Posted: April 16, 2020
As we know, molecular marker identification allows for more rational use of existing therapies. When markers can be identified more effectively and quickly, patient care advances. In the following interview, Martin Filipits, PhD, discusses liquid biopsy’s role in marker identification and the downstream effects of its use. Dr. Filipits is a group leader at the Institute of Cancer Research, Medical University of Vienna, Vienna, Austria.
Q: To what extent might liquid biopsy complement or supplant radiographic imaging in the detection of early recurrence of definitively treated NSCLC?
A: At present, liquid biopsy can only complement but not replace radiographic imaging in the detection of early recurrence in operable NSCLC. However, the assessment of minimal residual disease by the detection of circulating tumor DNA (ctDNA) is very promising. In a publication by Chaudhuri et al., post-surgical detection of ctDNA correlated with relapse and preceded the radiologic detection by a median of 5.2 months in 72% of patients.1 It remains to be seen, however, whether early detection of relapse by liquid biopsy will prolong survival of patients compared to detection of relapse by radiographic imaging.
Q: Do you envision a time when we might be able to lengthen the period between routine scans, using abnormal results on liquid biopsy as a prompt to order new imaging?
A: Imaging intervals may be extended based on the results of liquid biopsy. Patients without detectable ctDNA and absence of clinical signs of tumor progression may be selected for longer imaging intervals. However, this strategy must be proven and validated within clinical trials before it can be recommended for implementation in clinical routine.
Q: Are there any roles of liquid biopsy in the prediction of chemotherapy efficacy or toxicity?
A: The presence of ctDNA after surgery is a powerful prognostic factor in several solid tumors, including NSCLC. Whether liquid biopsy is also a predictive marker for chemotherapy or immunotherapy efficacy has to be determined in appropriate clinical trials. Circulating tumor DNA may be an important marker for resistant disease. Determination of residual disease after adjuvant chemotherapy may be a surrogate marker for drug resistance in the adjuvant setting after complete resection of tumors.
Q: In your opinion, is there a future for PD-L1 expression in blood as a prognostic or predictive biomarker? Or do you think that tumor mutational burden (TMB) and micro-satellite instability (MSI) in blood will be the major players as biomarkers for immunotherapy?
A: PD-L1 expression in tissue assessed by immunohistochemistry is simple, fast, inexpensive, and it is already used in everyday clinical practice in many countries based on the approval of immunotherapies. Currently, tissue-based PD-L1 expression is studied at the RNA level by polymerase chain reaction testing, but it is unclear whether PD-L1 at the RNA level is more accurate or a better biomarker than immunohistochemistry. I don’t see a future for PD-L1 expression in blood, but there will be other blood-based biomarkers. Blood-based TMB is feasible and was recently shown by Gandara et al. to predict atezolizumab benefit.2 These findings are interesting but require further studies before blood-based TMB or MSI can be recommended for clinical routine use.
Q: Will this strategy have a role in detecting new primaries? Or is the shed rate of circulating tumor-free DNA in disease confined to the thorax likely to be too low?
A: Currently, there is no role for liquid biopsy in detecting new primaries, but this may change in the future. One limitation of this strategy may be the low rate of shedding in early-stage NSCLC. Nevertheless, clinical studies on the role of liquid biopsy for early detection of new primaries are warranted.
Q: Are there differences in the various platforms and panels currently available?
A: There may be differences in the platforms and panels. For example, the most commonly used sequencing platforms are currently provided by Ion Torrent and Illumina. Ion Torrent uses pH measurements to read nucleotide sequences, whereas Illumina uses a fluorescence-based strategy for reading the bases in a nucleotide sequence. In addition to the difference in sequencing technology, there are differences in type of data generation, the error rates, and the reproducibility. Therefore, both internal as well as external validation is of critical importance before implementation in everyday clinical practice. In particular, the analytical validity, the clinical validity, and the clinical utility of each method must be assessed in suitable studies.
Q: What is the optimal frequency of liquid biopsy in its monitoring of targeted therapy?
A: Several trials in patients with advanced EGFR-mutated NSCLC have shown that treatment monitoring using liquid biopsy is feasible and clinically meaningful. I would suggest liquid biopsy before the start of treatment, 6 to 12 weeks after treatment initiation, and thereafter every 3 months until clinical progression. This strategy, however, requires confirmation within clinical trials. ✦
1. Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling. Cancer Discov. 2017;7(12):1394- 1403.
2. Gandara DR1, Paul SM2, Kowanetz M, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018;24(9):1441-1448.