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Genomic signatures of DCIS define biology and correlate with clinical outcomes

Presented by
Dr Siri Strand, Stanford University, CA, USA
SABCS 2021

Based on molecular analysis of 677 ductal carcinoma in situ (DCIS) samples, several subtypes of DCIS were identified as well as an 812-gene profile predictive for recurrence.

DCIS consists of a molecularly heterogeneous group of premalignant lesions, with variable risk of invasive progression. Understanding biomarkers for invasive progression could help individualise treatment recommendations based upon tumour biology and reduce overtreatment. As part of the National Cancer Institute’s Human Tumor Atlas Network (HTAN), Dr Siri Strand (Stanford University, CA, USA) and colleagues conducted comprehensive genomic analyses on 2 large DCIS case-control cohorts with a 7.1-year median follow-up (TBCRC 038 and RAHBT) [1,2].

Gene expression analysis of 677 DCIS samples from 481 patients resulted in an 812-gene profile, which was predictive for recurrence (AUC 0.72). Based on the RNA expression of all coding genes, 3 clusters were identified, referred to as ER low, quiescent, and ER high. The ER-low cluster had significantly higher levels of ERBB2 and lower levels of ESR1 compared to quiescent and ER-high clusters. Quiescent cluster lesions were less proliferative and less metabolically active than ER high and ER-low subtypes. Based on DNA copy number aberrations, 6 subtypes of DCIS were identified. Focusing on the stromal component of DCIS from laser capture microdissection, 4 distinct DCIS-associated stromal clusters were identified. A “normal-like” stromal cluster with ECM organisation and PI3K-AKT signalling, a “collagen-rich” stromal cluster, a “desmoplastic” stromal cluster with high fibroblast and total myeloid abundance, mostly associated with macrophages and myeloid dendritic cells (mDC), and an “immune-dense” stromal cluster.

“Comprehensive genomic profiling in 2 independent DCIS cohorts with longitudinal outcomes shows distinct DCIS stromal expression patterns and immune cell composition. RNA expression profiles reveal underlying tumour biology that is associated with later ipsilateral breast events in both cohorts. These studies provide new insight into DCIS biology and will guide the design of diagnostic strategies to prevent invasive progression,” said Dr Strand.

  1. Strand SH, et al. The Breast PreCancer Atlas DCIS genomic signatures define biology and correlate with clinical outcomes: An analysis of TBCRC 038 and RAHBT cohorts. GS4-07, SABCS 2021 Virtual Meeting, 7–10 December.
  2. Strand SH, et al. 2021 bioRxiv doi: 1101/2021.06.16.448585.

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