Liquid Biopsy Holds Its Own in Tumor Profiling

According to results from the largest liquid biopsy study to date, the genetic changes detected by analyzing circulating tumor DNA (ctDNA) in blood samples largely reflect those identified through conventional tissue biopsy. The data were presented by Philip Mack, PhD, director of molecular pharmacology at the University of California, Davis, Comprehensive Cancer Center in Sacramento, during the American Society of Clinical Oncology's annual meeting in Chicago, IL, June 3–7.

The investigators used Guardant360 (Guardant Health), a commercially available liquid biopsy that profiles 70 genes, to assay blood samples from 15,191 patients with 50 cancer types. They looked for four classes of genetic changes: point mutations, small insertions or deletions, amplifications, and chromosome fusions. Guardant360′s digital sequencing platform “is highly sensitive,” Mack said, “which was crucial for our study, because even at very low ctDNA fractions—often below 0.4% of the total DNA in circulation—we were able to detect genetic abnormalities.”

Mack reported that the mutation patterns detected via liquid biopsy were “highly consistent” with published tissue biopsy data from The Cancer Genome Atlas (TCGA). In EGFR, for example, “the exact same activating mutations reported in tumor tissue by TCGA were observed in our study,” he said. When the investigators compared ctDNA sequencing data with matched tissue biopsy results from 386 patients, they found that the former's overall accuracy was 87%, increasing to 98% in cases where blood and tumor samples were collected less than 6 months apart.

The key difference with ctDNA sequencing, Mack added, is that it detected the presence of resistance mutations such as T790M and C797S in EGFR. T790M typically emerges as non–small cell lung cancer begins to circumvent erlotinib (Tarceva; Genentech). Although antitumor activity can be restored with next-generation tyrosine kinase inhibitors like osimertinib (Tagrisso; AstraZeneca), secondary resistance mutations, namely C797S, often appear.

“These alterations aren't present in the tumor at the time of an initial tissue biopsy—you'd need follow-up biopsies of metastatic lesions to spot them,” Mack explained. “That's still the gold standard, but if you could use plasma instead—and I think our study shows that this is feasible—it would be much less invasive for patients.”

Liquid biopsies are “a useful alternative to tissue-based testing, especially for patients with tumors that are challenging to access,” said Sumanta Kumar Pal, MD, a medical oncologist at City of Hope Comprehensive Cancer Center in Duarte, CA. “Given the availability of other platforms besides Guardant360, rigorously defining which one provides optimal results will be key.” Pal also opined that to fully utilize blood tests in cancer, an oncologist should enroll the patient in a clinical trial like NCI-MATCH or MyPathway.

“A tissue biopsy will always be required upon initial diagnosis to assess the cancer's morphological features,” Mack emphasized. “I see ctDNA analyses as having more of a complementary role, mainly for serial assessments of a tumor's evolving sensitivity to therapy as disease progression occurs.” –Alissa Poh

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