There is a clinical need for minimal residual disease (MRD) assays in NSCLC to improve treatment stratification and accelerate adjuvant drug development, according to Charles Swanton, PhD, FRCP, of The Francis Crick Institute, Cancer Research UK, and University College London Cancer Institute, United Kingdom.
Dr. Swanton received the 2021 International Society of Liquid Biopsy (ISLB) award for outstanding scientific contribution in late 2021, and during his award lecture he detailed progress in tracking tumor evolution through liquid biopsy.
In lung cancer, adjuvant therapy is not typically offered to patients diagnosed with stage I disease but is offered to those with stage II-III disease, Dr. Swanton said.
“Post-resection adjuvant therapy decision making relies on pathology-based risk stratification, with an increased pTNM [pathological tumor, node, metastasis] staging associated with increased risk of death,” Dr. Swanton said. “This decision-making strategy in the adjuvant setting results in overtreatment of patients who would otherwise be cured by surgery alone and the undertreatment of patients with stage I disease not cured by surgery alone.”
The absence of better prediction results in large adjuvant trials.
“MRD represents a specific biomarker of impending disease relapse that could guide focused treatment escalation in low disease burden settings and reduce overtreatment,” Dr. Swanton said.
MRD Detection With TRACERx
Dr. Swanton and colleagues have taken a phylogenetic approach to MRD profiling that could lead to novel classification of the NSCLC relapse process, directing adjuvant treatment strategy, and inform the type of relapse process (polyphyletic, polyclonal, or monoclonal).
Tracking Cancer Evolution through Therapy/Rx (TRACERx) clinical studies are designed to decipher tumor evolutionary trajectories. During his presentation, Dr. Swanton discussed TRACERx and presented data from some studies in early NSCLC.
TRACERx is an anchored multiplex polymerase chain reaction (PCR) approach to MRD detection that tracks up to 200 mutations per patient.
“We call these tumor-informed personalized ctDNA detection methods,” Dr. Swanton said.
Dr. Swanton discussed some of the data from the TRACERx lung study released in 2020.1 Results showed that circulating tumor DNA (ctDNA) could be detected at or before relapse in the majority of patients. Additionally, the ctDNA panel indicated relapse before disease recurrence showed up on standard imaging.
“We can have tumor-informed biomarkers tell us in real-time whether a patient is in need of adjuvant therapy escalation and, secondly, whether that patient is responding to treatment in the absence of clear disease on imaging,” Dr. Swanton said. “Large-scale personalized enrichment panels also enable phylogenetic profiling of relapsed or relapsing lung cancer, facilitating novel classification of the relapsed process into mono- and polyphyletic disease.”
Dr. Swanton also discussed ECLIPSE (Extraction of Clonality from Liquid Biopsies), a novel informatic tool designed to work with personalized enrichment panels that enables accurate determination of subclone cancer cell fraction (CCF) from plasma ct analyses.
“ECLIPSE allows tumor phylogenies to be reconstructed from ctDNA using tumor biopsy from the primary tumor and large-scale personalized enrichment panel data,” Dr. Swanton said. “Leveraging this tool can enable accurate CCF estimations from single-region tumor biopsies, longitudinal tracking of tumor evolution over time, and phylogenetic classification of the relapse process.”
Dr. Swanton discussed results of a study that used ECLIPSE with a liquid biopsy assay to analyze plasma samples of patients in the TRACERx study. Data from the study showed multiplex-anchored PCR sequencing of the plasma samples enhanced MRD lead times relative to standard-of-care surveillance scanning and allowed holistic sampling of clonal dynamics, with prognostic implications for disease progression.
“ECLIPSE can overcome some of the challenges of illusion clonality of somatic variants common with only one tumor sample,” Dr. Swanton said. “It also enables longitudinal tracking of subclonal dynamics over time and identifies shifts in subclonal composition in line with therapy.”
These liquid biopsy advances have led researchers to begin to think about trial design in the context of the MRD tools. Right now, there are two different MRD adjuvant trial designs in progress.
The first is a landmark trial design. This trial is enriched for a small population of patients with lower disease-free survival and high event rates and targets these patients for early escalation to combination therapy.
“We know this is an at-risk population that needs adjuvant trial escalation,” Dr. Swanton said.
The second trial type uses a longitudinal sample.
“There are some patients that will be ctDNA negative at landmark testing who will become ctDNA positive up to 2 years later in the adjuvant setting,” Dr. Swanton said. “ctDNA monitoring is feasible at frequencies exceeding imaging and decreases the screen failure rate.”
Dr. Swanton acknowledged, though, that it is too soon to know if this approach will be translatable into routine practice.
A current example of using ctDNA in adjuvant decision making was a trial testing adjuvant immunotherapy with atezolizumab in urothelial carcinoma. The study demonstrated that a ctDNA tumor-informed approach was able to show that patients who are ctDNA-positive specifically benefited from atezolizumab.
“This illustrates that these MRD tools developed from TRACERx in a tumor-informed manner may be beneficial to select patients who will derive benefit from trial escalation in the adjuvant setting,” Dr. Swanton said.
Based on TRACERx data and other data, Dr. Swanton concluded that the field is primed to leverage MRD as an adjuvant biomarker in solid tumors.
Dr. Swanton reported receiving relevant research support from Archer Diagnostics and Natera and has patents in the field of clonal ctDNA tracking.
- 1. International Association for the Study of Lung Cancer. TRACERx Data Show That Tracking MRD With ctDNA Heralds Disease Relapse. Accessed January 20, 2022.