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Constantine)Alifrangis
1
,)Ursula)McGovern
1
,)Alex)Freeman
3
,)Thomas)Powles
4
,)and)Mark)
Linch
1,2)*
)
!
1
Department!of!Oncology,!University!College!London!Hospital,!London,!UK.!
2
Department!of!Oncology,!University!College!London!Cancer!Institute,!London,!UK.!
3
Department!of!Pathology,!University!College!London!Hospital,!London,!UK.!
4
Centre! for! Experimental! Cancer! Medicine,! Barts! Cancer! Institute,! Queen! Mary!
University!of!London,!London,!UK.!!
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*E-mail:!m.linch@ucl.ac.uk!
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6$2)0"-*/.)
• Combining! sequencing! and! transcriptom ic! technologies! might! improve! the!
identifica tio n !of!clinically!relevant!bladder!cancer!subgroups.!
• Molecular! subtyping!has! helped! us! to!identify!bladder! tumours!that!respond!well!to!
cytotoxic!chemotherapy.!
• Targeted!therapies!have!had!a!limited!role!in!bladde r! cance r! man a ge ment,!but!the!
next!generation!of!specific!targets!are!showing!promise,!as!exemplified!by! fib ro b last !
growth!factor!receptor!3!(FGFR3).!!
• Immun e! checkpoint! inhibition ! leads! to! de ep ! and! durable! responses ! in! a! small!
subgroup!of!patients.!!
• Composite! molecular! signatures! are! show ing! promise! as! predictors! of! treatm ent!
response!and!should!be !tested!in!prospe ctive!clinical!trials.!
• Real-time! serial! biopsies! during! the! course! of! treatment! will! be! required! to! help!
direct!therapy!in!an!evolving!tumour!land sc ap e.!
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75./('%/)
Bladder! cancer! is! a! heterogeneous! group! of! tumours! w ith! at! least! 40! histological!
subgroups!that!lea d s!to!~165,000!deaths!w orldwide!each!year
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.!Patients!with! localized!
disease!can!be!cured!with!surg ical!resection!or!radiothe rap y,!but!such!c urative!options!
are!limited!in!the!setting!of!recu rrent!disease!or!distan t!spread,!in!whic h!case!sy stemic!
therapy!is!used!to !control!disease!an d!palliate!symptom s.!Cytotoxic!ch em othera py !has!
been!the!mainstay!of!treatment!for!advanced! bladder! cancer,!bu t !high-quality!evidence!
is! lacking! to! info rm! the! managem en t! of! rare! subgrou ps! that! are! often! exclud ed! from !
studies.! Advances! in! molecular! pathology,! the ! development! of! targeted! therapies,! and!
the! resurgence! of! immunotherapy! has! led! to! the! reclassification! of! bladder! cance r!
subgroups!and!rigorous!efforts!to!define!predictive!biom arkers!for!cancer!therapies.!In!
this! Review,! we! present! the! current! evidence! for! the! m anagement! of! conventional,!
variant,! an d! divergent! urothelial! cancer! su btyp es,! as! well! as! nonurothelial! bladder!
cancers,! and! discuss! how! the! integration! of! genomic,! transcripto m ic! and! proteomic!
characterisation!of!bladder!cancer!could!guide!future!therapies.!!
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9:8;)<*/("+ & %/-" * ))
For! the! first! time!in!over!30!years ,!the!treatm en t!algorithm !for!advance d!bladde r!cancer!
is! rap idly! evolving,! wit h ! an! expan d e d! range! of! effective! therapies! beyond! cytotoxic!
chemotherapy! now! approved! (=<>?) 8).! With! novel ! and! still-em erging! therapeutic!
advances!in!the!fields!of!imm u n o th er ap y !and!molecularly !targeted !therap y,!a!renew ed !
focus! o n! bladd er ! cancer! subtyp es! has! emerged! in! an ! attem p t! to! personalize! systemic!
therapy.!The!vast!majority!of!bladder!cancers!are!urothelial!carcinomas,!but!up!to!10%!
are! nonurothelial! carcinomas! 9> ;!
2
.! Urothelial! carcinomas! (previously! known! as!
transitional! cell! carcinoma)! can! be! subdivided! according! to! their! histopathological!
characteristics! into ! conventional! urothelial! carcinom a! 9> ;! ,! urothelial! carcinoma! with!
divergent! differentiation! 9>;! ,! or! variant! urothelial! carcinoma! 9> ;
@
.The! importance! of!
these! categorisations! for! the! correct! diagnosis,! treatment,! and! prognostication! of!
bladder! cancer! is ! recognized! in! the! 2016! WHO! revised! classification! and! pathology!
guidelines!for!urogenital!cancers
3
!(A7BCD) 8).!However,!most!therapeu tic!clinical!trials!
have! historically! not! included! patients! w ith! nonurothelial! carcinoma! and! have! not!
reported!on!the!dive rgen t!or!variant!urothelial!carcinoma!subg roup s.!The!management!
of! these! rare! histologies,! therefore,! has! bee n! ba sed! on ! extrap olated! data! from ! other!
tumour!types!and!limited!clinical!experience!(for!exam p le,!sm all!case!series)!without!a!
deep!biological!understanding.!
