2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Novel Approaches in Advanced Urothelial Cancer
Identifying Predictive Biomarkers and Therapeutic Targets
Because urothelial cancer is relatively chemotherapy sensitive,
yet only a fraction of patients respond to any given
regimen, there has been much interest in developing tools
to allow more rational use of existing and future drugs.
DNA-repair genes, or their protein products, have been of
particular interest as predictive biomarkers on the basis of
the mechanism of action of the conventional cytotoxics used
in the management of urothelial cancer. In a retrospective
study, levels of the DNA-repair genes ERCC1, RRM1,
BRCA1, and caveolin-1, in tumor tissue from 57 patients
with bladder cancer treated with cisplatin-based combination
chemotherapy, were analyzed. 18 The median survival
of patients in this cohort was higher in patients with low
ERCC1 levels (25.4 vs. 15.4 months; p � 0.03). However,
development of ERCC1 as a potential prognostic and/or
predictive biomarker has been hampered by difficulties with
analytic validation.
The genomic complexity of most solid tumors suggests
that relying on a single gene or protein as a predictive
biomarker is unlikely to yield major improvements in patient
selection. Alternatively, gene “signatures” of response
to chemotherapy may be more attractive. The conventional
approach to predictive gene expression model development
is limited, however, because the signature is applicable only
to the particular drug or combination and patient population
for which the signature was developed. To overcome these
limitations, Theodorescu and colleagues have developed a
novel bioinformatics approach known as Coexpression Extrapolation
(COXEN). 19 COXEN uses the publicly available
gene-expression profiling data and drug sensitivity data
from the NCI-60 cell line panel as a “Rosetta Stone” to
predict chemotherapy sensitivity of gene-expression–profiled
tumor samples. A neoadjuvant study to demonstrate
the clinical utility of COXEN in treatment selection for
patients with urothelial cancer is currently being planned.
Profiling tumors for potentially “actionable” genomic mutations
also offers the potential for personalized application
of targeted therapeutics. Sjodahl and colleagues performed
mutation analyses of 16 genes (FGFR3, PIK3CA, PIK3R1,
PTEN, AKT1, KRAS, HRAS, NRAS, BRAF, ARAF, RAF1,
TSC1, TSC2, APC, CTNNB1, and TP53) in 145 urothelial
cancer samples. 20 Notably, this study confirmed that FGFR3
and PIK3CA mutations were most commonly found in noninvasive
low-grade tumors, although a smaller proportion of
muscle-invasive specimens also harbored these mutations.
The potential importance of adenomatous polyposis coli
signaling and the mammalian target of rapamycin (mTOR)
regulatory tuberous sclerosis complex genes (TSC2 and
TSC2) were also identified in this study. Actionable mutations/aberrations
found in other solid tumors, such EGFR
mutations and EML4-ALK fusions, have been identified
very rarely in urothelial cancer specimens.
Targeting Oncogenes
Although activating mutations in EGFR are not detected
in urothelial cancer, overexpression or amplification of
EFGR pathway family members are present in a subset of
tumors, and have been implicated in the pathogenesis of the
disease. Multiple phase II trials have explored single-agent
inhibitors of the EGFR pathway using different agents,
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methods of patient selection, and trial designs. A study of
lapatinib as second-line therapy in patients with metastatic
urothelial cancer reported a response rate of only 1.7%;
however, stable disease was correlated with EGFR overexpression,
and, to some extent, HER2 overexpression. 21 A
randomized discontinuation trial of lapatinib in patients
with tumors harboring HER2 gene amplification, which
included patients with urothelial cancer, demonstrated no
objective responses in the urothelial cancer cohort. 22 Trials
combining chemotherapy with inhibitors of the EGFR pathway
have yielded more intriguing results, but the single-arm
nature of these trials has precluded an assessment of the
contribution of the EGFR pathway inhibitor, and few randomized
trials have been initiated.
Although activating mutations in FGFR3 are most commonly
found in non–muscle-invasive urothelial cancer, recent
studies have demonstrated the presence of FGFR3
mutations in 10% to 20% of muscle-invasive urothelial
cancer specimens. 23 Dovitinib is a small-molecule inhibitor
of several tyrosine kinase receptors, including the vascular
endothelial growth factor receptor (VEGFR) and fibroblast
growth factor receptor (FGFR), and has demonstrated inhibition
of tumor growth and proliferation in urothelial carcinoma
models. A multicenter, two-stage, open-label phase II
trial is currently evaluating the safety and efficacy of
dovitinib in patients with advanced urothelial carcinoma
who have experienced disease progression despite prior
systemic therapy, both in cohorts with and without FGFR3
mutations (NCT00790426).
Targeting Angiogenesis
MATTHEW D. GALSKY
Multiple lines of evidence support a therapeutic role for
targeting the tumor vasculature in urothelial cancer. The
triplet of gemcitabine, cisplatin, and the anti-VEGF antibody
bevacizumab in a phase II of 43 chemotherapy-naïve
patients with metastatic urothelial cancer, demonstrated an
overall response rate of 73% and an encouraging median
overall survival of 19.1 months; it is currently being explored
in a randomized trial by the Cancer and Leukemia
Group B. 24
On the basis of preclinical studies demonstrating synergistic
antitumor activity by combining VEGFR and plateletderived
growth factor receptor (PDGFR) kinase inhibitors,
phase II trials of sorafenib, sunitinib, and pazopanib, have
been performed in urothelial cancer and demonstrated modest
antitumor activity with the latter drugs. 25-26 Although
supported by preclinical studies showing additive to synergistic
activity, the combination of GC plus sunitinib was
poorly tolerated in a phase II trial as a result of hematologic
toxicity. 27
Two randomized phase II trials evaluating the impact of
adding antiangiogenic therapy to cytotoxic regimens in
urothelial carcinoma have been reported. In a placebocontrolled
phase II trial of docetaxel with or without vandetanib,
a small-molecule inhibitor of the VEGFR and
epithelial growth factor receptor (EGFR) tyrosine kinases, in
the second-line setting, the combination failed to improve
outcomes. 28 Similarly, a trial of GC with or without
sorafenib failed to improve outcomes, but closed early as a
result of poor accrual limiting the power to detect differences
between the arms. 29