RT Journal Article
SR Electronic
T1 Early assessment of molecular progression and response by whole-genome circulating tumor DNA in advanced solid tumors
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP molcanther.1060.2019
DO 10.1158/1535-7163.MCT-19-1060
A1 Davis, Andrew A.
A1 Iams, Wade T.
A1 Chan, David
A1 Oh, Michael S
A1 Lentz, Robert W.
A1 Peterman, Neil
A1 Robertson, Alex
A1 Shah, Abhik
A1 Srivas, Rohith
A1 Wilson, Timothy J
A1 Lambert, Nicole J.
A1 George, Peter S.
A1 Wong, Becky
A1 Wood, Haleigh W.
A1 Close, Jason C.
A1 Tezcan, Ayse
A1 Nesmith, Ken
A1 Tezcan, Haluk
A1 Chae, Young Kwang
YR 2020
UL http://mct.aacrjournals.org/content/early/2020/05/05/1535-7163.MCT-19-1060.abstract
AB Treatment response assessment for patients with advanced solid tumors is complex and existing methods require greater precision. Current guidelines rely on imaging, which has known limitations, including the time required to show a deterministic change in target lesions. Serial changes in whole-genome (WG) circulating tumor DNA (ctDNA) were used to assess response or resistance to treatment early in the treatment course. 96 patients with advanced cancer were prospectively enrolled (91 analyzed and 5 excluded), and blood was collected before and after initiation of a new, systemic treatment. Plasma cell-free DNA libraries were prepared for either WG or WG bisulfite sequencing. Longitudinal changes in the fraction of ctDNA were quantified to retrospectively identify molecular progression (MP) or major molecular response (MMR). Study endpoints were concordance with first follow-up imaging (FFUI) and stratification of progression-free survival (PFS) and overall survival (OS). Patients with MP (n=13) had significantly shorter PFS (median 62d vs. 310d) and OS (255d vs. not reached). Sensitivity for MP to identify clinical progression was 54% and specificity was 100%. MP calls were from samples taken a median of 28d into treatment and 39d before FFUI. Patients with MMR (n=27) had significantly longer PFS and OS compared to those with neither call (n=51). These results demonstrated that ctDNA changes early after treatment initiation inform response to treatment and correlate with long-term clinical outcomes. Once validated, molecular response assessment can enable early treatment change minimizing side effects and costs associated with additional cycles of ineffective treatment.