Liquid Biopsies Again

A recent ASCO/CAP panel reported on the current status of liquid biopsies and use of ctDNA. We have recently examined this area and although of some interest it is not yet clinically acceptable. In OncLive they report on the Panel. They note:

ctDNA assays is challenging because of the lack of prospective trial data compared with available research on standard biopsies for tumor genotyping. At present, just the cobas EGFR Mutation Test v2 for non–small cell lung cancer (NSCLC) has demonstrated sufficient clinical utility to gain FDA approval. Polymerase chain reaction–based ctDNA assays for EGFR in NSCLC and KRAS in colorectal cancer are available for commercial use in Europe, but— as was the case for cobas—their clinical utility was established using retrospective analysis. There is limited evidence of clinical validity of ctDNA analysis in other tumor types and for variants that were not analyzed as part of the ctDNA studies for EGFR in lung cancer and KRAS in colorectal cancer. A wide range of ctDNA assays have been developed and clinically studied for detection of potentially targetable variants, such as BRAF variants in melanoma and PIK3CA and ESR1 variants in breast cancer. Although several liquid biopsy tests are commercially available, their clinical utility has not been established.

The ASCO report states:

1. There is not enough evidence, at this time, to know whether use of the majority of ctDNA tests in advanced cancer is justified, outside of screening for participation in, or during, a clinical trial.

2. There is not enough evidence, at this time, to support the routine use of ctDNA tests for early-stage cancer, making treatment decisions, monitoring how well a treatment is working, finding remaining cancer cells, or for cancer screening, except screening for participation in, or during, a clinical trial.

3. There are inconsistent findings when testing with liquid biopsies versus testing with tumor tissue, so negative liquid biopsy results should be confirmed with tumor tissue genotyping. 

The ASCO paper notes:

Evidence on the Use of ctDNA Assays for Treatment: Selection in Advanced Cancer The clinical validity of ctDNA assays has been the subject of multiple studies in select cancer types. In general, PCR-based assays for detection of oncogenic driver variants have very high diagnostic specificity, but more modest diagnostic sensitivity. For example, in lung cancer, in a review of five studies that used tissue genotype as the reference standard, specificities for canonical driver variants averaged 96% (95% CI, 83% to 99%), and sensitivities averaged 66% (95% CI, 63% to 69%). For variants selected before treatment, such as the EGFR T790M variant in the setting of acquired resistance, sensitivities remained moderate, whereas specificities showed more variability (range, 40% to 78%), a difference believed to be a result of the genomic heterogeneity of treatment resistance. PCR-based ctDNA assays for KRAS genotyping in colorectal cancer have also been systematically analyzed and demonstrate high specificity and moderate sensitivity. Fundamentally, there are two paradigms to demonstrate clinical utility and the adoption of ctDNA as a clinically useful test. The most reliable are prospective clinical trials to test the clinical utility of ctDNA as a stand-alone diagnostic test. No such trial has been reported to date. A second strategy is to assess whether ctDNA provides the same information as tissue genomic evaluation.

Overall there may be some conceptual utility and it is an area worth further study but the efficacy and utility is open to question as we had noted.

Reference:

Merker et al, Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review, March 2018, http://ascopubs.org/doi/abs/10.1200/JCO.2017.76.8671?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed