TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer.

PURPOSE: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from metastatic castration-resistant prostate cancer (mCRPC) patients starting a new line of AR signalling inhibitors (ARSi). EXPERIMENTAL DESIGN: Between March 2014 and April 2017, we recruited mCRPC patients (n=168) prior to ARSi in a cohort study encompassing 10 European centres. Blood samples were collected for comprehensive profiling of CellSearch-enriched circulating tumour cells (CTCs) and circulating tumour DNA (ctDNA). Targeted CTC RNA-seq allowed the detection of eight AR splice variants (ARVs). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss-of-heterozygosity, mutations and structural rearrangements in ctDNA. Clinical or radiological progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox-regression models. RESULTS: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumour burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value (HR 1.88, 95%CI 1.18-3.00, p = 0.008), and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs 7.51 vs 2.62 months, p < 0.0001), which was validated in an independent mCRPC cohort (n=202) starting first-line ARSi (median, 14.3 vs 6.39 vs 2.23 months, p < 0.0001). CONCLUSIONS: In an all-comer cohort, tumour burden estimates and TP53 outperform any AR perturbation to infer prognosis

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.The Belgian Foundation Against Cancer (grant number C/2014/227); Kom op tegen Kanker (Stand up to Cancer), the Flemish Cancer Society (grant number 00000000116000000206); Royal College of Surgeons/Cancer Research UK (C19198/A1533); The Cancer Research Funds of Radiumhemmet, through the PCM program at KI (grant number 163012); The Erling-Persson family foundation (grant number 4-2689-2016); the Swedish Research Council (grant number K2010-70X-20430-04-3), and the Swedish Cancer Foundation (grant number 09-0677)

Collective Labor Supply and Child Care Expenditures: Theory and Application

In this study we examine the collective labor supply choices of dual-earner parents and take into account child care expenditures. We find that the individual labor supplies are hardly affected by changes in the prices of child care services. In addition, the child care price effects on the individual labor supplies are much smaller than the wage effects. Furthermore, we find that the additional earnings due to an increase in household non-labor income minus the child care expenditures are mainly transferred to the female partner.

Phenomenological model for the formation of heterogeneous tracks in pyrochlores irradiated with swift heavy ions

Expérience GANIL/IRRSUDZirconate and titanate pyrochlores were irradiated with swift heavy ions in order to investigate the effects of the chemical composition on the structural changes induced by high electronic excitation. Both transmission electron microscopy and X-ray diffraction results show that the structural modifications induced by irradiation with 120-MeV U ions are strongly dependent on the sample composition: Gd2Ti2O7 is readily amorphized, whereas Gd2Zr2O7 is transformed into a radiation-resistant anion-deficient fluorite structure. For Sm2Zr2O7, Eu2Zr2O7 and Nd2Zr2O7, more complex behavior is observed, since both pyrochlore-fluorite phase transformation and amorphization occur. A new phenomenological model (the heterogeneous track overlap model, HTOM), which assumes a direct impact mechanism coupled with a single track overlap process, is proposed to describe the formation of heterogeneous track structures consisting of mixed anion-deficient fluorite and amorphous domains. The pyrochlore composition mainly influences the structure of ion tracks (and weakly their diameter), and essentially concerns the amount of amorphous phase vs the amount of fluorite counterpart

Effect of the ambient atmosphere on the surface reactivity of materials for the realization of reference mass standards

International audienceSecondary mass standards are usually made of stainless steel. One of the main problems in mass metrology is the stability of such stainless steel standards. Consequently, new materials have been investigated for the realization of mass standards, and this has led to the selection of nickel-based superalloys. The stability of materials is strongly dependent on surface reactivity; accelerated oxidation tests were performed, either in dry or wet air, and after a kinetic study, microstructural analysis of the oxide films was performed by scanning electron microscopy. The structure of the oxide films was also characterized by grazing x-ray diffraction and finally by x-ray photoelectron spectrometry (XPS) analysis. XPS associated with sputtering by argon ions allowed us to differentiate the nature of the oxides from the outer surface to a given depth in the film

Have European Stocks become More Volatile? An Empirical Investigation of Idiosyncratic and Market Risk in the Euro Area

"We examine the dynamics of idiosyncratic risk, market risk and return correlations in European equity markets using weekly observations from 3515 stocks listed in the 12 euro area stock markets over the period 1974-2004. Similarly to""Campbell et al. (2001)"", we find a rise in idiosyncratic volatility, implying that it now takes more stocks to diversify away idiosyncratic risk. Contrary to the US, however, market risk is trended upwards in Europe and correlations are not trended downwards. Both the volatility and correlation measures are pro-cyclical, and they rise during times of low market returns. Market and average idiosyncratic volatility jointly predict market wide returns, and the latter impact upon both market and idiosyncratic volatility. This has asset pricing and risk management implications." Copyright (c) 2007 The Authors Journal compilation (c) 2007 Blackwell Publishing Ltd.