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Editorial

Referring to the article published on pp. 974

983 of this issue

Time to Focus on the Rare

Encouraging Progress in the

Management of Non

clear Cell Renal Cell Carcinoma

Archie

[1_TD$DIFF]

Fernando

*

The Urology Centre, Guy

s and St Thomas

Hospital, London, UK

Our misconception that renal cancer is a single disease

entity that should be managed the same surgically and

medically has hampered

[5_TD$DIFF]

our progress in the management of

non

clear cell renal cell carcinoma (nccRCC). The majority

of our advances in the management of renal cancer have

been in the realm of clear cell renal cell carcinoma (ccRCC).

We have made relatively few strides in the non

clear cell

subtypes. Once metastatic, nccRCC is characterised by

resistance to traditional systemic therapies and poor

survival

[1 3] .

The European Association of Urology (EAU) Renal Cell

Carcinoma Guideline Panel conducted a systematic review

of the data available on the systemic treatment of advanced

nccRCC

[4] .

The panel concluded that there was little

evidence that nccRCCs are less responsive to mammalian

target of rapamycin inhibitors and vascular endothelial

growth factor

targeted therapy than ccRCC, and made a

weak recommendation that sunitib may be marginally

better than everolimus for the systemic treatment of

advanced nccRCC

[4] .

As a follow-on from this, in this

month

s issue of

European Urology

, Giles et al

[5]

make a

compelling

call to action

for increased collaboration and

research into nccRCC. They preferentially use the term rare

kidney cancer (RKC), which they deem more inclusive than

nccRCC. The authors highlight three key shortcomings of

the current lines of investigation into RKCs and make

recommendations for improvement.

First, Giles et al

[5]

highlight that the current approach of

considering all RKCs to be one disease is flawed. RKCs

encompass over a dozen histological entities that vary

widely in their prognosis and response to treatments

[6] .

The strategy of continuing to consider them one disease

is likely to lead us in to the same pitfalls as considering all

RCCs to be the same, and should be abandoned. We must

assess the different subtypes separately regardless of the

small numbers involved.

Furthermore, we continue to use predominantly histo-

logical criteria rather than molecular/genetic profiling to

classify tumours and target treatment. We now know that

tumours within the same histological class behave and

respond to treatment differently

[4 8]

. For example,

response rates to foretinib (oral broad kinase inhibitor

targeting MET among other receptors) were 50% in those

with papillary RCC (pRCC) who had germline MET mutation,

compared with 8% in those who did not have the MET

mutation

[7] ,

and MET-driven pRCC has significantly better

progression-free survival and overall response rates with

savolitinib (selective MET inhibitor) compared with MET-

independent pRCC (6.2 mo and 18% vs 1.4 mo and 0%;

p

<

0.001)

[8] .

We also know that the molecular patterns of

tumours cross histological class boundaries. A comprehen-

sive pan-RCCmolecular analysis by Chen et al

[9]

shows that

tumours share greater molecular similarity with tumours

grouped in different histological categories. In the light of

this knowledge, use of histological classification alone

seems inadequate and begs two questions: (1) is our

stringent adherence to established histological boundaries

preventing

[6_TD$DIFF]

advancement in this disease? and (2) are the

overall poor outcomes of systemic treatments because of

the heterogeneity of the population being studied rather

than

failure

of the drugs? Perhaps we should shift to a

molecular classification of tumours, for example, MET

amplified, VHL altered, SDH deficient, PDL1 expressing, in

addition to the traditional histological subtypes. Molecular/

genetic profiling of tumours prior to inclusion in trials offers

a much more comprehensive way of assessing diagnosis,

E U R O P E A N U R O L O GY 7 2 ( 2 0 17 ) 9 8 4 9 8 5

available at

www.scienced irect.com

journal homepage:

www.europeanurology.com

DOI of original article:

http://dx.doi.org/10.1016/j.eururo.2017.06.040

.

* The Urology Centre, Guys and St Thomas Hospital, Great Maze Pond, London SE1 9RT, UK. Tel. +44 207 1887388; Fax: +44 207 1886793.

E-mail address:

archanafernando@hotmail.com . http://dx.doi.org/10.1016/j.eururo.2017.07.028

0302-2838/© 2017 Published by Elsevier B.V. on behalf of European Association of Urology.