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Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease in which molecular stratification is needed to improve clinical outcomes. The identification of predictive biomarkers can have a major impact on the care of these patients, but the availability of metastatic tissue samples for research in this setting is limited.To study the prevalence of immune biomarkers of potential clinical utility to immunotherapy in mCRPC and to determine their association with overall survival (OS).From 100 patients, mCRPC biopsies were assayed by whole exome sequencing, targeted next-generation sequencing, RNA sequencing, tumor mutational burden, T-cell-inflamed gene expression profile (TcellinfGEP) score (Nanostring), and immunohistochemistry for programmed cell death 1 ligand 1 (PD-L1), ataxia-telangiectasia mutated (ATM), phosphatase and tensin homolog (PTEN), SRY homology box 2 (SOX2), and the presence of neuroendocrine features.The phi coefficient determined correlations between biomarkers of interest. OS was assessed using Kaplan-Meier curves and adjusted hazard ratios (aHRs) from Cox regression.PD-L1 and SOX2 protein expression was detected by immunohistochemistry (combined positive score ≥1 and5% cells, respectively) in 24 (33%) and 27 (27%) mCRPC biopsies, respectively; 23 (26%) mCRPC biopsies had high TcellinfGEP scores (-0.318). PD-L1 protein expression and TcellinfGEP scores were positively correlated (phi 0.63 [0.45; 0.76]). PD-L1 protein expression (aHR: 1.90 [1.05; 3.45]), high TcellinfGEP score (aHR: 1.86 [1.04; 3.31]), and SOX2 expression (aHR: 2.09 [1.20; 3.64]) were associated with worse OS.PD-L1, TcellinfGEP score, and SOX2 are prognostic of outcome from the mCRPC setting. If validated, predictive biomarker studies incorporating survival endpoints need to take these findings into consideration.This study presents an analysis of immune biomarkers in biopsies from patients with metastatic prostate cancer. We describe tumor alterations that predict prognosis that can impact future studies.

Background Loss of ataxia telangiectasia mutated (ATM), a key protein regulating DNA repair signaling, has been suggested to increase sensitivity to DNA damaging agents. We conducted a study analyzing the loss of ATM protein expression in colorectal cancer and correlated this with clinical outcomes. Materials and Methods The clinical outcomes data and tumor samples from metastatic colorectal cancer patients referred to the Royal Marsden Hospital Drug Development Unit (United Kingdom) from 2012 to 2016 and providing consent for a molecular characterization study were analyzed. Immunohistochemistry (IHC) slides were assessed by a pathologist for nuclear staining intensity of ATM and semiquantitatively scored. ATM loss was defined as a nuclear H-score of ≤ 10. Results Of 223 colorectal cancer samples, ATM IHC loss was identified in 17 (8%). ATM loss was independent of the RAS and RAF mutational status. ATM loss was associated with superior overall survival after first-line oxaliplatin-based therapy (49 vs. 32 months; hazard ratio [HR], 2.52) but not with irinotecan-based therapy (24 vs. 33 months; HR, 0.72). ATM loss was not prognostic for survival from the diagnosis (50 vs. 44 months; HR, 1.43). Conclusion ATM could be considered a biomarker for the development of novel DNA repair targeting agents and treatment of colorectal cancer.

Early-phase cancer clinical trials are becoming increasingly accessible for patients with advanced cancer who have exhausted standard treatment options and later phase trial options. Many of these trials mandate research tissue biopsies. Research biopsies have been perceived as ethically fraught due to the perception of potential coercion of vulnerable human subjects. We performed an audit of two years of practice to assess the safety of ultrasound (US)-guided research biopsies, and to look at the yield of a simultaneous tumour next-generation sequencing (NGS) and immunohistochemistry (IHC) molecular characterisation programme. We show that in our institution, US-guided research biopsies were safe, produced adequate tumour content and in a selected subset who underwent in-house NGS sequencing, showed a high rate of actionable mutations with 30% having a Tier 1 variant. Nevertheless, these research biopsies may only provide direct benefit for a minority of patients and we conclude with a reflection on the importance of obtaining truly informed consent.

