Abstract P1-06-23: Extracellular matrix in Young Onset Breast Cancer – A dynamic niche as a therapeutic target

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Abstract Background: Breast cancer (BC) incidence in young women is on the rise as reported over the last decade and presents with aggressive features and high metastatic rates. Young Breast Cancer (YBC), as defined by ESMO would be <=40 years of age, has worse prognosis and is postulated to represent a distinct pathological entity compared to older breast cancer (OBC). In our prior analysis with YBC, we had analyzed TCGA breast cancer data for differential gene expression between the young and older breast cancers (>60y), and the most significant set of genes pointed to those coding for the Extra Cellular Matrix (ECM) (n=98 for <=40 and n=493 for >60 FDR <0.05). The ECM is a highly dynamic 3D network of structural and bioactive macromolecules secreted in part by cancer associated stromal cells such as fibroblasts (CAFs), known to prime the pre-metastatic niche in the breast environment. We thus hypothesized that progression of YBC could be associated with age-related expression differences in ECM associated genes due to remodeling and reactivation of the paracrine pathways, highlighting its relevance in metastasis of BC. The aim of this study was to analyze gene expression differences of ECM degrading and ECM processing genes which seem to be associated with YBC. We also aim to examine the role of ECM remodeling in YBC using patient-derived primary culture models of tumour-cells and cancer associated fibroblasts (CAFS) to understand the metastasis pattern. Methods: This study was conducted at Sri Shankara Cancer Hospital and Research Center, Bangalore after obtaining Institutional Ethical Committee approval. In-silico analysis of TCGA-BRCA, RNAseqV2 was conducted with clinical data. A set of ECM associated 17 gene panel of collagens, laminins and matrix metalloproteinases was established using differentially expressed genes from the TCGA RNA seq findings. This gene set was tested on a 55 primary retrospective FFPE specimens of YBC and a control group of 35 OBC using q-RT-PCR. A patient-derived primary culture was established and differentially separated for CAFs. Results: 55 YBC (≤40years) and 32 OBC (≥60 years) with complete clinical information were included in the study. Median age of YBC and OBC was 37 and 67 years respectively. Although discontinuous in series, 44% were hormone receptor positive, 34% were Triple negative and 22% were HER2 expressing in the YBC. In OBC they were 75%, 12.5% and 12.5% respectively. Median tumour size was 3cm in both groups. Interestingly we found expression levels of ECM degrading genes to be significantly higher in YBC (p<.05) A comprehensive score generated based on combined score of 4 genes showed a significant association with an event of distant metastasis at a median follow up of 24 months. We also found that this score was not significantly associated with molecular subtypes of breast cancer showing age as an independent factor (p=0.21) Patient derived primary culture from biopsy of YBC and an OBC is established, and CAFs isolated. Identification of CAF secretome and validation of select markers with Immunohistochemistry to support our findings is underway. Conclusion: Our work suggests ECM changes in YBC play a significant role in creating a supportive microenvironment for cancer cell aggressiveness. More investigations of YBC tumour cell and CAF secretome using primary culture models are underway. This could pave ways to understand role of ECM in progression to metastasis leading to possibilities for novel therapeutic interventions. A large validation study with collaborators at Mayo Clinic is underway. Citation Format: Lohita Krishna Kanyadhara, Srinath B S, Sulakshana Srihari, PS Hari, DurgaDevi Veeraiyan, Vikas Choudhary, Wude Ewunetu Zeleke, Savitha S. Sharma, Megha Sarvothama, Keerthi Shetty, Ramray Bhatt, Mallar Banerjee, Pooja Advani, Aruna Korlimarla. Extracellular matrix in Young Onset Breast Cancer – A dynamic niche as a therapeutic target [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-06-23.

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