Relation between circulating biomarkers at diagnosis of early luminal-like breast cancer and subsequent risk of distant metastases.

Abstract

1077 Background: Predicting development of distant metastases after treatment of early luminal breast cancer (BC) remains a major challenge. Besides clinical-pathological features of the primary tumor, baseline circulating factors could also play a role as prognostic biomarkers. Methods: Patients with newly diagnosed early BC (grade 2/3, ER+, HER2-non- amplified) were selected from our institutional BC registry, with associated blood biobank collecting baseline plasma/serum samples at diagnosis. Circulating biomarkers potentially modulating the metastatic process (chemokines, micro-RNAs (miRNAs), Leukemia Inhibitory Factor (LIF), and osteopontin), and serum-induced functional myeloid interferon (IFN)) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) signaling-responses, were measured at early BC diagnosis (before any treatment) in patients who subsequently developed distant metastasis within five years after diagnosis and therapy (META group) and in a 1:1 control group of patients, pairwise matched for age, tumor grade, stage, and histological subtype, who remained disease-free for at least seven years (NON-META group). All blood biomarkers were analyzed pair-wisely using the univariable Wilcoxon signed rank test (two-tailed). Multiple testing correction was done by applying a false discovery rate (FDR) of 0.05. In addition, a multivariable logistic regression analysis (MVA) was performed to find blood biomarkers signatures that can predict the development of metastases at first diagnosis of early BC. Results: 102 matched patient pairs were included. Univariable paired analysis showed significantly increased baseline expression of LIF (p=0.012) and six miRNAs (miR-143-3p: p=0.015; miR-197-3: p:<0.001; miR-223-3p: p=0.006; miR-223-5p: p=0.045; miR-338-3p: p=0.045; miR-365a-3p: p=0.025), and decreased serum-induced myeloid -IFN-responses (p=0.023) and ten miRNAs (let-7b-5p: p=0.006; miR-106a-5p: p=0.045; miR-106b-5p: p=0.015; miR-107: p=0.014; miR-144-3p: p=0.015; miR-15a-5p: p=0.045; miR-15b-3p: p=0.032; miR-185-5p: p=0.045; miR-18a-5p: p=0.015; miR-30b-5p: p=0.045) in the META group compared to the NON-META group. MVA yielded a seven-biomarker signature, which includes miR-197-3p (p=0.008), miR-139-5p (p<0.001), LIF (p=0.007), miR-106b-5p (p=0.003), serum-induced IFN/ISG response (p=0.006), miR-652-3p (p=0.015), and miR-133b (p=0.025) with a C-index of 0.79 (0.70-0.88) to predict distant metastases. After 5-fold internal cross-validation, C-index was 0.63 (0.52-0.74). Conclusions: Baseline circulating miRNAs, LIF, and serum-induced IFN-response levels at early luminal BC diagnosis are associated with subsequent distant metastases. Further external validation is required to confirm the prognostic value of these biomarkers.