Metastatic disease is responsible for the majority of cancer-related deaths1. We report
the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours
from 421 prospectively recruited patients in TRACERx who developed metastatic disease,
compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases
diverged early, before the last clonal sweep in the primary tumour, and early divergence
was enriched for patients who were smokers at the time of initial diagnosis. Simulations
suggested that early metastatic divergence more frequently occurred at smaller tumour
diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83%
of late divergence cases being misclassified as early, highlighting the importance
of extensive primary tumour sampling. Polyclonal dissemination, which was associated
with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node
disease contributed to metastatic relapse in less than 20% of cases, representing
a hallmark of metastatic potential rather than a route to subsequent recurrences/disease
progression. Metastasis-seeding subclones exhibited subclonal expansions within primary
tumours, probably reflecting positive selection. Our findings highlight the importance
of selection in metastatic clone evolution within untreated primary tumours, the distinction
between monoclonal versus polyclonal seeding in dictating site of recurrence, the
limitations of current radiological screening approaches for early diverging tumours
and the need to develop strategies to target metastasis-seeding subclones before relapse.
