The Brave New World of Circulating DNA as a Diagnostic Tool in Oncology

In the 1997 dystopian sci-fi thriller “Gattaca,” Ethan Hawke plays a character named Vincent whose future is rendered bleak by eugenics-driven genetic predeterminism. DNA testing shortly after birth predicts him to be of unhealthy stock, with limited lifespan, not likely fit for high-level employment, and thus not worthy of the societal advantages offered to those of more favorable genotype. Without revealing any spoilers, suffice it to say that Vincent does everything he can to buck the system.

I think we all know that a buccal swab can’t give us nearly so much information as that, and the ill-fated Theranos saga would suggest that simple blood tests to diagnose a wide range of disease remain more in the domain of fiction than science. However, in the last 15 years, there have been substantial advances in genetics technology that do reveal information available in the bloodstream before detectable by a scan or noticed by the patient. And so, in the world of oncology, analyses of circulating tumor DNA (ctDNA) are being studied as tools to screen for cancer, monitor cancer patients’ status and guide treatment recommendations.

Predating the capacity to analyze ctDNA are a host of tests that measure proteins in the serum that are produced or shed by various tumors. Many remain informative and are discussed elsewhere in this issue. Early studies transitioned away from serum protein markers (or counts of actual circulating whole tumor cells) toward using ctDNA for monitoring of patients with advanced cancers.^{1, 2} Monitoring with ctDNA held the promise of tracking disease burden while simultaneously identifying emerging mechanisms of resistance, such as certain mutations in lung cancer patients treated with first generation EGFR inhibitors.³

Since 2016, the U.S. FDA has approved several ctDNA tests for use in advanced cancers. These tests impact oncologists’ decisions around use of targeted therapies by detecting driver and resistance mutations in the circulation. As a result, tumor tissue testing can often be avoided, which is particularly useful when it is not readily available or would necessitate risky invasive procedures.

Tracking treatment response with ctDNA in advanced cancers can also identify patients benefiting from systemic therapies. For instance, although predicting which patients respond to immunotherapy has remained a challenge, recent studies suggest that ctDNA clearance could be an early response indicator that is more accurate than routine scans.⁴

Moving ctDNA testing into earlier disease settings requires cutting-edge, ultrasensitive technologies that have been evolving on a rapid time scale. Cheaper, faster and more accurate DNA analysis approaches open up new opportunities for test development, such as for the detection of miniscule amounts of residual disease after curative intent treatment that is not yet apparent on scans.^{5, 6} Termed “molecular residual disease” (MRD), such tests could someday be routinely used to guide treatment decisions by identifying patients destined to recur. Many ongoing studies are evaluating whether MRD tests lead to better outcomes either by improving cure rates among MRD-positive patients or reducing unnecessary side effects among MRD-negative patients. MRD can also be used in the surveillance setting, especially when the optimal surveillance strategy is not defined, such as in head and neck cancer as discussed on page 25 in this issue.

Intuitively, it might be thought that leakage of aberrant DNA fragments into the bloodstream would occur at the earliest hint of a cancer’s development. Indeed, ambitious efforts are now underway to use ctDNA as a scalable and (hopefully) cost-effective means of cancer screening. There are only four cancer types with screening tests recommended for routine use by the U.S. Preventative Services Task Force,⁷ and approximately 70% of cancer deaths in the U.S. are from cancer types lacking a recommended screening test.⁸ As a common source of biomarkers across cancer types, ctDNA tests have the potential to address this glaring gap. Such tests could also improve equitable access to screening for cancer types with existing recommended tests (e.g., colonoscopy⁹) where significant disparities in access continue to persist. For now, the cost of the advanced methods required to profile ctDNA could be prohibitive, but these costs are expected to keep falling over time. Sensitivity for early-stage solid cancers also must improve for certain cancer types to give the best possible chance of identifying curable cancers and reducing overall mortality.

How will radiation oncologists be called upon to order, interpret and act on ctDNA results in the future? With rising availability of these tests, our profession has a duty to study how they should be integrated into existing workflows and to advise patients on their optimal usage. It is important to recognize that results can vary widely between cancer types and can be affected by a variety of tumor, host and treatment factors. In general, metastatic cancers produce higher ctDNA levels than localized ones. Kinetics of ctDNA during a course of radiotherapy can be particularly complex and unpredictable, and clearance may be slower than after surgery. These examples underscore the importance of rigorous evaluation of the utility of ctDNA in different clinical scenarios.

Gattaca's Vincent embraced self-determination to achieve his goals and was not held back by any perceived genotypic deficiency. In a similar vein, the latest profiling approaches mean that future ctDNA testing can break away from the shackles of simple genetic sequence. Chromatin “epigenomic” features that determine tumor biology and behavior can now be systematically assessed within ctDNA, opening up new exciting applications in cancer diagnostics. Epigenomic profiling methods already underlie the latest advancements in multi-cancer screening and MRD detection, and many more enabling methods are now being tested. So unlike the dystopian future faced by Vincent, ctDNA gives radiation oncologists much to look forward to.