Liquid biopsy has another important advantage over tissue biopsy. The genetic changes that drive tumor growth often differ in different parts of the tumor. Because tissue biopsy removes only small pieces of the tumor, key mutations can be missed, depending on what area of the tumor is sampled. Analysis of ctDNA provides information on all the different genetic changes that may be present in the tumor. Detection of tumor-specific mutations in a blood draw is an attractive alternative when tissue biopsies are not feasible. It is easy to do in any clinic and avoids biopsy-related complications. The ctDNA assay also facilitates disease monitoring and can potentially identify mutations in metastatic lesions and treatment-induced resistant mutations not observed in the original, archival tumor biopsy. Q. Please discuss some of the findings from a large study in which liquid biopsy was used. You reported on this at last year’s sessions of the American Society of Clinical Oncology. Dr Mack: This study included 15,191 patients with advanced lung cancer (37%), breast cancer (14%), colorectal cancer (10%), and other cancers (39%). Each patient provided one or more blood samples for analysis of ctDNA. This study assessed the accuracy of liquid biopsies, as compared to tumor samples, in two ways. First, it compared the patterns of genomic changes in ctDNA to those found in 398 patients with available results of genetic testing of the tumor tissue. When ctDNA was positive for key abnormalities in EGFR, BRAF, KRAS, ALK, RET, and ROS1 that drive tumor growth, the same mutations were reported in tissue 94- 100% of the time. Q. How do you know that liquid biopsy provides an accurate snapshot of the tumor? Dr Mack: The study also assessed consistency in the distribution and frequencies of specific changes in ctDNA against previously published data from genomic analyses of tumor tissue, including data from The Cancer Genome Atlas. The studies showed highly significant concordance between the ctDNA and the published data. The findings suggest that liquid biopsy provides an accurate snapshot of the genomic landscape of the tumor. Across multiple cancer genes and different classes of alterations, correlations typically ranged from 0.92-0.99. However, ���� The GIST and Sarcoma Journal one general exception was found in which ctDNA findings were often not seen in tumor biopsies: detection of new genomic alterations associated with resistance to targeted cancer drugs, such as the EGFR T790M resistance mutations in patients on EGFR inhibitor therapy. The study hypothesized that these alterations would be absent in the tissue-based population data because those patients had yet to receive treatment. In summary, the results of the assay were compared with publicly available, population-scale tumor-sequencing data, most notably from The Cancer Genome Atlas. We found that ctDNA mutation patterns were highly consistent with distribution in tumor tissue by the The Cancer Genome Atlas. This was seen with commonly altered tumor suppressors and oncogenes alike. In the cancer genes we evaluated, we saw the exact same hot-spot and activating mutations as observed in The Cancer Genome Atlas and other publications, at very similar frequencies. Furthermore, we identified additional mutations associated with emergent resistant mechanisms that are not normally present at the time of initial biopsy. Most of the ctDNA alterations were found at very low levels, with half occurring at a frequency below 0.4% of the total DNA in the circulation. Anecdotally, alterations observed at ctDNA fractions as low as 0.06% responded to treatment, which highlights the importance of assay sensitivity. Q. What are the next steps in determining the value of circulating DNA testing? Dr Mack: The next step for researchers is to work to increase the sensitivity of the Guardant360 assay to detect mutations at an extremely low ctDNA level, which is necessary for some tumors and will also enable its use in earlierstage cancers. In about 15% of patients, no tumor DNA could be detected by the ctDNA test. There are simply tumors that do not shed DNA into the circulation at detectable levels, so we are bound to miss them. More importantly, we need to perform rigorous clinical testing of digital next-generation sequencing approaches to prove they can predict patient benefit from targeted treatment as well as-or perhaps better than-repeat tissue biopsies. This class of technologies has earned the right to be validated in the clinical trial setting. ■ ment and response trends that can help our members reach tomorrow’s cure. We reduce the lethal lag time between discoveries of important data to communication to the GIST community.” However, as we observe Sarcoma Awareness Month, it is hardly a time for self-congratulation but for rethinking our mission statements and asking ourselves how close we are coming to fulfilling all of those lofty goals we set for ourselves as we strive toward the cure that always seems to elude our grasp but perhaps soon will be within our reach. Jonathan C. Trent, MD, PhD Editor-in-Chief Editor’s Memo (continued from page 6)
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