Study Finds Liquid Biopsies More Effective than Traditional Biopsies in Detecting Cancer Drug Resistance

Liquid biopsies based on blood samples do a better job than traditional biopsies in analyzing both the genetic diversity of the patient's cancer and how tumors evolve drug resistance at the molecular level. That is the finding of a new study from a group of researchers from, among other institutions, Harvard, the Broad Institute of MIT and Massachusetts General Hospital (MGH).

What's At Stake

Like other organisms, tumors evolve to survive adverse environmental changes. A tumor that shrinks in response to one drug may undergo evolutionary change enabling it to fend off the cancer drug and reemerge. Being able to rapidly detect cancer drug resistance and evolutionary patterns is thus crucial to finding a new drug that the tumor will still respond to.

Cancer diagnosis has traditionally relied on tissue biopsies as the principal source of this information. But in addition to being invasive, tissue biopsies provide a glimpse of only one location in a single tumor, which limits their effectiveness to the extent tumor cells may be genetically distinct from one another. Liquid biopsies, by contrast, are performed on patient blood samples containing DNA from tumors, i.e., circulating tumor DNA or ctDNA, which can be isolated and analyzed. But in spite of the advantages of liquid biopsies, tissue biopsy remains the mainstay of cancer diagnosis.

The Study

Are doubts about the effectiveness of liquid biopsy vis-à-vis traditional tissue biopsy warranted? Previous case reports and small case series suggest that liquid biopsy (specifically, cell-free DNA (cfDNA)) may better capture the heterogeneity of acquired resistance. However, the effectiveness of cfDNA versus standard single-lesion tumor biopsies has not been directly compared in larger-scale prospective cohorts of patients following progression on targeted therapy.

The new study, published online in the Sept. 9, 2019 issue of Nature Medicine, is the largest to date to directly compare liquid biopsy to tumor biopsy in the setting of cancer resistance. The researchers studied 42 patients with different molecular forms of gastrointestinal cancer who were undergoing treatment with targeted drugs and developed drug resistance. When the patients showed signs of drug resistance, the researchers analyzed their tumors using both liquid and tissue biopsies. Utilizing PhylogicNDT computational tools developed at the Broad Institute, they analyzed the tumor DNA and their resistance mutations.

The head-to-head comparison of liquid and tissue biopsies revealed that in 78% of cases, the liquid biopsies unearthed clinically relevant genetic alterations linked to drug resistance that were not identified through standard tissue biopsies. Whole-exome sequencing of serial cfDNA, tumor biopsies and rapid autopsy specimens elucidated substantial geographic and evolutionary differences across lesions. "Our findings suggest that liquid biopsy may be the preferred clinical modality for assessing how patients' tumors have evolved after they've become resistant to therapy," notes co-senior author Ryan Corcoran, an investigator at MGH and Harvard Medical School.

The Implications

Validation of liquid biopsies, however, may not be the most significant finding from the study. "Remarkably, we found that nearly every patient we analyzed had developed not just one, but multiple drug resistance mechanisms simultaneously, and this may be more common than we previously thought," said Gad Getz, co-senior author of the study, director of the Cancer Genome Computational Analysis Group at the Broad and the Paul C. Zamecnik Chair in Oncology at the MGH Cancer Center. The authors characterize this as "a real paradigm shift that and will force us to rethink" the potential advantages of liquid biopsies over tissue biopsies in treating cancer drug resistance.

Takeaway: Although this is exciting stuff, popping champagne corks would be premature. "To really map out the full landscape of cancer resistance mechanisms, we need much larger studies that span a variety of drugs and cancer types," notes Getz.