Getting Smart with Clinical Trials

For oncology trials, liquid biopsy technology holds great promise. Applications include screening patients for trial enrollment, monitoring the success of therapy, and diagnosing disease recurrence. Beyond clinical trials, as the technology advances, it could be used to find cancers in their most nascent stages and inform prognoses.

Liquid biopsy involves analyzing blood or other bodily fluids, such as urine, saliva, or cervical fluid, for genetic information that provides indications of disease state. In cancer, the most frequently used sources of this information are circulating tumor cells and circulating tumor DNA (ctDNA).

Tissue biopsies and imaging are the current gold standards for cancer diagnosis. Imaging tests can identify masses, but they can’t find microscopic metastases or characterize a solid tumor’s cellular composition. For that, you need tissue biopsy: a sample of tissue is removed using a needle, endoscope, or surgery, and is prepared, either as formalin-fixed paraffin-embedded or frozen samples. Tissue gathered in this way allows for histological analysis of cell shape, location, and concentration. It can also be used to determine mutation composition.

However, tissue biopsies have drawbacks – they’re invasive for the patient and time-consuming for the scientist. A recent study reported a median span of 27 (1) days between ordering a test on non-small cell lung cancer (NSCLC) patients with acquired resistance, to receiving the results. Liquid biopsy, on the other hand, is less invasive, less expensive, and significantly faster, taking just three days from the blood draw. It’s also more revealing than imaging; ctDNA, which can foreshadow resistance, can show up as early as 10 months before the tumor’s mass is captured by imaging (2).

That said, liquid biopsy also has downsides. For instance, similar to tissue biopsy, it can produce false negatives. Tumors are not homogenous, and not all tumor material finds its way into bodily fluids. Therefore, it is still necessary for clinical trials to corroborate liquid biopsies with tissue biopsies and imaging.

In clinical trials, I believe liquid biopsy would provide the most immediate value in the screening of patients for studies for targeted therapy, especially when tissue samples are not available. Currently, patients who are not eligible for needle biopsy and do not have adequate archival tissue samples are excluded from studies of targeted therapies, as the available methods cannot confirm that their cancer carries the targeted mutation. Therefore, liquid biopsy could potentially expand the number of patients who could benefit from targeted treatment studies.

Another area in which I see liquid biopsies being successfully implemented is in monitoring cancer progression. Liquid biopsy can be used to reassess patient response to treatment with each blood draw. Because it can detect tumor progression or shrinkage long before imaging, it allows for earlier treatment modification or intervention. In fact, a recent study (3) showed that liquid biopsy could determine the effectiveness of immunotherapy within two weeks of treatment. The researchers saw an increase in ctDNA levels in the blood, which indicated the tumor cells were dying. Because immunotherapy can often result in the appearance of the tumor growing larger (“pseudo-progression”) liquid biopsy may be a useful tool for physicians by providing a more objective assessment of treatment response. Providers may also be able to identify the persistence of micro-metastases that increase the risk of recurrence, but cannot be identified through standard medical imaging.

Beyond speed and sensitivity, liquid biopsy can help physicians identify cancer patients at the greatest risk for recurrence, and use that information to inform treatment decisions. In a recent study, investigators harnessed the technology to determine the prognoses of patients with Stage II colon cancer with no metastasis (4). After surgery, they found that the presence of target ctDNA correlated with relapse. Physicians could use this information to either reassure patients who are unlikely to experience a relapse, or more expediently start post-surgical treatment on those with an increased risk of recurrence. Such data may push clinicians to more confidently adopt liquid biopsy technology.

And for companies hoping to commercialize liquid biopsy tests? They must demonstrate to regulatory agencies that liquid biopsy-guided treatment positively affects patient outcomes.