Early Assessment of Molecular Progression and Response by Whole-genome Circulating Tumor DNA in Advanced Solid Tumors

Abstract

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. Ninety-six 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 ¼ 13) had significantly shorter PFS (median 62 days vs. 310 days) and OS (255 days 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 28 days into treatment and 39 days before FFUI. Patients with MMR (n ¼ 27) had significantly longer PFS and OS compared with those with neither call (n ¼ 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.

Early identification of disease progression in ALK-rearranged lung cancer using circulating tumor DNA analysis

“…In contrast, %Δt-MAD showed increased sensitivity. These results suggest that ΔVAF mean could be a more relevant ctDNA metric for clinical utility in the advanced setting where specificity is a critical performance assay criterion and greater ctDNA shedding occurs 44 , whereas %Δt-MAD could be applied at early disease stages. Nonetheless, residual false-positive and false-negative calls of disease status based on ctDNA evaluations could still take place due to tumors that shed minimal amounts of ctDNA; due to cases with apparent disagreement between molecular progression and imaging evaluations; and due to clearance of tumors leading to ctDNA shedding during earliest cycles of treatment.…”

“…These somatic changes are then used for early screening, treatment monitoring, and detection of residual disease. In parallel, untargeted sWGS approaches to liquid biopsy have been successful in other cancer entities 39 , 43 , 44 and have been shown to reflect tumor status, even in cases without detectable SNVs 27 . Our data show that ΔVAF mean offers better specificity than %Δt-MAD in discriminating progressive versus non-progressive disease.…”

“…53 , 55 ). This approach is complementary to monitoring of early ctDNA changes after therapy initiation, which have been shown to predict therapy durability 44 .…”

Assessing tumor heterogeneity: integrating tissue and circulating tumor DNA (ctDNA) analysis in the era of immuno-oncology - blood TMB is not the same as tissue TMB

“…WGS has been successfully utilized to study the relationship between PFS/OS and molecular progression (increase in ctDNA)/major molecular response (decrease in ctDNA). 27 Both WES and gene panels lend equally well to bTMB calculation at the 1021 gene level with Pearson r values ranging from 0.85 to 0.91 depending on indication. 21 Concordance between bTMB and tTMB Given the convenience of ctDNA, bTMB calculation has been readily performed and its predictive value studied.…”

Association between plasma somatic copy number variations and response to immunotherapy in patients with programmed death-ligand 1-negative non-small cell lung cancer

“…Several previous studies also evaluated ctDNA at baseline or longitudinal ctDNA dynamics to assess the tumor response to systemic therapy, including chemotherapy and targeted therapy. 26 – 28 Especially in the case of immunotherapy, previous explorative studies have mainly focused on using point mutations to evaluate the blood TMB; however, the suitable panel size and kind of variants that should be included for TMB calling is still controversial.…”