Adverse events were mostly low grade. The most common grade 3 toxicities with olaparib were anaemia (22%) and neutropenia (8%). Olaparib dose reductions, interruptions and discontinuations occurred in 28%, 52% and 12%, respectively. There was no approximately 3 years.
prospective, multi-center, observational, case-control studies with longitudinal follow-up. Plasma cfDNA was subjected to a targeted methylation sequencing assay using high-efficiency methylation chemistry to enrich for methylation targets, and a machine-learning classifier determined cancer status and predicted TOO. Observed methylation fragments characteristic of cancer and TOO (cancer "signals") were combined across targeted regions and assigned a relative probability of cancer and of a specific TOO. Test performance was also assessed in a subgroup of participants with clinical suspicion of cancer but without pathologic diagnosis or treatment at the time of enrollment. Results: Performance is reported at 99.3% specificity (95% confidence interval [CI], 98.3-99.8%) (ie, a combined false positive rate across all cancers of <1%-a level required for population-level screening). Across all cancers, stage I-III sensitivity was 43.9% (95% CI, 39.4-48.5%). Combined cancer detection sensitivity (95% CI) was 18% (13-25%) in stage I (n¼185), 43% (35-51%) in stage II (n¼166), 81% (73-87%) in stage III (n¼134), and 93% (87-96%) in stage IV (n¼148). TOO was predicted for 96% of all cancers detected; of these, TOO was correct in 93% of cases. Among participants enrolled with suspicion of cancer and subsequently confirmed to have cancer (n¼75), cancer detection across all stages was 46.7% (35/75; 95% CI, 35.1-58.6%) and TOO prediction accuracy was 97.1% (34/ 35; 95% CI, 85.1-99.9%). None of the non-cancer participants in the subgroup (n¼15) had a cancer signal (ie, specificity was 100%). Conclusion: Detection of multiple cancers across stages using methylation signatures in plasma cfDNA was achieved with a single, fixed, low, false positive rate, and simultaneously provided accurate TOO prediction. This targeted methylation assay is undergoing validation in preparation for prospective clinical investigation as a cancer detection diagnostic.
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