Abstract 6521: Subtype-specific molecular signatures of field cancerization in patients with sporadic breast cancer

Abstract Background: We have previously shown the presence of molecular field cancerization in patients with sporadic breast cancer. Given the heterogeneity of breast cancer, we hypothesized that such field cancerization is likely to be subtype-specific. Methods: RNA exome sequencing was performed on 360 samples obtained from 75 breast cancer patients undergoing mastectomy; 25 cases were selected from each subtype: hormone receptor (HR) positive, Her2 positive, triple negative (TN) breast cancer. Four sites were sampled from each patient: primary tumor (A), adjacent normal parenchyma within 2cm of the tumor (B), 2 separate, histologically normal sites at least 2cm away from the tumor (C &D) or, if available, tissue from the unaffected contralateral breast (E). Normal breast tissue (N) from cancer-free controls was obtained from reduction mammoplasty. Tumor-associated genes (TAGs) were identified by comparison of primary tumor to tissue from cancer free controls. We estimated tumor content that was shared across samples B-E by applying deconvolutional analysis to the tumor associated genes, to calculate indices that ranged from 0, indicating normal, to 1, indicating tumor. Molecular field-associated genes and pathways were identified by Spearman’s correlation coefficient analysis between the differential genes/pathways and ISTC. Results: Across all subtypes, the proportion of tumor content present in the histologically normal breast tissue samples (samples B, C, D, E) obtained from cancer patients ranged from 80% in tissue adjacent to the tumor to approximately 50% in tissue obtained from the contralateral breast. We found over 600 deregulated genes to constitute the molecular field across all of the 3 major subtypes tested (Her2+, HR, and TNBC), of which approximately 20% were shared in the molecular field of all 3 subtypes of breast cancer. Among the 664 genes noted to be part of the molecular field in TNBC, 23.8% were unique to this subtype. In contrast, only 13% of the genes that constituted the field cancerization in the Her2 and HR+ subtypes were subtype-specific. PIP3-AKT, TCR signaling, and DNA synthesis were among the top pathways specifically activated in the molecular field of the Her2+ subtype of breast cancer. The molecular field of HR+ breast cancer was uniquely characterized by upregulation in the mitotic cell cycle, G1- S transition, and RB pathway. The field of cancerization in the TNBC subtype showed an upregulation in MEK-MAPK, mTOR, and JNK-JUN-TAK1 pathways. Conclusions: Our study suggests the presence of a breast cancer molecular field effect that extends beyond the adjacent normal breast tissue and includes the entire mammary gland. A substantial proportion of this field cancerization is subtype specific with uniquely deregulated pathways within each subtype. These findings provide new opportunities for developing subtype-specific chemoprevention strategies. Citation Format: Anjana Bhardwaj, Zhenlin Ju, Constance Albarracin, Celestine Trinidad, Preethi Gunaratne, Jing Wang, Randa El-Zein, Isabelle Bedrosian. Subtype-specific molecular signatures of field cancerization in patients with sporadic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6521.