ctDNA Biomarker Indicates MRD Positivity and Relapse in NSCLC

July 2020 Vol 11, No 7


Lung Cancer

Data from the TRACERx lung study suggest that circulating tumor DNA (ctDNA) may be a biomarker for the detection of postsurgical minimal residual disease (MRD) in patients with non–small-cell lung cancer (NSCLC), suggesting which patients are at higher risk of relapse and require more aggressive adjuvant therapy.

According lead author Chris Abbosh, MD, University College London, UK, this discovery paves the way for future clinical trials to guide the dosage of adjuvant therapy for NSCLC patients who are MRD-positive after surgery.

Dr Abbosh presented the study at the 2020 virtual meeting of the American Association for Cancer Research. The study included 78 patients who had patient- specific anchored-multiplex polymerase chain reaction (AMP) enrichment panels developed for analysis, and 608 plasma samples were tested. All patients had undergone surgery for stage I-III NSCLC.

Primary tumor excision was performed, then complete multiregion sampling was obtained, and the samples were submitted for deep whole-exome sequencing. Variants, including 100 clonal single nucleotide variants, 50 neoantigens, and 50 subclonal variants were then prioritized based on clonality/subclonality, high copy number status, and low background sequencing noise.

Dr Abbosh explained that this process optimizes MRD sensitivity and enables phylogenetic tracking. An AMP was then constructed against the variant positions being tracked and was applied to cell-free DNA (cfDNA) in the preoperative and postoperative settings.

Why MRD-Driven Trials?

“The traditional adjuvant trials are challenging because you need hundreds, if not thousands, of patients to adequately power these studies, and you need to follow- up patients for many years. These challenges largely arise from the fact that you’re dealing with a heterogeneous patient population, which includes some patients who are cured by surgery and some patients who have residual or metastatic disease, and you can’t differentiate between these populations,” Dr Abbosh explained.

“The promise of an MRD-driven adjuvant trial is that you can differentiate between these populations, and you can conduct adjuvant trials in smaller, more relevant populations when you are only escalating treatment in patients who are destined to relapse from their disease,” he continued.

By contrast, MRD-driven adjuvant trials rely on low recruitment numbers, rapid read-out of study data, therapy escalation only in patients who are destined to relapse, and an opportunity to establish disease-free survival surrogates who are predicated on MRD clearance.

“The field of NSCLC is ready for MRD-driven adjuvant trials,” Dr Abbosh stated.

Study Findings

Based on the 2020 TRACERx lung study data, non-adenocarcinoma histology continues to show a correlation with preoperative ctDNA shedding in NSCLC. Of 88 early-stage preoperative samples, 49% of lung adenocarcinomas were detected, 100% of lung squamous-cell carcinomas were detected, and 75% of other NSCLCs were detected.

The 50-variant AMP-MRD assay in the study was validated and showed an 89% sensitivity for mutant DNA at a mutant-allele frequency of 0.008% when 25 ng of DNA was entered into the assay. The specificity was 100% (95% CI, 92%-100%). The sensitivity had a linear relationship with DNA input and the number of variants tracked.

Of 42 patients who suffered a relapse in the TRACERx lung study, ctDNA was detected at or before clinical relapse in 38 of them. Median ctDNA lead time in these relapsed patients was 164 days (range, 6-1022), and the median time to relapse from surgery was 362 days (range, 41-1143).

No ctDNA was detected for 100% of the patients with a second primary, which indicates that the specificity of the MRD assay is more successful testing primary tumors. The median disease-free survival in relapsed patients with no detectable ctDNA preoperatively was 640 days (range, 404-1242).

Using large-scale personalized enrichment panels, clonal evolution from therapy to relapse can be monitored. Relapse can also be categorized as monoclonal or polyclonal and find clear subclonal dynamics during systemic intervention for disease recurrence.

Data from the TRACERx lung study show that AMP personalized cfDNA detect low-frequency variant DNA accurately and at low assay DNA inputs that are consistent with an MRD setting. The study also shows that MRD lead times are impacted by preoperative shedding dynamics. Overall, surveilling MRD can expose relapse ahead of standard-of-care imaging surveillance.

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Last modified: August 10, 2023

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