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Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multiarm, multistage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3 years after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomised patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000 mg + prednisolone 5 mg (SOC + AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards and flexible parametric models, accounting for baseline stratification factors. One thousand and three patients were contemporaneously randomised (November 2011 to January 2014): median age 67 years; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% unassessable; median PSA 97 ng/mL. At 6.1 years median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC + AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95% CI: 0.50-0.71; P = 0.31 × 10 -9 ) favoured SOC + AAP, with 5-years survival improved from 41% SOC-alone to 60% SOC + AAP. This was similar in low-risk (HR = 0.55; 95% CI: 0.41-0.76) and high-risk (HR = 0.54; 95% CI: 0.43-0.69) patients. Median and current maximum time on SOC + AAP was 2.4 and 8.1 years. Toxicity at 4 years postrandomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC + abiraterone acetate + prednisolone, irrespective of metastatic disease risk group., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Triple negative breast cancer (TNBC) is an aggressive variant of breast cancer that lacks the expression of estrogen and progesterone receptors (ER and PR) and HER2. Nearly 50% of patients with advanced TNBC will develop brain metastases (BrM), commonly with progressive extracranial disease. Immunotherapy has shown promise in the treatment of advanced TNBC; however, the immune contexture of BrM remains largely unknown. We conducted a comprehensive analysis of TNBC BrM and matched primary tumors to characterize the genomic and immune landscape of TNBC BrM to inform the development of immunotherapy strategies in this aggressive disease., Methods: Whole-exome sequencing (WES) and RNA sequencing were conducted on formalin-fixed, paraffin-embedded samples of BrM and primary tumors of patients with clinical TNBC ( n = 25, n = 9 matched pairs) from the LCCC1419 biobank at UNC-Chapel Hill. Matched blood was analyzed by DNA sequencing as a comparison for tumor WES for the identification of somatic variants. A comprehensive genomics assessment, including mutational and copy number alteration analyses, neoantigen prediction, and transcriptomic analysis of the tumor immune microenvironment were performed., Results: Primary and BrM tissues were confirmed as TNBC (23/25 primaries, 16/17 BrM) by immunohistochemistry and of the basal intrinsic subtype (13/15 primaries and 16/19 BrM) by PAM50. Compared to primary tumors, BrM demonstrated a higher tumor mutational burden. TP53 was the most frequently mutated gene and was altered in 50% of the samples. Neoantigen prediction showed elevated cancer testis antigen- and endogenous retrovirus-derived MHC class I-binding peptides in both primary tumors and BrM and predicted that single-nucleotide variant (SNV)-derived peptides were significantly higher in BrM. BrM demonstrated a reduced immune gene signature expression, although a signature associated with fibroblast-associated wound healing was elevated in BrM. Metrics of T and B cell receptor diversity were also reduced in BrM., Conclusions: BrM harbored higher mutational burden and SNV-derived neoantigen expression along with reduced immune gene signature expression relative to primary TNBC. Immune signatures correlated with improved survival, including T cell signatures. Further research will expand these findings to other breast cancer subtypes in the same biobank. Exploration of immunomodulatory approaches including vaccine applications and immune checkpoint inhibition to enhance anti-tumor immunity in TNBC BrM is warranted., Competing Interests: JP is an inventor on patent applications for the Breast PAM50 assay. BV and JP report equity and consulting fees for GeneCentric Therapeutics. CA receives research funding from PUMA, Lilly, Merck, Seattle Genetics, Nektar, Tesaro, G1-Therapeutics, ZION, Novartis, and Pfizer; compensated consultant role: Genentech (1/2019-), Eisai (1/2019-), IPSEN (2/2019-), Seattle Genetics (11/15/2019-11/15/2020); Astra Zeneca (3/2020-6/2020), Novartis (5/2020-5/2022), Immunomedics (10/1/2020-9/22/2021), Elucida (9/2020); and royalties from UpToDate and Jones and Bartlett. LC has received institutional research funding from Syndax, Novartis, NanoString Technologies, AbbVie, Seattle Genetics, and Veracyte. An immediate family member has a royalty-sharing agreement and investorship interest in licensed IP to startup company Falcon Therapeutics that is designing neural stem-cell-based therapy for glioblastoma multiforme. She has uncompensated relationships with Sanofi, Novartis, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, AstraZeneca/Daiichi Sankyo, Aptitude Health, Exact Sciences and Eisai. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Routh, Van Swearingen, Sambade, Vensko, McClure, Woodcock, Chai, Cuaboy, Wheless, Garrett, Carey, Hoyle, Parker, Vincent and Anders.)

