The presence of cell-free DNA (cfDNA) in plasma has long been appreciated to rise in response to a spectrum of physiological and disease states.5 The distinction of ctDNA depends on detection of tumour-associated mutations in circulating cfDNA, typically in the form of single-nucleotide variants (SNVs). Using a threshold of detection of two SNVs to score a plasma sample positive for ctDNA, Abbosh and colleagues showed clear correlations of ctDNA presence in plasma with primary tumour proliferative index (Ki67); lymphovascular invasion; and degree of tumour necrosis. They also revealed a strong correlation with tumour volume that has implications for detection of minimal or residual disease (see below). Strikingly, the study revealed a preferential association between presence of ctDNA and tumour histological subtype, whereas pre-operative plasma from 30 out of 31 lung squamous cell carcinoma (LuSC) patients scored positive: only 11 out of 58 cases of lung adenocarcinoma (LuAD) scored positive. Importantly, this pattern was preserved in a subgroup comparison of stage-matched (stage I) LuSC and LuAD cases (16 out of 17 (94%) detected versus 5/39 (13%) detected, respectively). Furthermore, non-adenocarcinoma histology was the single strongest determinant of ctDNA presence.3 This may reflect a greater propensity for LuSC to be micro-metastatic, even at Stage I, but also suggests that ctDNA analysis will have little value for a large proportion of LuAD cases.

The next phase of the study compared longitudinal detection of ctDNA, pre- and post-operatively, with periodic clinical assessment and chest radiography, in a subset of NSCLC samples, including both LuSC and LuAD. CtDNA was detected in 13 of 14 relapse cases, on average some 70 days prior to clinical confirmation by CT imaging. On the other hand, ctDNA was detected in 1 of 10 cases with no evidence of clinical relapse (at the time of publication). In a small number of cases, tracking the number of SNVs post-operatively appeared to reflect resistance or indeed sensitivity to adjuvant chemotherapy, as three patients whose plasma SNV numbers rose while receiving chemotherapy all relapsed within 1 year, while one patient that exhibited a sharp decrease in SNVs remained relapse-free 688 days later.3 While these data are certainly encouraging, they suggest that further studies in larger cohorts are warranted.

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