Genomic and spatial analysis of local recurrences following risk-adapted breast radiotherapy in the IMPORT trials

Abstract: Background: Ipsilateral breast tumour recurrences (IBTR) that occur after breast-conserving surgery (BCS) and breast radiotherapy may be ‘true recurrences’ or independent ‘new primaries’. Contralateral breast cancers (CBC) are usually assumed to be new primary tumours. Understanding the patterns of occurrence of these entities, and/or being able to reliably distinguish between the two, could have important implications for tailoring patient management at primary presentation and at IBTR/CBC diagnosis. Methods: The clonal relationship between index, and ipsilateral and contralateral subsequent breast tumours was assessed in 112 paired samples from two breast radiotherapy trials, IMPORT LOW and IMPORT HIGH, using copy number profiling and targeted sequencing of DNA. The spatial relationships between the index tumour beds, radiotherapy dose distributions and subsequent tumours were analysed via computational co-registration of cross-sectional imaging. Results: In the IMPORT HIGH cohort, where patients were at higher risk of IBTR, 61% of IBTRs were clonally related to the index tumour compared with only 32% from the IMPORT LOW cohort. There was no difference in the spatial distributions relative to index tumour beds of related compared to unrelated subsequent tumours. Related IBTRs occurred in a higher proportion of those diagnosed less than 5 years after index treatment, compared with those diagnosed after 5 years (66% vs 24%). Four of 18 CBCs in the IMPORT HIGH cohort, but none from IMPORT LOW, were genomically similar to the index cancers. Conclusions: These findings show that IBTRs near the index tumour bed are not always true recurrences and also strongly suggest that some CBCs are metastases.