Background: Prostate radiotherapy (RT) is a first-line option for newly diagnosed men with low-burden metastatic prostate cancer. The current criterion to define this clinical state is based on manual bone metastasis counts, but enumeration of bone metastases is limited by interobserver variations, and it does not account for metastasis volume or lesional coalescence. The automated bone scan index (aBSI) is a quantitative method of evaluating bone metastatic burden in a standardised and reproducible manner., Objective: To evaluate whether aBSI has utility as a predictive imaging biomarker to define a newly diagnosed metastatic prostate cancer population that might benefit from the addition of prostate RT to standard of care (SOC) systemic therapy., Design, Setting, and Participants: This is an exploratory analysis of men with newly diagnosed metastatic prostate cancer randomised in a 1:1 ratio to either SOC or SOC + prostate RT within the STAMPEDE "M1|RT comparison"., Intervention: The SOC was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December 2015. Men allocated RT received either a daily or a weekly schedule that was nominated before randomisation., Outcome Measurements and Statistical Analysis: Baseline bone scans were evaluated retrospectively to calculate aBSI. We used overall (OS) and failure-free (FFS) survival as the end points. Treatment-aBSI interaction was evaluated using the multivariable fractional polynomial interaction (MFPI) and subpopulation treatment effect pattern plot. Further analysis was done in aBSI quartiles using Cox regression models adjusted for stratification factors., Results and Limitations: Baseline bone scans for 660 (SOC: 323 and SOC + RT: 337) of 2061 men randomised within the "M1|RT comparison" met the software requirements for aBSI calculation. The median age was 68 yr, median PSA was 100 ng/mL, median aBSI was 0.9, and median follow-up was 39 mo. Baseline patient characteristics including aBSI were balanced between the treatment groups. Using the MFPI procedure, there was evidence of aBSI-treatment interaction for OS (p = 0.04, MFPI procedure) and FFS (p <  0.01, MFPI procedure). Graphical evaluation of estimated treatment effect plots showed that the OS and FFS benefit from prostate RT was greatest in patients with a low aBSI. Further analysis in quartiles based on aBSI supported this finding., Conclusions: A low automated bone scan index is predictive of survival benefit associated with prostate RT in men with newly diagnosed metastatic prostate cancer., Patient Summary: The widely used bone scan can be evaluated using an automated technique to potentially select men with newly diagnosed metastatic prostate cancer who might benefit from prostate radiotherapy., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Abiraterone acetate received licencing for use in only "high-risk" metastatic hormone-naïve prostate cancer (mHNPC) following the LATITUDE trial findings. However, a "risk"-related effect was not seen in the STAMPEDE trial. There remains uncertainty as to whether men with LATITUDE "low-risk" M1 disease benefit from androgen deprivation therapy (ADT) combined with abiraterone acetate and prednisolone (AAP)., Objective: Evaluation of heterogeneity of effect between LATITUDE high- and low-risk M1 prostate cancer patients receiving ADT + AAP in the STAMPEDE trial., Design, Setting, and Participants: A post hoc subgroup analysis of the 2017 STAMPEDE "abiraterone comparison". Staging scans for M1 patients contemporaneously randomised to ADT or ADT + AAP within the STAMPEDE trial were evaluated centrally and blind to treatment assignment. Stratification was by risk according to the criteria set out in the LATITUDE trial. Exploratory subgroup stratification incorporated the CHAARTED criteria., Outcome Measurements and Statistical Analysis: The primary outcome measure was overall survival (OS) and the secondary outcome measure was failure-free survival (FFS). Further exploratory analysis evaluated clinical skeletal-related events, progression-free survival (PFS), and prostate cancer-specific death. Standard Cox-regression and Kaplan-Meier survival estimates were employed for analysis., Results and Limitations: A total of 901 M1 STAMPEDE patients were evaluated after exclusions. Of the patients, 428 (48%) were identified as having a low risk and 473 (52%) a high risk. Patients receiving ADT + AAP had significantly improved OS (low-risk hazard ratio [HR]: 0.66, 95% confidence interval or CI [0.44-0.98]) and FFS (low-risk HR: 0.24, 95% CI [0.17-0.33]) compared with ADT alone. Heterogeneity of effect was not seen between low- and high-risk groups for OS or FFS. For OS benefit in low risk, the number needed to treat was four times greater than that for high risk. However, this was not observed for the other measured endpoints., Conclusions: Men with mHNPC gain treatment benefit from ADT + AAP irrespective of risk stratification for "risk" or "volume"., Patient Summary: Coadministration of abiraterone acetate and prednisolone with androgen deprivation therapy (ADT) is associated with prolonged overall survival and disease control, compared with ADT alone, in all men with metastatic disease starting hormone therapy for the first time., (Copyright © 2019. Published by Elsevier B.V.)

