Staatsexamen, Ludwig Maximilian Universitat Munchen (2013)
Doctor of Medicine, Ludwig Maximilian Universitat Munchen (2014)
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Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.
View details for DOI 10.1038/s41587-021-00981-w
View details for PubMedID 34294911
Patients with Diffuse Large B-cell Lymphoma (DLBCL) in need of immediate therapy are largely under-represented in clinical trials. The diagnosis-to-treatment interval (DTI) has recently been described as a metric to quantify such patient selection bias, with short DTI being associated with adverse risk factors and inferior outcomes. Here, we characterized the relationships between DTI, circulating tumor DNA (ctDNA), conventional risk factors, and clinical outcomes, with the goal of defining objective disease metrics contributing to selection bias.We evaluated pretreatment ctDNA levels in 267 patients with DLBCL treated across multiple centers in Europe and the United States using Cancer Personalized Profiling by Deep Sequencing. Pretreatment ctDNA levels were correlated with DTI, total metabolic tumor volumes (TMTVs), the International Prognostic Index (IPI), and outcome.Short DTI was associated with advanced-stage disease (P < .001) and higher IPI (P < .001). We also found an inverse correlation between DTI and TMTV (RS= -0.37; P < .001). Similarly, pretreatment ctDNA levels were significantly associated with stage, IPI, and TMTV (all P < .001), demonstrating that both DTI and ctDNA reflect disease burden. Notably, patients with shorter DTI had higher pretreatment ctDNA levels (P < .001). Pretreatment ctDNA levels predicted short DTI independent of the IPI (P < .001). Although each risk factor was significantly associated with event-free survival in univariable analysis, ctDNA level was prognostic of event-free survival independent of DTI and IPI in multivariable Cox regression (ctDNA: hazard ratio, 1.5; 95% CI [1.2 to 2.0]; IPI: 1.1 [0.9 to 1.3]; -DTI: 1.1 [1.0 to 1.2]).Short DTI largely reflects baseline tumor burden, which can be objectively measured using pretreatment ctDNA levels. Pretreatment ctDNA levels therefore have utility for quantifying and guarding against selection biases in prospective DLBCL clinical trials.
View details for DOI 10.1200/JCO.20.02573
View details for PubMedID 33909455
High-dose therapy and autologous stem cell transplantation (HDT/ASCT) is an effective salvage treatment for eligible patients with follicular lymphoma (FL) and early progression of disease (POD). Since the introduction of rituximab, HDT/ASCT is no longer recommended in first remission. We here explored whether consolidative HDT/ASCT improved survival in defined subgroups of previously untreated patients. We report survival analyses of 431 patients who received frontline rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for advanced FL, and were randomized to receive consolidative HDT/ASCT. We performed targeted genotyping of 157 diagnostic biopsies, and calculated genotype-based risk scores. HDT/ASCT improved failure-free survival (FFS; hazard ratio [HR], 0.8, P = .07; as-treated: HR, 0.7, P = .04), but not overall survival (OS; HR, 1.3, P = .27; as-treated: HR, 1.4, P = .13). High-risk cohorts identified by FL International Prognostic Index (FLIPI), and the clinicogenetic risk models m7-FLIPI and POD within 24 months-prognostic index (POD24-PI) comprised 27%, 18%, and 22% of patients. HDT/ASCT did not significantly prolong FFS in high-risk patients as defined by FLIPI (HR, 0.9; P = .56), m7-FLIPI (HR, 0.9; P = .91), and POD24-PI (HR, 0.8; P = .60). Similarly, OS was not significantly improved. Finally, we used a machine-learning approach to predict benefit from HDT/ASCT by genotypes. Patients predicted to benefit from HDT/ASCT had longer FFS with HDT/ASCT (HR, 0.4; P = .03), but OS did not reach statistical significance. Thus, consolidative HDT/ASCT after frontline R-CHOP did not improve OS in unselected FL patients and subgroups selected by genotype-based risk models.
View details for DOI 10.1182/bloodadvances.2020002546
View details for PubMedID 32941649