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

03/15/2023

Written
by Alison Ivey, RN, MS, MBA, OCN, CCRP 

from UF
Health Cancer Center

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

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

As
a biomarker, ctDNA can be used for a variety of purposes including the
detection of potentially targetable mutations, to follow the activity of a
particular intervention and potentially to determine the presence of residual
cancer that may not be detectable by conventional scans. ctDNA has also been
used to predict the likelihood of cancer recurrence. This application has been
found to be especially useful in cancers where there is debate over the utility
of certain treatment approaches. For example, oncologists have grappled with
balancing the risks and benefits of adjuvant chemotherapy for patients with
stage II colon cancer. The DYNAMIC trial (Tie et al, 2022)

ⁱ randomized patients with stage II colon cancer to either ctDNA directed
adjuvant therapy or the standard approach based on review of clinical and
pathologic prognostic factors. In the ctDNA testing arm, those with positive
ctDNA results (presumably because there was still some cancer in their body
releasing the ctDNA) received chemotherapy while those who tested negative
(presumably cancer free) underwent surveillance. Those in the control arm were
treated per clinician discretion. The primary endpoint of the study was
recurrence-free survival (RFS) at 2 years. The researchers concluded that the
ctDNA guided approach was non-inferior to the standard approach. They noted
that 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 further
chemotherapy.

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

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

The
Centers for Medicare & Medicaid Services has approved ctDNA testing to
assist with risk stratification and recurrence monitoring in a number of cancers
including colon, bladder and, most recently, breast cancer. While testing is
now approved for some indications, further refinement of this tool through our
current NRG studies and others will hopefully result in the development of a
powerful tool for the management of patients with a variety of solid tumors in
various stages of their disease.