Background: Little is known about the prognostic significance of somatically mutated genes in metastatic melanoma (MM). We have employed a combined clinical and bioinformatics approach on tumor samples from cutaneous melanoma (SKCM) as part of The Cancer Genome Atlas project (TCGA) to identify mutated genes with potential clinical relevance. Methods: After limiting our DNA sequencing analysis to MM samples ( n = 356) and to the CANCER CENSUS gene list, we filtered out mutations with low functional significance (snpEFF). We performed Cox analysis on 53 genes that were mutated in ≥3% of samples, and had ≥50% difference in incidence of mutations in deceased subjects versus alive subjects. Results: Four genes were potentially prognostic [ RAC1, FGFR1, CARD11, CIITA ; false discovery rate (FDR) < 0.2]. We identified 18 additional genes (e.g., SPEN, PDGFRB, GNAS, MAP2K1, EGFR, TSC2 ) that were less likely to have prognostic value (FDR < 0.4). Most somatic mutations in these 22 genes were infrequent (< 10%), associated with high somatic mutation burden, and were evenly distributed across all exons, except for RAC1 and MAP2K1 . Mutations in only 9 of these 22 genes were also identified by RNA sequencing in >75% of the samples that exhibited corresponding DNA mutations. The low frequency, UV signature type and RNA expression of the 22 genes in MM samples were confirmed in a separate multi-institution validation cohort ( n = 413). An underpowered analysis within a subset of this validation cohort with available patient follow-up ( n = 224) showed that somatic mutations in SPEN and RAC1 reached borderline prognostic significance [log-rank favorable ( p = 0.09) and adverse ( p = 0.07), respectively]. Somatic mutations in SPEN , and to a lesser extent RAC1 , were not associated with definite gene copy number or RNA expression alterations. High (>2+) nuclear plus cytoplasmic expression intensity for SPEN was associated with longer melanoma-specific overall survival (OS) compared to lower (≤ 2+) nuclear intensity ( p = 0.048). We conclude that expressed somatic mutations in infrequently mutated genes beyond the well-characterized ones (e.g., BRAF, RAS, CDKN2A, PTEN, TP53 ), such as RAC1 and SPEN , may have prognostic significance in MM.

Background: Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy., Methods: We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK. Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open-label in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use (from December, 2015), and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December, 2015. Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomisation. The primary outcome was overall survival, measured as the number of deaths; this analysis had 90% power with a one-sided α of 2·5% for a hazard ratio (HR) of 0·75. Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. This trial is registered with ClinicalTrials.gov, number NCT00268476., Findings: Between Jan 22, 2013, and Sept 2, 2016, 2061 men underwent randomisation, 1029 were allocated the control and 1032 radiotherapy. Allocated groups were balanced, with a median age of 68 years (IQR 63-73) and median amount of prostate-specific antigen of 97 ng/mL (33-315). 367 (18%) patients received early docetaxel. 1082 (52%) participants nominated the daily radiotherapy schedule before randomisation and 979 (48%) the weekly schedule. 819 (40%) men had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0·76, 95% CI 0·68-0·84; p<0·0001) but not overall survival (0·92, 0·80-1·06; p=0·266). Radiotherapy was well tolerated, with 48 (5%) adverse events (Radiation Therapy Oncology Group grade 3-4) reported during radiotherapy and 37 (4%) after radiotherapy. The proportion reporting at least one severe adverse event (Common Terminology Criteria for Adverse Events grade 3 or worse) was similar by treatment group in the safety population (398 [38%] with control and 380 [39%] with radiotherapy)., Interpretation: Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer., Funding: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Using next-generation sequencing (NGS) to guide cancer therapy has created challenges in analyzing and reporting large volumes of genomic data to patients and caregivers. Specifically, providing current, accurate information on newly approved therapies and open clinical trials requires considerable manual curation performed mainly by human "molecular tumor boards" (MTBs). The purpose of this study was to determine the utility of cognitive computing as performed by Watson for Genomics (WfG) compared with a human MTB., Materials and Methods: One thousand eighteen patient cases that previously underwent targeted exon sequencing at the University of North Carolina (UNC) and subsequent analysis by the UNCseq informatics pipeline and the UNC MTB between November 7, 2011, and May 12, 2015, were analyzed with WfG, a cognitive computing technology for genomic analysis., Results: Using a WfG-curated actionable gene list, we identified additional genomic events of potential significance (not discovered by traditional MTB curation) in 323 (32%) patients. The majority of these additional genomic events were considered actionable based upon their ability to qualify patients for biomarker-selected clinical trials. Indeed, the opening of a relevant clinical trial within 1 month prior to WfG analysis provided the rationale for identification of a new actionable event in nearly a quarter of the 323 patients. This automated analysis took <3 minutes per case., Conclusion: These results demonstrate that the interpretation and actionability of somatic NGS results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing could potentially improve patient care by providing a rapid, comprehensive approach for data analysis and consideration of up-to-date availability of clinical trials., Implications for Practice: The results of this study demonstrate that the interpretation and actionability of somatic next-generation sequencing results are evolving too rapidly to rely solely on human curation. Molecular tumor boards empowered by cognitive computing can significantly improve patient care by providing a fast, cost-effective, and comprehensive approach for data analysis in the delivery of precision medicine. Patients and physicians who are considering enrollment in clinical trials may benefit from the support of such tools applied to genomic data., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2017.)

