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Evaluation of the current knowledge limitations in breast cancer research: a gapanalysis

Breast Cancer Research 2008, 10:R26 doi:10.1186/bcr1983

Alastair Thompson (a.m.thompson@dundee.ac.uk)Keith Brennan (keith.brennan@manchester.ac.uk)

Angela Cox (a.cox@sheffield.ac.uk)Julia Gee (gee@cardiff.ac.uk)

Diana Harcourt (Diana2.Harcourt@uwe.ac.uk)Adrian Harris (aharris.lab@cancer.org.uk)

Michelle Harvie (Michelle.Harvie@smuht.nwest.nhs.uk)Ingunn Holen (I.Holen@Sheffield.ac.uk)

Anthony Howell (Anthony.Howell@christie.nhs.uk)Robert Nicholson (nicholsonri@cardiff.ac.uk)

Michael Steel (cms4@st-and.ac.uk)Charles Streuli (charles.streuli@manchester.ac.uk)

ISSN 1465-5411

Article type Research article

Submission date 30 August 2007

Acceptance date 27 March 2008

Publication date 27 March 2008

Article URL http://breast-cancer-research.com/content/10/2/R26

This peer-reviewed article was published immediately upon acceptance. It can be downloaded,printed and distributed freely for any purposes (see copyright notice below).

Articles in Breast Cancer Research are listed in PubMed and archived at PubMed Central.

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Breast Cancer Research

© 2008 Thompson et al., licensee BioMed Central Ltd.This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Research��ar ticle�

Evaluation� of� the� current� knowledge� limitations� in� breast� cancer�

research:� a� gap� analysis �

Alastair�T hompson1�K eith�B rennan2,�A ngela�C ox3,�J ulia�G ee4,�D iana�H arcourt5,�A drian�

Harris6,�M ichelle�H arvie7,� Ingunn� Holen8,�A nthony� Howell9,�R obert�N icholson10,�

Michael�S teel11,�C harles�S treuli12�

On�be half�of � Breast�C ancer�C ampaign�G ap� Analysis�M eeting,�2�N ovember� 2006,�

London,�U K.�

1Department�of �S urgery� and�M olecular� Oncology,�U niversity�o f�D undee,� Ninewells�

Avenue,�D undee,�D D1�9 SY,�U K.�a .m.thompson@dundee.ac.uk�

2Wellcome�T rust�C entre�f or�C ell�M atrix�R esearch,�F aculty�of � Life�S ciences,�U niversity�o f�

Manchester,� Oxford�R oad,�M anchester,�M 13�9P T,�U K.�ke ith.brennan@manchester.ac.uk�

3Institute�f or�C ancer�S tudies,�U niversity�o f�S heffield�M edical�S chool,�B eech�H ill�R oad,�

Sheffield,�S 10�2R X,� UK.�a .cox@sheffield.ac.uk�

4Tenovus�C entre�f or�C ancer�R esearch,�W elsh�S chool�of �P harmacy,�C ardiff�U niversity,�

Redwood�B uilding,� King�E dward�V II�A venue,�C ardiff,�C F10�3N B,�U K.�

gee@cardiff.ac.uk� �

5The�C entre�f or�A ppearance�R esearch,�S chool�of � Psychology�U niversity�of �t he�W est�of �

England,� Frenchay�C ampus,�C oldharbour� Lane,� Bristol,�B S16�1Q Y,�U K.�

Diana2.Harcourt@uwe.ac.uk�

6Cancer�R esearch�U K�M olecular�O ncology� Laboratories,�W eatherall� Institute�of �

Molecular�M edicine,�J ohn�R adcliffe�H ospital,�U niversity�of �O xford,�H eadley�W ay,�

Headington,�O xford,�O X3�9D S,�U K.�a harris.lab@cancer.org.uk�

7Family�H istory� Clinic,�N ightingale� &�G enesis�P revention�C entre,�W ythenshawe�

Hospital,� Southmoor�R oad,�M anchester,�M 23�9 LT,UK.�

Michelle.Harvie@smuht.nwest.nhs.uk�

8Academic�U nit�of �C linical�O ncology,�S chool�of � Medicine�a nd� Biomedical�S ciences,�

University�o f�S heffield,� Beech�H ill�R oad,�S heffield,�S 10�2R X,� UK.�

I.Holen@Sheffield.ac.uk�

2�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

9Breast�C ancer�P revention�C entre,�S outh�M anchester�U niversity�H ospitals�N HS�T rust,�

Wilmslow�R oad,�M anchester,�M 20�4B X,�U K.�A nthony.Howell@christie.nhs.uk�

10Tenovus�C entre�f or�C ancer�R esearch,�W elsh�S chool�of �P harmacy,�C ardiff�U niversity,�

Redwood�B uilding,� King�E dward�V II�A venue,�C ardiff,�C F10�3N B,� UK.�

nicholsonri@cardiff.ac.uk�

11University�of �S t�A ndrews,�B ute�M edical�S chool,�U niversity�o f�S t�A ndrews,�F ife,�K T16�

9TS,�U K.�c ms4@st-and.ac.uk�

12Wellcome�T rust�C entre�f or�C ell�M atrix�R esearch,�F aculty�of � Life�S ciences,�U niversity�

of�M anchester,�O xford�R oad,�M anchester,�M 13�9 PT,�U K.�

charles.streuli@manchester.ac.uk�

Corresponding� author:�A lastair�T hompson:�l wilde@breastcancercampaign.org��

3�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Abstract�

Background �A �g ap�a nalysis�w as� conducted�t o�de termine�w hich�a reas�of �br east�c ancer�

research,�i f�t argeted�b y� researchers�a nd� funders,� could�pr oduce�t he� greatest�i mpact�on�

patients.��

Methods� Fifty�s ix�B reast�C ancer�C ampaign� grant� holders�a nd�pr ominent�U K�br east�

cancer�r esearchers�pa rticipated�i n�a � gap� analysis�of �c urrent�br east�c ancer�r esearch.� Before,�

during�a nd�f ollowing�t he� meeting,� groups�i n�s even�ke y� research� areas�pa rticipated�i n�

cycles�of �pr esentation,�l iterature�r eview�a nd�di scussion.�S ummary�pa pers�w ere�pr epared�

by�e ach� group�a nd�c ollated�i nto�t his�pos ition�pa per�hi ghlighting�t he� research�g aps,� with�

recommendations�f or�a ction.�

Results �G aps�w ere�i dentified�i n�a ll�s even�t hemes.� General�ba rriers�t o�pr ogress�w ere�l ack�

of�f inancial� and�pr actical� resources,�a nd�poor � collaboration�be tween�di sciplines.�C ritical�

gaps�i n�e ach�t heme�i ncluded�( 1)� genetics:�know ledge�o f� genetic� changes,�t heir�e ffects�a nd�

interactions;�( 2)�i nitiation�of �br east�c ancer:�how �de velopmental�s ignalling�p athways�c ause�

ductal�e longation�a nd�br anching� at�t he�c ellular�l evel�a nd�i nfluence�s tem�c ell�d ynamics,�

and�how �t heir�di sruption�i nitiates�t umour�f ormation;�( 3)�pr ogression�of �b reast�c ancer:�

deciphering�t he�i ntracellular�a nd�e xtracellular�r egulators�of �e arly�p rogression,�t umour�

growth,�a ngiogenesis�a nd�m etastasis;�( 4)�t herapies�a nd�t argets:�unde rstanding�w ho�

develops�a dvanced�di sease;�( 5)�di sease�m arkers:�i ncorporating�i ntelligent�t rial�de sign�i nto�

all�s tudies�t o�e nsure�ne w� treatments�a re�t ested�i n�p atient�g roups�s tratified�us ing�

biomarkers;�( 6)�p revention:�s trategies�t o�pr event�o estrogen-receptor�ne gative�t umours�a nd�

the�l ong-term�e ffects�of � chemoprevention�f or�o estrogen-receptor�pos itive�t umours;�( 7)�

psychosocial�a spects�of �c ancer:��t he�us e�of �a ppropriate�ps ychosocial�i nterventions,�a nd�

the�pe rsonal�i mpact�of � all�s tages�o f�t he�di sease�a mong�pa tients�f rom�a �r ange�of �e thnic�a nd�

demographic�ba ckgrounds.��

Conclusion �T hrough�r ecommendations�t o�a ddress�t hese�ga ps�w ith�f uture� research�,�t he�

long-term�be nefits�t o�pa tients�w ill�i nclude:�be tter�e stimation�of �r isk�i n�f amilies�w ith�br east�

cancer�a nd�s trategies�t o�r educe�r isk;�be tter�pr ediction�of �dr ug�r esponse�a nd� patient�

prognosis;�i mproved�t ailoring�of �t reatments�t o�pa tient�s ubgroups� and�de velopment�of �ne w�

therapeutic� approaches;�e arlier�i nitiation�of �t reatment;�m ore�e ffective�us e�of ��r esources�f or�

screening�popul ations;�a n�e nhanced�e xperience�f or�pe ople�w ith�or �a t�r isk�of � breast�c ancer�

4�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

and�t heir�f amilies.�T he� challenge�t o�f unding�bodi es�a nd�r esearchers�i n� all�di sciplines�i s�t o�

focus�on�t hese� gaps�a nd�t o�dr ive�a dvances�i n�know ledge�i nto�i mprovements�i n�pa tient�

care.�

5�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Introduction�

Significant�a dvances�i n�t he�pr evention,�di agnosis� and�m anagement�of �br east�c ancer�ha ve�

been�m ade�i n�r ecent� years�ba sed�on�t he�c linical� application�of �s cientific�di scoveries.�

However,�br east�c ancer�r emains�a �c omplex�di sease�pr ocess� affecting�m illions�w orld�w ide,�

where� further� advances�i n�s cientific�know ledge� and�c linical�c are�c ould�i mprove�m any�

lives.� It�i s�t imely�t o�r eview�t he�c urrent�pos ition�of �br east�c ancer�r esearch�a s� funding�

bodies,�r esearchers�a nd� clinicians�w ork�i n�a n�e xciting�a ge�of �di scovery�but �ha ve�l imited�

resources.�� �

In� November�2006,�t he�r esearch�c harity� Breast�C ancer�C ampaign,� convened�a �pa nel�of �

leading�b reast� cancer�r esearchers,�a s� an�i nitial�e vent,�t o�de bate�a nd�i dentify� the�l imitations�

of�c urrent�r esearch�i nto�t he�pa thophysiology,�de tection,�t reatment,�pr evention�a nd�

psychosocial�a spects�of �b reast�c ancer.�T he� aims�of �t his�a nalysis�w ere:�

(i)� To�de termine�t he� gaps�i n�our �know ledge�of �b reast�c ancer�t hat,�i f�r esolved,�

could�r esult�i n�be nefits�t o�pa tients�

(ii)� To�e ncourage�br east�c ancer�r esearchers� and�f unding�bodi es�w orldwide�t o�

focus�t heir�r esources�on�t he�hi ghlighted�a reas�o f�r esearch�t o� achieve�a �

substantive�i mpact�f or�pa tients.�

(iii)� To�m ake�r ecommendations�f or�pr iority�a ction.�

This�g ap� analysis�r epresents�a �uni que�i nsight�i nto�br east�c ancer�r esearch�i n� the�U K�a nd�

the�c hallenges�i nvolved�i n�di recting� efforts�t o�a reas�i n�ne ed�of �f urther�i nvestigation�l ikely�

to�r esult�i n�a dvances�i n�t he�m anagement�of �br east�c ancer.�

6�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Materials� and� methods�

Current�a nd�f ormer�m embers�of �t he� Breast�C ancer�C ampaign�S cientific� Advisory� Board�

leading�s cientists�a nd�c linicians�r esident�i n�t he�U K�w ere�i nvited�t o�pa rticipate�i n�t he� gap�

analysis�m eeting.�T he�c hoice�of �pa rticipants�w as�b ased�on�publ ication�r ecord,�r esearch�

activity�a nd� clinical�s tature,�a nd�s elected�us ing�a �d ata�ba se�o f�r esearchers�d eveloped�s ince�

the�i nception�of �B reast�C ancer�C ampaign�i n�1988.��

Seven�ke y�r esearch�a reas�w ere�s elected� for�r eview�i n�t he�g ap� analysis�b y�t he�B reast�

Cancer�C ampaign� and�t he�S cientific�A dvisory� Board�t aking�i nto�a ccount�U K,�E uropean�

and�U SA�t hemes�i n�s cientific�m eetings�f ocussed�o n�br east�c ancer�a nd�U K� Government�

analyses�of �r esearch�f unding�s treams:��

(i)� Genetics�of �br east�c ancer�

(ii)� Initiation�of �br east�c ancer�

(iii)� Progression�of �br east�c ancer�

(iv)� Therapies� and�t argets�i n�br east�c ancer�

(v)� Disease�m arkers�i n�br east�c ancer�

(vi)� Prevention�of �br east�c ancer�

(vii)� Psychosocial� aspects�of �b reast�c ancer.��

Prior�t o�t he�e vent,�pa rticipants�w ere� asked�t o�r eview�r elevant�l iterature� and� construct�s hort�

presentations�s ummarising�t heir� areas�of �e xpertise� and�i dentifying�pot ential� research�

gaps.� Key�pa rticipants�ha d�a lready� conducted,�pub lished�a nd/or�r eviewed�s ystematic�

evidence,�l iterature� reviews�a nd�e vidence�ba sed� guidelines.�A s�a �r esult�t hey� were�

considered�t o�be �opi nion� leaders�i n�t heir� field.�F urther,�a dditional,�s ystematic�l iterature�

reviews�f or�e ach�of �t he�s even�a reas�und er�c onsideration�w as�not �pe rformed.�

For�e ach�t heme,�s ix�t o�t en�U K�br east�c ancer�r esearchers�o f�na tional�or �i nternational�

standing�i n�t heir�f ields�of �r esearch�w ere�i nvited� and�a ccepted�pa rticipation�i n�t he�e vent.�

Twenty�t hree�i nvitees�de clined�t o�c ontribute�t o�t he�ga p�a nalysis.��

On�2�N ovember�2006�t he�one �da y�m eeting�w as�c onvened�i n� London,�U K.� In�i nitial�

subgroup�s essions,�e ach� participant� gave� a�pr esentation�t o�t heir�g roup�on�p re-agreed�

7�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

topics�r elevant�t o�t he� gap�a nalysis� for�t heir�a ssigned�br east�c ancer�r esearch� area�on� which�

he�or �s he�i s�e xpert.��C onstructive�de bate�o f�t he�c ontent�a nd�t he�i ssues�r aised� by�t he�

presentations�w as� explored�f urther.� Breast�C ancer�C ampaign�s taff�m embers�a cted�a s�

facilitators�t hroughout�t he�a nalysis�pr ocess.�

Issues�e xplored�dur ing�t he�ga p�a nalysis�w ere�s tructured�a round�t he� following�que stions:��

(i)� What�do�w e�a lready�kno w?�

(ii)� What�a re�t he� gaps�i n�our � knowledge?�

(iii)� What�a re�t he�pr oblems�t hat�ne ed�t o�be �ov ercome�t o�f ill�t hese�ga ps?�

(iv)� What�a re�t he�t ranslational�i mplications?�

After�c ollating�t he�i nformation�r esulting�f rom�t hese�di scussions�f or�e ach�of �t he�s even�

themes,�t his�f our�poi nt�s tructure�w as�us ed�t o�pr esent�t he�c ontent�of �e ach�t heme�t o�t he�

other�pa rticipants�a nd�t o� discuss�t heir�f indings�i n�a n�ope n�f orum.��

This�i terative�pr ocess�c ontinued�a s�e vidence�ba sed�e xpert�opi nion�f rom�t he�one �da y�

meeting�w as�c ross� referenced,�s haped� and�de veloped�dur ing�s ubsequent�w eeks.�E ach�

group� formulated�a �s ummary�p aper�f or�t heir� research�a rea,�i ncorporating� key� references,�

which�w as�t hen� circulated�t o�t he�pa rticipants�of �t he�r espective� groups�f or�f urther�

refinement.�T hese�s even� themes�w ere�c ollated�i nto�a �uni fied�pos ition�pa per,�pr esented�

here.�

8�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Results� and� discussion�

1.�G enetics�of �B reast�C ancer�( Table�1) �

What�do�w e� know?�

Several� genes�be aring�hi gh-penetrance�m utations� have�be en�i mplicated�i n�i nherited�

predisposition�t o�br east�c ancer,�t he�m ost�i mportant�of �t hese�be ing�i n�t he� BRCA1�a nd�

BRCA2�g enes.�H owever,� BRCA1�a nd�B RCA2�a ccount�f or�l ess�t han�5% �of � all�br east�

cancer,�a nd�i n�r ecent� years,�br east�c ancer�s usceptibility� genes�ot her�t han� BRCA1�a nd�

BRCA2�ha ve�be en�i dentified.�T hese� genes�f all�i nto�t wo�br oad�c ategories:��

(i)� Those�c ontaining�r are�m oderate-penetrance�a lleles�s uch�a s� CHEK2,� ATM�a nd�

BRIP1 �[ 1,2,3]� �

(ii)� Those�c arrying�m ore�c ommon�l ow-penetrance�a lleles�[ 4].�L arge� genome-wide�

association�a nd�c andidate�g ene�s tudies�t o�i dentify�t he�l atter�a re�j ust�be ginning�t o�be ar�f ruit�

[5-8].��

Intermediate�ph enotypes� such�a s�r adiosensitivity� and�m ammographic�de nsity� have�qui te�

strong� genetic�c omponents�a nd�f urther�s tudy�of �t hese�m ay�pr ovide�s ome�i nsight�i nto�

novel�br east�c ancer�s usceptibility� genes.�

Since�t he�br east� cancer� genes� BRCA1�a nd� BRCA2� were� cloned�i n�1994�a nd� 1995,�

research�e fforts�ha ve�c oncentrated�on�d eveloping� an�unde rstanding�of �t he� cellular�

functions�of �t he�l arge�m ultidomain�pr oteins�e ncoded�b y� BRCA1�a nd� BRCA2�a nd�t he�

mechanisms�b y� which�l oss�of �t heir�f unctions�c auses�br east�c ancer.�A n�und erstanding�of �

these�m echanisms�i s�r elevant�not �onl y�t o�f amilies� with� BRCA1�a nd� BRCA2�m utation�

carriers�but �a lso�i n�s poradic�br east�c ancer,�i n�w hich�t he�s ame�or �r elated� genetic�pa thways�

may� also�be �a berrant.�

Cells�de ficient�i n�B RCA1�a nd�B RCA2�a re�e xquisitely�s ensitive�t o�D NA-damaging� agents�

and�a re�d efective�i n�r epairing�D NA�doubl e-strand� breaks�b y�hom ologous�r ecombination,�

being�i mpaired�i n�t he�r ecruitment�a nd�f ilament�f ormation�of �t he�r ecombination�pr otein�

RAD51�[ 9,10].�M ore�r ecently,�ne w�f unctions�ha ve�be en�i dentified� for�bot h�pr oteins:�

9�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

BRCA1�a nd�i ts�pa rtner� BARD1�f orm�a n�E 3-ubiquitin�l igase�t hat�i s�r ecruited�t o�s ites�of �

DNA�da mage�a nd�a ctivated�b y�t he�D NA�d amage� checkpoint,�pr omoting�ubi quitylation�

[11].�T he�f irst�i n�vi vo�s ubstrate�f or�s uch�ubi quitylation�e vents�ha s�be en�i dentified�a s�C tIP�

[12].��

An�i mportant�de velopment�i n�r ecent� years�ha s�b een�t he�i dentification�of �t he�l inks� between�

the�B RCA1�a nd� BRCA2�pa thways�a nd�pr oteins�i nvolved�i n�F anconi� anaemia.�S everal�

genes�c ause�F anconi�a naemia,�a nd�m ost�of �t hese�e ncode�pr oteins�t hat�a re�i nvolved�i n�a �

complex�t hat�ubi quitylates�F ANCD2�a t�K 561.�T he� FANCD1,� FANCJ�a nd� FANCN �g ene�

products�a ct�dow nstream�of �t his�s tep.� FANCD1�w as�f ound�t o�be �t he� BRCA2�g ene�[ 13].�

FANCJ�e ncodes� BRIP1,� which�i nteracts�w ith�t he� BRCT�dom ain�of �B RCA1�a nd,�of �not e,�

mutations�i n�t his�g ene�c an�a lso�c ause�b reast�c ancer�[ 3].�L astly,� FANCN �e ncodes�P ALB2,�

which�i nteracts�w ith� BRCA2,�a nd�i s�a lso�a �br east�c ancer�s usceptibility� gene�[ 14].�

What�ar e�t he�gaps ?�

There�r emain� gaps�i n�our �know ledge�of � cancer�pr edisposition�g enes,�bot h�i n�i dentifying�

genes�r esponsible� for�l ow�pe netrance�di sease�a nd�t he�i nteractions�w ith�e nvironmental�

factors.� Increasing�know ledge�of � BRCA1�a nd� BRCA2�a cts�a s�a n� exemplar�r esulting�i n�

improved�pa tient�c are.�H owever,�d eficiencies�r emain�i n�our �unde rstanding� of�how �

BRCA1�or �B RCA2�d ysfunction�c auses�br east�c ancer,�f or�e xample�i t�i s�unc lear�w hy�

BRCA1�de ficiency�i s�a ssociated�w ith�t riple-negative�( basal-like)�br east�c ancer.��W e�a lso�

need�t o�f ind�ot her�pr oteins�t hat�i nteract�w ith�B RCA1�a nd�B RCA2�a nd� elucidate�t he�pos t-

translational�m odifications�t hat�oc cur�a s� a�r esult�o f�t hese�i nteractions.�F or� example,�t he�

functional�c onsequences� of�C tIP�ubi quitylation�a nd�i ts�i mplications�f or�R AD51�

recruitment�a re�not � yet�k nown;�f urthermore,�i t�i s�l ikely�t hat�t here�a re�ot her� substrates�f or�

BRCA1/BARD1.�

Only�a � relatively�s mall�pr oportion�of �br east�c ancers�a re�c aused�b y�l oss�of � BRCA1�or �

BRCA2�f unction;�m ost�a rise�a s�a �r esult�of �s omatic�m utation�or �c hanges�i n�e xpression�of �a �

number�of �ot her� genes.�T he�l ist�of �g enes�s howing� somatic�poi nt�m utations�i n�br east�

cancers�i s�be ginning�t o�b e�i dentified�us ing� genome-wide�s equencing�a pproaches�[ 15].�

10�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Epigenetic�c hanges�s uch� as�D NA�m ethylation�a nd� histone�m odification�c an� cause�l oss�or �

gain�of � gene� expression,�a nd�ge nome-wide�s creens�f or�t hese�a re�be ing� actively�pur sued.�

More�w ork�i s�ne eded�i n� both�of �t hese�a reas.�

To�da te,�l ittle�ha s�be en�d one�t owards�c ataloguing� larger-scale� genetic�r earrangements,�

such�a s�t ranslocations,�de letions�a nd�a mplifications,�w hich�oc cur� frequently�a nd�a re�

hallmarks�of �t umour�c ells�a nd�ha ve�be en�pa rticularly�us eful�i n�t he�ha ematological�

malignancies.�T hese� changes� also�ne ed�t o�be � related�t o�t umour�s ubtype.�R eciprocal�

translocations�s eem�t o�be �c ommon;�f or�e xample,�one �t ranslocation�c auses�a bnormal�

expression�of �t he�N RG1�g ene�w hich� encodes�l igands�of �t he�e pidermal� growth�f actor�

receptor�( EGFR)�f amily�[ 16].�W ork�ha s�be gun�t o�c haracterise�a nd� catalogue�t hese�e vents�

using�hi gh-resolution�D NA�m icroarrays.� In�f uture� it�w ill�be �i mportant�t o�de vise�

approaches�t o�e xamine�s equence�l evel,�e pigenetic�a nd�l arge-scale� changes� together�a nd�

relate�t hese�t o�c linical�f eatures�t o�f orm�a �c omplete� and�i ntegrated�pi cture.�

As�c ommon,�l ow�pe netrance�a lleles� continue�t o�be �i dentified,�F uture� challenges�l ie�i n�

identifying�t he�c ausative� variants�w ithin�t he�ha plotype�bl ocks�c ontaining�t he�a ssociated�

marker�s ingle�nuc leotide� polymorphism�( SNP).�F irst,�t his�r equires�hi gh-throughput�

sequencing�c apacity�t o�d etect�a ll�c ommon�va riants�i n�ha plotype�bl ocks�s panning�t ypically�

30–150kb,�i n�a t�l east�48�pe ople.�S econd,�c ase�a nd�c ontrol�D NA�c ollections�f rom�non -

European�popul ations�a re�ne eded�t o�s eparate�a lleles�t hat�a re�c ompletely� correlated�i n�

European�popul ations.�T hird,�s ensitive�bi ological� assays�ne ed�t o�b e�de veloped�t o�

determine�t he�di fferences�i n�f unction�of �t he�pot entially�c ausative�a lleles.� It� will�be �

important�t o�e ncourage�a � high�de gree�o f�c ollaboration�be tween�r esearch� groups,�i n�

particular�b etween� epidemiology� and�ba sic�bi ology.� Furthermore,�t hese�s tudies�w ould�

benefit�f rom�s hared�r esources�i ncluding�f irst�c lass�s ample�c ollections,�s uch�a s�a �U K�

national�c ontrol�s et.�

A�pot entially�us eful�but �c urrently�unde r-developed�a pproach�i s�t o�e xamine� other�

phenotypes�l inked�w ith�br east�c ancer�t hat�a re�t hemselves�ge netically�d etermined.�T hese�

11�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

include�m ammographic�d ensity,�r adiation�s ensitivity,�c ell�m igration�a nd� circulating�l evels�

of�hor mones�a nd� growth�f actors.��

What�ar e�t he�pr oblems?�

The�num bers�of �p atients�r equired�f or� gene�s earches�r equire�l arge�na tional� and�

international�c onsortia.�T he�qua lity,�qu antity�a nd� form�of �t he�c linical�m aterial�( blood�

derivatives,�f rozen�t issue,�f ormalin�f ixed�t issues),�a nd�t he�ha ndling�or �p roducts�f rom�t hese�

present�a �s ignificant�c hallenge.�T he�i ncreasing�s ophistication�of �e quipment�a nd�t he�l evel�

of�t echnical� expertise�a re�r eflected�i n�t he�ne ed�t o�i ntegrate�t he�d ata�i n�a �m eaningful� way�

presenting�a �s ubstantial�b ioinformatics�c hallenge.� Techniques�f or�hi gh-throughput�r e-

sequencing�a re�be ing�d eveloped�but �f unding�i s�n eeded�t o�m ake�t hese� accessible.�

Thus,�t his�t ype�of �r esearch�i s�pa rticularly�r esource� intensive�a nd�r equires�a �h igh�l evel�of �

collaboration.�

�Translational� implications�

Therapies�b ased�on�de veloping�unde rstanding�o f�t he�r ole�of � BRCA1�a nd� BRCA2�i n�D NA�

repair� are� already�i n�c linical�t rials�( including�c isplatin�a nd�P ARP�i nhibitors),�a nd�

improving�our �unde rstanding�of �t he�m any� functions�of �B RCA1�a nd� BRCA2�w ill�no�doubt �

generate�f urther�t argets�f or�t herapy.� Increasing�e fforts�t o�unde rstand� genetic�e vents�s hould�

allow�us �t o:�

(i)� Classify�br east�t umours�a ccording�t o�t he�s ignalling�pa thways�t hat�a re�

disrupted�a nd�t o�pr edict�p rognosis�a nd� response�t o� therapy�

(ii)� Determine�t he� relevance� of�s omatic�e vents�t o�pr ognosis�a nd�r esponse�t o�

therapy�

(iii)� Generate�ne w,�t argeted�t herapies�b ased�on�t arget� discovery.�

Identifying� combinations�of �i nherited�va riants�t hat�pr edispose�t o�br east�c ancer�w ill�a llow�

us�t o�e stimate�r isk�be tter� in�f amilies�w ith�br east�c ancer�a nd�h elp�t o�c haracterise�de fective�

signalling�p athways.�D NA�c ollections�f rom�c ancer�pr evention�t rials�a nd� clinical�t rials�of �

radiotherapy� and�c hemotherapy�a re�und erway�t o� relate�D NA�v ariants�t o�t reatment�

response.�W hile�t he�t rial� populations�of �t he�U K,�E urope�a nd�t he� US�m ay�p rovide�

12�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

complimentary�d ata,�i nternational�e xchanges�of �s uch�i nformation�s hould�e nhance�f uture�

patient�m anagement.��

13�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

2.�I nitiation�o f�B reast�C ancer�( Table�2) �

To�de cipher�t he�m olecular�ba sis�of �t he�i nitiation�a nd�pr ogression�of �br east�c ancer,�i t�i s�

critical�t hat�w e�f ully�und erstand�t he�ke y� features�a nd�g enes�i nvolved�i n�nor mal�m ammary�

development.�C hanges�t o�de velopmental�pr ocesses�m ay�l ead�t o�t umour�i nitiation�a nd�t he�

influences�of � endocrine�a gents,� growth�f actors�a nd�e nvironmental�c arcinogens�on�nor mal�

and�de veloping�br east�c omponents�i s�l argely�unkn own,���

What�do�w e� know?�

Significant�pr ogress�ha s� been�m ade�i n�d etermining�t he�l ocal�f actors�t hat�c ontrol�a ll�s tages�

of�m ammary�de velopment,�l argely�t hrough�t he� generation�of �a n� extensive�a rray�o f�

transgenic�a nd�kno ckout� mouse�s trains�[ 17].� Such�a nimal�m odels�a re� complemented�b y�

classic�e mbryological� approaches�t hat�e nable�t he�t ransplantation�of �a � complete�m ammary�

gland,�du ctal�r udiments�o r,�m ore�r ecently,�s tem�c ells�i nto�c leared�f at�pa ds�[ 18-20].�T hese�

approaches�ha ve�i mparted�c onsiderable�kno wledge�a bout�a �w ide� array�of �d evelopmental�

signalling�p athways�t hat� are�now �kno wn�t o�be �d ysregulated�i n�t umours.�F or�e xample,�

amphiregulin/EGFR�s ignalling�i s�r equired�f or�t he� branching�a nd�out growth�of �t he�duc tal�

epithelial�t ree�dur ing�pub ertal�de velopment�[ 21,22],�w hile�ove r-expression�of �bot h�t he�

ligand�a nd� receptor,�a nd�t he�r elated� receptor�E rbB2,�i s�a ssociated�w ith�poor �pr ognosis�i n�

breast�c ancer�[ 23].�O ther�e xamples�i nclude�t he� IGF,�i ntegrin,�N otch,�N F-!B,�S TAT,�

TGF-� and�W nt�pa thways�[ 24-29].�

What�ar e�t he�gaps ?�

Tissue�a rchitecture�

Many�o f�t he�s ignalling�p athways�c ontrolling�nor mal�m ammary�d evelopment�ha ve�be en�

identified�a nd�t he� genetic�c ircuit�di agrams�t hat�l ink�t he�di fferent�pa thways� are�e merging�

[17].�H owever,�i t�i s�not �c lear�how �t hese�s ignals�c ause�duc tal�e longation�or � branching�a t�

the�c ellular�l evel,�or �e ven�how �t hey�m aintain�nor mal�duc tal�or �a cinar�a rchitecture.�

Although�a nalysis�ha s� focussed�on�e pithelial�c ells,�t he�s tromal,�e ndothelial�a nd�i mmune�

components�a re� also�c rucial�f or�de velopment�[ 30].�F or�e xample,�f ibroblasts�a nd�

macrophages�a re�r equired�f or�duc tal� growth�[ 31].� However,�m any�of �t he�s troma-derived�

signals�a re�poor ly�unde rstood,�a s�i s�t he�r eciprocal� communication�be tween� epithelium�

14�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

and�s troma�a nd�t he�s ignalling�pa thways� controlled� by�i nteraction�of �l uminal�a nd�

myoepithelial�c ells.�

In� addition,�t he�i mportance�of �c ell�a dhesion�a nd�t he�e xtracellular�m atrix�ha s�be en�

underestimated,�a lthough�i t�i s�be coming�i ncreasingly�c lear�t hat�bot h�a dhesion�a nd�m atrix-

derived�s ignals�m odify�m any�s ignalling�pa thways� and�pr ovide�a �s patial�c heckpoint�f or�

developmental�de cisions�[ 32].� Critically,� changes�i n�c ell�a dhesion,�t hrough� matrix�

remodelling�o r�a ltered�a dhesion�r eceptors,�unde rpin�bot h�t issue�di sorganisation�i n�e arly�

breast�c ancer�a nd�pr ogression�t o�m alignancy�[ 33,34],�but �t heir�i nvolvement� in�t umour�

initiation�i s�not �w ell�unde rstood.�

Stem�c ells�

The�r ecent�de velopment�of �t echnologies�a llowing� enrichment�of �m ammary� gland�s tem�

cells�ha s�be en� a�s ignificant�s tep�f orward�[ 19,20,35].�H owever,�i t�i s�s till�not � possible�t o�

purify�t hese�c ells�t o�hom ogeneity,� and�w e�do�not �f ully�unde rstand�t heir�l ocation�w ithin�

the�duc ts�or �t he�m echanisms�i nvolved�i n�t heir�di fferentiation�i nto�l uminal�a nd�

myoepithelial�c ells�[ 36,37].�M oreover,�i t�i s�not �c ertain�w hether� cancer�s tem�c ells�a re�

derived�f rom�no rmal�s tem�c ells�or �a n�i ntermediate�pr ogenitor�c ell,�or �how � they� are�

influenced�b y�s tromal�f actors�[ 38].�I n�f act,�i t�i s�f ar� from�c lear�t hat�t umours�a re�de rived�

from�s tem/progenitor�c ells�a t�a ll,�a s�oppos ed�t o�r eprogrammed�di fferentiated�c ells,�l et�

alone�w hether�di fferences�be tween�c ancer�s tem�c ells�m ight�be �r esponsible�f or�t he�

development�of �di fferent� tumour�s ubtypes.��

Although�c onsiderable�pr ogress�ha s�be en�m ade�t owards�unde rstanding�t he� mechanisms�

controlling�e pithelial�a poptosis�i n�t he�m ammary� gland,�w e�know �l ittle�a bout�t he�

sensitivity�of �s tem/progenitor�c ells�t o�a poptosis�s ignals�[ 39,40].�C ells�of �t he�m ain�duc ts�

survive�i nvolution,�w hile�a lveoli�a nd�t erminal�duc ts�a re�l ost,�a lthough�t he�r eason�f or�t his�

difference�i s�not �c lear.�

15�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

We�a lso�ha ve�l ittle�unde rstanding�of �how � early�p regnancy�a nd�f unctional�di fferentiation�

of�t he�br east�pr otects�a gainst�c ancer,� and�w hether� this�i s�r elated�t o�s tem�c ell�d ynamics�

[41].�

Consequently,�w e�ur gently�ne ed�m ore�a ppropriate�i n�vi vo�a nd�c ulture�m odels�t o�r esolve�

the�m echanisms�of �bot h� normal�br east�de velopment�a nd�t umour�i nitiation.� Furthermore,�

use�of �t hese�s ophisticated�m odels�ne eds�t o�be come�m ore�w idespread.�

What�ar e�t he�pr oblems?�

Culture�m odels�

Breast�c ancer�h as�t raditionally�be en�s tudied�b y�c ell�a nd�m olecular�bi ologists�us ing�l ong-

lived�c ell�l ines�t hat�a re�d erived�f rom�l ate�s tage�t umours�a nd�w hich�di splay�f ew�of �t he�

cellular�pr operties�of �nor mal�br east�e pithelial�c ells.� In� addition,�w e�now �a ppreciate�t hat�

breast�c ancer�i nvolves� growth�i n�t hree�di mensions�a nd�t he�c ontribution�of �v arious�br east�

cell�t ypes.�F urthermore,�t echniques�f or�s tudying�t he�i nitiation�a nd�pr ogression�of �c ancer�

are�l argely�r estricted�t o�a nalysing�t he�l uminal�e pithelium.�R ecently�t here�h as�be en�a �s hift�

from�t wo-dimensional�t o�t hree-dimensional�c ulture�m odels,�w hich�be tter� reflect�t he�t issue�

environment�f ound�i n�vi vo�[ 42,43].�H owever,�m ost�of �t hese�m odels�s till�c ontain�onl y�

luminal�e pithelial�c ells.� In�t he�f uture,�c ulture�m odels�c ontaining� all�m ammary�c ell�t ypes,�

as�w ell�a s�t hose�a menable�t o�e xamining�duc tal�br anching,�m odelling�t he�s tem�c ell�ni che,�

and�e ven� assessing� whether�a n�i solated� cell�i s�a �s tem�c ell,�w ill�pr ovide�f ertile�a venues� for�

analysis�[ 44].��

Excellent�i maging�t echnologies�a re�e merging�t o�e xplore�t he�d ynamic�na ture� of�m ammary�

gland�d evelopment�a nd�n eoplasia�bot h�i n�c ulture�a nd�i n�vi vo;�a pplying�t hem�t o�hum an�

cancer�c ells�a nd�e nsuring�t heir�w idespread�us e�w ill�be �of �e normous�va lue�[ 45,46].�

Genetic�a nalyses�

Expression�of �t ransgenes�or �ge ne�a blation�s pecific�t o�t he�m ammary� gland�i s�us ually�

achieved�b y�pl acing�t he�t ransgene�o r�C re�r ecombinase�unde r�t he�c ontrol�of � a�m ilk�g ene�

promoter�or �t he�M MTV� promoter�[ 47].�H owever,�t hese�pr omoters�a re�a ctive�onl y�i n�

16�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

luminal�e pithelium�a nd,�i n�t he�c ase�o f�t he�m ilk�pr otein�g enes,�l imited�t o�a �pa rticular�

developmental�s tage.�M ore�r ecently,�t he�ke ratin�5� promoter�ha s�be en�us ed�t o�t arget�

myoepithelial�a nd�b asal�c ells�[ 48].�D espite�t his,�a �w ider�va riety�o f�pr omoters�w ould�

improve�t he�s patial�a nd/or�t emporal�c ontrol� gene�o f�e xpression.�T his�w ill�be �he lped�

considerably�b y� generating�a n� atlas�of �m ammary� gland�d evelopment.�F urther�r efining�

markers�t o�i dentify�s tem� and�pr ogenitor�c ells,�a nd� fibroblasts,�w ill�pi npoint� other�va luable�

promoters.�G reater�us e�of �i nducible�t ransgene�s ystems,�s uch�a s�t he�T et-On� system,�w ill�

allow�t ransgene� expression�t o�be �r estricted�t o�s pecific�t ime�i ntervals�[ 49].� �

Another�s ignificant�pr oblem�w ith�e xisting�pr omoters�i s�t hat�t heir�e xpression�i n�t he�

luminal�e pithelium�de pends�on�i ts�di fferentiation;�a ctivity�i s�t herefore�l ost�i f�a �t ransgene�

causes�t ransdifferentiation�or �de differentiation�w ithin�a �t umour.�T he�pr oblem�c an�be �

overcome�t hrough�t he�de velopment�of �‘ hit�a nd�r un’�t ransgenics.�T hese�i nclude�l ines�

where�t he� expression�of �a �t ransgene�i s�unde r�t he�c ontrol�of �a �hous ekeeping� gene�but �i s�

prevented�b y� a�l ox-stop-lox�c assette.�E xcision�of �t he�s top�c odon�b y�c rossing�w ith�m ice�

carrying� a� gland-specific� Cre�r ecombinase�t hen�l eads�t o�c ontinuous�a nd�c onsistent�

transgene� expression.�T hese�a nd�s imilar�s ophisticated�s trategies�w ill�a llow� the�m ore�

realistic�a ctivation�of �br east�c ancer�onc ogenes,�a nd�w ill�pr ovide�be tter�opp ortunities�t o�

understand�how �t hey� cause�di sease�w ithin�t he�c orrect�t issue�e nvironment.� It�w ould�a lso�be �

valuable�t o�pr oduce�a �s eries�of �t ransgenic� reporter� gene�m ice� equivalent�t o�t he�T OPGAL�

strain,�t o�m onitor�c hanges�i n�de velopmental�s ignalling�pa thways�[ 50].�

There�w ill�a lso�be � great�b enefit�i n�ge nerating�be tter�m ouse�m odels�of �s pecific�t ypes�o f�

human�br east�c ancer,�r anging�f rom�t riple�n egative� breast�c ancer�( oestrogen� receptor�

negative,�pr ogesterone� receptor�ne gative�a nd�H ER2�ne gative)�t o�oe strogen�r eceptor�

positive�t umours.�S imilarly,�s traightforward�p rotocols�f or�i mplanting�a nd� growing�

primary�hum an�c ancer� cells�i n�t he�c leared�m ammary� fat�pa d�of �i mmunocompromised�

mice�a re� required.�S ignificant�pr ogress�ha s�be en�m ade�i n� generating�s uch�hu manised�

models,�but �i t�i s�s till�not � possible�t o�i mplant�i ndividual�c ells�[ 51]. � �

17�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Translational� implications�

