Crucial considerations for pipelines to validate circulating biomarkers for breast cancer

ABSTRACT

Despite decades of progress in breast imaging, breast cancer remains the second most common cause of cancer mortality in women. The rapidly proliferative breast cancers that are associated with high relapse rates and mortality frequently present in younger women, in unscreened individuals, or in the intervals between screening mammography. Biomarkers exist for monitoring metastatic disease, such as CEA, CA27.29 and CA15-3, but there are no circulating biomarkers clinically available for early detection, prognosis, or monitoring for clinical relapse. There has been significant progress in the discovery of potential circulating biomarkers, including proteins, autoantibodies, nucleic acids, exosomes, and circulating tumor cells, but the vast majority of these biomarkers have not progressed beyond initial research discovery, and none have yet been approved for clinical use in early stage disease. Here, the authors review the crucial considerations of developing pipelines for the rapid evaluation of circulating biomarkers for breast cancer.

KEYWORDS:

• Biomarker discovery
• autoantibodies
• PRoBE principles
• pipeline
• validation
• breast cancer
• early detection

Key issues

• Circulating biomarkers for breast cancer have the potential to provide rapid, cost-effective, and minimally invasive window to molecular changes both in the breast and at distant metastatic sites.

• These biomarkers have potential applications for risk assessment, early detection, prognosis, detection of early relapse, molecular profiling for treatment selection, and monitoring disease progression and evolution.

• Circulating biomarkers are especially needed for the diagnosis and monitoring of the high-grade tumors that are associated with increased morbidity and mortality.

• Hundreds of potential breast cancer biomarkers have been identified by research laboratories. However, only the circulating biomarkers CEA, CA27.29, and CA15-3 are in clinical use for the management of metastatic disease.

• Emerging circulating breast cancer biomarkers include proteins, immune markers, exosomes, miRNA, and circulating tumor DNA.

• This high false discovery rate in the initial stages of biomarker research can be limited by following established standards for discovery and validation, recognizing the impact of breast cancer heterogeneity, and using high-quality biospecimens.

• It is critical to incorporate the prospective specimen collection, retrospective blinded evaluation design within strategic, independent, and blinded phases of biomarker development and validation.

• There are multiple biorepositories available for select clinical applications including the NCI Early Detection Research Network Breast Cancer Reference Set for validating breast cancer biomarkers.

Financial & competing interests disclosure

The paper was funded by the Early Detection Research Network U01 CA117374.

KS Anderson is a consultant for and has stock options with Provista Diagnostics and is on an institutional patent submission for breast cancer serologic biomarkers.

The other authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.