Distinct molecular profiles of interval and screen-detected tumors in a real-world breast cancer registry.

Abstract

e15587 Background: Interval breast cancers (BC) are detected between routine screening mammograms and are associated with worse prognosis, requiring more aggressive treatment compared to screen-detected BC identified during scheduled mammograms. Identifying molecular differences between interval BC and screen detected BC may lay the foundation for developing novel therapies. In this study, we compared gene expression profiles of interval BC to screen-detected BC. Methods: This analysis included a subset of 2260 patients enrolled in the FLEX Registry (NCT03053193), an ongoing, prospective study evaluating primary tumor samples from stage I-III BC patients who receive 70-gene risk of recurrence testing (70GS), 80-gene molecular subtyping (80GS), and consent to collection of clinically annotated full genome data. Interval BC were diagnosed < 12 months following a normal screening mammogram. Breast tumors were classified by 70GS as having a Low Risk (LR) or High Risk (HR) of distant metastases. Tumors were classified as Luminal, HER2, or Basal type by 80GS. Differential gene expression analysis was performed with limma and subsequent pathway analysis with DAVID and GSEA. Differences in the proportion of 70GS or 80GS results, 70GS index, and Ki67 were assessed by Chi-squared test or t-test. Results: In this study, 81% (1834/2260) of patients had screen-detected BC and 19% (426) had interval BC. A higher proportion of interval BC (51%) were HR compared to screen-detected BC (44%; p = 0.01). Most LR tumors were invasive ductal carcinoma (78% interval and 73% screen-detected) and over 99% were Luminal type. Between the two LR groups, 70GS indices were similar and there was no significant difference in transcriptional profiles. Basal and HER2 subtypes were more frequent among HR interval BC compared to screen-detected BC (p = 0.03). HR interval BC had 70GS indices of higher risk compared to HR screen-detected BC (p = 0.02). Differentially expressed genes in HR interval BC compared to HR screen-detected BC were associated with MYC signaling and mitosis, which was concordant with higher Ki67 by IHC (p = 0.007). Conclusions: This real-world data analysis shows interval BC are not all biologically High Risk and can be further stratified by the 70GS, aiding in treatment decisions. Preliminary results suggest that following 70GS LR classification, there is no biological difference between interval BC and screen-detected BC. In contrast, there are distinct biological processes associated with HR interval BC, which may have implications in the management of these cancers. Clinical trial information: NCT03053193.