Clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancers defined by genomic analysis

Ductal Carcinoma In Situ (DCIS) is the most common form of pre-invasive
breast cancer and despite treatment a small fraction (5-10%) of DCIS
patients present with invasive disease many years later. A fundamental
biologic question is whether the invasive disease recurring in the same
breast is established by tumor cells in the initial DCIS or
represents new unrelated disease. To address this question, we
performed genomic analyses on the initial pure DCIS lesion and paired
invasive recurrent tumors in 95 patients together with single cell DNA
sequencing in a subset of cases. Our data shows that in 75% the
invasive recurrence was clonally related to the initial DCIS,
suggesting that the tumor cells were not eliminated during the initial
treatment with surgery +/- radiotherapy. Surprisingly however, 18% were
clonally unrelated to the DCIS, representing new independent lineages,
and 7% of cases were ambiguous. Our findings show that although DCIS
is often the precursor of invasive recurrence, a significant fraction
of invasive recurrences are unrelated to the initial DCIS. This
knowledge is essential for accurate risk evaluation of DCIS treatment
de-escalation strategies and the identification of predictive
biomarkers.EGA study EGAS00001006306