ctDNA for early cancer diagnosis

With the development of oncological precision tools, such as sequencing of circulating tumour DNA, we may be closer to early and effective responses to cancer.

Using ctDNA to improve patient treatment

Circulating tumour DNA (ctDNA) analysis has an established role in the identification of treatable driver mutations in solid tumours and has potential future uses in cancer diagnosis and monitoring. The concept of 'molecular response', defined as ctDNA reduction during treatment, correlates with traditional assessments such as radiographic response and survival. Recently, the ctDNA-guided approach to de-escalate adjuvant chemotherapy in stage 2 colorectal cancer has reduced the use of chemotherapy without compromising recurrence-free survival. The use of ctDNA for early cancer detection is still under evaluation.

New research from the UC Davis Comprehensive Cancer Center in Sacramento, USA, shows that blood tests used to search for circulating tumour DNA can help detect cancers earlier and guide the use of targeted therapies. The case report describes a case in which ctDNA monitoring in a patient with known prostate adenocarcinoma led to the early detection of asymptomatic urothelial carcinoma (UC).

A second neoplasm detected by ctDNA analysis

A 73-year-old Hispanic male, smoker, with biochemically recurrent, non-metastatic castration-sensitive prostate cancer, well controlled with androgen deprivation therapy (ADT), was longitudinally monitored with ctDNA. Somatic DNA variants were found that were not present in prostate tissue, including an FGFR3-TACC3 gene fusion, raising the suspicion of a second malignancy.

Nine years earlier, the patient had been diagnosed with prostate adenocarcinoma, Gleason 4 + 3, with PSA 15.4 ng/mL. He had undergone intensity-modulated radiotherapy and 16 months of ADT with PSA reduced to 0.08 ng/mL. Four years later, the PSA had increased to 6.36 ng/mL. The patient refused prostatectomy and was restarted with ADT. Since then, the PSA has remained stable at <0.1 ng/mL.

About 8 years after the prostate adenocarcinoma diagnosis, the patient underwent DNA sequencing of the original tumour and started longitudinal ctDNA monitoring. Liquid biopsies for ctDNA monitoring were performed approximately every 3 months. After one year (9 years after the diagnosis of prostate adenocarcinoma), the liquid biopsies started to show molecular abnormalities that were absent in the original prostate tissue. Therefore, a second neoplasm was investigated. Imaging showed a left ureteral mass, a pathological para-aortic lymph node and liver lesions. Liver biopsy confirmed a metastatic UC (mUC). DNA sequencing on the biopsy showed the FGFR3ex18-TACC3ex12 fusion, which was not detected in the primary UC biopsy.

The research article explores in detail the molecular alterations involved in fibroblast growth factor receptors (FGFR), highlighting their importance in carcinogenesis. The researchers reported the efficacy of the drug erdafitinib, an FGFR inhibitor, in patients, showing an initial positive response followed by a rapid re-emergence of some mutations. The analysis addresses the therapeutic management of mUC, considering the use of ctDNA as a longitudinal monitoring tool.

By sequencing ctDNA will we be able to detect cancer months or years before it manifests in CT?

This case report highlights the potential of ctDNA monitoring to transform clinical oncology practice. The use of these new technologies may enable early detection of cancer, identification of personalised therapeutic targets and monitoring of treatment response. The use of ctDNA for early cancer detection is still under investigation, but encouraging results suggest a future role in the management of cancer patients.

  1. Huang Q, Mitsiades I, Dowst H, Zarrin-Khameh N, Noor AB, Castro P, Scheurer ME, Godoy G, Mims MP, Mitsiades N. Incidental detection of FGFR3 fusion via liquid biopsy leading to earlier diagnosis of urothelial carcinoma. NPJ Precis Oncol. 2023 Nov 18;7(1):123. doi: 10.1038/s41698-023-00467-9. PMID: 37980380; PMCID: PMC10657397.