The Role of Liquid Biopsy in Determining Prognosis, Treatment in Surgical Oncology

As liquid biopsy utilization continues to increase, so does the number of potential ways for it to be used in perioperative cancer settings, such as in screenings, provision of prognostic information, and genomic profiling, according to a recent narrative review.

The review, published in The Surgeon, explored the current bodies of evidence showing the use of liquid biopsy in perioperative settings and identified ways that it could be applied and studied in the future. Liquid biopsy was also found to be useful in aiding providers in making decisions on therapeutic targets and adjuvant therapies.

“The rapidly evolving concept of the liquid biopsy has the potential to become the cornerstone for decision-making around surveillance and adjuvant therapies the era of personalised medicine,” wrote the authors.

The period of time prior to a patient undergoing surgery for their cancer is considered to be a critical time for determining the risk of postoperative metastatic disease. Damaged tissue or manipulation of the tumor during resection can result in shedding of tumor cells and may decrease tumor-related antiangiogenic factors, increase proangiogenic factors, and suppress cell-mediated immunity. Surgery can also increase immune-suppressing hormones and proinflammatory cytokines and reduce natural killer cell populations.

Most conventional methods of monitoring patients for cancer recurrence are expensive or invasive or lack sensitivity. Liquid biopsies represent a minimally invasive measure to gather diagnostic, therapeutic, and prognostic information in various forms of cancer and refer to the analysis of exosomes in blood derived from tumor cells to detect circulating tumor DNA (ctDNA) as well as cell-free DNA (cfDNA), a subpopulation of ctDNA. ctDNA and cfDNA can be used as biomarkers in cancer screening and monitoring response and can serve as a predictor for disease recurrence in perioperative settings.

“Identifying patients at high risk for disease recurrence in the immediate postoperative period has the potential to allow surgeons and clinicians to make more informed adjuvant treatment decisions and tailor surveillance to the individual patient,” the authors said.

The review was based on a comprehensive literature search up to June 2020 and contained papers relevant to the application of liquid biopsy in surgical oncology settings, primarily focusing on the perioperative period.

The biggest limitation of quantitative analyses of cfDNA obtained using liquid biopsies is that concentration levels can vary greatly between patients, which can be attributed to a number of non–cancer-related physiological conditions. However, examinations of the ratio between long and short cfDNA fragments, also known as the integrity index, can help to overcome these limitations.

Detection methods for ctDNA collected from liquid biopsies can be either targeted approaches that look for mutations in common hotspots for mutations or untargeted approaches that screen the entire genome to look for new genetic aberrations. Targeted detection methods can let genetic alterations go undetected if not localized in a mutational hotspot. Genome-wide analysis, while being more comprehensive, can lack sensitivity. However, this is expected to improve as technology advances.

“As technology improves, identifying specific mutations related to a patient’s tumor that can be detected in the blood as ctDNA will allow for repeated analysis of the tumor’s genetic profile through a simple blood draw without the need for repeat tissue biopsies,” the authors noted.

Research has demonstrated that high levels of cfDNA are indicators of poor prognosis in several major cancer groups, including colorectal, breast, lung, melanoma, pancreatic, prostate, and renal cancers. Additionally, ctDNA has the potential to stratify patients into high or low risk for recurrence in the perioperative period, and simple quantification of cfDNA has consistently been shown to be helpful in predicting poor outcomes and disease recurrence across many forms of malignant tumors.

Several studies have found that in colorectal cancer populations, patients who experience disease recurrence have higher levels of cfDNA than those who remain disease-free.

Analysis of ctDNA in patients with cancer can also help to determine whether a patient is expected to benefit from or be resistant to chemotherapy and/or radiotherapy after surgery, which can help providers make decisions on whether to administer adjuvant therapy.

Although not much is known about the effects of surgery on cfDNA levels, it is thought that manipulating primary tumors during resection can result in some tumor cells being relocated elsewhere, potentially leading to a higher risk of metastases, and higher levels of cfDNA in surgery settings.

ctDNA analysis using liquid biopsy could help overcome challenges posed by conducting single biopsy of a tumor, which can fail to detect both intertumoral and intermetastatic heterogeneity, thus creating more challenges surrounding whether to prescribe adjuvant therapies.

“ctDNA contains the genetic alterations identical to the tumour themselves and perhaps most importantly, can account for heterogeneity as the circulating DNA is released from all tumour cells within the patient,” wrote the authors.

The authors added that “if cfDNA release becomes targetable in the future, it could add another tool for the surgeon to utilize in the perioperative period to improve their patient's outcomes.”

Reference

Jordan PR, O’Leary DP, Fleming CA, Wang J, Redmond HP. The relevance of liquid biopsy in surgical oncology: the application of perioperative circulating nucleic acid dynamics in improving patient outcomes. Surgeon. Published online August 4, 2021. doi:10.1016/j.surge.2021.06.006