EURURO Vol. 72 No. 4

565 656

Platinum Priority – Editorial
Referring to the article published on pp. 557–564 of this issue
Applying Precision Oncology to Renal Cell Carcinoma:
Emerging Challenges
John T. Leppert
a Department of Urology, Stanford University, Stanford, CA, USA; b Department of Medicine, Stanford University, Stanford, CA, USA; c Veterans Affairs, Palo
Alto Health Care System, Palo Alto, CA, USA; dStanford Kidney Cancer Research Program, Stanford University, Stanford, CA, USA
Many researchers are urgently working to develop precision
oncology, a process to personalize a patient’s treatment
based on the specific biology of their cancer. On the surface,
kidney cancer (renal cell carcinoma, RCC) appears ideally
suited to precision oncology approaches. More than 25 yr
ago, the role of VHL loss in hypoxia signaling and RCC
development was discovered . In 2013, The Cancer
Genome Atlas project published a comprehensive molecu-
lar evaluation of clear cell RCC Our deeper understand-
ing of RCC biology has accelerated drug development to the
point that there are now ten approved systemic therapies.
Yet these new discoveries and therapies have resulted in
only modest improvements in patient survival. Patients
now live long enough to matriculate through multiple
treatments, increasing their exposure to significant side
effects before ultimately succumbing to their disease.
Currently, the potential of precision oncology to mini-
mize futile toxicity and maximize patient survival remains
unfulfilled. There are no established biomarkers for
metastatic RCC and a number of reasons why candidate
biomarkers fail to improve patient outcomes . Careful
evaluation suggests that applying precision oncology in
metastatic RCC may be more challenging than anticipated,
as RCC patients are less likely to have a genetic alteration
that suggests a druggable target when approved treatments
fail .
The development of next-generation sequencing tech-
nology has allowed researchers to detect mutations in
circulating cell-free DNA. The significance of these genomic
alterations in RCC is not known. Can circulating tumor DNA
be used to select treatment, or identify early treatment
response or progression, or elucidate specific mechanisms
of resistance? In this issue of European Urology, Pal et al
begin to address these questions in a large cohort of
220 patients with metastatic RCC. For each patient, the
number and type of genomic alterations identified were
assessed and correlated with receipt of either first-line or
subsequent systemic therapies.
1. Applying circulating tumor DNA assays to RCC
The circulating tumor DNA assay used in the report applies
targeted sequencing of 73 common genomic alterations.
While this generic approach trades sensitivity for portabili-
ty across cancer types, it is notable that at least one genomic
alteration was found in nearly 80% of patients. However, an
RCC-specific assay would probably identify additional
genetic alterations, as this assay does not include four of
the nine most frequent tissue-based mutations described by
the TCGA (PBRM1 32.9%; SETD2 11.5%; BAP1 10.1%;
KDM5C 6.7%) or seven of the ten most frequent mutations
described by Scelo et al (PBRM1 39.4%; SETD2 19.1%; BAP1
11.7%; ZFHXY 9.6%; CSMD3 8.5%; FAT3 7.5%; KDM5C 7.5%). In
addition, the frequency of VHL genomic alterations (23%) is
much lower than expected, as multiregion sequencing of
metastatic RCC consistently identified VHL loss as the truncal
event . Furthermore, additional VHL alterations will be
missed, as this approach is not designed to detect epigenetic
changes (eg, inactivation by hypermethylation) or gene loss
(eg, loss of chromosome 3p), which are thought to be a
common events in clear cell RCC .
The specificity of the genomic alterations identified is
also not yet well characterized. Previous reports on specific
circulating tumor DNA mutations (eg, KRAS mutations)
ava ilable at
journal homepage:
DOI of original article: .
* Department of Urology, Stanford University, Grant S-289, 300 Pasteur Drive, Stanford, CA 94305, USA.
E-mail address: .
0302-2838/Published by Elsevier B.V. on behalf of European Association of Urology.