Dr. Nitzan Rosenfeld of the Cancer Research UK Cambridge Institute – University of Cambridge in Cambridge, UK and colleagues used sensitive personalised assays to detect ctDNA in 363 plasma samples from 88 patients with early-stage non-small cell lung cancer (NSCLC). Exome sequencing of the primary tumour was used to design personalised assays targeting 48 variants unique to each patient. ctDNA was detected before treatment in 51% of patients, and after treatment in 64.3% of patients who had recurrence of their primary tumour. Detection at Landmark timepoint after treatment was associated with shorter recurrence-free survival (RFS) and overall survival (OS) times. The study team published the findings on 16 March 2022 in the Annals of Oncology and concluded that detection of minimal residual disease (MRD) after treatment for early-stage NSCLC can identify patients for further intervention.
The authors wrote in the background that in patients with early NSCLC, routine surveillance after treatment is performed using serial radiological imaging to detect macroscopic disease recurrence, with limited sensitivity. Biomarkers with high specificity and sensitivity for detection of MRD are needed to better identify patients at risk of relapse, and those who could benefit most from additional adjuvant and/or maintenance therapy while avoiding over-treatment for patients who have been successfully cured. New methods can detect ctDNA in plasma to fractional concentrations as low as a few parts per million, and clinical evidence is required to inform their use.
The study team assessed ctDNA levels in plasma from 88 patients with stage IA to IIIB NSCLC who underwent treatment with curative intent by surgery and/or radical (chemo)radiotherapy. The study team used patient-specific assays tracking up to 48 somatic variants for each patient, with the aim to determine whether ctDNA detection after treatment could predict patient outcomes.
In particular, the study team analyzed 363 serial plasma samples from 88 patients with early-stage NSCLC from whom 48.9% had stage I disease, 28.4% had stage II disease and 22.7% had stage III disease. Analyzed patients had predominantly adenocarcinoma (62.5%) and were treated with curative intent by surgery (61 patients), surgery and adjuvant chemotherapy/radiotherapy (8 patients), or chemoradiotherapy (19 patients). Tumour exome sequencing identified somatic mutations and plasma was analyzed using patient-specific RaDaR™ assays with up to 48 amplicons targeting tumour-specific variants unique to each patient.
ctDNA was detected before treatment in 24% of patients with stage I disease, 77% of patients with stage II and 87% of patients with stage III disease, and in 26% of all longitudinal samples. The median tumour fraction detected was 0.042%, with 63% below 0.1% and 36% below 0.01%.
ctDNA detection had clinical specificity >98.5% and preceded clinical detection of recurrence of the primary tumour by a median of 212.5 days. ctDNA was detected after treatment in 18 of 28 patients (64.3%) who had clinical recurrence of their primary tumour.
Detection within the Landmark timepoint 2 weeks-4 months after treatment end occurred in 17% of patients and was associated with shorter RFS (hazard ratio [HR] 14.8, p < 10-5) and OS (HR 5.48, p < 0.0003). ctDNA was detected 1-3 days after surgery in 25% of patients yet was not associated with disease recurrence. Detection prior to treatment was associated with shorter OS and RFS (HR 2.97 and 3.14, p = 0.01 and p = 0.003).
The authors concluded that analysis of ctDNA before and after treatment with curative intent of patients with early-stage NSCLC demonstrated that detection of ctDNA using sensitive personalised assays can inform patient prognosis and help guide patient treatment.
The study adds to the accumulating evidence that supports the utility of ctDNA testing for detection of residual disease and recurrence. This may be used as a sensitive tool for identifying patients at high risk of relapse who may benefit from additional adjuvant therapy or may be eligible for enrolment into clinical trials. In the future, ctDNA testing may allow identification of patients at lower risk of relapse, for whom it may be possible to consider less intensive or shorter treatment courses.
This work was supported by The University of Cambridge, Cancer Research UK grants and the European Research Council under the European Union’s Seventh Framework Programme/ERC grant agreement. The LUCID study was supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and the Cambridge Clinical Trials Unit. Inivata provided analysis of samples using the RaDaR™ assay. The Cancer Molecular Diagnostics Laboratory is supported by Cambridge NIHR Biomedical Research Centre, Cambridge Cancer Centre and the Mark Foundation of Cancer Research.
Reference
Gale D, Heider K, Ruiz-Valdepenas A, et al. Residual ctDNA after treatment predicts early relapse in patients with early-stage nonsmall cell lung cancer. Annals of Oncology; Published online 16 March 2022. DOI: https://doi.org/10.1016/j.annonc.2022.02.007