In! this! Review,! w e! outline! how! new ! molecular! ap proaches,! such! as! DNA!
sequencing!and!RNA!profiling,!have!uncovered!distinct! biological!subtypes!of!urothelial!
carcinoma! th at! are! prognostic,! predictive! of! treatment! responses,! and ,! in! many!
instance s,! align! with! the! morpholo gical! phe no typ e.! We! discuss! how ! this! molecular!
taxonom y! and! histopathological! evidence! cou ld! support! the! deployment! of!
chemotherapy,! imm u n e -checkpoint!inhibitors!(ICIs),! and! targeted!agents!for!advanced!
bladder! cancer.! In! addition,! we! discuss! the! pathology-driven! management! of! variant!
urothelial! carcinoma! and! nonurothelial! carcinoma! and! co mm ent! o n! promising! future!
therapies.)
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9:8;)!"#$%&#'()0("3-#-*1)'*+)%#'..-3-%'/-"*))
Advances! in!sequencing!technology!over! the! past! 15! years!have! enabled! international!
collaborative!efforts!to!catalogue!the! spectrum! of! so matic! m utations! in! solid! tum ou rs,!
includin g ! urothelial! bladder! cancer
4
.! Our! understanding! of! the! pattern! of! genomic!
aberrations! and! their! in flu e n ce ! on! tumour! biology! and! behaviour! has! changed!
substantially!as!a!direct! result!of!this! w ork.!Early! work!exploring! phen otypes!of! bladder!
cancer! postulated! that! bladder! cancer! develops! along! two! distinct! pathways,! th e !
!
!
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papillary! and! non-papillary! pathways.! In! this! model,! 80%! of! tumou rs! are! papillary!
exophytic! lesions! arising! from! hyperplastic! epithelium! and! are! non-muscle-invasiv e!
bladder! cancers! (NMIB Cs)! that! have! a! propensity! for! recurrence! but! are! rare ly! life-
threatening,! whereas! ~20%! are! non-papillary! high-grade! muscle-invasive! bladder!
cancers!(MIB Cs)!arising!from!carcinoma!in!situ!th at!cause!the!most!morbidity!and!have!
a! propensity! for! m etastatic! spread
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;! these! tumours! rarely! arise! from! papillary!
precursors.!
Work! over! the! past! decade! using! gene! expression! and! somatic! mutational!
profiling! in! MIBC! has! defined! the! luminal! 9>;! an d! basal! 9>;! subgro ups! as! comm only !
recurring! subtypes,! a lt h o ugh! discr e pancies! b e t ween! th e ! v a ri o u s ! c la s s ifi ca t io ns! have!
beenreported! (=<>?) E)
6-9
,! and! su bsequ ent! efforts! have! been! m ade! to! consolidate! th e!
major! molecular! taxonomies.! Substantial! work! in! this! area! has! been! undertaken! by!
groups! at! Lund! University,! The! Cancer! Genome! Atlas! (TCGA ),! University! of! North!
Carolina!at!Charlotte!(UNCC),!and!MD!Anderson!Cancer!Centre!(MDACC).))
Luminal!bladder!cancers!can!be!further!separated!into!u ro thelial- lik e!urothelial!
carcinomas!(TCGA!cluster!I),!which!are!enriched!fo r!FGFR 3!and!KDM6A!mutations,!and!
genomically! unstable!urothelial! carcinomas! (TCGA! cluster! II),! which ! are! characterized!
by! overexpression! of! peroxisome! proliferator-activated! receptor! γ! (PPAR-γ)! and!
enrichment! fo r! TP53! and! ERCC2! mutations
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,! with! some! studies! having! demonstrated!
overexpression! of! the! oestrogen! receptor! α! (ER α)
10
.! The! characteristics! of! basal-like!
tumours! have! been! variously! described! by! different! groups,! inc lu d in g! the! UNCC
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! and!
MDACC
7,10
,! and! these! tum ou rs! correspond! to! the! TCG A! cluster! III! (and! arg uab ly! the!
claudin-low!TCGA !cluster!IV )!and!the!Lu n d!University !squam ous -like!grou p
9
.!Basal-like!
tumours! are! en riched! for! ep ithe lia l–mesenchymal! tran sition! (EMT)! gene! signatures
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,!
with! los s!of!RB1!and!NFE2L2!as!well!as!dysregulation!of!nuclear!factor-κB!(NF-κB)!and!
hypoxia-ind u cib le ! facto r! 1-α! (HIF1α)! signalling.! A! 2016! consensus! meeting
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! clarified!
the!m olec ular!taxono m y!with!respect!to!the!existence!of!a!basal-squamous-lik e!(BAS Q )!
subset,! defined!by! overexpression!of!cy tokeratin! 5 ! (KRT5)! and !KRT14!and!concurrent!
downregulation! of! urothelial! markers! forkhead! box! protein! A1! (FOXA1)! and! trans-
acting!T-cell-specific!transcription!factor!GATA3!(GATA3).!)
Further! incremental! gains! in! mole cu la r! tax on o my! have! been! made! using!
multiplatform!approaches!for!molecular!phenotyping,!which!have!expanded!and!re vised!
the! molecular! classifications.! A! 2017! TCGA! study! of! 412! MIBCs! int eg ra te d ! th e! use! of!
whole-exome! sequencing,! copy! num ber! analysis,!methylation! analysis,!and!RNA-based!
and!proteomic!inputs
13
.!This!study!reve aled!>50!recurrently!mutated!genes!and!th at!a!
high!mutational!burden!in!bladder!cancer!was!related!to!apolipoprotein!B!mRNA!editing!
