PURPOSE: Tumour-promoting stromal modifications is an early event in breast cancer. They have been linked to the development of the invasive breast disease and thus have been proposed as therapeutic and diagnostic targets but with minimal translational success. This project aims at evaluating “cystine rich with EGF like domains 2” (CRELD2) – a tumour cells’ secreted protein that mediates breast cancer-tumour-stroma crosstalk, as the first in class biomarker of the early invasive breast cancer. METHODOLOGY: This is a prospective, correlational study. 58 patients who fit the inclusion criteria were recruited from the Royal Adelaide Hospital Breast Outpatient Department. Pre-operative, intra-operative, post-operative blood samples and intra-operative tumour core biopsy tissues were collected for analysis. Highly sensitive CRELD2 ELISA assay was developed, and tumour core biopsy homogenates and blood serum were tested to determine CRELD2 levels. This data was analysed against the patient’s tumour and disease phenotype, particularly poor prognostic markers. RESULTS: There were 38 tumour core biopsies obtained. Of these, detectable systemic CRELD2 was found in 20 patients (52%) and tumour lysates were CRELD2-positive in 22 patients (57.9%). Presence or absence of CRELD2 in patients’ plasma was linked with its levels in tumour tissue (76.8%). Intra-tumoral concentration of CRELD2 strongly correlated with the tumour grade. Most importantly, patients with tumours producing high levels of CRELD2 were found at significant risk of having axillary lymph node metastasis. CONCLUSION: Our findings show the utility of CRELD2 as a novel biomarker of early invasion in breast cancer.