Breast cancer is the second most common cancer globally and the incidence is consistently increasing. To reduce potential illness and death many countries have implemented population mammographic screening programs that promote early detection and intervention. These programs have resulted in increased diagnoses of pre-cancerous lesions such as ductal carcinoma in situ (DCIS) and atypical ductal hyperplasia (ADH). There is a significant lacuna in our understanding of early breast cancer progression. Existing studies suggest that less than half of DCIS lesion will recur/progress to invasive disease if left untreated or treated with only surgery. However, there are limited tools that provide prognostic insight or delineate which lesions posses invasive potential. Therefore, out of an abundance of caution most patients undergo surgery to remove these lesions, often with adjuvant radiotherapy for DCIS. This indicates a need for robust prognostic biomarkers to guide clinical decision making. We propose by characterising the molecular changes in early lesions and their local microenvironment we can reveal biomarkers that better stratify indolent and aggressive lesions and identify therapeutic vulnerabilities for precision prevention.
We have established a cohort of formalin-fixed paraffin-embedded samples from human normal breast (reduction mammoplasties) and several pre-cancerous lesions (ADH, low, and high nuclear-grade DCIS). All pre-neoplastic lesions have had the diagnoses reviewed and confirmed by two qualified pathologists. To define the specific changes in the lesions and the surrounding stroma we have used manual microdissection to isolate each compartment. Then we have extracted the RNA and DNA for bulk RNAseq and Whole Genome Sequencing with the PeterMac Genomics Core. Our first fifteen samples have been assessed which includes samples of normal breast tissue (n = 3), ADH (n = 4), low-grade and high-grade DCIS (n = 4 per grade). Here we will align the transcript changes in epithelium and stroma with copy number changes and mutations in the epithelial component across our spectrum of normal and pre-neoplastic breast tissue. Thus, producing a detailed portrait of the molecular underpinnings of breast cancer initiation and its relationship with the local microenvironment. We believe this understanding could reveal potential prognostic biomarkers, and novel therapeutic targets.