound guided systematic biopsy sensitivity remained stable and low across multiparametric magnetic resonance imaging Likert scores of 35% to 52%. For definition 2 (clinically significant prostate cancer and any cancer) sensitivity increased with higher multiparametric magnetic resonance imaging scores. The negative predictive value varied due to varying disease prevalence but for all cancer thresholds it declined with increasing multiparametric magnetic resonance imaging scores. CONCLUSIONS: In the setting of multiparametric magnetic resonance imaging Likert scores 1-2 transrectal ultrasound guided systematic biopsy revealed Gleason 3 + 4 disease in only 1 of 20 men. Further, for any clinically significant prostate cancer definition transrectal ultrasound guided systematic biopsy had poor sensitivity and variable but a low negative predictive value across multiparametric magnetic resonance imaging scores. Men who undergo transrectal ultrasound guided systematic biopsy without targeting in the setting of a multiparametric magnetic resonance imaging score of 3 to 5 should be advised to undergo repeat (targeted) biopsy.

Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial.

Background: Doravirine (DOR), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), is active against wild-type Human Immunodeficiency Virus (HIV)-1 and the most common NNRTI-resistant variants, and has a favorable and unique in vitro resistance profile. Methods: DRIVE-AHEAD is a phase 3, double-blind, non-inferiority trial. Antiretroviral treatment-naive adults with ≥1000 HIV-1 RNA copies/mL were randomized (1:1) to once-daily, fixed-dose DOR at 100 mg, lamivudine at 300 mg, and tenofovir disoproxil fumarate (TDF) at 300 mg (DOR/3TC/TDF) or to efavirenz at 600 mg, emtricitabine at 200 mg, and TDF at 300 mg (EFV/FTC/TDF) for 96 weeks. The primary efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 48 (Food and Drug Administration snapshot approach; non-inferiority margin 10%). Results: Of the 734 participants randomized, 728 were treated (364 per group) and included in the analyses. At week 48, 84.3% (307/364) of DOR/3TC/TDF recipients and 80.8% (294/364) of EFV/FTC/TDF recipients achieved <50 HIV-1 RNA copies/mL (difference 3.5%, 95% CI, -2.0, 9.0). DOR/3TC/TDF recipients had significantly lower rates of dizziness (8.8% vs 37.1%), sleep disorders/disturbances (12.1% vs 25.2%), and altered sensorium (4.4% vs 8.2%) than EFV/FTC/TDF recipients. Mean changes in fasting low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) were significantly different between DOR/3TC/TDF and EFV/FTC/TDF (-1.6 vs +8.7 mg/dL and -3.8 vs +13.3 mg/dL, respectively). Conclusions: In HIV-1 treatment-naive adults, DOR/3TC/TDF demonstrated non-inferior efficacy to EFV/FTC/TDF at week 48 and was well tolerated, with significantly fewer neuropsychiatric events and minimal changes in LDL-C and non-HDL-C compared with EFV/FTC/TDF. Clinical Trials Registration: NCT02403674.

High EMSY expression defines a BRCA-like subgroup of high-grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum.

