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showed excellent agreement with tissue analysis
[10],
while comparisons of commercially available tissue-based
and circulating tumor DNA assays have found low concor-
dance rates
[11]. It is interesting that in this study the most
common genomic alteration identified in patients with
metastatic RCC was
TP53
, occurring in 35% of patients. This
is markedly higher than tissue-based analyses and may
reflect the selection of these clones or the detection of
unrelated background p53 mutations.
Moreover, the precision of the assay (the ability to detect
the same genomic alterations on repeat tests) is also not
known. In this study, only 17 patients had serial samples,
and these showed decreasing agreement with increasing
time between tests (illustrated in Supplementary Fig. 2 in
[6] ). This could illustrate a new challenge: temporal genetic
heterogeneity. Analogous spatial heterogeneity is seen
when multiple locations within a primary tumor or
metastasis are sequenced, for which as many as five
biopsies are required for an 80% likelihood of identifying
80% of genetic mutations
[12]. However, the loss of initially
detected genomic alterations in subsequent tests is difficult
to reconcile with this branched evolution model for
metastatic RCC, which would suggest that the number of
alterations increases with tumor progression
[8] .2.
Does circulating tumor DNA detect tumor
evolution?
It is important to note that the circulating tumor DNA was
analyzed at one time point for the vast majority of patients.
As a result, it is not possible to know if the signature of
genomic alterations evolved while receiving therapy. The
total number of genomic alterations was not significantly
different when comparing patients receiving first-line
versus subsequent therapies. While several specific geno-
mic alterations (
TP53
,
p
= 0.02;
NF1
,
p
= 0.01) were more
common in patients receiving subsequent therapies, this
did not account for multiple comparisons, and may not be
reproducible in future studies.
3.
The future of precision oncology in RCC
Metastatic RCC, like all cancers, employs myriad strategies
to grow, invade, metastasize, and evade the host immune
response. These actions are orchestrated via a unique
genomic landscape, with several frequent mutations and a
long right tail of rare variants. The report by Pal et al
[6]illustrates the potential of circulating tumor DNA in
evaluating an additional dimension of genomic diversity
to monitor therapeutic response, and suggests a future in
which a blood test can be used to help guide therapy.
While a single blood test to deliver precision oncology
would be remarkable, successful biomarker development
will probably require multiple emerging technologies and
complementary approaches. Building on this initial report
by Pal et al
[6], future efforts to optimize circulating tumor
DNA analysis using RCC-specific panels, or even panels
tailored to mutations identified at the time of surgery, will
further increase the sensitivity of these assays. Circulating
tumor DNA will require robust validation before routine
clinical use, but is a promising technology poised to help
overcome the challenges in applying precision oncology
to RCC.
Conflicts of interest:
The author has nothing to disclose.
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