Usually, quantification of circulating miRNA is just a quality control measure when extracting miRNA from plasma samples. A few years ago in our lab, we started to notice some interesting trends. At that time, we were studying a cohort of breast cancer (BC) patients who had the infamous "triple negative" or TNBC subtype, meaning their outcome was sadly dismal. While the cf-miRNA levels in plasma were usually within a certain range, for a lot of the TNBC patients they were off the charts!!!

What was really surprising to us, was when we looked into the clinical data. If circulating miRNAs were high, the patients mostly had advanced disease, or worse, had already succumbed to their cancer.

Baseline cf-miRNA levels predict risk of progressive breast cancer

At this point, our findings were just speculative. We then took a larger BC cohort (250 patients, 356 plasma samples) and measured cf-miRNA levels. We wanted to know if the amount of cf-miRNAs at diagnosis was predictive of the outcome. Surprisingly, high cf-miRNA levels significantly correlated with advanced age, tumor stage, grade and likelihood of metastasis at diagnosis. We could also demonstrate a significant association with relapse and death in the more aggressive Luminal B and TNBC subtypes. Multivariate analysis confirmed that baseline cf-miRNA level is an independent prognostic factor for both disease progression and overall survival.

Since disease progression may go unnoticed by conventional response monitoring, biomarkers to predict risk of aggressive disease are sought after. In particular, blood based biomarkers, also known as "liquid biopsy" markers are advantageous, being relatively easy to obtain from a standard blood draw. 

cf-miRNA levels for disease monitoring

For a subset of our cohort, we were able to perform longitudinal sampling over the course of their disease. In the patients who were still alive at the last time of sampling (n=21, approx. 3 years post-diagnosis), cf-miRNA levels remained low, whereas for the group of patients who died (n=27) there was an increase in cf-miRNA levels as the disease progressed. Interestingly, circulating miRNAs were elevated prior to clinical detection of progressive disease.

Clinical Relevance

As far as we are aware, this is the first study exploring global circulating miRNA as a predictive marker in BC. We believe that our findings hold significant value for BC clinicians, who have a need to better stratify patients according to risk.

Low-risk patients could be spared unnecessary treatment, while those at high-risk of relapse can be more closely monitored. 

Circulating miRNA is an ideal liquid biopsy marker. The quantification is simple, affordable, quick and can complement current standard methods. Secondly, work from our group and others has proven that cf-miRNA is highly stable in blood. Finally, the technical variability of standard methods such as qPCR would not hinder the clinical implementation of such a marker. 

While the results are promising, we would now like to validate the findings in independent cohorts and in different cancer types.