Background Metastatic CC prognosis remains poor. Molecular characterisation (MC) allows better understanding of the mutations (mut) driving carcinogenesis or treatment resistance. We report the cervical tumour MC of pts in a P1 unit and its clinical implications. Methods CC pts referred to the P1 unit of The Royal Marsden Hospital from 2011-18 underwent tumour molecular profiling using OncoCartaTM (Sequenom), TruSeq® Cancer Amplicon (Illumina), GeneReadTM custom DNA damage (Qiagen) or FoundationOne® panel. Retrospective data was extracted from electronic medical records. Results Of the 37 pts (median age: 34.7 years) analysed, 45.9% had squamous histology, and 37.8% were FIGO stage 2 at diagnosis; 34 different pathogenic mut were identified with 70.3% of pts having mut. PIK3CA mut were the most common (32.4%), followed by KRAS (13.5%), APC (8.1%), TP53 (8.1%), PTEN (5.4%), KDR (5.4%), ATM (5.4%), STK11 (5.4%) and BRCA1 (5.4%). 40.5% (15/37) patients had a potentially actionable mutation. Median overall survival (mOS) was 36 months (mo) in study population, 33 mo in KRAS mut, 40 mo in PIK3CA mut, 52 mo in APC mut and 40 mo in the mut-negative group; however, this difference was not statistically significant. In the KRAS mut group, 60% were adenocarcinoma and 40% adenosquamous. All KRAS mut pts had FIGO stage 2/3 at diagnosis. 80% had visceral metastasis when referred to the P1 unit; whereas in the PIK3CA mut group, tumour histologies were 33.3% squamous, 25% adenocarcinoma, 25% adenosquamous, 8.3% mucinous, 8.3% uncommon histologies. In the PIK3CA mut group, 75% were stage 1/2 at diagnosis, and 41.6% had visceral metastasis when referred. 5.4% (2/37) of pts were allocated to a P1 trial based on the finding of a PIK3CA mut with a mOS of 40 mo compared to 36 mo for the total population (p = 0.6). One pt received an AKT inhibitor (i) but developed progressive disease (PD) after 3 cycles; the other received a PI3K i with PD after 4 cycles. Conclusions Our study corroborates existing knowledge of the association between KRAS mut and adenocarcinoma histology in CC which confers worse prognosis. The high rate of potentially actionable mut indicates the increasing scope for targeted treatment trials in CC, thus prompting early MC which may improve pt allocation to P1 trials. Legal entity responsible for the study The Institute of Cancer Research and The Royal Marsden Foundation Trust. Funding The Institute of Cancer Research and The Royal Marsden Foundation Trust. Disclosure S. Banerjee: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Honoraria/reimbursement: Tesaro; Honoraria (self), Honoraria/reimbursement: Clovis; Honoraria (self), Honoraria/reimbursement: Merck Serono; Honoraria (self), Honoraria/reimbursement: Nucana; Honoraria (self), Honoraria/reimbursement: Immunogen; Honoraria (self), Honoraria/reimbursement: Seattle Genetics; Honoraria (self), Honoraria/reimbursement: Roche; Honoraria (self), Honoraria/reimbursement: Gamamabs. J.S. de Bono: Honoraria (self), Non-remunerated activity/ies: Astellas Pharma; Honoraria (self), Research grant / Funding (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (self): Genentech/Roche; Honoraria (self): Pfizer; Honoraria (self), Non-remunerated activity/ies: Sanofi; Honoraria (self): Bayer; Honoraria (self): Boehringer Ingelheim; Honoraria (self): Merck Serono; Honoraria (self): Merck Sharp & Dohme; Non-remunerated activity/ies: Genmab; Non-remunerated activity/ies: GlaxoSmithKline; Non-remunerated activity/ies: Orion Pharma GmbH; Non-remunerated activity/ies: Qiagen; Non-remunerated activity/ies: Taiho Pharmaceutical; Non-remunerated activity/ies: Vertex; Licensing / Royalties, Royalties paid to Institution, no personal income: Abiraterone Rewards to Inventors; Licensing / Royalties, Royalties paid to Institution, no personal income: PARP inhibitors and DNA repair defects. U. Banerji: Honoraria (self), Precision Medicine - Advanced Prostate Cancer Meeting, London UK -30/11/2018: Astellas; Honoraria (self), Advisory / Consultancy, Translational Clinical Oncology Advisory Board, London, 24/07/2018; FIH Precision Oncology SAB, Frankfurt, 10-11/11/2015: Novartis; Advisory / Consultancy, Clinical Advisory Board, London, 19/03/2018 and 12/02/2015: Karus Therapeutics; Advisory / Consultancy, GI Advisory Board, London, 2/12/2017: Phoenix ACT; Honoraria (self), European Digestive Oncology Research Forum, London, 27-28/11/2017: Eli Lilly; Honoraria (self), KOL ERK Workshop, New Orleans, 17/04/2016; HSP90 Workshop, Washington DC,8/03/2014: Astex; Honoraria (self), AUY922 meeting, New Jersey, USA,12/02/2015: Vernalis; Research grant / Funding (institution), ONX-0801:Funding for investigator-initiated Phase I trial: Onyx Pharmaceuticals; Research grant / Funding (institution), ONX-0801:top-up funding for investigator-initiated phase I trial: BTG International; Research grant / Funding (institution), RAF/MEK: funding for investigator-initiated phase I trial: Chugai; Research grant / Funding (institution), TAX-TORC: funding for investigator-initiated phase I trial: AstraZeneca; Research grant / Funding (institution), FRAME: funding for investigator-initiated phase I trial: Verastem. A. Minchom: Travel / Accommodation / Expenses: Loxo; Advisory / Consultancy: Janssen; Honoraria (self): Faron; Speaker Bureau / Expert testimony: Bayer Media Event. J. Lopez: Advisory / Consultancy: Genmab; Advisory / Consultancy: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Research grant / Funding (institution), Travel / Accommodation / Expenses: Basilea. All other authors have declared no conflicts of interest.