The capture of whole, circulating tumor cells (CTCs) was the initial focus of liquid biopsies. Now, the definition of liquid biopsy has expanded to include the collection of cell-free DNA (cfDNA), along with various species of cell-free RNA and exosomes, all of which are capable of providing information on the disease status of patients with cancer.
This expansion in scientific and technological approaches is expected to become particularly meaningful in the diagnosis and treatment of non—small cell lung cancer (NSCLC). Although hurdles remain before liquid biopsy is seen in routine clinical practice for patients with NSCLC, its considerable potential and the energy being applied to its development suggest that everyday clinical use of liquid biopsy is inevitable.Wide Range of Possibilities
Compared with conventional tissue biopsy of tumors, liquid biopsy offers advantages in NSCLC. A blood draw is minimally invasive for the patient, can be done at the point-of-care, and can be performed serially and inexpensively to monitor disease progression, an approach not possible with tissue biopsies in the lungs.
Liquid biopsy for NSCLC has potential applications in both screening and in monitoring. Survival rates for NSCLC are low, despite advances in treatment of the disease, because patients often present with advanced disease. The availability of screens to detect validated biomarkers of the disease from CTCs, cfDNA, or other elements in blood may make it practical to one day perform routine screening for lung cancer, particularly for smokers.
Additionally, a key benefit to liquid biopsies is the potential for overall characterization of disease progression and genetic variation. Intratumoral heterogeneity is a common feature of primary tumors, but the particular sample collected in a tissue biopsy may not be representative of the tumor as a whole. Heterogeneity also exists between the primary tumor and metastases. Liquid biopsy can address this issue by detecting DNA that is shed by cancer cells in all parts of a tumor, as well as by secondary, metastatic tumors.
The major reason for studying heterogeneity is detection of mutations for the assignment of targeted therapies. In this way, liquid biopsy is a crucial component of the shift to personalized medicine. For NSCLC, this relates in particular to the detection of mutations in exon 20 of the EGFR gene, where 50% to 60% of acquired resistance to inhibitors of EGFR’s tyrosine kinase activity is associated with point mutation T790M.1 Other key mutations in NSCLC have now been identified (Figure)
.Many Hurdles Remain
Despite the widely acknowledged potential of liquid biopsy, its integration into everyday clinical practice in oncology has yet to occur.
Alberto Bardelli, PhD, associate professor, Turin University School of Medicine, Italy, expressed the need for further data when summarizing a session on liquid biopsy that he chaired at the 2014 European Society for Medical Oncology(ESMO) Congress. “I have no doubt liquid biopsy will become routine, but right now the evidence is lacking,” he said.
Standardization of analytical processes for liquid biopsy and the development of robust commercial platforms for the analysis of biomarkers in body fluids are being actively pursued.
“There are biomarkers with the potential to be introduced into daily clinical practice in the near future, but success depends on robust validation in sufficiently large, independent, prospectively designed studies,” said Paul Hofman, MD, PhD, a team leader at the Institute for Research on Cancer and Aging in Nice, France.
The signals from a growing body of research are promising. In February, investigators reported that cfDNA was successfully used to assess EGFR mutations in plasma and serum samples from patients with NSCLC collected as part of the EURTAC trial.1 They were able to correlate the type of EGFR mutation, particularly L858R, with overall survival (OS), progression-free survival (PFS), and response to therapy outcomes.
In April, researchers presenting at the AmericanAssociation for Cancer Research (AACR) Annual Meeting reported that liquid biopsies in NSCLC treatment could provide key data on disease progression earlier than other methods available.2
Jonas A. Nilsson, PhD, a researcher in the Department of Radiation Sciences at UmeÃ¥ University in Sweden, and colleagues analyzed the efficacy of monitoring EML4-ALK fusion gene rearrangements in the blood platelets and plasma of 77 patients with NSCLC.
They determined that reverse transcription-polymerase chain reaction testing allowed real-time monitoring of the disease and earlier identification of patients who have developed resistance to treatment with crizotinib, an ALK inhibitor.
“We showed that if we detected EML4-ALK in the platelet fraction before therapy starts and it does not disappear during treatment, it indicates that the patient is not responding to the therapy, which is associated with a shorter time to recurrence and, therefore, other therapies could be tried,” Nilsson said in a statement.Types of Liquid BiopsiesCirculating Tumor Cells