As a tumor grows, it may shed fragments of its DNA into the patient’s bloodstream. After treatment, if part of the tumor remains or it begins to grow again, more of this circulating tumor DNA (ctDNA) may enter the blood. That raises the possibility that detecting ctDNA could help clinicians monitor molecular or minimal residual disease—cancer that remains after treatment and cannot be detected by traditional imaging methods.

Here, our Curious Dr. George talks ctDNA with two leaders at Natera, a company that develops ctDNA tests: Chief Medical Officer Paul Billings, MD, PhD, and VP Medical Affairs, Oncology, Alexey Aleshin, MD, MBA.

Curious Dr. George: When initially diagnosed, potentially lethal cancers found at advanced stages can pose quandaries for treatment and management. Many advanced technologies are now being applied to address these challenges. How might the detection of ctDNA be used to assess molecular residual disease and assist in cancer monitoring and management?

Drs. Billings and Aleshin: Treating advanced-stage cancer is challenging. While treatments are available, they have toxicities and can impact patients’ quality of life. Moreover, as tumors evolve over time, they may become treatment resistant. Determining treatment resistance early can have significant clinical implications.

With the advent of next-generation sequencing, it is now possible to sequence the tumor tissue and identify a set of mutations that are specific to the patient’s tumor. These mutations, which are linked to early tumor development and are not related to specific response to treatment, can be tracked later by analyzing free-floating fragments of tumor DNA—circulating tumor DNA (ctDNA)—in the patient’s blood, without the need for any additional biopsy.

Moreover, the short half-life of ctDNA provides a real-time snapshot of subtle changes in the tumor burden, and is far more effective than a radiological scan that relies on detecting a visible lesion. Such a personalized and tumor-informed approach has emerged as a sensitive, non-invasive, and cost-effective tool for identifying tumor molecules (molecular residual disease) down to a single molecule in a tube of blood.

Immunotherapy has fundamentally changed how cancer is managed. However, only a fraction of patients respond to immunotherapy, while all patients are at risk of developing side effects from this treatment. An example of how ctDNA could address this issue is a hypothetical patient who was treated with pembrolizumab (Keytruda) for her non-small cell lung cancer. Initial imaging showed a mixed result that was difficult to interpret. However, ctDNA showed a markedly elevated ctDNA level suggestive of progression. This allowed the oncologist to reconcile ambiguous findings on imaging and alter the patient’s clinical course by switching to an alternative therapy.

Our recently published study, in Nature Cancer, highlights the advantage of monitoring ctDNA dynamics in a cohort of patients with 25 different types of histologies. The study showed significantly better outcomes for patients who cleared their ctDNA posttreatment, indicating exceptional response. The study also illustrated molecular progression as early as 6 weeks in a percentage of patients who received, on average, two cycles (six weeks) of additional treatment, which could have been avoided. This shows a clear utility of ctDNA that could have enabled an earlier switch to alternative treatment with a higher degree of efficacy and a lower financial burden.

More recently, the U.S. Food and Drug Administration (FDA) approved pembrolizumab as a first-line treatment for patients with unresectable or metastatic mismatch repair deficient/microsatellite instability status (dMMR/MSI-H) colorectal cancer (CRC), which constitutes 15 percent of metastatic CRC (mCRC) patients. The remaining have a microsatellite-stable status. Both of these subtypes have shown poor expression of CEA, which is a commonly used protein biomarker. Many studies have alluded to its poor sensitivity, specificity, and unreliability in predicting treatment response or risk of relapse. We recently presented a few case examples at the Society for Immunotherapy of Cancer (SITC) conference that highlight a physician’s experience in treating patients with mCRC and the value of ctDNA over conventional methodologies.

In summary, there is strong scientific evidence showing that the incorporation of ctDNA analysis into routine clinical practice can help physicians make better-informed decisions for patients battling an aggressive disease.

Drs. Billings and Aleshin can be reached at pbillings@natera.com.

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