EURURO Vol. 72 No. 5

e135 860

Letter to the Editor
Re: Thomas Powles, Robert A. Huddart, Tony Elliott,
et al. Phase III, [2_TD$DIFF]Double-blind, [3_TD$DIFF]Randomized [4_TD$DIFF]Trial that
[5_TD$DIFF]Compared [6_TD$DIFF]Maintenance [7_TD$DIFF]Lapatinib versus [8_TD$DIFF]Placebo after
[9_TD$DIFF]First-line [10_TD$DIFF]Chemotherapy in [11_TD$DIFF]Patients with [12_TD$DIFF]Human
[13_TD$DIFF]Epidermal [14_TD$DIFF]Growth [15_TD$DIFF]Factor [16_TD$DIFF]Receptor 1/2-positive
[17_TD$DIFF]Metastatic [18_TD$DIFF]Bladder [19_TD$DIFF]Cancer. J Clin Oncol 2017;35:48–55
[20_TD$DIFF]Knowing HER2 Status is Not Enough: A Molecular
Subtype Approach to Bladder Cancer is Also Needed
[1_TD$DIFF]Muscle-invasive bladder cancer is a lethal disease with a 5-
yr survival rate of only 50% despite radical surgery.
Neoadjuvant cisplatin-based combination chemotherapy
improves survival by 5–8% at a cost of high numbers needed
to treat for each patient saved. Immunotherapy was
previously only applicable in non–muscle-invasive disease,
administered as bacillus Calmette-Gue´ rin instillations.
However, the advent of checkpoint inhibitors has added a
new dimension in immunotherapy for metastatic bladder
cancer. Nevertheless, compared tomost other malignancies,
survival for bladder cancer patients has not improved
during the last decades. In breast cancer, patient selection
and targeted treatments have contributed to improved
survival rates, with anti-HER2–directed therapies as a
cornerstone (trastuzumab and lapatinib) for individualized
therapy. As HER2 overexpression is a common feature in
muscle-invasive bladder cancer, even more frequently
overexpressed than in breast cancer [1], such a treatment
strategy also seems a valid option for invasive bladder
cancer. However, up to now studies investigating this
concept have either closed prematurely after recruiting only
13 (NCT02006667) and five (NCT02013765) patients with
HER2 overexpression, or failed to show survival benefits [2].
The reasons for the negative outcomes in these studies
can be sought among new insights into HER2 status at the
DNA, RNA, and protein levels, which have highlighted
discrepancies between fluorescence in situ hybridization
and immunohistochemistry [3]. Furthermore, in advanced
bladder cancer, HER2 amplification rates have been
associated with specific molecular subtypes [3,4] . Kiss
et al [3] showed that HER2 expression (mRNA and protein)
is primarily associated with clusters I and II in the TCGA
classification system. Similarly, Eriksson et al [4] showed
that HER2 expression (mRNA and protein) is associated
with the urobasal (Uro) and genomically unstable (GU)
subtypes, with clinically positive HER2 rates of 54% and 47%,
respectively. Importantly, the Uro and GU tumor types
differ radically at the genomic, transcriptional, and pheno-
typic levels [4], and hence HER2 positivity may have
different implications in the Uro and GU molecular
contexts.
It has been demonstrated in breast cancer that the
molecular subtype of HER2-positive tumors influences the
outcome of HER2-directed therapy. In a randomized phase
3 study of HER2-positive tumors (paclitaxel plus trastuzu-
mab with or without lapatinib), the pathological complete
response rate was 70% for the HER2-enriched breast cancer
subtype, compared to 34% for the luminal A and 36% for the
luminal B subtypes. In a subsequent multivariable analysis
including intrinsic tumor subtypes, the authors showed that
an immune-cell gene signature was independently associ-
ated with response, pointing to yet another level of
complexity when selecting patients/tumors for HER2-
directed treatment [5].
Taken together, evidence from the recently published
negative but well-designed study in advanced bladder
cancer [2] and recent findings that HER2-positive tumors
come in different ‘‘flavors’’ [3,4] suggest that knowing HER2
status alone is not enough; molecular profiling is also
required to obtain a more complete picture.
Conflicts of interest: The authors have nothing to disclose.
Acknowledgments: The authors’ research is supported by grants from
The Swedish Cancer Society (CAN 2014/448) and Lund Medical Faculty
(ALF).
References
[1]
[2]
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[3]
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[4]
ava ilable at
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0302-2838/# 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.