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We recapitulated similarities between the most recently
discovered claudin-low tumors and TCGA cluster IV
[10,15]. However, while Kardos et al
[15]found claudin-
low tumors to be evenly distributed between clusters III and
IV, in our dataset claudin-low tumors were enriched in
cluster IV (75%). Both clusters III and IV are basal tumors
with a strong mesenchymal signature, and both show the
highest degree of immune infiltration. Patients with
claudin-low tumors had the worst prognosis irrespective
of treatment strategy in our analysis, suggesting also that
these patients derived little or no benefit from NAC.
Importantly, although these tumors showed the highest
rate of immune infiltration, the benefit of checkpoint
inhibition was limited in this subtype in the IMvigor 210
[23_TD$DIFF]
and the CheckMate 275 trial
[[24_TD$DIFF]
18,19]. These patients should
be targeted with priority for inclusion in clinical trials of
novel agents.
Although we observed clear relationships between OS
after NAC and molecular subtypes, we did not observe a
clear effect on pathological response to NAC. The lack of this
expected association
[4]may simply be due to sample size
and patient selection, as well as surgical downstaging with
TUR alone. However, our findings resemble those in breast
cancer, where pathological response relates to outcome in
some, but not all, molecular subtypes
[20]. In our series, the
lack of association between pathological response and OS
was observed primarily in the basal tumors. Prospective
validation in a larger cohort is required to resolve this issue
in MIBC.
Limitations of this study include the retrospective
design. Moreover, our analysis is also confounded by
comparisons between patient cohorts from different
studies. This makes validation in prospectively collected
cohorts necessary. Since the clinical characteristics of the
cohorts used were different and an unknown proportion of
the Lund dataset was not treated with a curative intent, we
were not able to match non-NAC with NAC cohorts to
perform a direct comparison of the impact of NAC between
subtypes. Nonetheless, the relative differences in OS
between subtypes in the NAC and non-NAC settings
suggest a differential impact of the subtypes on outcome
after NAC.
5.
Conclusions
We provide the most compelling data to date that suggest a
relationship between molecular subtypes and response to
cisplatin-based NAC in MIBC. With or without NAC, patients
with luminal tumors do well, implying that NAC is perhaps
unnecessary in this subtype. Immune-infiltrated luminal
tumors appear to have limited benefit from NAC, but have
been shown previously to respond best to checkpoint
inhibition, suggesting an alternative for systemic therapy in
these patients. Claudin-low tumors have the worst outcome
regardless of NAC treatment, and novel therapies are
urgently needed for this patient cohort. The impact of
NAC on OS was greatest in patients with basal tumors,
which raises the hypothesis that these patients should be
prioritized for NAC. These findings require prospective
validation before this single-sample classifier can be used in
clinical practice.
Author contributions:
Peter C. Black had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design:
Seiler, Wright, van der Heijden, Douglas,
Dall’Era, Boormans, Davicioni, Black.
Acquisition of data:
Seiler, Erho, Palmer-Aronsten, Buerki, Lam, Davicioni,
Black.
Analysis and interpretation of data:
Seiler, Erho, Ashab, Choeurng, Wang,
Choi, McConkey, Kardos, Sjo¨dahl, Hoadley, Kim, Black.
Drafting of the manuscript:
Seiler, Erho, Wang, Choeurng, Davicioni,
Ashab, Black.
Critical revision of the manuscript for important intellectual content:
Winters, Douglas, van Rhijn, van de Putte, Kardos, Todenho¨fer, Kiss,
Buerki, Choi, McConkey, Sjo¨dahl, Hoadley, Lerner, Van Kessel, Zwarthoff,
North, Crabb, Sommerlad, Thalmann, Davicioni, Kim, Wright, van der
Heijden, Dall’Era.
Statistical analysis:
Wang, Choeurng.
Obtaining funding:
Davicioni.
Administrative, technical, or material support:
Buerki, Lam, Palmer-
Aronsten, Davicioni.
Supervision:
Black.
Other:
None.
Financial disclosures:
Peter C. Black certifies that all conflicts of interest,
including specific financial interests and relationships and affiliations
relevant to the subject matter or materials discussed in the manuscript
(eg, employment/affiliation, grants or funding, consultancies, honoraria,
stock ownership or options, expert testimony, royalties, or patents filed,
received, or pending), are the following: Hussam Al Deen Ashab:
Employment GenomeDx. Nicholas Erho: Employment, GenomeDx.
[13_TD$DIFF]
Natalie Q. Wang: Employment, GenomeDx. Voleak Choeurng: Employ-
ment, GenomeDx. Ewan A. Gibb: employment, GenomeDx. Beatrix
Palmer-Aronsten: employment, GenomeDx. Lucia L. Lam: employment,
GenomeDx. Christine Buerki: employment, GenomeDx. Elai Davicioni:
employment, GenomeDx. Seth P Lerner: consulting or advisory role:
Oncogenex, Sitka, Nucleix, Vaxiion, Taris BioMedical, Telesta Therapeu-
tics, UroGen, Ferring. David J. McConkey: stock or other ownership:
ApoCell; patents, royalties, other intellectual property: Pending patent_
UTSC.P1206US. Woonyoung Choi: patents, royalties, other intellectual
property: pending: Methods of characterizing and treating molecular
subset of muscle-invasive bladder cancer. William Y. Kim: patents,
royalties, other intellectual property: pending: BASE47. Simon J. Crabb:
honoraria: Bayer, Astellas Pharma, Janssen; consulting or advisory role:
Bayer, Sanofi, Astellas Pharma, Janssen, Pfizer, Roche. Scott North:
honoraria: Janssen-Ortho, Astellas Pharma, Novartis, Pfizer, Sanofi
Canada; consulting or advisory role: Janssen Oncology, Astellas Pharma,
Novartis, Sanofi Canada, Pfizer, Roche Canada, Merck, AstraZeneca. Ellen
C. Zwarthoff: honoraria: MDxHealth; patents, royalties, other intellec-
tual property: Erasmus MC. Michiel S. van der Heijden: consulting or
advisory role: Roche/Genentech, Astellas Pharma, AstraZeneca/MedIm-
mune; travel, accommodations, expenses: Novartis, Astellas Pharma,
MSD Oncology. Peter C. Black: consulting or advisory role: Abbvie,
Astellas Pharma, Janssen Oncology, Amgen, Novartis, BioCancell, Sitka,
Cubist, Bayer, Merck, Sanofi Canada, Biosyent, Ferring, Lilly, Roche
Canada, Spectrum Pharmaceuticals; patents, royalties, other intellectual
property: 1. PCT/CA2014/000787. Canada. 2014-11-03 Cancer Biomark-
ers and Classifiers and uses thereof; 2. #61899648 United States. 2013-
03-13 Bladder cancer signature.
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