J O U R N A L C L U B
Essential Peer-Reviewed Reading in Kidney Cancer
The peer-reviewed articles summarized in this section were selected by the
Guest Editor, Brian M. Shuch, MD, for their timeliness, importance, relevance,
and potential impact on clinical practice or translational research.
Sunitinib alone or after nephrectomy in metastatic
renal-cell carcinoma. Méjean A, Ravaud A, Thezenas S,
et al. N Engl J Med. 2018 Aug 2; doi: 10.1056/NEJMoa
1803675.
Summary: Cytoreductive nephrectomy has been the standard
of care in metastatic renal-cell carcinoma for 20 years,
supported by randomized trials and large, retrospective
studies. However, the efficacy of targeted therapies has
challenged this standard. This phase 3 trial randomly assigned,
in a 1:1 ratio, patients with confirmed metastatic
clear-cell renal-cell carcinoma at presentation who were
suitable candidates for nephrectomy to undergo nephrectomy
and then receive sunitinib (standard therapy) or to
receive sunitinib alone. Randomization was stratified
according to prognostic risk (intermediate or poor) in the
Memorial Sloan Kettering Cancer Center prognostic
model. Patients received sunitinib at a dose of 50 mg daily
in cycles of 28 days on and 14 days off every 6 weeks. The
primary end point was overall survival. A total of 450 patients
were enrolled from September 2009 to September
2017. At interim analysis, the median follow-up was 50.9
months, with 326 deaths observed. The results in the
sunitinib-alone group were noninferior to those in the
nephrectomy-sunitinib group with regard to overall
survival. Median overall survival was 18.4 months in the
sunitinib-alone group and 13.9 months in the nephrectomy
sunitinib group. No significant differences in
response rate or progression-free survival were observed.
Adverse events were as anticipated in each group.
Conclusion: Sunitinib alone was not inferior to nephrectomy
followed by sunitinib in patients with metastatic
renal-cell carcinoma who were classified as having
intermediate-risk or poor-risk disease.
VHL substrate transcription factor ZHX2 as an
oncogenic driver in clear cell renal cell carcinoma.
Zhang J, Wu T, Simon J, et al. Science. 2018 Jul 20;361
(6399):290-295.
Summary: Inactivation of the von Hippel-Lindau (VHL)
E3 ubiquitin ligase protein is a hallmark of clear cell renal
cell carcinoma (ccRCC). Identifying how pathways affected
by VHL loss contribute to ccRCC remains challenging.
A genome-wide in vitro expression strategy was used to
identify proteins that bind VHL when hydroxylated. Zinc
fingers and homeoboxes 2 (ZHX2) was found as a VHL
target, and its hydroxylation allowed VHL to regulate its
protein stability. Tumor cells from ccRCC patients with
VHL loss-of-function mutations usually had increased
abundance and nuclear localization of ZHX2.
Conclusion: Functionally, depletion of ZHX2 inhibited
VHL-deficient ccRCC cell growth in vitro and in vivo.
Mechanistically, integrated chromatin immunoprecipitation
sequencing and microarray analysis showed that
ZHX2 promoted nuclear factor B activation. These studies
reveal ZHX2 as a potential therapeutic target for ccRCC.
Validation of the 16-gene recurrence score in patients
with locoregional, high-risk renal cell carcinoma from
a phase III trial of adjuvant sunitinib. Rini BI, Escudier
B, Martini JF, et al. Clin Cancer Res. 2018 Sep 15;24(18):
4407-4415.
Summary: Adjuvant sunitinib prolonged disease-free
survival in patients with locoregional high-risk renal cell
carcinoma (RCC) in the S-TRAC trial (ClinicalTrials.gov
NCT00375674). The 16-gene Recurrence Score (RS) assay
was previously developed and validated to estimate risk for
disease recurrence in patients with RCC after nephrectomy.
This analysis further validated the prognostic value
of RS assay in patients from S-TRAC and explored the association
of RS results with prediction of sunitinib benefit.
The analysis was prospectively designed with prespecified
genes, algorithm, endpoints, and analytical methods.
Primary RCC was available from 212 patients with
informed consent; primary analysis focused on patients
with T3 RCC. Gene expression was quantitated by RT-PCR.
Time to recurrence (TTR), DFS, and renal cancer-specific
survival (RCSS) were analyzed using Cox proportional
hazards regression. Baseline characteristics were similar
between patients with and those without RS results, and
between the sunitinib and placebo arms among patients
with RS results. RS results predicted TTR, DFS, and RCSS
in both arms, with the strongest results observed in the
placebo arm. When high versus low RS groups were
compared, HR for recurrence was 9.18 95% confidence
interval (CI), 2.15-39.24) in the placebo arm; interaction
of RS results with treatment was not significant.
Conclusion: The strong prognostic performance of the
16-gene RS assay was confirmed in S-TRAC, and the RS
assay is now supported by level IB evidence. RS results may
help identify patients at high risk for recurrence who may
derive higher absolute benefit from adjuvant therapy.
An empirical approach leveraging tumorgrafts to
dissect the tumor microenvironment in renal cell
carcinoma identifies missing link to prognostic
inflammatory factors. Wang T, Lu R, Kapur P, et al. Cancer
Discov. 2018 Sep;8(9):1142-1155.
Summary: By leveraging tumorgraft (patient-derived
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