Blood-based biomarkers in breast cancer: From proteins to circulating tumor cells to circulating tumor DNA

Abstract

Biomarkers are the key to personalized treatment in patients with breast cancer. While tissue biomarkers are most useful in determining prognosis and upfront predicting response to therapy, circulating protein biomarkers such as CA 15-3 and carcinoembryonic antigen are mainly used in monitoring response to endocrine or chemotherapy in patients with advanced disease. Although several centers measure biomarkers in asymptomatic patients following curative surgery for primary breast cancer, the clinical utility of this practice is unclear. Promising new biomarkers for breast cancer include circulating tumor DNA and circulating tumor cells. In contrast to circulating protein biomarkers, measurement of circulating tumor DNA-based biomarkers is potentially useful in identifying mechanisms of resistance to ongoing therapies as well as identifying new targets for further treatment. To increase clinical utility, both the established and emerging circulating biomarkers should where possible be incorporated into randomized trials evaluating new therapies in patients with breast cancer.

Circulating tumor cells and the metastatic process: the complexity of malignancy

“…In fact, the purified cells pool contains epithelial and non-epithelial phenotypes together with normal blood vessel, stromal cells or other cells normally present in the circulation [137] . These evidences, as reported by a huge number of studies, confirm that the main challenge of CTCs isolation and characterization are the lack of specific standardized procedures that strongly restrict their use in clinical practice [134,169,170] .…”

“…Despite progress achieved in terms of prevention, diagnosis and treatment, drug resistance and tumor relapse, whose severity and probability are specific for each patient, remain one of the principal issue in breast cancer. Therefore, as a good clinical practice, it has been established that a patient's 5-year follow up, since primary tumor, could lead to an early detection of recurrence or metastasis and to a more specific and efficient therapy [169] . Canonical tissue biopsy represent on one side a costly, painful and hard to repeat procedure.…”

“…Nevertheless, even if it has been demonstrated a correlation between single or combined circulating biomarker levels and recurrence incidence, many issues need to be solved [175][176][177][178] . For instance, there are still problems associated with the lack of a validated clinically relevant level to establish, for each biomarker, a cut-off parameter [169] . Furthermore, it has been demonstrated that biomarker prognostic efficacy depends on the recurrence site.…”

“…In fact, higher levels of biomarkers were detected in BC distant metastases, such as bone or liver, than in loco-regional or lung recurrence [179] . Additionally, these biomarkers are inappropriate to figure out mechanisms of therapy resistance [169] . For these reasons, nowadays, the detection of CTCs from patient blood samples appears as a powerful tool in the management of early and advanced BC patients [138] .…”

Testing considerations for phosphatidylinositol‐3‐kinase catalytic subunit alpha as an emerging biomarker in advanced breast cancer

“…In recent years focus has shifted to DNA‐based biomarkers. In contrast to tissue‐based testing, ctDNA assays are minimally invasive, making them ideal for serial monitoring 52 . Compared with protein‐based biomarkers, ctDNA has a greater dynamic range and shorter half‐life (<2.5 hours), which allows it to be a more sensitive indicator of tumor progression and treatment response.…”