Статья

Residual ctDNA after treatment predicts early relapse in patients with early-stage non-small cell lung cancer

Davina GaleCancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Centre - Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UKKatrin HeiderCancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Centre - Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UKAndrea Ruiz-ValdepeñasCancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Centre - Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UKSophie HackingerInivata Ltd, The Glenn Berge Building, Babraham Research Park, Babraham, Cambridge, UKMarc D. PerryInivata Ltd, The Glenn Berge Building, Babraham Research Park, Babraham, Cambridge, UKGiovanni MarsicoInivata Ltd, The Glenn Berge Building, Babraham Research Park, Babraham, Cambridge, UKViona RundellCambridge Clinical Trials Unit - Cancer Theme, Cambridge, UKJerome WulffCambridge Clinical Trials Unit - Cancer Theme, Cambridge, UKGeeta G. SharmaInivata Ltd, The Glenn Berge Building, Babraham Research Park, Babraham, Cambridge, UKH. KnockCambridge Clinical Trials Unit - Cancer Theme, Cambridge, UKJosé Luís CastedoCancer Research UK Cambridge Centre - Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK; Royal Papworth Hospital NHS Foundation Trust, Cambridge, UKWendy N. CooperCancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Centre - Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UKHeng ZhaoCancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Centre - Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UKChristopher G. SmithCancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Centre - Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UKSumedha GargCancer Molecular Diagnostics Laboratory, Clifford Allbutt Building, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UKS. AnandCancer Molecular Diagnostics Laboratory, Clifford Allbutt Building, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UKKaren HowarthInivata Ltd, The Glenn Berge Building, Babraham Research Park, Babraham, Cambridge, UKDavid GilliganRoyal Papworth Hospital NHS Foundation Trust, Cambridge, UK; Addenbrooke's Hospital, Cambridge, UKSusan HardenAddenbrooke's Hospital, Cambridge, UKDoris M. RasslCancer Research UK Cambridge Centre - Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK; Royal Papworth Hospital NHS Foundation Trust, Cambridge, UKRobert C. RintoulCancer Research UK Cambridge Centre - Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK; Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK; Department of Oncology, University of Cambridge Hutchison-MRC Research Centre, Cambridge Biomedical Campus, Cambridge, UK. Electronic address: [email protected]Nitzan RosenfeldCancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Centre - Cambridge, Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Cambridge, UK; Inivata Ltd, The Glenn Berge Building, Babraham Research Park, Babraham, Cambridge, UK. Electronic address: [email protected]

2022en

ABI

Аннотация

•Sensitive personalized assays were used to detect ctDNA in 363 plasma samples from 88 patients with early-stage NSCLC.•Exome sequencing of the primary tumour was used to design personalized assays targeting 48 variants unique to each patient.•ctDNA was detected pretreatment in 51% of patients and after treatment in 64.3% who had recurrence of their primary tumour.•Detection at a landmark timepoint after treatment was associated with shorter recurrence-free and overall survival times.•Detection of minimal residual disease after treatment of early-stage NSCLC can identify patients for further intervention. BackgroundIdentification of residual disease in patients with localized non-small cell lung cancer (NSCLC) following treatment with curative intent holds promise to identify patients at risk of relapse. New methods can detect circulating tumour DNA (ctDNA) in plasma to fractional concentrations as low as a few parts per million, and clinical evidence is required to inform their use.Patients and methodsWe analyzed 363 serial plasma samples from 88 patients with early-stage NSCLC (48.9%/28.4%/22.7% at stage I/II/III), predominantly adenocarcinomas (62.5%), treated with curative intent by surgery (n = 61), surgery and adjuvant chemotherapy/radiotherapy (n = 8), or chemoradiotherapy (n = 19). 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.ResultsctDNA was detected before treatment in 24%, 77% and 87% of patients with stage I, II and III disease, respectively, and in 26% of all longitudinal samples. The median tumour fraction detected was 0.042%, with 63% of samples <0.1% and 36% of samples <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 18/28 (64.3%) of patients who had clinical recurrence of their primary tumour. Detection within the landmark timepoint 2 weeks to 4 months after treatment end occurred in 17% of patients, and was associated with shorter recurrence-free survival [hazard ratio (HR): 14.8, P <0.00001] and overall survival (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 before treatment was associated with shorter overall survival and recurrence-free survival (HR: 2.97 and 3.14, P values 0.01 and 0.003, respectively).ConclusionsctDNA detection after initial treatment of patients with early-stage NSCLC using sensitive patient-specific assays has potential to identify patients who may benefit from further therapeutic intervention. Identification of residual disease in patients with localized non-small cell lung cancer (NSCLC) following treatment with curative intent holds promise to identify patients at risk of relapse. New methods can detect circulating tumour DNA (ctDNA) in plasma to fractional concentrations as low as a few parts per million, and clinical evidence is required to inform their use. We analyzed 363 serial plasma samples from 88 patients with early-stage NSCLC (48.9%/28.4%/22.7% at stage I/II/III), predominantly adenocarcinomas (62.5%), treated with curative intent by surgery (n = 61), surgery and adjuvant chemotherapy/radiotherapy (n = 8), or chemoradiotherapy (n = 19). 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%, 77% and 87% of patients with stage I, II and III disease, respectively, and in 26% of all longitudinal samples. The median tumour fraction detected was 0.042%, with 63% of samples <0.1% and 36% of samples <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 18/28 (64.3%) of patients who had clinical recurrence of their primary tumour. Detection within the landmark timepoint 2 weeks to 4 months after treatment end occurred in 17% of patients, and was associated with shorter recurrence-free survival [hazard ratio (HR): 14.8, P <0.00001] and overall survival (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 before treatment was associated with shorter overall survival and recurrence-free survival (HR: 2.97 and 3.14, P values 0.01 and 0.003, respectively). ctDNA detection after initial treatment of patients with early-stage NSCLC using sensitive patient-specific assays has potential to identify patients who may benefit from further therapeutic intervention.

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Идентификаторы

DOI: 10.1016/j.annonc.2022.02.007

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