Purpose: To evaluate germline variants in hereditary cancer susceptibility genes among unselected cancer patients undergoing tumor-germline sequencing., Experimental Design: Germline sequence data from 439 individuals undergoing tumor-germline dyad sequencing through the LCCC1108/UNCseq™ (NCT01457196) study were analyzed for genetic variants in 36 hereditary cancer susceptibility genes. These variants were analyzed as an exploratory research study to determine whether pathogenic variants exist within the germline of patients undergoing tumor-germline sequencing. Patients were unselected with respect to indicators of hereditary cancer predisposition., Results: Variants indicative of hereditary cancer predisposition were identified in 19 (4.3%) patients. For about half (10/19), these findings represent new diagnostic information with potentially important implications for the patient and their family. The others were previously identified through clinical genetic evaluation secondary to suspicion of a hereditary cancer predisposition. Genes with pathogenic variants included ATM, BRCA1, BRCA2, CDKN2A, and CHEK2 In contrast, a substantial proportion of patients (178, 40.5%) had Variants of Uncertain Significance (VUS), 24 of which had VUS in genes pertinent to the presenting cancer. Another 143 had VUS in other hereditary cancer genes, and 11 had VUS in both pertinent and nonpertinent genes., Conclusions: Germline analysis in tumor-germline sequencing dyads will occasionally reveal significant germline findings that were clinically occult, which could be beneficial for patients and their families. However, given the low yield for unexpected germline variation and the large proportion of patients with VUS results, analysis and return of germline results should adhere to guidelines for secondary findings rather than diagnostic hereditary cancer testing. Clin Cancer Res; 22(16); 4087-94. ©2016 AACRSee related commentary by Mandelker, p. 3987., (©2016 American Association for Cancer Research.)

Background: Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is known about the genetic basis of sporadic papillary renal-cell carcinoma, and no effective forms of therapy for advanced disease exist., Methods: We performed comprehensive molecular characterization of 161 primary papillary renal-cell carcinomas, using whole-exome sequencing, copy-number analysis, messenger RNA and microRNA sequencing, DNA-methylation analysis, and proteomic analysis., Results: Type 1 and type 2 papillary renal-cell carcinomas were shown to be different types of renal cancer characterized by specific genetic alterations, with type 2 further classified into three individual subgroups on the basis of molecular differences associated with patient survival. Type 1 tumors were associated with MET alterations, whereas type 2 tumors were characterized by CDKN2A silencing, SETD2 mutations, TFE3 fusions, and increased expression of the NRF2-antioxidant response element (ARE) pathway. A CpG island methylator phenotype (CIMP) was observed in a distinct subgroup of type 2 papillary renal-cell carcinomas that was characterized by poor survival and mutation of the gene encoding fumarate hydratase (FH)., Conclusions: Type 1 and type 2 papillary renal-cell carcinomas were shown to be clinically and biologically distinct. Alterations in the MET pathway were associated with type 1, and activation of the NRF2-ARE pathway was associated with type 2; CDKN2A loss and CIMP in type 2 conveyed a poor prognosis. Furthermore, type 2 papillary renal-cell carcinoma consisted of at least three subtypes based on molecular and phenotypic features. (Funded by the National Institutes of Health.).

Background: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas., Methods: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes., Results: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma., Conclusions: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).