Timing evolution of lobular breast cancer through phylogenetic analysis

Background Late distant recurrence is a challenge for the treatment of invasive lobular carcinoma (ILC) of the breast. Despite in-depth characterisation of primary ILC, the molecular landscape of metastatic ILC is still only par-tially understood. Methods We retrospectively identified 38 ILC patients from the tissue banks of six European institutions. DNA extracted from patient matched primary and metastatic FFPE tissue blocks was whole genome sequenced to com-pute somatic copy number aberrations. This, in turn, was used to infer the evolutionary history of these patients. Findings The data show different metastatic seeding patterns, with both an early and late divergence of the meta-static lineage observed in ILC. Additionally, cascading dissemination from a metastatic precursor was a dominant rule. Alterations in key cancer driver genes, such as TP53 or CCND1 , were acquired early while additional aberrations were present only in the metastatic branch. In about 30% of the patients, the metastatic lineage harboured less aber-rations than the primary tumour suggesting a period of tumour dormancy or prolonged adaptation at the distant site. This phenomenon was mostly observed in tumours from de novo metastatic patients. Interpretation Our results provide insights into ILC evolution and offer potential paths for optimised ILC care. Copyright (C) 2022 The Authors. Published by Elsevier B.V.