Continuing�t o�s tudy�nor mal�br east�de velopment�w ill�pr ovide�m any�us eful�i nsights�i nto�t he�

earliest�s tages�of �b reast�c ancer�i nitiation.�T umour� development�de pends�on� signals�

between�t he�s troma,�m yoepithelial�c ells�a nd�l uminal�c ells,�a nd�t herefore� gaining�a �b etter�

understanding�of �how �t hese�c ells�c ommunicate�i n� normal�m ammary� gland� and�e arly�

breast�di sease�w ill�pr ovide�ne w�oppor tunities�f or�i ntervention.��

In� addition,�w e�know �l ittle�a bout�t he� genetic�c hanges�t hat�oc cur�i n� atypias,�l obular�or �

ductal�c arcinoma�i n�s itu�( DCIS)� [52],�a lthough�t hey� are�m ost�l ikely�t o�b e�w ithin�

components�of �t he�s ignalling�pa thways�t hat� control�nor mal�de velopment.�P roducing�

timelines�of �t hese�m utations�f or�di fferent�br east�c ancer�s ubtypes,�s imilar�t o�t hose�

generated�f or� colon�c ancer�[ 53],�w ould�be �a �m ajor�s tep�f orward.�M olecular� profiling�of �

breast�c ancers�ha s�be gun� to�c lassify�t umours�[ 54],�a nd�r elating�t hem�t o�t he� TNM�

classification�w ill�be �c linically�v aluable�f or�bi omarker�a nalysis� and�t herapy.�D ifferences�

between�pr ofiles�m ay�r epresent�a lterations�i n�s pecific�s ignalling�pa thways,�s o�m apping�

this�i nformation�ont o�a �t imeline�of �w hen�m utations�oc cur�i n�br east�c ancer� will�e nable�

clinicians�t o�t ailor�s pecific�t reatments�t o�i ndividuals.�

18�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

3.�P rogression�of �B reast�C ancer�( Table�3) �

Intracellular�i nputs�

What�do�w e� know?� �

The�oe strogen� receptor,�r eceptor�t yrosine�ki nase�( RTK)�a nd�D NA� repair�pa thways� are�

key� research� areas�t o�und erstand�t he�i ntracellular�i nputs�f or�gr owth�a nd�pr ogression�of �

invasive�br east�c ancer.�.� �

It�i s�now �e stablished�t hat�s teroid�hor mone/�oe strogen�r eceptor�a lpha�( ERa)� input,�a �

fundamental�dr iver�f or�t he�gr owth�of �m any�b reast� cancers,�s hould�not �be �c onsidered�

independent�of �a dditional�s ignalling�n etworks.�T his�nuc lear�E Ra�m ay�i nterplay�w ith�E Rb �

and�t here�i s�e merging�e vidence�t hat�m embrane-localised�E Ra�m ay� also�ha ve�a �r ole.�A �

web�of �R TK�s ignalling� also�c ontributes�t o�br east�c ancer� growth�a nd�p rogression,�a nd�

these�pa thways� can�i nteract�w ith�E R�w hen�pr esent�[ 55-57].� Previous�e xperimental�

deciphering�of �E R� and�R TK�pa thways�ha s�p rovided�pr oof�of �p rincipal�t hat�us eful�

biomarkers�a nd�t herapies�( for�e xample�e ndocrine�t herapies,� erbB�a nd�ki nase�i nhibitors)�

can�s tem�f rom�c oncerted� research�i n�br east�c ancer� growth�s ignalling�bi ology�[ 58].��

DNA�da mage�r esponse�( DDR)�pa thways� and�m echanisms�f or�m itotic�c hromosome�

segregation�a re�a lso�of �i nterest�w hen� considering� breast�c ancer� growth,�pr ogression�a nd�

selectivity.�T hey�c an�b e�s ubject�t o�ge netic�a lteration,�a ssociating� with�t umorigenesis�f or�

inherited�( for� example�B RCA�pr oteins)�a nd�f or�s poradic�( for�e xample�A urora�A :�30–60% �

overexpression)�br east�c ancer�be cause�t hey�c ause� genetic�i nstability�t hat�m ay�p ermit�

secondary� alteration,�a ccelerating�t he�de velopment�of �c ancer.�E qually,�t here�a re�m ajor�

implications�f or�t herapeutic�e fficacy,�f or�e xample�f or�pol y� (ADP-ribose)�po lymerase�

inhibitors�a nd�B RCA�m utations,�a nd�a lso�r esistance�t o�t axanes�w hen�A urora�A �i s�

amplified�[ 59].��

What�ar e�t he�gaps ?�

Research�i nto�E R�a nd�R TK�s ignalling�i s�i ntense.�F urther�de ciphering�t he�c omplexities�of �

breast�c ancer�s ignal�t ransduction�pa thways,�t heir�r egulation�a nd�i nterplay,�i ncluding�

19�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

elucidating�do wnstream� gene�e ffects�i s�i mportant,�not �l east�be cause�t herapeutic�r esistance�

is�a �pe rsistent�pr oblem�f or�a ll�t herapies�t argeting�k nown�pa thways.��

There� are� also�l imitations�i n�our �a bility�t o�s ubsequently�e valuate�R TK� and� ER�s ignalling�

aspects�e merging� from�e xperimental�s tudies�i n�c linical�di sease� and�t o�r apidly�t ranslate�

findings�i nto�c linically�us eful�bi omarkers� and�t argets�f or�ne w�d rug�de velopment.� �

Furthermore,�t he�br eadth� of�D DR�a nd�m itotic�r egulator�a lterations�unde rlying�t he�

pathogenesis�of �br east�c ancer�a nd�i ts�s ubtypes,�or �t he�poi nt�a t�w hich�D DR�a lterations�

might�c ontribute�t o�di sease�pr ogression�i s�unknow n.�

��

Extracellular�i nputs�

What�do�w e� know?�

Local�pa racrine�pa thways,�( for�e xample�t hose�i nvolving�T GF!s),�c ell�i nvasion�i nto�t he�

extracellular�m atrix�a nd�a ngiogenesis�a ll�c ontribute�t o�c ancer� growth� and� metastasis.�

Selective�i nhibitors�of �a nti-Src�a nd�a nti-HGF/Met,�f or�s ome�of �t he�i dentified�pa thways�

involved�i n�m etastasis�a nd�i nhibition�of �a ngiogenesis��( for�e xample�b y�t argeting�va scular�

endothelial�gr owth�f actor�s ignalling)�a re�a lready�i n�c linical�pr actice�[ 60].��

What�ar e�t he�gaps ?�

Substantial�que stions�r emain�a bout�t he�bi ology�o f�a ngiogenesis�a nd�m etastasis.�W hile�

studies�of �a ggressive�b reast�c ancer�c ells�i n�vi tro�ha ve�a llowed�s ignificant�p rogress�i n�

understanding�a dhesion�a nd�m igration�t hrough�m atrix,�m atrix�de gradation�( including�

mechanisms�of �m atrix�m etalloproteinases)� and�i n� vitro�i nvasiveness,�s ubsequent�

translational�a pplications�ha ve�pr oved�l imited.� �

We�ha ve� yet�t o�f ully� explore�t he�br eadth�of �pot ential�pos itive�a nd�ne gative�r egulators�of �

invasion�a nd�m etastasis,�t heir�m echanisms�a nd�i nterplay,� and�t he�r ole�of �t he� interaction�of �

tumour�c ells�w ith�t he�s tromal�m icroenvironment�a nd�i mmune�s ystem�dur ing�m etastasis.�

The�pr opensity�f or� cancer�t o�m etastasise,�a pparently�s electively,�t o� certain� end�or gans�i s�

poorly�und erstood.��W hether�hum an�br east�c ancers�c ontain�i nherently�m igratory�s tem�

20�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

cells�or �w hether�m etastatic�c apacity�i s�a cquired,� and�a lso�t ime-dependent�p rogression�

events,�not ably�do rmancy� and� reactivation�of �m icrometastasis�a t�pa rticular�s econdary�

sites,�r emain�poor ly�de fined.��

Equally,�l ittle�i s�know n�a bout�t he�e merging�r elationship�be tween�r esistance� to�

conventional�t herapies�( for�e xample�e ndocrine�t herapies)�a nd�m etastasis�[ 61],�or �t he�

degree�o f�r edundancy�o f� invasive�e lements�or �a ngiogenic�pa thways�t hat�m ay� contribute�t o�

therapeutic� resistance�t o� anti-invasive�a nd�a nti-angiogenic� approaches.�

Ductal�c arcinoma� in�s itu�an d�v ery�e arly�pr ogression�i n�br east�c ancer�

What�do�w e� know?��

Around�50% �of �D CIS�w ill�pr ogress�t o�i nvasive�di sease�i f�unt reated,�w ith�12 –20%�

recurring�l ocally�a t�10� years�de spite�br east�c onserving�s urgery�a nd�r adiotherapy.� Links�

have�be en�s uggested�be tween�e arly�pr ogression�a nd�m echanistic�a lterations�bot h�w ithin�

the�e pithelial�c ells�a nd�i n�t he�i nterplay�w ith�a ssociated�ba sement�m embrane,�

myoepithelial�a nd�s tromal�c ells,�a nd�m echanical�c onstraints�[ 62,63].�H ER2�pos itivity�a nd�

HER4�ne gativity,�a nd�hi gh�l evels�of �c yclo-oxygenase-2�( COX-2)�m ay�h ave�s ome�

relevance�t o�i nvasive�r ecurrence�[ 64].�

What�ar e�t he�gaps ?��

There�i s�s till�a �s ubstantial�g ap�i n�ou r�know ledge�o f�t he�c ausative� factors�und erlying�

progression�of �D CIS�t o�i nvasive�di sease� and,�i n�ge neral,�t here� are�no� compelling�

biomarkers�t hat�c an�r obustly�p redict�i nvasive� recurrence.�W e�a lso�l ack�bi omarkers�t hat�

can�s elect�f or�pa tients�w ho�m ight�be nefit�f rom�e xisting�t herapies,�s ince�E R�a nd�H ER2�

(and�E GFR)�s tatus�a re�no t�r outinely�m easured�i n�D CIS�out �w ith�c linical�t rials�a nd�s o�

treatment�i s�c urrently�b ased�on�m orphological�a ssessment.�E qually,�t here�a re�f ew�t argets�

in�D CIS�t o�s ubvert�pr ogression�ot her�t han�E R�f or� ER�pos itive�D CIS,�w ith�E R-negative�

DCIS�t hus�be ing�pa rticularly�p roblematic.�

Issues�r egarding�t he�ve ry�e arly�pr ogression�of �br east�c ancer�r eflect�t hose�f or�i nvasive�

breast�c ancer.�T here�a re�s ubstantial�g aps�i n�our � ability�t o�p erform�bi ological�i nvestigation�

21�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

of�t he�i ntracellular�a nd�e xtracellular�f actors� (notably�i nterplay�b etween�s troma,�

myoepithelial�a nd� epithelial�c omponents)�unde rlying� growth�a nd�pr ogression�of �D CIS,�t o�

dynamically�m onitor�e arly� progression,�a nd�t o�s ubsequently�m anipulate�i mplicated�

pathways�t o�a ddress�t heir�t herapeutic�pot ential.�

What�ar e�t he�pr oblems?� �

Improved�pr eclinical�m odels�

We�ne ed�t o�de velop�be tter�pr eclinical�m odels�i n�or der�t o�r eveal�m ore� accurately�t he�

mechanisms�i nvolved�i n�g rowth�a nd�pr ogression�of �br east�c ancer�a nd�t o� evaluate�

potential�t argets.�T his�i s�pa rticularly�i mportant�w hen�t rying�t o�i nterpret�t he� mechanisms�

of�m etastasis�be cause�di ssemination�c ommonly�oc curs�a t�i naccessible�s ites,�m aking�

clinical�r esearch�m aterial�e xtremely�di fficult�t o�ob tain.�H owever,�i t�i s�e qually�r elevant�i f�

we�a re�t o�bui ld�on�f indings�m ade� using�i n�vi tro�m onolayer�c ulture�s tudies�f or�gr owth�

signalling�m echanisms.��

Models�a re�ne eded�t o�a llow�r esearchers�t o�i nvestigate�m ore�a ccurately�t he� influence�of �

microenvironment,�t he�i mpact�of �t he�i mmune�s ystem�a nd�s ite-specific�m etastasis,�a nd�

time-dependent�pr ogression�i ncluding�t he�phe nomenon�of �dor mancy.� In�vi vo�m odels�w ill�

be�e ssential�t o�s tudy�t hese�a reas,�a nd�r esearchers� may� also�be nefit�f rom�i n�vi tro�t hree-

dimensional�a ssays� encompassing�s tromal�c omponents,�m atrix�a nd�t umour�e pithelial�c ells�

[65],�a s�w ell�a s�s tudies�o ver�e xtended�c ulture�t ime�i n�vi tro�a nd�a ssociated�a nimal�m odels.��

Increased�us e�o f� genetically�m odified�a nimal�m odels�w ill�be �va luable,�a s�w ill�g enetic�

manipulation�of �i ndividual�t argets�( for�e xample�us ing�R NAi)�a lone�or �i n�c ombination�

with�e xisting�a gents�i n�m odel�s ystems�t o�a ddress�h ow�m echanisms�of � growth�a nd�s pread�

might�be �e xploited�t o�pr ovide�ne w�t argeted�t herapies.�S tudies�of �ve ry�e arly� progression�

will�a lso�r equire�i mproved�m odels,�not ably�us e�of � in�vi tro�c ultures�of �pr imary�o r�

mammosphere�D CIS�( again�e xtending�t o�l onger-term�c ulture),� and�of �hum an�D CIS�

xenograft� and�t ransgenic� (for�e xample�M MTV/HER2)�m odels.��

22�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Alongside�t argeting�i ndividual�c andidate�e lements,�m ore�s peculative� approaches�a re�

warranted�t o�br oadly�s creen�f or�s ynthetic�l ethality,�f or�e xample�us ing�R NAi�l ibraries.�W e�

will�a lso�ne ed�t o�e mbrace�f ully�i n�vi vo�i maging�t echnologies�t o�de cipher�t he�d ynamics�o f�

metastasis�( and�e qually�o f�ve ry�e arly�pr ogression)� at�a �c ellular�l evel�a nd�r elate�t his�t o�

signalling�m echanisms�( for�e xample�us ing�i n�vi vo�f luorescent� reporter�a ssays).��

Powerful�r eal-time�i maging�s tudies�i n�a nimal�m odels�a re� emerging�w hich�i ndicate�t hat�

the�m otile�phe notype�m ay� be�t ransient�a nd� confined�t o�a �s ubpopulation�of � cells�a t�t he�

tumour�pe riphery�i n�di sease�m etastasising�i n�vi vo�S uch�he terogeneity�i s�not �e asily�

modelled�w ith�i n�vi tro�s tudies.�T hese�obs ervations�i llustrate�t he�pow er�of �i maging�

systems�f or�d eciphering� breast�c ancer�bi ology,�w here�t he�d ata�ha ve�i mplications�f or�

interpreting�w hole�t umour�m icroarray/proteomic�p rofiles�a nd�c learly�c onfirm�t hat�t ime-

dependent�s tudy�of �m etastasis�a t�a �c ellular�l evel�i s�e ssential.��

Appropriate� clinical�s amples�

Appropriate� clinical�s amples�a re�n eeded�t o�t ranslate�e xperimental�f indings� into�us eful�

predictive�bi omarkers,�a nd�t o�c onfirm�t hat�t herapeutic�s trategies�s temming� from�ba sic�

research�a re�r elevant�i n�p atients.�M eaningful�s tudy�w ill�r equire,�w here�pos sible,�i mproved�

access�t o�c linical�m aterial�w ith�pa rallel�t herapeutic�r esponse� and�s urvival�d ata,�

encompassing�t issue�m icroarray�( TMA)�a nd�f ull-section�r esources.�S tudies�w ill�be nefit�

from�i mproved�a ccess�t o� clinical�s amples�of �pr imary,�l ocal�r ecurrent,�l ymph�node �a nd�

distant�m etastatic�( where�a ccessible)�br east�c ancer,�i deally� comparing�m atched�s amples�

from�pa tients�t o�t rack�pot ential�bi omarkers�of �p rogression.�S tudies�of �ve ry�e arly�

progression�w ill�a lso�ne ed�i ncreased�a ccess�t o�c linical�D CIS�m aterial�t o�ve rify�t he�

relevance�of � experimental�a ssociations�w ith�i nvasive�r ecurrence,� considering� gene�

expression�s ignatures�bot h�f or�D CIS� and�i nvasive� disease,�pr eferably�f rom�t he�s ame�

patient.��

It�i s�a lso�i mportant�t hat�r esearchers�obt ain�m aterial�f rom�s equential�s amples�( with�pa rallel�

outcome�da ta),�t aken�be fore�a nd�dur ing�t reatment� with�c onventional�t herapies,�a nd�f rom�

biologically�di rected�i nnovative�t rials�of �t argeted� therapies.�C linical�t rial�d esign�s hould�

23�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

increasingly�i ncorporate�i mproved�t issue�c ollection�a nd�pa thology�s upport�( which�ha s�

often�be en� considered� as� an�a fterthought).� Experience�i ndicates�t hat�n eoadjuvant�s tudies�

and,�w here�pos sible,�a ccess�t o�pa tient�s amples�t reated�l onger�t erm�w ill�be �p articularly�

valuable.��

Studying�s amples�obt ained�dur ing�t reatment�w ith� anti-invasive�a gents�( or,�i ndeed,�a ny�

new�a gents)� will�a llow�r esearchers�t o�e valuate�t he� ability�of �bi omarkers�a nd�c ellular�

endpoints�s temming�f rom�e xperimental�s tudies�t o�pr ovide�s urrogates�f or� drug� response,�

an�i mportant�a im�i n�t he�a bsence�of �l ong-term�out come�da ta.�T his�c ould�be � achieved�b y�

examining�c irculating�t umour�c ells�a nd�s ampling� lymph�node s�dur ing�t reatment.� In�

addition,�e valuation�of �a nti-invasive�a gents�c ould� benefit�s ignificantly�f rom�

improvements�i n�t umour�t issue�i maging�of �f unctional�r eporters.�

These�ne eds�f or�c linical�t issue�c learly�r epresent�a �s ignificant� challenge,�p articularly� given�

that�r esearch�m ust�c omply� with�t he�e thical�a nd�l egal�c onsiderations.�T o�be � achievable,�

patient�r ecruitment�t o�t rials�m ust�be �i mproved�a nd,�c ollection�a nd�s haring�of �t issue�

resources�c oordinated.�F or�D CIS�s tudies,�s equential�c linical�s amples�t aken� pre-

operatively�dur ing�t reatment�w ith�c urrently�a vailable�a gents�( endocrine�t herapies,�e rbB�o r�

COX-2�i nhibitors)�or �w ith�e merging�ne w�t herapies,�a re�ne eded�t o�c onfirm� mechanisms�

and�pr edictive� capacity,� and�s o�e nhanced�t rial�de sign�a nd�b etter�r ecruitment�of �D CIS�

patients�i s�a lso�e ssential.�

Consideration�of �ge ne�pr ofiles�

Greater�a ttention�ne eds�t o�be �g iven�t o�ge ne�pr ofiles�a nd�t he�i mpact�of � genetic�l esions�i n�

malignant�e pithelial�c ells�a nd�i n�t he�s tromal�ba ckground�i n�c linical�t rial�de sign�a nd�du ring�

selection�of �pa tients�f or�t herapy.�E xpression�pr ofiling�a t�t he�m RNA�a nd�p rotein�l evel�ha s�

revealed�s everal�s ubtypes�of �br east�c ancer,�a nd�i t�i s�i mportant�t hat�i ntracellular�a nd�

extracellular�pr ocesses�of �g rowth�a nd�pr ogression�a re�f urther� explored�i n�r elation�t o�t hese,�

both�t hrough�m odels�t hat�a im�t o�r ecapitulate� each� class�a nd�t hrough�r epresentative�

clinical�m aterial.��

24�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

The�non- tumour�c ontent� of�bi opsies�s hould�a lso�be �c onsidered�s ince�e vidence�i s�e merging�

to�s uggest�t hat�t his�ha s�a � significant� effect�on� gene�e xpression�pr ofiles�[ 66].�E qually,�

several�s tudies�i ndicate�t he�i mportance�o f�c onsidering�s pecific�l esions�i n�r elation�t o�

therapeutic� response�f or� example�A urora�ki nase�o verexpression�a nd�t axane�r esistance,�

BRCA2�l oss�a nd�r esponse�t o�pl atinum-based�t herapy�[ 67],�t opoisomerase� II�a lpha�

amplification�a nd�e pirubicin�r esponse�[ 68].�C onsidering�t hese�pa rameters�m ay�not �onl y�

improve�pa tient�s tratification�f or�m ore�e ffective�t rial�de sign,�but �m ay� also�a llow�s maller�

patient�c ohorts�t o�be �s tudied,�i f�t hese�a re�s elected�r ationally�f or�t herapy� according�t o�t he�

status�of �t he�dr ug�t arget�o r�m olecular�l esion.�

Improved�r esearch�r eagents�

Better� research� reagents� are�ne eded�t o�c ontinue�t o�a ccurately�de fine�ne w�p athways�i n�

experimental�m aterial�a nd�t o�s tudy�c linical�s amples�t o�ve rify�t hese�pa thways�a s�

biomarkers�i n�r elation�t o�pa thology�a nd�out come.�

Signalling�m echanisms�i n�c linical�s amples�c an�b e�de tected�us ing�i mmunohistochemistry,�

including�t he�us e�o f�phos pho-specific� antibodies�[ 69,70].�H owever,�i f�a ssociations�a re�t o�

be�a ccurate� and�m eaningful,�t his�ur gently�r equires�a ssays�t hat�ha ve� a�r eproducible,�

sensitive�a nd�s pecific�p erformance�i n�s uch�m aterial,�i ncorporating�i mproved�qua lity�

control�a s�ha s�be en�a chieved�f or�E Ra�a nd� HER2�a ssays�[ 71-73].�T echnologies�s uch�a s�

fluorescence� resonance�e nergy�t ransfer�( FRET)�h ave�t he�pot ential�t o�m easure�i nterplay�

between� elements�( for�e xample�r eceptor�di merisation)�i n�s uch�m aterial.�H owever,�i n�a ll�

instances�t hese�m ethodologies�w ill�r equire�c onsensus�r egarding�e valuation� which��s hould�

also�a im�f or�qua ntitative� analysis,� for�e xample�t hrough�i mage� analysis.�M ore�a ccurate�

quantification�m ay�pot entially�i ncorporate�l uminescent�qua ntum�dot s�a s�a n�a lternative�

approach�t o�vi sualise�t umour�m arkers.��

Research�t o� reveal�ne w�b iomarkers�a nd�d rug�t argets�i n�e xperimental�a nd�c linical�m aterial�

will�a lso�i ncreasingly�n eed�t o�i ncorporate�hi gh-throughput� gene�pr ofiling�w ith�

microarrays�a nd�T MA�v alidation,�a s�w ell�a s�pr oteomics.� In�t hese�l atter� areas,�qua lity�

control�ur gently�ne eds�t o� be�a ddressed�a nd�bi oinformatic�c apabilities�m ust� be�

25�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

significantly�e nhanced�o n�a �na tional�l evel�i f�w e�a re�t o�m anage� and�m eaningfully�i nterpret�

the�i ncreasing�vol ume�of � signalling�d ata�t hat�w ill�e merge�i n�r elation�t o�c ellular�e ndpoints�

and�c linical�out come.��

Research�i nfrastructure�

Overcoming�t hese�v arious�ba rriers�h as�obvi ous�i mplications�f or�r esearch�i nfrastructure.�

Studies�w ill�ne ed�t o�be �i ncreasingly�m ultidisciplinary�i f�w e� are�t o�i dentify� relevant�

determinants�of �br east�c ancer� growth�a nd�pr ogression;�f or�e xample�r equiring�i ntegration�

of�m ultiple�e xpression/signalling�s tudies,�bi oinformatics,�i maging�t echnologies,�i mproved�

in�vi tro�a nd�i n�vi vo�m odels,�g enetic�m anipulation�a nd�c linical�e xamination.�T his�w ill�

depend�on�a �b ackbone�o f�r ealistic�s upportive�f unding,�not �onl y�t o�m aintain� core�s trategies�

and�a ssociated�qu ality� control,�but �t o�e nsure�a ccess�t o�ne w�t echnologies�t o� pursue�

innovative�r esearch� avenues�( for� example�i n�vi vo � imaging,� genetically� engineered�m odels�

and�hi gh-throughput�ge nomic�s creening).��

A�c ritical�m ass�of � expert�s taffing�i s� essential,�i ncluding�e xpanding�t he�br east�c ancer�

research�t alent�pool �t hrough�i mproved� research�t raining�a nd�m ore� clearly�s tructured�

career�d evelopment.�T he� need�f or� carefully�c ollected�a nd�doc umented�c linical�t issue�w ith�

serial�bi opsies�t aken�dur ing�t herapy�w ith�de fined�t reatments,�T MAs,�s amples�f rom�di stant�

sites�a nd�l ocal�r ecurrences�m ade�a vailable�t o�i nvestigators�i s�ke y.�R ecent�l egislative�

changes�ha ve�m ade�t his� more�di fficult�a nd�bot h�s urgical�a nd�pa thology�s upport�a re�

needed� at�s enior�l evel.� Both�s pecialities�ha ve�s uffered�s evere� cutbacks;� collaborative�

contributions�b y�a cademics�i n�t hese�a reas�a re�i mportant�a nd�de serve�f unding,�i n�a ddition�

to�s upporting�t he�hi ghest� quality�pe er�r eviewed�i ndependent�r esearch.��

Pathology�t raining�w ill�be �i ncreasingly�i mportant� as�w e�e xpand�our �t echnical�c apabilities�

for�i nvestigating� clinical� material.�S tandardisation�of �a ntibodies�a nd�ot her� reagents�i s�

needed�t o�c ompare� results�be tween�i nvestigators.� Research� would�a lso�be nefit�f rom�

increased�s haring�of � experimental�a nd�c linical�r esources.� Finally,�i ncreased� investigator-

driven � studies�a nd�c ollaboration�w ith�i ndustry�w ill�be �e ssential�i f�w e� are�t o�i mprove�

26�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

patient�r ecruitment�f or�c linical�s tudies�a imed�a t�unde rstanding�bi ological�f actors�dr iving�

selective�r esponse.��

Translational� implications� �

If�r esearch�c an�b e�t ailored�t o�t he�di verse�que stions�a bout�t he�i ntracellular� and�

extracellular�pr ocesses�u nderlying�b reast�c ancer� growth�a nd�pr ogression,�t his�s hould�l ink�

tumour�m echanisms�t o�di sease�c lassification�a nd�p rognosis.��

To�s ome�e xtent�t his�pr ocess�i s�unde rway�t hrough� microarray�s tudies,�w hich�ha ve�l ed�t o�

the�c lassification�of �i nvasive�br east�c ancer�i nto�f our�c ategories� –�l uminal,�ba sal,�

HER2/neu�ove r-expressing�a nd�no rmal�[ 74]�–�a nd�t he�de velopment�of �va rious�g ene�

expression�s ignatures�t hat�c an�pr edict�out come.�H owever,� we�ne ed�t o�bui ld�on�t hese�

studies;�f irst,�s o�w e�c an�i dentify� earlier�pa tients�a t� increased�r isk�of �di ssemination�a nd�

therefore�a llow�s election� for�a nti-invasive�t herapy� and,�s econd,�t o�pr ovide� robust�

biomarkers�t o�e ffectively�pr edict�t herapeutic�r esponse�w ith�g rowth�i nhibitors.�F illing�t he�

gaps�out lined�f or�ve ry� early�pr ogression�m ay�i mprove�s election�of �p atients�w ith�D CIS�f or�

adjuvant�r adiotherapy�or � endocrine�t herapies,�w hile�a voiding�unn ecessary�t reatment�i n�

others.��

Equally,�i t�i s�l ikely�t hat� we�w ill�r eveal�c ellular�t argets�f or�de veloping�ne w� agents�t o�t arget�

breast�c ancer�pr ogression�e ffectively�a nd�s electively�( as� well�a s�be ing�a ble�t o�m easure�t he�

target�pa thways�d ynamically�dur ing�t herapy�t o�m onitor�c linical�e fficacy�of � novel�

inhibitors�a nd�i mprove�t rial�de sign).�T ogether,�s uccessful�r esearch�s hould�a llow�t herapy�

to�be �i ncreasingly�i ndividualised�a nd�i nclude�c ombination�s trategies�a iming� to�m aximally�

subvert�t umour�r esistance�a nd�di sease�pr ogression,�i mproving�t he�out look�f or�pa tients.� �

27�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

4.�T herapies�an d�T argets�i n�B reast�C ancer� (Table�4) �

Treatment�of �b reast�c ancer�ha s�i mproved�ov er�t he� past�de cades,�a nd�ha s�l ed�t o�a n�

increased�s urvival�r ate�f or�pa tients�w ith�t umours�c onfined�t o�t he�br east.�T his�i s�pa rtly�due �

to�br east�s creening�r esulting�i n�e arly�di agnosis�but �a lso�t he�a ppropriate�s election�f or�

patients�of �t he�s urgical� approach,�r adiotherapy,� chemotherapy�r egimen�a nd� more�r ecent�

therapies.��

What�do�w e� know?�

The�i ntroduction�of �ne w�t herapeutic�s trategies� –�i ncluding�ne wer� adjuvant�e ndocrine�

treatments,�r adiotherapy� scheduling,� chemotherapy� combinations�a nd�nov el�a gents�s uch�

as�t rastuzumab�–�ha s�c ontributed�t o�t he�i ncrease�i n�di sease-free� and,�i n�s ome�c ases,�

overall�s urvival.�H owever,�br east�c ancer�r ecurs,�s ometimes�m any� years�a fter�di agnosis,�

and�t he�t reatment�o f�m etastatic�di sease�r emains�pa lliative.�T hus,�not �a ll�t herapies�us ed�a re�

effective�a nd� a�pr oportion�of �pa tients�( perhaps�a � majority�f or�s ome�t herapies)� get�one �or �

more�t reatments�w hich� either�a re�not �r equired�or �f ail�t o�s tem�t he�di sease.�

Selection�of �m ultimodality� therapy�f or� an�i ndividual�pa tient�b y� a�m ultidisciplinary�t eam�i s�

based�on�t he�e xtensive�e vidence�ba se�f or�i ndividual�a nd�c ombination�t herapies�

summarised�e lsewhere.�

What�ar e�t he�gaps ?�

Incomplete�unde rstanding�of �t he�bi ology�of �b reast�c ancer� �

Our�unde rstanding�of �t he�m any� cellular�a nd�m olecular�pr ocesses�i nvolved�i n�t he�

development�of �br east�c ancer�i s�s till�i ncomplete.�T his�ha mpers�t he�i dentification�of �ne w�

therapeutic�t argets�a s�w ell�a s�t he�opt imal�us e�of �t he�t argets�w e�know �a bout.� We�ha ve�

limited�know ledge�of � which�s ignals�dr ive�b reast�c ancer� cell� growth,� and�ho w�t hey�

promote�t he�i nvasive�na ture�of �t he�di sease.� In� addition,�t he�r ole�of �t he�s urrounding�

healthy�t issues�i n�t umour�de velopment,�bot h�a t�t he�pr imary�a nd�m etastatic�s ites,�ne eds�t o�

be�c larified.��

28�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Current�t hinking�i s�t hat�t o�e radicate�c ancer�c ells� we�m ay�ne ed�a �c ombination�of �t herapies�

targeting�t he�t umour�c ells,�t heir�m icroenvironment�a nd,�pot entially,�t heir�bl ood�s upply.� �

We�c annot�de termine�w ho�g oes�on�t o�d evelop�a dvanced�di sease�

Despite�our �be st�e fforts�a �pr oportion�of �pa tients�w ill�de velop�a dvanced�di sease,�a nd�w e�do�

not�c urrently�ha ve�r eliable�t ools�t o�pr edict�w ho�t hese�pa tients�a re.� By�us ing� tumour�g rade,�

pathological�node �s tatus,� tumour�s ize�a nd�ot her�pa thology�f eatures,� a�num ber�of �m odels�

have�be en�de signed�t o�a ssess�t he�r isk�of �pa tients�d eveloping�m etastatic�di sease�i ncluding�

the�N ottingham�P rognostic� Index�a nd�A djuvant�O nline.�H owever,�t here� are�no�

established�m olecular�m arkers�us ed�i n�c linical�pr actice�t o�de termine� with�c ertainty�

whether�a �b reast�t umour�i s�l ikely�t o�m etastasise�t o� other�s ites,�a nd�t herefore� no�e asy�w ay�

of�s electing�pa tients�a t�e arly�s tages�of �t he�di sease� who�w ill�r equire�m ore�i ntensive�

treatment�t o�pr event�t umour�pr ogression.��

In� addition,�t here�a re�no�s imple,�non- invasive�m ethods�a vailable�f or�d etecting�t he� early�

stages�o f�t umour�pr ogression,�a nd�pa tients�of ten�p resent�w ith�r elatively� advanced�

(symptomatic)�di sease.��

Insufficient�know ledge�t o�pr ovide�pr ecise,�i ndividualised�t herapies�

One�of �t he�m ain�pr oblems�w hen�t reating�br east�c ancer�i s�t o�de termine� which�pa tients�w ill�

benefit�f rom�pa rticular�t herapeutic�s trategies,�e nsuring�opt imal�r esults�f or� each�i ndividual�

patient.�N ot�onl y�i s�t his�ke y�t o� achieving�t he�b est�pos sible�out come�f or�pa tients�w ho�a re�

likely�t o�r espond�t o�a ny� given�t reatment,�but �a lso�t o�a void�t reating�t hose�w ho�w ill�not �

benefit.��

A�f ew�t argeted�t reatments�a re�a vailable�( for�e xample�e ndocrine�t reatments� and�

trastuzumab)�t hat�r ely�on �i dentifying�a � receptor�pr esent�on�t he�t umour�c ells.�

Understanding�t he�bi ology� of�b reast�c ancer�be tter�i s�l ikely�t o�he lp�us �de velop�ne w�a nti-

cancer�a gents�t hat�e ffectively�t arget�s pecific�r eceptors�pr esent�i n�onl y� a�s ubset�of �pa tients.��

29�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

In� addition�t o�t he�bi ological�c haracteristics�of �t he�t umours,�e ach�p atient�ha s� an�i ndividual�

capacity�t o�m etabolise�dr ugs.�T his�l eads�t o�va riations�i n�dr ug�ha lf-life�t hat� may�p artly�

explain�w hy�t he�r esponse�r ate�va ries�be tween�pa tients�r eceiving�i dentical�t reatments.�F or�

example,�m any�c ommonly� used� anti-cancer� agents�( including�c isplatin,�dox orubicin,�

tamoxifen�a nd�e toposide)�a re�m etabolised�i n�t he�l iver�b y�e nzymes�of �t he�p4 50�g roup,� and�

there�a re�doc umented�va riations�i n�t he�a ctivity�of �t hese�e nzymes�be tween�i ndividuals.��

Finally,�t he�opt imisation�a nd�c ombination�of �t he�c urrent�t herapies�t o�f it�i ndividual�

patients�i s�of ten�ba sed�on �a �t rial�a nd�e rror� approach,�r ather�t han� a�c lear�und erstanding�of �

the�bi ology�of �t he�t umour.��

How�t o�de cide�w hen�t o�s top�t reatment?�

We�l ack�s uitable�m ethods�f or�e arly�d etermination� of�r ecurrence� and�t reatment�f ailure�

For�m ost�c urrent�t herapies,�t here�i s�l ittle�l ong�t erm�da ta�t o�s upport�w hen�i t�i s�s afe�t o�s top�

treatment.� If�p atients�e xperience�no�s ide-effects�a nd�a re�f ree� from�c ancer�t hey� are�l ikely�

to�w ant�t o�c ontinue�t heir� therapies�e ven�i n�t he�a bsence�of � any�pr oven�be nefit.�T here�a re�

no�e asy,�non- invasive,� reproducible�m ethods�a vailable�f or�r outinely�m onitoring�

subclinical�di sease�pr ogression�a nd�r esponse�t o� adjuvant�t reatment,�a nd�w e� rely�on�

patients�t o�pr esent�w ith�s ymptoms�i n�or der�t o�e stablish�w hether�t he�t umour�ha s�r ecurred.�

Who�w ill�de velop�dr ug-resistant�t umours?� �

The�ba sis�of �dr ug�r esistance�i s�not �w ell�unde rstood,�a nd�a s�a �c onsequence� we�ha ve�no�

reliable�m ethods�of �pr edicting�w ho�w ill� go�on�t o�d evelop�r esistance�t o�t he�c ommonly�

used�t herapies.�W e�do�no t�know �how �t o�a void�a �r esistant�phe notype�d eveloping,�a nd�i s�i t�

not�c lear�w hether� changes�i n�t he�f requency�of �dr ug�a dministration�a nd/or�l ength�of �

treatment�c ontribute�t o�t his�pr ocess.�

Incomplete�unde rstanding�of �t he� role�of �t he�i mmune�s ystem�

We�do�not �f ully�und erstand�how �be st�t o�us e�t he�i mmune�s ystem�t o�our �a dvantage�i n�br east�

cancer�t reatment,�e ither� as�a �va ccine�or �i n�t he�f orm�of �i mmunotherapy.� Lack�of �s uitable�

model�s ystems�f or�s tudying�t he�i mmune�r esponse,�a s�w ell�a s�t he�m any�f undamental�

30�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

differences�b etween�t he�s pecies�m ost�c ommonly�u sed�( rodents)� and�hum ans�ha ve�

hampered�p rogress�i n�t his�a rea.� In�a ddition�w e�a lso�l ack�unde rstanding�of �h ow�t umour�

cells�s uppress�t he�i mmune�r esponse�t o� ensure�t heir�s urvival�a nd� growth.�

How�do�a nti-cancer�t reatments�a dversely�a ffect�c ancer�c ells?�

Experimentally,�i t�i s�be coming�a pparent�t hat�t reatment�of �br east�c ancer�c ells�w ith�

endocrine�t herapies� can�r apidly�a ctivate�a lternative�s ignal�t ransduction�pa thways,�w hich�

may�l imit�t he�i nitial�a nti-tumour�r esponse,�a llow�r esistance�t o�de velop�a nd,�ul timately,�

encourage�i nvasive�b ehaviour�[ 75].�F or�e xample,� EGFR/HER2�s ignalling�i s�t riggered�b y�

anti-oestrogens�i n�va rious�hor mone-responsive�b reast�c ancer�m odels�t hat�m aintain�

residual�dow nstream�ki nase�a ctivity,�pr oliferation�a nd�c ell�s urvival�[ 76].� Interestingly,�

‘compensatory’�i nduction�of �a lternative�s ignal�t ransduction�i s�a �phe nomenon�s hared�b y�

other�t ypes�of �a nti-cancer�t herapy,�i ncluding�a nti-growth�f actors,� chemotherapy� and�

radiotherapy�[ 77-79].��

The�f ull�br eadth� and�c ellular�i mpact�of �s uch� compensatory�s ignalling�i s�l argely�unknow n�

in�br east�c ancer.� To�f ill�t his�g ap�w e�ne ed�t o�us e�hi gh-throughput�di scovery� tools�t o�pr ofile�

multiple�s ignalling�pa thways� and�t o�e xplore�t he�c oncept�i n�a �br oader�p anel� of�m odels�

reflective�of �t he�va rious�br east�c ancer�s ubtypes.� In�a ddition,�a lthough�c hanges�i n�s ome�

signalling� elements�( for�e xample�H ER2,�a ctivity�o f�va rious�ki nases�i ncluding�M APK,�

JNK�a nd�p38) �ha ve�be en� reported�t o�be �i n�pl ace�b y�t he�t ime�of �r elapse,�t he�d rug-induced�

concept�i s�l argely�un explored�i n�pa tients.�W e�ne ed�i ncreased�a ccess�t o�‘ on�t herapy’�

clinical�s amples�t o�r ectify� this.��

What�ar e�t he�pr oblems?�

There� are�m any� reasons�f or�t hese� gaps�i n�our �kno wledge,�i ncluding:��

(i)� A�l ack�of �s uitable�m odel� systems�r eflecting�t he�c omplexity�a nd�di versity� of�

breast�c ancer��

(ii)� Limited�a ccess�t o�c linical�m aterial�f rom�pa tients�b efore� and,�i n�pa rticular,�

during�t reatment� �

31�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

(iii)� A�s evere�l ack�of �m aterial�f rom�m etastatic�de posits�m ade�a vailable� for�s tudies�

of�t arget�hi ts�a nd�bi ological�r esponse�t o�t herapies.� �

The�ne oadjuvant�m odel�p rovides�a �w indow�of �opp ortunity�w here�t herapy�c an�be �t ested�i n�

vivo�i n�hum ans�t o�a ssess�t he�e ffects�of �a n�i ntervention.� It�a llows�bi ological�e valuation�of �

tumour�m arkers�a nd�no rmal�t issue�r esponses�b y�h istological,�bi ochemical,�m olecular,�

imaging�or �c linical�t echniques.�H owever,�ne oadjuvant�s tudies�ha ve�not �us ually�i nvolved�

adequate�num bers�of �pa tients�f or�w hat� can�be �i ntensive�s tudy�a nd�i ndividual�c entres�o ften�

recruit�t oo�f ew�pa tients�i n�s pecific� groups�t o�e nsure�m eaningful� analysis;�a �m ulticentre�

approach�i s�r equired�t o� ensure�pr ogress.�

Identifying�n ew�t herapeutic�t argets�i s�ha mpered�b y� our�l imited�unde rstanding�of �t he� role�

of�t he�t umour�m icroenvironment�a nd�i nteractions� with�c ancer�s tem�c ells�i n� the�

development�a nd�pr ogression�of �br east�c ancer.� In� addition�w e�do�not �unde rstand�t he�

mechanisms�unde rlying�t he�a cquired�r esistance�t o� anti-cancer�t herapies.�T here�a re�t oo�

few�s tudies�a cross�di sciplines�t o�i ncrease�ou r�unde rstanding�o f�t he�r ole�of �t he�i mmune�

system,�a n� area�w here�t here�i s�a �l ack�of �a ppropriate�m odel�s ystems�a nd�i nsufficient�hi gh-

quality�s tudies�c arried�ou t�i n�hum ans.�N ot�e nough� attention�ha s�be en�pa id�t o�how �dr ug�

metabolism�b y�i ndividuals�a ffects�r esponse�t o�t reatment.�T his�i mportant�poi nt�i s�not �

considered�i n�dr ug�t rials�on�a n�i ndividual�ba sis,�or �l inked�t o�m easurements� of�r esponse,�

but�m ay�pa rtly� explain�w hy�t here�i s�s uch�va riation�be tween�p atients�r eceiving�i dentical�

treatments.�A s�a ssays� for�dr ug�m etabolising�c ytochrome�p450s �be come� available�( for�

example�2D 6�f or�t amoxifen�m etabolism),�t his�m ay�m ove�i nto�c linical�pr actice.�

