Identifying Mechanisms of Resistance by Circulating Tumor DNA in EVOLVE, a Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer at Time of PARP Inhibitor Progression.

PURPOSE: To evaluate the use of blood cell-free DNA (cfDNA) to identify emerging mechanisms of resistance to PARP inhibitors (PARPi) in high-grade serous ovarian cancer (HGSOC). EXPERIMENTAL DESIGN: We used targeted sequencing (TS) to analyze 78 longitudinal cfDNA samples collected from 30 patients with HGSOC enrolled in a phase II clinical trial evaluating cediranib (VEGF inhibitor) plus olaparib (PARPi) after progression on PARPi alone. cfDNA was collected at baseline, before treatment cycle 2, and at end of treatment. These were compared with whole-exome sequencing (WES) of baseline tumor tissues. RESULTS: At baseline (time of initial PARPi progression), cfDNA tumor fractions were 0.2% to 67% (median, 3.25%), and patients with high ctDNA levels (>15%) had a higher tumor burden (sum of target lesions; P = 0.043). Across all timepoints, cfDNA detected 74.4% of mutations known from prior tumor WES, including three of five expected BRCA1/2 reversion mutations. In addition, cfDNA identified 10 novel mutations not detected by WES, including seven TP53 mutations annotated as pathogenic by ClinVar. cfDNA fragmentation analysis attributed five of these novel TP53 mutations to clonal hematopoiesis of indeterminate potential (CHIP). At baseline, samples with significant differences in mutant fragment size distribution had shorter time to progression (P = 0.001). CONCLUSIONS: Longitudinal testing of cfDNA by TS provides a noninvasive tool for detection of tumor-derived mutations and mechanisms of PARPi resistance that may aid in directing patients to appropriate therapeutic strategies. With cfDNA fragmentation analyses, CHIP was identified in several patients and warrants further investigation.

Data sharing in the age of predictive psychiatry: an adolescent perspective.

BACKGROUND: Advances in genetics and digital phenotyping in psychiatry have given rise to testing services targeting young people, which claim to predict psychiatric outcomes before difficulties emerge. These services raise several ethical challenges surrounding data sharing and information privacy. OBJECTIVES: This study aimed to investigate young people's interest in predictive testing for mental health challenges and their attitudes towards sharing biological, psychosocial and digital data for such purpose. METHODS: Eighty UK adolescents aged 16-18 years took part in a digital role-play where they played the role of clients of a fictional predictive psychiatry company and chose what sources of personal data they wished to provide for a risk assessment. After the role-play, participants reflected on their choices during a peer-led interview. FINDINGS: Participants saw multiple benefits in predictive testing services, but were highly selective with regard to the type of data they were willing to share. Largely due to privacy concerns, digital data sources such as social media or Google search history were less likely to be shared than psychosocial and biological data, including school grades and one's DNA. Participants were particularly reluctant to share social media data with schools (but less so with health systems). CONCLUSIONS: Emerging predictive psychiatric services are valued by young people; however, these services must consider privacy versus utility trade-offs from the perspective of different stakeholders, including adolescents. CLINICAL IMPLICATIONS: Respecting adolescents' need for transparency, privacy and choice in the age of digital phenotyping is critical to the responsible implementation of predictive psychiatric services.

Replicating patterns of prospect theory for decision under risk.

Prospect theory is among the most influential frameworks in behavioural science, specifically in research on decision-making under risk. Kahneman and Tversky's 1979 study tested financial choices under risk, concluding that such judgements deviate significantly from the assumptions of expected utility theory, which had remarkable impacts on science, policy and industry. Though substantial evidence supports prospect theory, many presumed canonical theories have drawn scrutiny for recent replication failures. In response, we directly test the original methods in a multinational study (n = 4,098 participants, 19 countries, 13 languages), adjusting only for current and local currencies while requiring all participants to respond to all items. The results replicated for 94% of items, with some attenuation. Twelve of 13 theoretical contrasts replicated, with 100% replication in some countries. Heterogeneity between countries and intra-individual variation highlight meaningful avenues for future theorizing and applications. We conclude that the empirical foundations for prospect theory replicate beyond any reasonable thresholds.