The path to a better biomarker: Application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice

Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying 651% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin\u2013stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC. \ua9 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd

A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns.

In cancer, the primary tumour's organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of cases a patient presents with a metastatic tumour and no obvious primary. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types produced by the PCAWG Consortium. Our classifier achieves an accuracy of 91% on held-out tumor samples and 88% and 83% respectively on independent primary and metastatic samples, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced accuracy. Our results have clinical applicability, underscore how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of circulating tumour DNA

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

Global perspectives on observing ocean boundary current systems

Ocean boundary current systems are key components of the climate system, are home to highly productive ecosystems, and have numerous societal impacts. Establishment of a global network of boundary current observing systems is a critical part of ongoing development of the Global Ocean Observing System. The characteristics of boundary current systems are reviewed, focusing on scientific and societal motivations for sustained observing. Techniques currently used to observe boundary current systems are reviewed, followed by a census of the current state of boundary current observing systems globally. Next steps in the development of boundary current observing systems are considered, leading to several specific recommendations

Electronic Nose Breathprints Are Independent of Acute Changes in Airway Caliber in Asthma

Molecular profiling of exhaled volatile organic compounds (VOC) by electronic nose technology provides breathprints that discriminate between patients with different inflammatory airway diseases, such as asthma and COPD. However, it is unknown whether this is determined by differences in airway caliber. We hypothesized that breathprints obtained by electronic nose are independent of acute changes in airway caliber in asthma. Ten patients with stable asthma underwent methacholine provocation (Visit 1) and sham challenge with isotonic saline (Visit 2). At Visit 1, exhaled air was repetitively collected pre-challenge, after reaching the provocative concentration (PC20) causing 20% fall in forced expiratory volume in 1 second (FEV1) and after subsequent salbutamol inhalation. At Visit 2, breath was collected pre-challenge, post-saline and post-salbutamol. At each occasion, an expiratory vital capacity was collected after 5 min of tidal breathing through an inspiratory VOC-filter in a Tedlar bag and sampled by electronic nose (Cyranose 320). Breathprints were analyzed with principal component analysis and individual factors were compared with mixed model analysis followed by pairwise comparisons. Inhalation of methacholine led to a 30.8 ± 3.3% fall in FEV1 and was followed by a significant change in breathprint (p = 0.04). Saline inhalation did not induce a significant change in FEV1, but altered the breathprint (p = 0.01). However, the breathprint obtained after the methacholine provocation was not significantly different from that after saline challenge (p = 0.27). The molecular profile of exhaled air in patients with asthma is altered by nebulized aerosols, but is not affected by acute changes in airway caliber. Our data demonstrate that breathprints by electronic nose are not confounded by the level of airway obstruction

Involvement of the PI3K/Akt pathway in myxoid/round cell liposarcoma

Molecular tumour pathology - and tumour genetic