These� gaps�m ay�b e�f illed�b y�de veloping�i mproved�m odel�s ystems�t hat�s eek� to�r eflect�t he�

complexity�of �t he�hum an�di sease,�c ombined�w ith�i ncreased�e fforts�t o�de sign�m ulticentre�

studies�us ing�c linical�m aterial�c ollected�a nd�pr ocessed�i n�a �uni form�w ay.�P articular�a reas�

that�w e�ne ed�t o�s trengthen�a re�t he�i ncreased�us e�of �ne oadjuvant�s tudies,�pr oviding�

researchers�w ith�va luable�c linical�m aterial�f rom�br east�c ancer�p atients�dur ing�t reatment�i n�

the�f orm�of �r epeated�bi opsies.� �

32�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Few�s tudies�ha ve�i nvolved�i nvestigations�of �m etastatic�de posits,�s o�our �unde rstanding�of �

the�bi ological� changes�o f�t he�t umour�c ells�a s�t hey� adapt�t o�ne w�e nvironments�i s�l imited.�

Not�m any�p atients�w ill�unde rgo�pr ocedures�t hat�a llow�c ollection�of �m aterial�f rom�

metastatic�s ites,�a nd�no�s ingle� centre�i s�l ikely�t o�be �a ble�t o�c ollect�s ignificant�num bers�of �

quality�s pecimens� for�r esearch.� As�bui lding�t hese�t ypes�o f�‘ bio�r epositories’�f or�f uture�

research�i s�l ikely�t o�t ake� many� years�t o�a ccumulate�num bers�t hat�a llow�m eaningful�d ata�

analysis,�t his�r equires�a � collaborative,�l ong-term�a pproach�f or�w hich�f unding�m ay�b e�

difficult�t o�obt ain�( most�f unding�bodi es�ope rate�on �a �t hree-�t o�f ive-year�t ime�s cale�be fore�

results�a re� expected).��

We�t herefore�s ee� an�ur gent�ne ed�f or�hi gh-quality,� comprehensive,�l ongitudinal�s ample�

collections�( tumour,�D NA,�s erum,�pl asma,�ur ine)� from�br east� cancer�pa tients,�c oupled�

with�e xtensive�c linical�i nformation.�W here�a ppropriate,�c ollaborations�w ith�r esearchers�i n�

other�f ields�( for�e xample� immunologists�w orking�i n�r heumatology�o r�a uto-immune�

diseases)�a re�ne eded.�

Translational� implications�

If�w e� could�f ill�t he�ga ps�i dentified�he re�w e� anticipate�t hat�w e�w ould�b e�a ble�t o�s elect�

patients�f or�a ppropriate�t herapy�m ore�a ccurately,� start�pa tients�on�t herapies�e arlier� and�

monitor�pr ogression�a nd� response.�W e�w ould�ha ve�a �be tter�und erstanding� of�how �t o�

sequence� and�c ombine�t herapies,� an�i ncreased� capacity�t o�d evelop�i nnovative�a nd�

immunologically�b ased�t herapies�t hat�s ubsequently� prove�s uitable�f or�t reating�t he�di sease.�

For�e xample,�pr oof�o f�pr inciple�e xperimental�da ta� reveal�t hat�i ntelligent�t argeting�of �

induced�s ignalling�a longside�t he�pr imary�t herapy�c an�a chieve�a �pr eviously�u nobtainable�

level�of �c ancer�c ell�ki ll�a nd�s ubstantially�i mprove� anti-tumour�r esponse�[ 76].� If�t he�dr ug-

induced�c oncept�i s�r eproduced�i n�vi vo,�r ationally� designed� combination�s trategies�c ould�

have�pot ential�t o�i mprove�i nitial�r esponse�a nd�de lay� resistance�a nd�pr ogression;�t his�

would�ha ve�a �pos itive�i mpact�on�br east�c ancer�s urvival�r ates.�W e�w ould�t hen�be �be tter�

placed�t o�de velop�dr ugs� with�a n�i mproved�t herapeutic�w indow�a nd�f ewer� side-effects,�

and�be �a ble�t o�i mprove�b reast�c ancer�s urvival�r ates. �

33�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

5.�D isease�M arkers�i n�B reast�C ancer�( Table�5) �

Developing�ne w�t reatments�f or�br east� cancer�a nd� refining�e xisting�r egimens�a re�c learly�

important�a nd�e xciting�a reas�of �r esearch.�T he�c hallenge�i s�t o�e nsure�t hat�n ew�t herapies�

reach�t he�pa tients�w ho�w ill�be nefit�m ost,�a nd�t o�i dentify�pa tients�f or�w hom�t he�ha rms�

outweigh�t he�b enefits,�or � for�w hom�t he�t reatment�w ill�be �i neffective�[ 80].� To�a chieve�

these�a ims�w e�ne ed�va lidated�pr edictive� and�pr ognostic�m arkers.��

What�do�w e� know?�

The�g old�s tandard�f or�c omparing�n ew�m arkers�i s�t esting�a gainst�hi gh-quality� pathological�

assessment�of �t umour�t ype,�s ize,�g rade�a nd�l ymph� node�s tage.��

Only�t wo�m arkers�h ave�b een�e stablished�s o�f ar�i n�t he�r outine�a ssessment�of � breast�c ancer:��

(i)� ER�( for�pr edicting�r esponse�t o�e ndocrine�t herapies)�[ 80]�

(ii)� HER2�( for�pr edicting� response�t o�t rastuzumab)�[ 80,81].�

Although�t heses�m arkers� for�pr edicting�t he� response�t o�e ndocrine� and�bi ological�t herapies�

are�a lready� available,� even�E R�a nd�H ER2�a re� far� from�pe rfect;�f or�e xample,� assessment�

of�H ER2�s tatus�w ill�s till�i nclude�s ome�non- responding�pa tients�[ 81].�

�Intelligent�t rial�de sign�i nvolving�m ultidisciplinary�t eams�i s�e ssential�t o�e nsure�ne w�

treatments�a re�t ested�i n�p atient�g roups�s tratified�us ing�bi omarkers.� Large-scale�s tudies�of �

invasive�br east�c ancer�t hat�ha ve�a nd� are�us ing�t hese�pr inciples�s uccessfully�i nclude�t he�

trials�of �t rastuzumab�a fter�a djuvant�c hemotherapy� in�H ER2-positive�br east� cancer�[ 81].�

Biomarker-based�t rials�m ay� also�be �us ed�t o�a ssess�t reatments�f or� advanced� breast�c ancer,�

but�m ay�be � confounded�b y� prior� exposure�of �s uch� cancers�t o�m ultiple�t herapies.��

Ideally,�how ever,�pr eoperative�( neoadjuvant)�s tudies�a re�r equired,�us ing�c linically�

relevant�m odels�a nd� crossover�de signs�t o�pr ovide� early�e vidence�o f�a �t herapeutic�e ffect�

and�t o�di fferentiate�r esponsive�f rom�non- responsive�gr oups�of �pa tients�[ 82].�

34�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

What�ar e�t he�gaps ?�

Innovative�t rial�a nd�s tudy� design�

Disease�m arker� concepts� should�be �a pplied�t o�t rials�of �t reatments�f or�p re-invasive�di sease�

including�D CIS�a nd�t o�m odels�of �s entinel�l ymph�n ode�a ssessment,�w here�f unding�i s�

limited�a nd�w here�l ong-term�f ollow-up�i s�r equired�t o�obt ain�r obust�c linical�da ta,�but �

where� we�ne ed�a �be tter�u nderstanding�of �t he�pa thophysiological�pr ocesses�i nvolved.�T wo�

areas� we�ne ed�t o�a ddress� are:��

(i)� The�l evel�of �s entinel�l ymph�node �i nvolvement�t hat�ha s�a �c linical�i mpact�

(ii)� Optimum�pr otocols�f or�pa thological�a ssessment�a nd�s ystems�f or� reproducibly�

categorising�c linically�r elevant�pa thological�m etastatic�di sease�[ 83].�

Additional�c hallenges�i nclude�r ecognising�t he�di fferences�be tween�l aboratory�s tudies� and�

in�vi vo�s tudies�i n�hum ans�w here�i nteractions�be tween�t umour�a nd�s troma,�t hree-

dimensional�e ffects�a nd� vascularisation�be come�r elevant.�F urthermore,�c ombining�

clinical,�r adiological,�pa thological� and� genomic�d ata�i n�t rial�popul ations�w ith�i nnovative�

trial�de signs�( such�a s�i n�t he�M INDACT�t rial�[ 84])�w ill�a llow�us �t o�r elate,�c ompare�a nd�

combine�e stablished�m arkers�t o,�a nd�w ith,�ne w�t echnologies�i n�a � range�of � settings.�

Success�de pends�on� close�m ultidisciplinary�c ollaboration�a t�a n�e arly�s tage,� as�w ell�a s�t he�

highest�qua lity�hi stopathological� and�s cientific�e valuation.�

Validating�n ew�m arkers�

New�m arkers�m ay�b e�be st�va lidated�i n�t rials�of �ne oadjuvant�or �a djuvant�t herapies�a nd�i n�

advanced�di sease,� where� clinical�da ta�a nd�out comes�a re� robust�a nd�s tatistically�

significant.�H owever,�l arge�num bers�of �p atients�m ay�b e�r equired�f or�s mall�i ncremental�

differences�i n�out come.�

The� key� question� is:� ‘does� introducing� a� new� marker� change� clinical� practice� and�

therefore� patient� outcome?’� In� the� past,� researchers� have� not� paid� enough� attention� to�

experimental� design� when� assessing� this;� consequently� the� results� have� not� always� been�

standardised,� reproducible� or� robust� enough� to� apply� to� clinical� practice.� Developing�

35�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

rigorously� controlled� reagents,� technical� methods� and� appropriate� interpretation� requires�

adequate� resources�a nd�t o�da te�t his�ha s�r arely�be en�f orthcoming.�

While�E R-negative�p atients�r arely�r espond�t o�hor mone�t herapies,� a�pr oportion�of �t hose�

classified�a s�ha ving�E R-positive�di sease�w ill�a lso�not �r espond�[ 85].�N o�r obust�va lidated�

markers�ha ve� yet�be en�de veloped�f or�pr edicting�r esponse�t o�c hemotherapy� or�

radiotherapy.�M any�m arkers�a re�f avoured�b y�l ocal�e nthusiasts�( eg�pr ogesterone�r eceptor�

[PgR],�P S2�a nd�c athepsin�D )�but �w e�ne ed�hi gh-quality� clinical�e vidence�t o�s upport�t heir�

more�w idespread�us e.��

Markers�i ndicative�of �r esistance�t o�t herapy� (for� example�E R-positive,�P gR-negative�

tamoxifen-resistant�c ancers)�ha ve�be en�p roposed,� but�t here�i s�l ittle�a greement�a bout�

methodology�or �c ut-offs� of�s cores� for�c linical� application,�or �i ndeed�t heir�o verall�va lue.� In�

addition,�s ome�m arkers� may�not �be �us eful�onc e�r egimens�o r�t herapies�a re� superseded.�W e�

therefore�ne ed�t o�c ompare,�a nd�pot entially�c ombine,�m arkers�s uch�a s�t he�E R�a nd�P gR�

with�pa thological�m arkers�( such�a s�hi stological�t ype,�gr ade� and�node �m etastasis),�w hich�

have�pr ognostic�i mportance.�F unding� for�r obust�s tudies�e valuating�t hese�m arkers�i s�

crucial,�but �i s�r arely�a chieved�w ithout�f inancial�s upport�f rom�t he�pha rmaceutical�i ndustry.�

��

Researchers� have� identified� validated� intermediate� end� points,� such� as� the� effects� on�

apoptosis,� proliferation� and� ER� down-regulation� (for� example� with� fulvestrant� therapy).�

However,� further� work� is� urgently� needed� using� tumour� pathology� (eg� lymphovascular�

invasion� and� microstaging)� and� molecular� biology,� and� exploring� the� potential� of� disease�

response� markers,� such� as� serum� proteomic� markers� and� circulating� tumour� cells.�

Subclass-specific� markers� based� on� microarray� approaches� have� been� identified� and�

validated� by� immunohistochemistry� [86,87],� but� have� yet� to� be� applied� in� clinical� trials�

and�c linical�pr actice.��

Therefore,� although� breast� cancer� can� be� classified� according� to� histology� and� expression�

of� RNA� and� protein,� for� example� into� basal,� HER2,� luminal� A� and� luminal� B� and� normal�

36�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

breast-like� subtypes� [86,87],� we� need� to� develop� this� further� to� predict� the� prognosis� of�

each�s ubtype� and�t he�l ikelihood�of �r esponse�t o�t herapies.��

A�f urther� challenge�i s�i n� understanding�t he�c omplex�f actors�i nfluencing�pr ognosis�a nd�i n�

improving�t he�qua lity�c ontrol�of �r eagents�us ed�i n�ne w�t echnologies�( such�a s�pr oteomics,�

phosphoproteomics,�e pigenetics�a nd�a ssays�of �m icroRNA)�s o�t hat�t hey�c an� be�e ffectively�

applied�t o�r outinely� available�c linical�m aterial.� In� particular,�i ntegrating�ol d�a nd�ne w�

methods�a nd�c ombining�t echniques�( such�a s�t issue�m icroarray,�i mmunohistochemistry,�

fluorescence�i n�s itu�h ybridisation,�da ta�s torage�a nd�a nalytical�m ethods)�m ay�a llow�us �t o�

develop�ne w� composite�pr ognostic�i ndices.�A �s ignificant�c hallenge�t o�t he�de velopment�

and�va lidation�of �pr edictive�m arkers�i s�c ounteracting�t he� effects�of �s toring�t umours�a nd�

blood�de rivatives�on�pr oteins�( including�phos phorylated�p roteins)�a nd�i n�pr oteomic�

studies.�W e�c learly�ne ed� careful�r esearch�i nto�t hese�pr ocesses�a nd�how �t o�t ake�t hem�i nto�

account.�

What�ar e�t he�pr oblems?�

Any�n ew�a ssays�t hat�a re� developed�m ust�s tand�up� to�t he�da y-to-day� challenges�o f�c linical�

practice.� The�qua lity�of �s ervice�d elivered�i n�r outine�c linical�pr actice�v aries,� even�f or�b asic�

markers�s uch� as�E R�a nd� HER2�[ 88].� RNA-dependent�a ssays�ha ve�be en� considered�l ess�

robust�t han�pr otein-�or �D NA-based� assays�i n�t he�b reast�c ancer�s etting.� However,�R NA�

based�P CR�t echnology�m ay� well�be come�a �s tandard�of �c are�a s�a n�i ntra-operative�

detection�m ethod�f or�t umour�i n�s entinel�l ymph�no des.�T echniques�m ust�un dergo�r egular�

quality�a ssurance�bot h�du ring�de velopment�( in�t he� research�s etting)�a nd�i n�s ubsequent�

laboratory�a nd� clinical�us e;�m arker�v alidation�r equires�t ime�a nd�r esources� and�

subsequently� convincing� the�pr ofessions�t o�a pply�t hem.��

Implementing�a dvances�i n�m olecular�unde rstanding�m ay�b e�l imited�t o�pa raffin�t issues�a s�

a�s ource�o f�s tandardised� and�s table�pr ocessed�m aterial�i n�t he�f oreseeable�f uture.�

