Circulating Tumor DNA: One of Our Newest Tools for Managing Solid Tumors

March 15 2023

Writtenby Alison Ivey, RN, MS, MBA, OCN, CCRP  from UFHealth Cancer Center

Theconcept of liquid biopsies for diagnosing and monitoring solid tumors is notnew, but it is gaining more traction as a tool in both clinical care and ourclinical trials. So, what is a liquid biopsy and how are we leveraging thistechnology to our patients’ benefit? As we know, biomarker testing isubiquitous, and we rely on the results to select appropriate therapies for manycancers. Traditionally we use tumor tissue to perform this testing, but thisrequires the tissue to be located in a relatively safe place for biopsy andalways requires an invasive procedure which comes with safety concerns. Alternative options not requiring an invasive procedure are clearly needed andwould certainly constitute a major advance. 

Circulatingtumor DNA (ctDNA) is comprised of fragments of DNA shed by tumor cells thatthen enter a bodily fluid and can be detected and quantitated by a simplesampling of the fluid.  As the tumor grows or shrinks from therapy, theamount of ctDNA detected by these tests similarly goes up and down,respectively. While ctDNA can be found in urine, stool, mucous, orcerebrospinal fluid, blood drawn peripherally is the most common source forliquid biopsies. This means sampling is non-invasive, quick, accessible, andeasily repeatable for serial monitoring during care.

Asa biomarker, ctDNA can be used for a variety of purposes including thedetection of potentially targetable mutations, to follow the activity of aparticular intervention and potentially to determine the presence of residualcancer that may not be detectable by conventional scans. ctDNA has also beenused to predict the likelihood of cancer recurrence. This application has beenfound to be especially useful in cancers where there is debate over the utilityof certain treatment approaches. For example, oncologists have grappled withbalancing the risks and benefits of adjuvant chemotherapy for patients withstage II colon cancer. The DYNAMIC trial (Tie et al, 2022) i randomized patients with stage II colon cancer to either ctDNA directedadjuvant therapy or the standard approach based on review of clinical andpathologic prognostic factors. In the ctDNA testing arm, those with positivectDNA results (presumably because there was still some cancer in their bodyreleasing the ctDNA) received chemotherapy while those who tested negative(presumably cancer free) underwent surveillance. Those in the control arm weretreated per clinician discretion. The primary endpoint of the study wasrecurrence-free survival (RFS) at 2 years. The researchers concluded that thectDNA guided approach was non-inferior to the standard approach. They notedthat there was a low rate of recurrence in those who were ctDNA negative,meaning this testing could help us better predict who may not need furtherchemotherapy.

NRGis continuing to help refine the potential value of ctDNA through the conductof several studies within the colorectal portfolio. The COBRA study (NRG-GI005)is investigating the utility of ctDNA as a biomarker to help identify patientswho may benefit from chemotherapy following resection of Stage IIA (low risk)colon cancer. The current standard of care in this population under study issurveillance after surgery; however, 10-15% of these patients may still recurand thus may benefit from the use of adjuvant chemotherapy if we couldspecifically identify them using ctDNA. In the COBRA study, patients will berandomized between surveillance or ctDNA-guided therapy. Those in the guidedtherapy group who test positive will receive either FOLFOX or CAPOX. Theprimary objectives are to assess the rate of ctDNA clearance and RFS in thosewith detectable ctDNA at baseline for those in the surveillance group vs thoseactively treated with adjuvant chemotherapy. The COBRA study activated in 2019and has enrolled 530/1408 subjects to date.

TheCIRCULATE-US study (NRG-GI008) also incorporates ctDNA but is investigating itsuse in patients with stage III and high-risk stage II colon cancer. While COBRAis designed to predict which patients need the additional chemotherapy,CIRCULATE-US is using ctDNA for two purposes: 1) Can we accurately predictsituations where the risk of chemo outweighs the benefit and, 2) for those thatwould benefit from chemo, can we help determine which treatment option may bemost effective? All subjects will be tested for the presence or absence ofctDNA following what is presumed to be curative surgery.  Those who arepositive (Cohort B) at baseline (i.e., high-risk) are randomized toFOLFOX/CAPEOX or FOLFIRINOX chemotherapy.  Those who are negative (CohortA) at baseline (i.e., low risk) will be randomized to either standardchemotherapy (FOLFOX or CAPEOX) or surveillance with serial ctDNAtesting.  Any patient randomized to surveillance who becomes ctDNApositive will be eligible for re-randomization after transfer to Cohort B andmanaged with chemotherapy.  The outcomes of the two groups is comparedusing disease free survival as the endpoint. The primary objectives are todetermine whether more aggressive adjuvant chemotherapy improves the outcomesfor ctDNA positive patients (Cohort B) and whether avoiding chemotherapy withclose ctDNA monitoring is not inferior to chemotherapy (Cohort A).  TheCIRCULATE-US study activated in 2022 and has enrolled 39/1912 subjects to datewith plans to soon open across Canada.

TheCenters for Medicare & Medicaid Services has approved ctDNA testing toassist with risk stratification and recurrence monitoring in a number of cancersincluding colon, bladder and, most recently, breast cancer. While testing isnow approved for some indications, further refinement of this tool through ourcurrent NRG studies and others will hopefully result in the development of apowerful tool for the management of patients with a variety of solid tumors invarious stages of their disease. 

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