Velimirovic, Marko2019-12-172019-052019-05-302019Velimirovic, Marko. 2019. Clinical Application of Liquid Biopsies for Disease Monitoring and Understanding Therapeutic Resistance in Metastatic Breast Cancer. Master's thesis, Harvard Medical School.http://nrs.harvard.edu/urn-3:HUL.InstRepos:42061460Purpose Biomarkers for early detection of disease progression in MBC are urgently needed. We explored on-treatment increase in ctDNA fraction as an early prognostic biomarker of subsequent disease progression. Methods Eighty four paired samples from 70 patients with MBC were analyzed for levels of ctDNA, CEA, and CA 15-3. Baseline specimens were collected at the time of initiation of a new line of therapy and on-treatment specimens were obtained 4-12 weeks later. Each patient underwent a CT scan of chest, abdomen and pelvis on 4-16 weeks (on average 7 weeks) later. Sequencing panel of 73 genes was used to quantify ctDNA. Genomic progression was predefined as an increase ≥25% in total MAF from baseline to on-treatment, in patients with MBC. Progression Free Survival (PFS) was estimated using univariate and multivariate Cox proportional hazards models, adjusting for tumor hormonal status, age at metastatic diagnosis, time elapsed and number of prior therapies received. Results Tumor-specific genetic mutations were detected in 89.3% of baseline and 84.5% of on-treatment specimens. Median follow-up time was 14.5 months (1.5-35.9 months).Patients with total average MAF increase ≥25% were more than twice as likely to have subsequent radiologic progression (OR= 2.04, CI 1.75-2.38, p<0.0001) and significantly shorter PFS (median 4.7 vs. 8.7 months; HR=2.57, 95% CI 1.57-4.22, log-rank p=0.0001), adjusting for other prognostic variables in multivariable analysis. Rise in CA 15-3 levels was prognostic of radiologic progression but not PFS. CEA level increase was not prognostic of either outcome. Conclusion Rise in ctDNA fraction as a surrogate of genomic progression during MBC treatment could be an independent biomarker of early disease progression before radiologic and clinical progression, and warrants further evaluation in additional studies.application/pdfenliquid biopsy, circulating tumor DNA, metastatic breast cancerThesis or Dissertation2019-12-17