ctDNA May Be a Biomarker for Postsurgery MRD Positivity and Relapse in Patients with NSCLC
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 increased risk for disease relapse and will require more aggressive adjuvant therapy.
According to lead investigator Chris Abbosh, MD, Principal Clinical Research Fellow, Research Department of Oncology, University College London Cancer Institute, England, this discovery paves the way for future clinical trials to guide the dosage of adjuvant therapy for patients with NSCLC who are MRD-positive after surgery.
Dr Abbosh presented the study at the 2020 American Association for Cancer Research virtual annual meeting.
The study included 78 patients who had patient-specific anchored-multiplex polymerase chain reaction (PCR) enrichment panels developed for analysis, and 608 plasma samples were tested. All patients had undergone surgery for stage I, II, or III NSCLC.
After primary tumor excision was performed, complete multiregion sampling was obtained, and the samples were submitted for deep whole-exome sequencing. Variants including 100 clonal single nucleotide, 50 neoantigens, and 50 subclonal variants were then prioritized based on clonality or subclonality, high copy number status, and low background sequencing noise.
Dr Abbosh explained that this process optimizes MRD sensitivity and enables phylogenetic tracking. An anchored-multiplex PCR was then constructed against the variant positions being tracked and was applied to cell-free DNA in the preoperative and postoperative settings.
Why MRD-Driven Studies?
MRD-driven adjuvant clinical trials have several advantages over conventional adjuvant studies, Dr Abbosh noted.
“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 clinical 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.
TRACERx Lung Study Findings
Based on the 2020 TRACERx lung study data, nonadenocarcinoma 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 anchored-multiplex PCR–MRD assay was validated in the study and showed an 89% sensitivity for DNA mutation at a mutation allele frequency of 0.008% when 25 ng of DNA was entered into the assay. The specificity was 100% (95% confidence interval, 92%-100%). The sensitivity had a linear relationship with DNA input and the number of variants tracked.
Of the 42 patients who had a relapse in the TRACERx lung study, 38 had ctDNA detected at or before clinical relapse. The median ctDNA lead time in these patients was 164 days (range, 6-1022 days), and the median time to relapse from surgery was 362 days (range, 41-1143 days).
No ctDNA was detected in 100% of the patients with a second primary tumor, which indicates that the specificity of the MRD assay is more successful in testing primary tumors. The median disease-free survival in patients with relapsed disease and no detectable ctDNA preoperatively was 640 days (range, 404-1242 days).
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 can find clear subclonal dynamics during systemic intervention for disease recurrence.
Data from the TRACERx study show that anchored-multiplex PCR personalized cell-free DNA can detect low-frequency variant DNA accurately and at low assay DNA inputs that are consistent with an MRD status. The study also shows that MRD lead times are affected by preoperative shedding dynamics. Overall, closely observing MRD can expose relapse ahead of standard-of-care imaging surveillance.
At Johns Hopkins Hospital, each specialist in my practice sees approximately 8 to 10 patients with nonmetastatic NSCLC per month, some of whom are not candidates for surgery based on physiologic parameters. In most cases, we follow the NCCN Guidelines or ASCO clinical practice guidelines in our management of patients with early-stage NSCLC, except in clinical scenarios where the patient may not fit into a particular category within the guidelines, or when we enroll a patient in a clinical trial. For example, we may determine that a neoadjuvant clinical study is appropriate for a patient with stage IB NSCLC, whereas this recommendation is not concordant with the NCCN Guidelines. There are also instances in which we apply recently published clinical study data when managing our patients—even before the NCCN Guidelines have been updated to reflect the most recent findings.
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