Liquid biopsies have potential clinical utility as dynamic biomarkers for treatment response. We analyzed serial changes in whole-genome (WG) cfDNA to identify patients with disease progression prior to routine imaging.
We prospectively collected clinical data and blood from 93 advanced cancer patients (40 lung, 25 breast, 28 other). Blood was collected prior to initiation of a new treatment and at one or two additional timepoints (median 21 and 42 days). We isolated plasma cfDNA and prepared sequencing libraries for each patient’s series for either WG sequencing or WG bisulfite sequencing. We quantified changes in the fraction of tumor-derived cfDNA over the initial course of treatment to predict progression vs. no progression. Treatment response at first follow-up imaging (FUI) was determined by RECIST 1.1 and clinical assessment. Study endpoints were agreement with FUI and progression-free survival (PFS) by cfDNA prediction.
Patients were treated with chemo- (34), immuno- (33), targeted- (16), or endocrine therapy (10). Patients with predicted progression by cfDNA (16), indicated by an increase in tumor fraction in either post-treatment blood sample, had shorter PFS (median 64 days) compared to patients without an increase (77; median 263 days), with a hazard ratio of 8.0 (95% confidence interval 4.1-15.6, log-rank P = 8x10-13). For cases where progression was correctly predicted using cfDNA (14), blood collection preceded imaging by a median of 40 days. Positive predictive value was 88% for disease progression and negative predictive value was 84%. Sensitivity for the assay was 54% and specificity was 97%. These findings were consistent in the subset of patients on immunotherapy (sensitivity 71%, specificity 100%, log-rank P = 5x10-12).
Our results show the ability to detect early disease progression with high specificity using liquid biopsy prior to first imaging. These findings were consistent across a variety of tumor histologies and types of treatment. This technology may enable early switching from ineffective therapy to a potentially effective alternative, increasing the value proposition of all delivered treatment.
The authors.
Lexent Bio, Inc.
A.A. Davis: Travel / Accommodation / Expenses: Menarini Silicon Biosystems. W. Iams: Travel / Accommodation / Expenses, Clinical Trial Visit: EMD Serono. N. Peterman: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. A. Robertson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Full / Part-time employment, 2016-2017: Color Genomics; Shareholder / Stockholder / Stock options, 2015-2018: Counsyl. A. Shah: Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options: Myriad. R. Srivas: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. N. Lambert: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options: Sequenom. T. Wilson: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options, Full / Part-time employment, Prior employment: Illumina; Shareholder / Stockholder / Stock options: Counsyl. P. George: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options: Hologic. B. Wong: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. J. Close: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. H. Wood: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. A. Tezcan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc. J.C. Spinosa: Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Full / Part-time employment: San Diego Blood Bank; Advisory / Consultancy: Gestalt Diagnostics; Advisory / Consultancy: SonicHealthUS. H. Tezcan: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Lexent Bio, Inc.; Shareholder / Stockholder / Stock options, 2015-2018: Counsyl. Y.K. Chae: Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Biodesix; Advisory / Consultancy: Counsyl; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech; Advisory / Consultancy: ImmuneOncia; Advisory / Consultancy: Hamni; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: Eli Lilly; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Lexent Bio, Inc.; Research grant / Funding (institution): Freenome. All other authors have declared no conflicts of interest.