PurposeDevelopment of ipsilateral breast carcinoma following a diagnosis of breast ductal carcinomain situ(DCIS) has been assumed to represent recurrence of the primary tumour. However, this may not be the case and it is important to know how often recurrences are new primary tumours to ensure appropriate individualised therapy.Experimental DesignIpsilateral primary-recurrence pairs (n=78) were sequenced to test their clonal relatedness. Shared genetic events were identified from whole exome sequencing (n=54 pairs) using haplotype-specific copy number and phylogenetic analysis. The remaining pairs were sequenced by a targeted panel or low-coverage whole genome sequencing. We included 32 non-recurrent DCIS to compare the genetic profiles between recurrent and non-recurrent disease to develop a predictive biomarker.ResultsWe found that 14% of DCIS recurrences were non-clonal, indicative of a new breast carcinoma. Four chromosomal changes (5q, 11q, 17q and 20q) andTP53mutation were enriched in clonal primaries compared with non-recurrent DCIS (p10% of recurrent tumours are new primaries provides genetic evidence that the presence of DCIS confers a risk of ade novobreast cancer as well as recurrence. Identifying a biomarker of such risks might allow preventive actions, such as genetic testing, chemoprevention with tamoxifen or aromatase inhibitors, or bilateral mastectomy. The corollary of these findings is thatde novoprimaries in DCIS biomarker studies may have undermined efforts to find a biomarker of recurrence by reducing statistical power, since a tumour cell-intrinsic marker is unlikely to be predictive for a new primary. Even if a tumour molecular biomarker could stratify between non-recurrent and recurrent patients, it will under-detect patients at risk of new primaries. This issue raises concerns about utilising only a tumour cell-intrinsic biomarker in the clinical setting.