BACKGROUND: Approximately half of high-grade serous ovarian carcinomas (HGSOCs) demonstrate homologous recombination repair (HR) pathway defects, resulting in a distinct clinical phenotype comprising hypersensitivity to platinum, superior clinical outcome, and greater sensitivity to poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors. EMSY, which is known to be amplified in breast and ovarian cancers, encodes a protein reported to bind and inactivate BRCA2. Thus, EMSY overexpression may mimic BRCA2 mutation, resulting in HR deficiency. However, to our knowledge, the phenotypic consequences of EMSY overexpression in HGSOC patients has not been explored. METHODS: Here we investigate the impact of EMSY expression on clinical outcome and sensitivity to platinum-based chemotherapy using available data from transcriptomically characterized HGSOC cohorts. RESULTS: High EMSY expression was associated with better clinical outcome in a cohort of 265 patients with HGSOC from Edinburgh (overall survival multivariable hazard ratio, 0.58 [95% CI, 0.38-0.88; P = .011] and progression-free survival multivariable hazard ratio, 0.62 [95% CI, 0.40-0.96; P = .030]). Superior outcome also was demonstrated in the Medical Research Council ICON7 clinical trial and multiple publicly available data sets. Patients within the Edinburgh cohort who had high EMSY expression were found to demonstrate greater rates of complete response to multiple platinum-containing chemotherapy regimens (radiological complete response rate of 44.4% vs 12.5% at second exposure; P = .035) and corresponding prolonged time to disease progression (median, 151.5 days vs 60.5 days after third platinum exposure; P = .004). CONCLUSIONS: Patients with HGSOCs demonstrating high EMSY expression appear to experience prolonged survival and greater platinum sensitivity, reminiscent of BRCA-mutant cases. These data are consistent with the notion that EMSY overexpression may render HGSOCs HR deficient.

Exploratory outcome analyses according to stage and/or residual disease in the ICON7 trial of carboplatin and paclitaxel with or without bevacizumab for newly diagnosed ovarian cancer.

OBJECTIVE: In the randomized phase 3 ICON7 trial (ISRCTN91273375), adding bevacizumab to chemotherapy for newly diagnosed ovarian cancer significantly improved progression-free survival (PFS; primary endpoint) but not overall survival (OS; secondary endpoint) in the intent-to-treat (ITT) population. We explored treatment effect according to stage and extent of residual disease. METHODS: Patients with stage IIB-IV or high-risk (grade 3/clear-cell) stage I-IIA ovarian cancer were randomized to receive six cycles of carboplatin and paclitaxel either alone or with bevacizumab 7.5 mg/kg every 3 weeks followed by single-agent bevacizumab for 12 further cycles (total duration 12 months). Post hoc exploratory analyses of subgroups defined by stage and extent of residual disease at diagnosis within the stage IIIB-IV population (European indication) was performed. RESULTS: The PFS benefit from bevacizumab was seen consistently in all subgroups explored. The PFS hazard ratio was 0.77 (95% confidence interval [CI], 0.59-0.99) in 411 patients with stage IIIB-IV ovarian cancer with no visible residuum and 0.81 (95% CI, 0.69-0.95) in 749 patients with stage IIIB-IV disease and visible residuum. As in the ITT population, no OS difference was detected in any subgroup except the previously described 'high-risk' subgroup. Safety results in analyzed subgroups were consistent with the overall population. CONCLUSIONS: Adding bevacizumab to front-line chemotherapy improves PFS irrespective of stage/residual disease. In patients with stage III with >1 cm residuum, stage IV or inoperable disease, this translates into an OS benefit. No OS benefit or detriment was seen in other subgroups explored.

Impact of retrospective data verification to prepare the ICON6 trial for use in a marketing authorization application.

