EURURO Vol. 72 No. 2

316 320

[3]
[4]
Akshay Sood, Firas Abdolla
Vattikuti Urology Institute, Henry Ford Hospital, Detroit, MI, USA
*Corresponding author. Vattikuti Urology Institute,
Henry Ford Hospital, 2799 West Grand Boulevard, Detroit,
MI 48202, USA.
E-mail address: (F. Abdollah).
# 2017 European Association of Urology.
Published by Elsevier B.V. All rights reserved.
Re: Clonal Evolution of Chemotherapy-resistant
Urothelial Carcinoma
Faltas BM, Prandi D, Tagawa ST, et al
Nat Genet 2016;48:1490–9
Experts’ summary:
Faltas et al performed whole-exome sequencing and clon-
ality analyses in urothelial bladder carcinomas to investigate
(1) clonal divergence between primary tumors and metasta-
ses and (2) the influence of chemotherapy on the genetic
landscape of tumor cell populations in advanced and meta-
static tumors. Having compared paired samples of primary
tumors and metastases, they concluded that metastatic
spread is an early event and that primary tumors and metas-
tases are therefore characterized by different genetic patterns.
Chemotherapy leads to significant changes in mutational
landscapes, as shown by analyses of paired tumor and meta-
static samples before and after chemotherapy. Furthermore,
they found clonal enrichment of mutations in pathways of
transmembrane transport of small molecules and of cell ad-
hesion (L1CAM, integrin) that seem to be involved in chemo-
therapy resistance.
Experts’ comments:
Prognostic and predictive biomarkers are indispensable tools
for individualized therapeutic concepts. In muscle-invasive
bladder cancer, for example, we are looking for biomarkers
able to predict the response to perioperative chemotherapy.
The aim of neoadjuvant and adjuvant therapy is to prevent
systemic progression, that is, the development of clinically
relevant metastases from micrometastases. Several putative
predictive markers for neoadjuvant therapy have been de-
scribed in primary tumor samples obtained via transurethral
resection . To date, the response of the primary tumor
according to cystectomy samples was the clinical endpoint in
most studies assuming that the biological background is
similar in primary tumors and metastases. Contradicting this
hypothesis, Faltas et al demonstrated clonal heterogeneity
between primary tumor samples and metastases, and be-
tween different metastatic sites (lymph nodes and distant
metastases). However, it has to be kept in mind that the
metastases were investigated only after treatment, so com-
parison of genetic alterations between primary tumors and
metastases could be biased by therapy-induced clonal evo-
lution. Thomsen et al by contrast, demonstrated the
diversity between primary tumors and metastases by ana-
lyzing treatment-naı¨ve samples. It therefore seems ques-
tionable to use primary tumor tissue for identification of
markers predictive of metastatic response. In addition, pro-
gression-free survival should define the clinical endpoint for
biomarker development rather than the response of the
primary tumor in the neoadjuvant setting. The biological
diversity between a primary tumor and its metastases is
even more important for treatment of metastatic disease.
Although it was recently shown that molecular markers may
serve as predictors of therapy response in advanced and
metastatic disease , the predictive accuracy should be
increased by analyzing metastatic samples instead of prima-
ry tumors. Faltas et al also demonstrated that chemotherapy
induced a significant increase in clonal mutations in post-
chemotherapy samples that were not present in chemother-
apy-naı¨ve tumors. Accordingly, selection of second-line ther-
apy should be based on molecular analysis of treated
metastatic lesions.
Comparison of therapy-naı¨ve and treated tumor samples
is very helpful in furthering our understanding of the
mechanisms of chemotherapy resistance, as shown by
identification of changes in cell adhesion and multidrug
resistance pathways. In this regard, one critical point of this
study is the heterogeneity of therapeutic regimens used
(gemcitabine-cisplatin [GC], methotrexate, vinblastine,
doxorubicin, cisplatin [MVAC], docetaxel-ramucirumab).
In conclusion, this paper is of high impact in the context of
our understanding of clonal evolution and heterogeneity in
bladder cancer. The consequences for both clinical and
research algorithms are evident. The time has come to
change the approach for biomarker development for
advanced and metastatic urothelial carcinomas. The tumor
samples must be suitable for the questions to be answered,
and liquid biopsies could be another reliable source of
material.
Conflicts of interest: The authors have nothing to disclose.
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