EURURO Vol. 72 No. 3

E74 476

Letter to the Editor
Reply to Ye Lei, Serdar Yildiz, and Minfeng Chen’s
Letter to the Editor re: James J[1_TD$DIFF]. Hsieh, David Chen,
Patricia Wang, [7_TD$DIFF]et [8_TD$DIFF]al. Genomic Biomarkers of a
Randomized Trial Comparing First-line Everolimus
and Sunitinib in Patients with Metastatic Renal
Cell Carcinoma. Eur Urol 2017;71:405–14
Kidney cancer care and translational research have made
marked strides over the past decade, including the
contemporary multi-omic analysis of human kidney tumors
, the approval of ten new drugs, and doubling of median
survival for patients with metastatic kidney cancer.
Nevertheless, there remains much room to improve, with
major challenges such as response heterogeneity, tumor
heterogeneity , resistance mechanisms, and the relative-
ly high incidence of recurrence after curative nephrectomy.
With the advent of next-generation sequencing (NGS)
technology, one promising approach is to integrate genomic
biomarkers into current clinical parameter-based nomo-
grams. The attempt to correlate genomic biomarkers and
targeted therapeutic response in kidney cancer began with
somatic mutations detected in exceptional responders to
mTORC1 inhibitors, recognizing MTOR activating mutations
and TSC1/TSC2 loss as promising candidates Our
current study reports a retrospective genomic biomarker
analysis using ultradeep targeted exome sequencing of
341 cancer genes on tumor materials of 220 patients with
clear cell renal cell carcinoma (ccRCC) who were treated
in RECORD-3, a large (n = 471) randomized trial comparing
first-line sunitinib to everolimus in treatment-naı¨ve meta-
static renal cancer Importantly, we demonstrated that
genomic classification based on PBRM1, BAP1, and KDM5C
mutations are of potential prognostic and predictive values,
supporting the role of genomic classification in prospective
studies
As pointed out by Chen and colleagues, many questions
remain and much needs to be done to validate our findings
using independent patient cohorts of similar clinical
characteristics and treatment schedules. We appreciate
the comments raised concerning the dynamic interaction
between the tumor cell/microenvironment and targeted
agents and its value in understanding the resistance
mechanism. In fact, for that exact reason our study focused
on analyzing genomic correlation with first-line progres-
sion-free survival (PFS) instead of second-line to avoid such
confounding factors. Although comparison of tumor geno-
mics before and after targeted treatment may be of high
translational interests for acquired drug resistance, its
practicability and value remain to be determined.
In terms of intratumor heterogeneity and its impact on
genomic/therapeutic correlation, multiregional sequencing
studies performed by Gerlinger et al and us have
demonstrated the highly heterogeneous intratumor and
intertumor nature of ccRCC, which is likely to diminish the
probability of detecting real correlations between cancer
genomics and targeted therapeutics. Fortunately, with the
relatively large number of tumor samples and focus
primarily on prevalent mutations (>10%), our study was
able to detect significant associations: patients with mutant
KDM5C experienced a prolonged response to sunitinib,
patients with mutant PBRM1 benefited equally from
inhibitors of mTORC1 and VEGF pathways, and patients
with mutant BAP1 fared poorly on either Hence, we
proposed four molecular subtypes of ccRCC based on
KDM5C, PBRM1, and BAP1 mutation profiles .
Smoking is one of the major risk factors in ccRCC, but its
influence on targeted therapy outcome is unknown. In our
ccRCC NGS cohort (n = 220), only eight patients have a
history of smoking; as expected, owing to this small
percentage (4%) of patients with a history of smoking,
analysis stratified according to smoking status was under-
powered and did not affect the original statistical findings
for these key genes.
Conflicts of interest: Mahtab Marker and David Chen are employees of
Novartis. James J. Hsieh is a consultant for Novartis, Eisai, and Chugai, and
has received research funding from Pfizer, Novartis, Eisai, and Cancer
Genomics Inc. The study was funded by Novartis and the sponsor played a
role in study design and conduct; data collection, management, analysis,
and interpretation; and manuscript preparation, review, and approval.
References
[1]
[2]
available at
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DOIs of original articles: .
0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.