Non-Invasive Biomarkers: Circulating Tumor DNA

Circulating tumor DNA (ctDNA) are DNA fragments of the tumor that are found in the bloodstream. These DNA fragments may end up in the bloodstream through various active or passive means. These include apoptosis, necrosis, and active secretion from the tumor cells.

As these tumor DNA fragments have the genetic changes that led to tumor development, ctDNA do not match the individual’s normal DNA and can therefore be differentiated and identified as the tumor DNA. Getting information from ctDNA can help diagnose the type of tumor present in the body. This approach is especially beneficial when dealing with inaccessible tumors.

A blood sample is taken from the patient through a minimally invasive blood test. CtDNA is quantified and analyzed through genomic technologies, including enzyme-polymerase chain reaction (PCR) assays, exome sequencing, and whole genome sequencing.

ctDNA has been investigated for several clinical purposes.

Diagnostic value for early-stage breast cancer

While ctDNA currently has limited diagnostic value for early-stage breast cancer due to the low levels of ctDNA in blood samples, there have been promising results in several studies regarding the use of ctDNA in detecting early-stage breast cancer. For example, a prospective study showed the ability to detect mutated gene molecules in ctDNA in pre-surgery blood samples of early-stage breast cancer patients with 93.3% sensitivity and 100% specificity.

Prognostic value for breast cancer

Elevated concentrations of ctDNA are linked to a more aggressive and possibly treatment-resistant form of the disease, and they have been identified in both early and advanced stages of breast cancer. While not currently used as a prognostic tool, ctDNA has a great potential in making a significant impact on determining prognosis in breast cancer. This is mainly due to its higher sensitivity than other tumor markers, such as circulating tumor cells (CTCs).

Tool to monitor and guide treatment in breast cancer patients

Studies have indicated a strong correlation between ctDNA levels and tumor burden, establishing ctDNA as a valuable tool for monitoring tumor burden dynamics in patients undergoing systemic therapy. This has significant potential implications for the management and guidance of breast cancer treatment.

Among breast cancer patients, over two-thirds of all cases are estrogen receptor-positive (ER-positive), meaning that the cancer cells grow in response to estrogen. Treatments for such cases often involve estrogen inhibition. Unfortunately, some patients with ER-positive breast cancer become resistant to estrogen receptor (ER) inhibition. One of the key challenges in treating ER-positive breast cancer is the development of ESR1 mutations. These mutations occur in the tumours of more than 20% of patients with ER-positive breast cancer who have become resistant to the ER inhibition. As such, early detection of ESR1 mutations is crucial for effective management of the disease.

Fortunately, recent advances have made it possible to detect ESR1 mutations through ctDNA application. This early detection before the disease’s progression can allow for an early change in therapeutic strategies. Moreover, ctDNA analysis can also be used to identify mutations linked to acquired drug resistance in advanced breast cancers. By analyzing ctDNA at various treatment stages, healthcare providers can gain insights into how the cancer is evolving and adjust their treatment strategy accordingly. Overall, ctDNA is a hopeful and powerful tool for managing ER-positive breast cancer.