EURURO Vol. 72 No. 5

e137 860

Letter to the Editor
Reply to Pontus Eriksson, Gottfrid Sjo¨dahl, and Fredrik
Liedberg’s Letter to the Editor re: Thomas Powles,
Robert A. Huddart, Tony Elliott, et al. Phase III, Double-
blind, Randomized Trial that Compared Maintenance
Lapatinib versus Placebo after First-line Chemotherapy
in Patients with Human Epidermal Growth Factor
Receptor 1/2-positive Metastatic Bladder Cancer. J Clin
Oncol 2017;35:48–55. Knowing HER2 Status is Not
Enough: A Molecular Subtype Approach to Bladder
Cancer is Also Needed
Protein Expression to Predict Outcome to Targeted
Therapy in Bladder Cancer: Too Little, Too Late?
[2_TD$DIFF]Until recently, personalized therapy in bladder cancer never
really materialized. Few personalized trials were performed
in the targeted therapy era, resulting in a plethora of negative
trials [1,2]. The maintenance lapatinib randomized trial was
a rare example of a personalized trial which also failed to
improve outcomes [3]. Therefore, either the drugs or the
biomarkers are ineffective, or both. While provocative work
is ongoing with fibroblast growth factor receptor-3 inhibi-
tors, overall it looks like randomized, personalized targeted
therapy studies have come to a halt. It may be that even with
a concerted effort into molecular analysis for targeted
therapy, the clinical trials may not occur due to doubt over
whether the drugs will work in such a mutational complex
tumor with such poor initial results. Results with chemo-
therapy have not been much better. Some preliminary work
with ERCC2 holds promise , but the only randomized,
personalized study focusing on p53 was unsuccessful
. Moving away from protein to gene expression analysis
has resulted in contradictory data too
This lack of enthusiasm for personalized, targeted trials
has coincided with a revolution with the development of
immune therapy in bladder. The first positive randomized
phase 3 trials for a generation showed benefit for
pembrolizumab over chemotherapy . [7_TD$DIFF]At [8_TD$DIFF]present,
[9_TD$DIFF]there [10_TD$DIFF]is [11_TD$DIFF]some [12_TD$DIFF]uncertainty [13_TD$DIFF]about [14_TD$DIFF]the [15_TD$DIFF]programmed [16_TD$DIFF]death
[17_TD$DIFF]ligand [18_TD$DIFF]1 [19_TD$DIFF]biomarker [20_TD$DIFF]in [21_TD$DIFF]urothelial [22_TD$DIFF]carcinoma. Programmed
death-ligand 1 results, measured using immunohistochem-
istry, have been very inconsistent with multiple methods of
testing and have harbored heterogeneous results .
However, data with atezolizumab has shown gene
expression (T effector signatures) and high mutational
burden correlating with outcome [12,13]. The second
generation of immune biomarkers holds much promise.
Detailed analysis with specific neoantigens has been
successful in other cancers.
Therefore, we agree with the statement ‘‘HER2 status
alone is not enough; molecular profiling is also required to
obtain a more complete picture,’’ but we also feel that
exploring targeted therapy alone may be behind us. Instead,
a combination of treatments, with molecular profiles
looking for a new generation of biomarkers is likely to be
the best way of helping patients in the future.
1. Conflicts of interest: Thomas Powles: honoraria (Roche/Genen-
tech, Bristol-Myers Squibb, Novartis), consulting or advisory role (Roche/
Genentech, Bristol-Myers Squibb, Merck), research funding (AstraZe-
neca/MedImmune, Roche/Genentech, GlaxoSmithKline).
References
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[27_TD$DIFF] .
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ava ilable at
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DOI of original article: .
0302-2838/# 2017 Published by Elsevier B.V. on behalf of European Association of Urology.