Identifying predictors of invasive recurrence based on molecular profiles of DCIS lesions

Abstract Introduction Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. Patients with DCIS are routinely treated by breast-conserving surgery often supplemented by radiotherapy, although many will never develop invasive disease. To date, no robust predictors of invasive breast cancer recurrence following DCIS have been identified. In our efforts to find such predictors, we performed gene expression, copy number and mutation analysis on two large DCIS cohorts with long-term follow-up. Methods Two nested case control series were analyzed, where cases are defined as DCIS with a subsequent invasive breast cancer and controls remained disease free during follow up. Cases and controls were matched on age and on follow up duration and were derived from two nation-wide cohort studies. The Sloane cohort is a prospective breast screening cohort from the UK, median follow up is 6 years (range 1-10). The Dutch cohort is population-based and had a median follow up of 13 years (range 2-23). We performed copy number analysis using CytoSNP array or low pass whole genome sequencing (lpWGS) on 310 controls and 196 cases, and RNA-seq on 295 controls and 206 cases. Results First analyses on the copy number data suggest that cases are genetically more aberrant with multiple regions of amplification compared to controls (p < 0.05). RNA-seq was used to classify DCIS into the PAM50 subtypes which did not appear to be predictive of recurrence. Initial RNA-seq analysis did not show consistent gene expression differences between cases and controls in the Sloane or Dutch cohorts, possibly explained by differences in clinical characteristics of the cohorts. A new computational method has been developed accounting for the differences in follow-up times, results will be presented at SABCS. Targeted sequencing revealed that the most common mutations were in PIK3CA and TP53, but there was no association with recurrence. Conclusion Only small molecular differences were identified between DCIS that recurs as invasive breast cancer and DCIS that remains disease-free. Currently, we are seeking to identify reproducible differences by a combined analysis of two population-based cohorts in a time dependent fashion. These will be presented at the SABCS. This work was supported by Cancer Research UK and by KWF Dutch Cancer Society (ref.C38317/A24043) Citation Format: Tycho Bismeijer, Ahmed A Ahmed, Michael Sheinman, Maria Roman-Escorza, Vandna Shah, Jeffrey R Marks, Lorraine M King, Anargyros Megalios, Lindy L Visser, Marlous Hoogstraat, Helen R Davies, Tapsi Kumar, Deborah Collyar, Hilary Stobart, Nicholas N Navin, Andrew Futreal, Serena Nik-Zainal, Shelley Hwang, Esther H Lips, Alastair Thompson, Lodewyk FA Wessels, Elinor J Sawyer, Jelle Wesseling, Grand Challenge PRECISION Consortium. Identifying predictors of invasive recurrence based on molecular profiles of DCIS lesions [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-22-05.