Is Circulating Tumor DNA Ready for Prime Time?
Evaluation of this Biomarker in the Era of Precision Medicine
Kidney Cancer Journal 25
Incremental but exciting progress toward the development of
a biomarker in metastatic renal cell carcinoma has put precision
medicine on the verge of making dramatic changes in detection
and surveillance. The utility of circulating tumor DNA
is gaining converts to a technology with potential translational
impact on clinical practice. But many issues remain to
be elucidated before this tool can move beyond the hypothesisgenerating
stage to becoming integrated into clinical practice.
As new non-invasive tools emerge in the era of precision
oncology, the landscape for diagnostic and prognostic
markers in renal cell carcinoma (RCC) is dramatically
changing. Next-generation sequencing (NGS) platforms,
including techniques that analyze tumor tissue for somatic
and germline cancer-associated gene alterations,
are beginning to have an impact on kidney cancer diagnoses.
Potentially - and therein lies the cautionary tale -
innovative blood-based tests, also known as liquid biopsies,
could begin to change the paradigm of RCC disease
management, thereby overcoming issues posed by traditional
radiological and histopathological examinations.
The need for and the presentation of new research on reliable
biomarkers in RCC remains a major focus, yet reliable
and confirmatory evidence for such methods
continues to be elusive for kidney cancer while substantial
progress has been made in other solid tumors which
readily employ treatment strategies based on actionable
genetic data.
Aside from its non-invasive advantages, other benefits
of liquid biopsies include multiple time point testing and
its ability to facilitate the diagnosis and monitoring of
evolving disease, offering clinicians a potentially contemporary
and prognostic marker to effectively track a
patient’s clinical course. Liquid biopsies such as circulating
tumor DNA (ctDNA) or circulating cell-free DNA
(cfDNA) constitute two promising avenues of exploration
in the era of precision oncology for RCC.
Circulating cell-free DNA. With a simple blood test, the
total quantity of DNA that is released into the peripheral
blood circulation and captured comprises circulating
cell-free DNA (cfDNA). Since this DNA is released from
both normal and tumor cells, isolated DNA fragments in
cfDNA are not only from the tumor but include normal
cellular DNA that is released from other molecular
processes like apoptosis, necrosis, and secretion of genomic
DNA fragments.1 The abundance and relative
fragmentation of cfDNA has been suggested to be a biomarker
for several solid tumors including RCC in numerous
studies.2-8 However, additional metrics of cfDNA
remain to be clarified and its clinical utility in RCC disease
management has yet to be fully elucidated. With
each study, differences in patient characteristics, RCC
disease characteristics, and most importantly the platform
used for cfDNA capture make it challenging to
unify conclusions. Although controversy surrounds efforts
to validate cfDNA as a clinical biomarker for RCC,
recent studies reviewed in this report suggest its utility
and promise for it being a non-invasive tool associated
with potential high sensitivity and specificity for RCC
management.
Circulating tumor DNA. Next generation sequencing
(NGS) of circulating tumor DNA (ctDNA) is an attractive
alternative to traditional tissue sequencing because it circumvents
the need for repeated, invasive tissue biopsies
to gain a contemporary mutational profile. In addition,
ctDNA analyses may also provide a more comprehensive
assessment of the total tumor as ctDNA is shed from separate
heterogeneous tumor sites.9 While the role of
ctDNA in other diseases like lung cancer and colorectal
cancer is well established, studies of ctDNA in metastatic
RCC (mRCC) are only hypothesis-generating to date. In
contrast to cfDNA, ctDNA is derived from the tumor itself
and usually represents a smaller fraction of cfDNA.
ctDNA is thought to be shed into circulation by apoptotic
and necrotic tumor cells in patients with cancer,10,11
highly prevalent in most advanced solid tumors except
for brain tumors,12 and has a half-life ranging from sixteen
minutes to a few hours.13-15 Because advanced tumors,
either pre-treated or at tumor progression, have a
higher mitotic index and undergo more rapid cell cycling
Ritesh R. Kotecha, MD
Medical Oncology Fellow
Department of Medicine
Memorial Sloan Kettering Cancer Center
New York, New York
Keywords: circulating free DNA, circulating tumor DNA, liquid biopsy,
biomarkers, diagnosis, tumor burden, hypermutation, metastatic
renal cell carcinoma, methylation.
Corresponding Author: Ritesh R. Kotecha, MD, Memorial Sloan Kettering
Cancer Center, 1275 York Avenue, New York, NY 10065. Email:
kotechar@mskcc.org
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