Abstract PR002: Genomic predictor can discriminate between high- and low-risk DCIS

Abstract Introduction: Ductal carcinoma in situ (DCIS) is considered a non-obligate precursor of invasive ductal carcinoma. With the aim of preventing a subsequent invasive cancer, all DCIS lesions are currently treated with surgical excision often supplemented with radiotherapy (RT). To prevent DCIS over- or undertreatment, a reliable marker of DCIS invasiveness risk is urgently needed. Methods: We studied two large DCIS cohorts: the Sloane cohort, a prospective breast screening cohort from the UK (median follow-up of 11 years), and a Dutch population-based cohort (NKI, median follow-up of 13 years). FFPE tissue specimens from patients with pure primary DCIS after breast-conserving surgery (BCS) +/- RT that did develop a subsequent ipsilateral event (DCIS or invasive) were considered as cases, whereas patients that did not develop any form of recurrence up to the last follow-up or death were considered as controls. We performed copy number analysis (CNA) and RNAseq analysis on 229 cases (80 DCIS only recurrences) and 344 controls. Results: DCIS was classified into the PAM50 subtypes using RNAseq data which revealed an enrichment of luminal A phenotype in DCIS that did not recur (P = 0.01, Fisher Exact test). No single copy number aberration was more common in cases compared to controls. RNAseq data did not reveal any genes significantly over/under-expressed in cases versus controls after FDR correction. However, by limiting the analysis to samples that had not had RT and excluding pure DCIS recurrences, we could develop a penalized Cox model from RNAseq data. The model was trained on weighted samples (to correct for the biased sampling of the case-control dataset) from the NKI series with double loop cross-validation. The genes were selected using the Elastic net framework of penalization. Using this predicted hazard ratio, the samples were split into high, medium, and low-risk quantiles, with a recurrence risk of 23%, 7% and 2%, respectively at 5 years (p = 10-10, Wald test). The NKI-trained predictor was independently validated in the Sloane No RT no DCIS recurrence cohort (p = 0.02, Wald test). GSEA analysis revealed proliferation hallmarks enriched in the recurrence predictor (FDR = 0.058). The RNAseq predictor was more predictive of recurrence than PAM50, clinical features (Grade, Her2 and ER) and the 12-gene Oncotype DCIS score (p < 0.001, permutation test using the Wald statistic) in both the NKI and Sloane series. Conclusion: Genomic profiling of two independent series of DCIS with outcome data did not reveal any clear associations with recurrence until analysis was limited to a set of samples who had not had radiotherapy and DCIS recurrences were excluded. We then identified an RNAseq-based classifier that could differentiate primary DCIS in low-, medium-, and high-risk groups, and validated it in an independent cohort. This classifier, if validated in other datasets, will allow us to identify women who do not need intensive treatment for their DCIS. Citation Format: Maria Roman Escorza, Michael Sheinman, Tycho Bismeijer, Ahmed A. Ahmed, Vandna Shah, Jeffrey R. Marks, Lorraine M. King, Anargyros Megalios, Lindy L. Visser, Marlous Hoogstrat, Helen R. Davies, Tapsi Kumar, Deborah Collyar, Hilary Stobart, Sarah Pinder, Nicholas N. Navin, Andrew Futreal, Serena Nik-Zainal, E. Shelley Hwang, Esther H. Lips, Alastair Thompson, Lodewyk F.A. Wessels, Jelle Wesseling, Elinor J. Sawyer. Genomic predictor can discriminate between high- and low-risk DCIS [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr PR002.