LBA55 An ultra-sensitive and specific ctDNA assay provides novel pre-operative disease stratification in early stage lung cancer

Circulating tumour DNA (ctDNA) detection has significant promise to inform patient care to predict clinical risk in early-stage tumours, optimise personalised adjuvant treatment regimens, and monitor for relapse in the minimal residual disease (MRD) setting. However, clinical applications, especially in low-shedding tumours such as lung adenocarcinomas (LUADs), are constrained by the limited sensitivity of clinically validated ctDNA detection approaches. We developed NeXT Personal, a whole genome based, tumour-informed platform for ultra-sensitive ctDNA detection, and analytically validated detection thresholds consistently within 1-3 parts per million (PPM) of ctDNA with >99.95% specificity. We analysed pre-operative plasma samples from an interim cohort of 171 patients with early stage lung cancer from the TRACERx study. ctDNA was detected pre-operatively in 81% of patients with lung adenocarcinomas (LUADs), including 52%, 88%, and 100% of those with pathological TNM (pTNM) stage I, II, and III disease, respectively; and in 100% of non-LUAD patients. Elevated pre-operative ctDNA levels correlated with poor overall survival (OS; ctDNA low HR=9.1; 95% CI:1·1-72.5; ctDNA high HR=23.6, 95% CI: 2·7-206.0) and relapse-free survival (RFS) in LUADs independent of stage (including in stage I patients). Importantly, this remained true among ctDNA-positive samples when ctDNA level was treated as a continuous variable (HR=1.5; 95% CI: 1.1-2.1), whilst elevated ctDNA levels also correlated with reduced RFS in non-LUADs (HR= 2.1, 95% CI= 1·0 to 4.4), independent of disease stage. Critically, LUAD patients with ctDNA present at below 80 PPM (the 95% limit of detection for our recently published ctDNA detection approach in TRACERx) experienced reduced OS compared to those in which ctDNA was not detected (p=0.002, HR=12.2). Our ultra-sensitive approach demonstrates superior analytic performance and prognostic prediction compared to other assays previously clinically validated in non-small cell lung cancer and provides an advanced stratification tool to guide adjuvant therapy in early-stage ctDNA-positive disease at high risk of relapse.