BACKGROUND: The ICON6 trial (ISRCTN68510403) is a phase III academic-led, international, randomized, three-arm, double-blind, placebo-controlled trial of the addition of cediranib to chemotherapy in recurrent ovarian cancer. It investigated the use of placebo during chemotherapy and maintenance (arm A), cediranib alongside chemotherapy followed by placebo maintenance (arm B) and cediranib throughout both periods (arm C). Results of the primary comparison showed a meaningful gain in progression-free survival (time to progression or death from any cause) when comparing arm A (placebo) with arm C (cediranib). As a consequence of the positive results, AstraZeneca was engaged with the Medical Research Council trials unit to discuss regulatory submission using ICON6 as the single pivotal trial. METHODS: A relatively limited level of on-site monitoring, single data entry and investigator's local evaluation of progression were used on trial. In order to submit a license application, it was decided that (a) extensive retrospective source data verification of medical records against case report forms should be performed, (b) further quality control checks for accuracy of data entry should be performed and (c) blinded independent central review of images used to define progression should be undertaken. To assess the value of these extra activities, we summarize the impact on both efficacy and safety outcomes. RESULTS: Data point changes were minimal; those key to the primary results had a 0.47% error rate (36/7686), and supporting data points had a 0.18% error rate (109/59,261). The impact of the source data verification and quality control processes were analyzed jointly. The conclusion drawn for the primary outcome measure of progression-free survival between arm A and arm C was unchanged. The log-rank test p-value changed only at the sixth decimal place, the hazard ratio does not change from 0.57 with the exception of a marginal change in its upper bound (0.74-0.73) and the median progression-free survival benefit from arm C remained at 2.4 months. Separately, the blinded independent central review of progression scans was performed as a sensitivity analysis. Estimates and p values varied slightly but overall demonstrated a difference in arms, which is consistent with the initial result. Some increases in toxicity were observed, though these were generally minor, with the exception of hypertension. However, none of these increases were systematically biased toward one arm. CONCLUSION: The conduct of this pragmatic, academic-sponsored trial was sufficient given the robustness of the results, shown by the results remaining largely unchanged following retrospective verification despite not being designed for use in a marketing authorization. The burden of such comprehensive retrospective effort required to ensure the results of ICON6 were acceptable to regulators is difficult to justify.

Genome-wide association study and meta-analysis in Northern European populations replicate multiple colorectal cancer risk loci.

Genome-wide association studies have been successful in elucidating the genetic basis of colorectal cancer (CRC), but there remains unexplained variability in genetic risk. To identify new risk variants and to confirm reported associations, we conducted a genome-wide association study in 1,701 CRC cases and 14,082 cancer-free controls from the Finnish population. A total of 9,068,015 genetic variants were imputed and tested, and 30 promising variants were studied in additional 11,647 cases and 12,356 controls of European ancestry. The previously reported association between the single-nucleotide polymorphism (SNP) rs992157 (2q35) and CRC was independently replicated (p = 2.08 × 10-4 ; OR, 1.14; 95% CI, 1.06-1.23), and it was genome-wide significant in combined analysis (p = 1.50 × 10-9 ; OR, 1.12; 95% CI, 1.08-1.16). Variants at 2q35, 6p21.2, 8q23.3, 8q24.21, 10q22.3, 10q24.2, 11q13.4, 11q23.1, 14q22.2, 15q13.3, 18q21.1, 20p12.3 and 20q13.33 were associated with CRC in the Finnish population (false discovery rate < 0.1), but new risk loci were not found. These results replicate the effects of multiple loci on the risk of CRC and identify shared risk alleles between the Finnish population isolate and outbred populations.

Variation at 2q35 (PNKD and TMBIM1) influences colorectal cancer risk and identifies a pleiotropic effect with inflammatory bowel disease.

To identify new risk loci for colorectal cancer (CRC), we conducted a meta-analysis of seven genome-wide association studies (GWAS) with independent replication, totalling 13 656 CRC cases and 21 667 controls of European ancestry. The combined analysis identified a new risk association for CRC at 2q35 marked by rs992157 (P = 3.15 × 10-8, odds ratio = 1.10, 95% confidence interval = 1.06-1.13), which is intronic to PNKD (paroxysmal non-kinesigenic dyskinesia) and TMBIM1 (transmembrane BAX inhibitor motif containing 1). Intriguingly this susceptibility single-nucleotide polymorphism (SNP) is in strong linkage disequilibrium (r2 = 0.90, D' = 0.96) with the previously discovered GWAS SNP rs2382817 for inflammatory bowel disease (IBD). Following on from this observation we examined for pleiotropy, or shared genetic susceptibility, between CRC and the 200 established IBD risk loci, identifying an additional 11 significant associations (false discovery rate [FDR]) < 0.05). Our findings provide further insight into the biological basis of inherited genetic susceptibility to CRC, and identify risk factors that may influence the development of both CRC and IBD.

Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study.

BACKGROUND: Men with high serum prostate specific antigen usually undergo transrectal ultrasound-guided prostate biopsy (TRUS-biopsy). TRUS-biopsy can cause side-effects including bleeding, pain, and infection. Multi-parametric magnetic resonance imaging (MP-MRI) used as a triage test might allow men to avoid unnecessary TRUS-biopsy and improve diagnostic accuracy. METHODS: We did this multicentre, paired-cohort, confirmatory study to test diagnostic accuracy of MP-MRI and TRUS-biopsy against a reference test (template prostate mapping biopsy [TPM-biopsy]). Men with prostate-specific antigen concentrations up to 15 ng/mL, with no previous biopsy, underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. The conduct and reporting of each test was done blind to other test results. Clinically significant cancer was defined as Gleason score ≥4 + 3 or a maximum cancer core length 6 mm or longer. This study is registered on ClinicalTrials.gov, NCT01292291. FINDINGS: Between May 17, 2012, and November 9, 2015, we enrolled 740 men, 576 of whom underwent 1·5 Tesla MP-MRI followed by both TRUS-biopsy and TPM-biopsy. On TPM-biopsy, 408 (71%) of 576 men had cancer with 230 (40%) of 576 patients clinically significant. For clinically significant cancer, MP-MRI was more sensitive (93%, 95% CI 88-96%) than TRUS-biopsy (48%, 42-55%; p<0·0001) and less specific (41%, 36-46% for MP-MRI vs 96%, 94-98% for TRUS-biopsy; p<0·0001). 44 (5·9%) of 740 patients reported serious adverse events, including 8 cases of sepsis. INTERPRETATION: Using MP-MRI to triage men might allow 27% of patients avoid a primary biopsy and diagnosis of 5% fewer clinically insignificant cancers. If subsequent TRUS-biopsies were directed by MP-MRI findings, up to 18% more cases of clinically significant cancer might be detected compared with the standard pathway of TRUS-biopsy for all. MP-MRI, used as a triage test before first prostate biopsy, could reduce unnecessary biopsies by a quarter. MP-MRI can also reduce over-diagnosis of clinically insignificant prostate cancer and improve detection of clinically significant cancer. FUNDING: PROMIS is funded by the UK Government Department of Health, National Institute of Health Research-Health Technology Assessment Programme, (Project number 09/22/67). This project is also supported and partly funded by UCLH/UCL Biomedical Research Centre and The Royal Marsden and Institute for Cancer Research Biomedical Research Centre and is coordinated by the Medical Research Council Clinical Trials Unit (MRC CTU) at UCL. It is sponsored by University College London (UCL).

Relationships among clinic, home, and ambulatory blood pressures with small vessel disease of the brain and functional status in older people with hypertension.

BACKGROUND: Subcortical small vessel disease, represented as white matter hyperintensity (WMH) on magnetic resonance images (MRI) is associated with functional decline in older people with hypertension. We evaluated the relationships of clinic and out-of-office blood pressures (BP) with WMH and functional status in older persons. METHODS: Using cross-sectional data from 199 older study participants enrolled in the INFINITY trial, we analyzed the clinic, 24-hour ambulatory, and home BPs and their relationships with WMH burden and mobility and cognitive outcomes. RESULTS: Volume of WMH was associated with clinic and 24-hour ambulatory systolic BP but not home systolic BP. The mobility measure, supine-to-sit time, had a significant association with 24-hour systolic BP and pulse pressure but not with diastolic BP or values obtained by home BP. Cognitive measures of processing speed (Trails Making Test Part A and the Stroop Word Test) were significantly associated with 24-hour systolic BP, but not clinic and home BPs. CONCLUSION: These data demonstrate that ambulatory BP measurements in older people are more strongly associated with WMH and certain measures of functional status compared to home BP measurements. Hence, home BP may not be a useful substitute for ambulatory BP for assessing subcortical small vessel disease and its consequences. Further longitudinal analyses comparing clinic and various types of out-of-office BP measures with small vessel brain disease are needed. Clinicaltrials.gov identifier: NCT01650402.

HIV and TB co-infection in the ART era: CD4 count distributions and TB case fatality in Cape Town.

BACKGROUND: In Cape Town, the roll-out of antiretroviral therapy (ART) has increased over the last decade with an estimated coverage of 63% of HIV- positive patients in 2013. The influence of ART on the characteristics of the population of HIV-positive patients presenting to the primary care TB programme is unknown. In this study, we examined trends in CD4 count distribution, ART usage and treatment outcomes among HIV-positive TB patients in Cape Town from 2009 to 2013. METHODS: Data from the electronic TB register on all newly registered drug-sensitive TB patients ≥18 years were analyzed retrospectively. Descriptive statistics were used to compare baseline characteristics, the CD4 count distribution and TB treatment outcomes both by year of treatment and ART status at the start of TB treatment. Survival analyses were used to assess the change in mortality risk during TB treatment over time, stratified by ART status at start of TB treatment. RESULTS: 118,989 patients were treated over 5 years. HIV prevalence among TB patients decreased from 50.9% in 2009 to 49.0% in 2013. The absolute number of HIV-positive TB cases declined by 13.2% between 2010 and 2013. More patients entered the TB programme on ART in 2013 compared to 2009 (30.0% vs 9.9%). Among these, the CD4 count distribution showed a year by year shift to higher CD4 counts. In 2013, over 75% of ART-naïve TB patients still had a CD4 count < 350 cells/mm3. ART initiation among ART-naive patients increased from 37.0 to 77.7% and TB case fatality declined from 7.4 to 5.2% (p < 0.001). In multivariate analysis a decrease in TB mortality was most strongly associated with CD4 count (Adjusted HR 0.82 per increase of 50 cells/mm3, 95% CI: 0.81-0.83, p < 001) and the initiation of ART during TB treatment (Adjusted HR 0.39, 95% CI: 0.35-0.42, p < 0.001). CONCLUSION: Comprehensive changes in the ART and TB treatment programmes resulted in incremental increases in ART coverage for HIV-positive TB patients and a subsequent decrease in TB case fatality due to increased ART uptake in HIV-positive ART-naïve patients. However TB still remained a major presenting opportunistic infection with the majority of cases occurring at low CD4 counts.

Comprehensive pharmacogenetic profiling of the epidermal growth factor receptor pathway for biomarkers of response to, and toxicity from, cetuximab.

BACKGROUND: Somatic mutations in the epidermal growth factor receptor (EGFR) intracellular signalling pathways predict non-response to cetuximab in the treatment of advanced colorectal cancer (aCRC). We hypothesised that common germline variants within these pathways may also play similar roles. METHODS: We analysed 54 potentially functional, common, inherited EGFR pathway variants in 815 patients with aCRC treated with oxaliplatin-fluoropyrimidine chemotherapy plus cetuximab. Primary endpoints were response and skin rash (SR). We had >85% power to detect ORs=1.6 for variants with minor allele frequencies >20%. RESULTS: We identified five potential biomarkers for response and four for SR, although none remained significant after correction for multiple testing. Our initial data supported a role for Ser313Pro in PIK3R2 in modulating response to cetuximab-in patients with KRAS wild-type CRCs, 36.4% with one allele encoding proline responded, as compared with 71.2% homozygous for allele encoding serine (OR 0.23, 95% CI 0.09 to 0.56, p=0.0014), and this association was predictive for cetuximab (pinteraction=0.017); however, independent replication failed to validate this association. No previously proposed predictive biomarkers were validated. CONCLUSIONS: Our study highlights the need to validate potential pharmacogenetic biomarkers. We did not find strong evidence for common germline biomarkers of cetuximab response and toxicity.