Advances� rely�on�ha ving� appropriate�t echnologies� and�t issues�a vailable�a nd� on�t raining�

for�s cientists�a nd�c linicians.�T he�t iming�a nd�qua lity� of� fixation�m ethods,�t issue�ha ndling�

and�pr eparation�a re�c ritical�bot h�i n�t rials�a nd�i n�r outine�c linical�us e.�C linical�t rials�ha ve�

37�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

rarely�d eveloped�s tandard�pr ocedures�f or� collecting�a nd�do cumenting�t issue,�a lthough,�

more�r ecent,�i nnovative�t rials�do�s o�[ 84].�E ven�t hen,�de livery�t ime�a nd�c osts�m ay�pr event�

techniques�a nd�m arkers�f rom�be ing� widely�us ed�i n�c linical�pr actice.��

Smaller�c ancers,�of ten�d etected�b y�br east�s creening,�pr esent�pa rticular�pr oblems.�N ot�onl y�

may�t here�be �l ittle�m aterial�f or�s tudying�t he�p rimary� tumour,�but �l ymph�nod e�

micrometastases�a re�m ore�l ikely�t o�be �p resent�t han�l arger�d eposits�a nd�m ay� change�t he�

classification�of �noda l�s tatus.�S uch�pa tients�m ay�s till�ha ve�a n�e xcellent�pr ognosis,�

although�c onventional�i ndices�r elating�node �i nvolvement�t o�di sease�be haviour�m ay� result�

in�a djuvant�( over)�t reatment�be ing� given.�

Additional�i ssues�i nfluencing�t he�d evelopment,�c hoice�a nd�us e�o f�m arkers�i nclude�t he�

impact�of �l egislation�( such�a s� Good�C linical�P ractice� and �G ood�L aboratory�P ractice)�a nd�

ethical�a pproval�pr ocesses�on�t he�f unding,�m anagement,�ow nership�a nd�a ccess�t o�t issue�

collections�a nd�a ssociated�c linical�da ta.�A cademic�pr essures�( particularly�t he�i nfluence�i n�

the�U K�of �t he�R esearch� Assessment�E xercise)�m ay� be� counterproductive�t o�c ollaborative�

translational�r esearch,� which�s hould�( but�m ay�not �be )�r ecognised�a s�o f�hi gh�va lue.� �

Translational� implications�

Integrating�e stablished� and�ne w�a pproaches�t o�p rediction�a nd�pr ognosis�c ontinues�t o�

present�c hallenges.�N etworks�of �c ollaboration�( for�e xample,�t issue�ba nking� and�c ollection�

of�l inked�pa tient,�t umour�a nd�m olecular�d ata)�e mploying�s ystems�bi ology�( eg�i nformation�

technology,�m odelling,�i dentification�of �ke y�nod es)�a re�s till�ne eded�f or�br east�c ancer�

research,�de spite� UK�a nd�E uropean�i nitiatives.�S uch�de velopments�c ould�s peed�t he�

development,�t esting� and�i mplementation�of �ne w� methods�of �de tection�a nd�m arkers�of �

disease�be haviour.�

We�ne ed�t o�r ecognise�t he�di versity�of �b reast�c ancer�us ing�bot h�t raditional�a nd�ne w�

markers�t o�i ndividualise�t herapy.�T raditionally,�t rials�ha ve�c lassed�a ll�w omen�w ith�br east�

cancer�a s� a�s ingle�popul ation�w ith�a �s ingle�di sease�a nd�m any�ha ve� focused� on�w omen�

who�ha ve�a � good�p rognosis.�F uture�s tudies�s hould�a lso�i nvestigate�ot her� groups,�s uch�a s�

38�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

women�l east�l ikely�t o�b enefit�f rom�a djuvant�t herapy�a nd�t hose�w ith�a �hi gher�r isk�of �

relapse.�T argeting�br east� cancer�t herapies�t o�t hose� most�l ikely�t o�be nefit�a nd�a voiding�

treatment�i n�pa tients�or �t umours�not �r esponsive�c ould�s ignificantly�f ocus�b enefits�on�

patients�l ikely�t o�r espond�but �a lso�pr event�a voidable�t oxicity.�

39�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

6.�P revention�of �B reast� Cancer�( Table�6) �

Prediction�an d�pr imary� prevention�of �br east�c ancer�

What�do�w e� know?�

Several�l arge-scale�r andomised�c ontrolled�t rials�s how�t hat�e ndocrine� chemoprevention�f or�

oestrogen-responsive�t umours�w orks�[ 89,90].�B reast�c ancer�p revention�pr ogrammes�ne ed�

to�t arget�w omen�a t�hi ghest�r isk.�R isk�pr ediction�pr ogrammes�pr edict�how �m any� cancers�

will�oc cur�i n�a �popul ation�[ 91],�bu t�w e�ne ed�t o�i mprove�t heir�s pecificity.�W e�c urrently�

need�t o�t reat�50� ‘high-risk’�w omen�t o�pr event�one �c ancer.�

Observational�s tudies�de fine�m ammographic�de nsity�a s�one � of�t he�s trongest� risk�f actors�

for�br east�c ancer� (relative�r isk�4.64�[ 3.64–5.91]�> � 75%�r elative�t o�< �5 %�de nsity)�[ 92].�

Expert�opi nion�s uggests� 20–80%�of �r isk�i s�l inked�t o�di et�[ 93].�M easurement�e rror�w ith�

accepted�di et�a ssessment� methods�( food�f requency�que stionnaires)�m ay,�ho wever,� fail�t o�

correctly�i dentify�di etary� risk�f actors.� For�e xample,�r ecent�s tudies�us ing�f ood�di aries,�but �

not�f ood�f requency�que stionnaires,�ha ve�l inked�di etary�f at�t o�r isk�[ 94,95].� Gene–

environment�( diet)�i nteractions�a re�a � further� complexity.�F ailure�t o�c onsider�ge notype�

may�m ask�s ignificant�a ssociations�w ith�di et;�l ikewise,�t he�e ffects�of � genetic�

polymorphisms�m ay� be�d etectable�onl y�w ith�s pecific�di etary� exposures�( ie�t he�e ffect�of �

dietary�i soflavone�i ntake� on�l evels�of �s ex-hormone�bi nding� globulin�a mong� women�w ith�

the�N -variant�of �t he�D 356N�ge ne)�[ 96].�

Observational�da ta�l ink�w eight� gain�t o�r isk�of �pos t-menopausal�br east�c ancer�a nd�l ack�of �

exercise�t o�bot h�pr e-� and� post-menopausal�br east�c ancer.�W eight�l oss�be fore�a nd�a fter�t he�

menopause�r educes�pos t-menopausal�r isk�b y�up�t o�40% �[ 97,98].�T he�obs ervational�na ture�

of�t hese�s tudies�m eans�t he�i ndependent� effect�of �e nergy�r estriction,�e xercise,�or �r eductions�

in�a diposity�on� risk�r eduction�i s�not �know n.�

What�ar e�t he�gaps ?�

The�l ong-term�e ffects�of � chemoprevention�f or�E R-positive�t umours�( beyond�f ive-year�

study�pe riods)� are�not �know n,�w hile�pr eventing�E R-negative�t umours�r emains�a �

challenge.�K ey�r esearch� areas�t o�i nform�t he�de velopment�of �c hemoprevention�a gents�a re�

40�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

to�unde rstand�w hat�i s�t he�t arget�c ell�( stem�o r�E R-negative�c ells)�a nd�t he�t arget�l esion�i n�

the�br east�( hyperplasia,� atypical�du ctal�h yperplasia,�h yperplastic� enlarged�l obular�uni t�or �

DCIS)� and�w hy�t he�E R�b ecomes�de regulated.�W e� need�s hort-term�i ntervention�s tudies�of �

preventive�a gents�a nd�s trategies,�us ing�p re-� and�p ost-intervention�bi opsies�a nd�f ine�ne edle�

aspirates�( Ki67,�E R).�

Risk�pr ediction�m odels�ne ed�t o�be �i mproved�b y�i ncluding�m odifiable� risk�f actors,�s uch�a s�

mammographic�de nsity�a nd�l ifestyle�f actors.�K ey� questions�t hat�ne ed�t o�be � resolved�

regarding�br east�de nsity� are:�w hat�do es�m ammographic�br east�de nsity� actually�m easure?�

And�i s�a bsolute�or �pe rcentage�br east�de nsity�m ost�r elated�t o�r isk?�P rospective�s tudies�of �

breast�de nsity�( using�s tandardised�m ethods)�a nd�d emographic�( body�s ize�a nd�dr ug�

history)�d ata�a re�r equired�t o�e lucidate�f actors�( ie� age� and�l ifestyle�f actors,�a nd�w eight)�

that�m odify�br east�de nsity,�a nd� whether�t hese�m odify�t he� relationship�be tween�de nsity�

and�r isk.�

Elucidating�t he� role�of �di et�i n�t he�a etiology�o f�br east�c ancer�r equires�pr ospective�s tudy�o f�

diet�a nd�ge netic�v ariation,�us ing�s ensitive�di etary� assessment�m ethods�( food�di aries).�T he�

relative�e ffects�of �e nergy� restriction,�e xercise�a nd� reduced� adiposity�on�r isk� are�unl ikely�

to�be �de termined�f rom�e pidemiology�a nd�ne ed�t o�b e�unr avelled�b y�s hort-term�c ontrolled�

biomarker�t rials.� In� addition,�t he�r ole�of �a dipose�t issue�a nd�i ts�s ecretory�pr oducts�

(oestrogen�a nd�a dipokines)�i n�br east�c ancer�de velopment�a nd�pr ogression�n eed�t o�be �

examined�f rom�l aboratory� studies.�S ince�w eight�l oss�i s�di fficult�t o�a chieve�a nd�m aintain,�

effective�w eight-loss�s trategies� and�t he�be nefits�of �e nergy�r estriction�m imetic�f or�c ancer�

prevention�ne ed�t o�b e�de termined�[ 99].�P sychosocial�r esearch�i s�r equired�t o� explore�t he�

health�be liefs�of �hi gh-risk�a nd�popul ation-risk�w omen,�a nd�t o�de termine�t heir�pot ential�

interest�i n�l ifestyle�o r�pha rmacological�s trategies�f or�br east�c ancer�pr evention.��

What�ar e�t he�pr oblems?�

Accrual�a nd�r etention�i n�pr evention�t rials�i s�a �pr oblem;�t here�i s�c urrently� around�a �10% �

uptake�a nd�a �30 %�dr op-out�r ate.�B etter�r isk�pr ediction�w ould�e nable�r ecruitment�t o�be �

targeted�a t�w omen�w ith�hi gher�l evels�of �r isk�a nd�m otivation.�W e�a lso�ne ed�t o�m ake�t he�

41�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

public�a ware�of �t he� cancer�pr evention�m essage�( as� with�t he� Know� Your�G ail�Sc ore�

campaign�i n�t he�U SA).� We�ne ed�m ore�di verse�r ecruitment�t o�s tudies�i n�t erms�of �a ge�a nd�

ethnicity.�

Transdisciplinary�i nput�i s�ne eded�w ithin�pr evention�t rials�( eg� geneticists,�e pidemiologists,�

nutritionists,�ps ychologists�a nd�c linicians)�t o�s tudy�t he�ps ychosocial,�c ompliance� and�

genetic�a spects�of �pr evention.�

We�a lso�ne ed�be tter�m odels�t o�r esearch�ne w�c hemoprevention�a gents,�s uch� as�s tem�c ell�

progenitor�a ssays� and�hu man�br east�t issue�i n�nude �m ice,�a nd�be tter�s urrogate�m arkers�of �

breast�c ancer�r isk.�F urther�m ammographic�de nsity�r esearch�r equires�s tandardised�

methods�of �m easurement�t hat�ne ed�t o�ke ep�p ace�w ith�t echnology�i n�br east�s creening� (eg�

digitised�m ammography� and�c omputer-aided�de tection�pr ogrammes).�

��

Funding�i s� an�i ssue�be cause�pr evention�a nd�ps ychosocial�r esearch�h as�not �be en�a �hi gh�

priority.� Intervention�s tudies�a re�l abour�i ntensive� and�of ten�r equire�m ore�f unding�t han�

basic�s cience�r esearch�or � than�t hat�c urrently� available�i n�pr oject� grants.��

Translational� implications�

Identifying� women�w ho� are�a t�hi gh�r isk�of �d eveloping�br east�c ancer� would�e nable�

clinicians�t o�t arget�c hemoprevention�m ore� effectively.� Likewise,�unr avelling�t he�l inks�

between�di et� and�l ifestyle,�ge netic�v ariation�a nd�r isk�w ould�e nable�us �t o�t arget�l ifestyle�

cancer�pr evention�s trategies�a t�t he�w omen�w ho�w ould�be nefit�m ost.�E lucidating�how �

lifestyle�f actors�i nfluence�r isk�w ould�unde rpin�a n�e vidence-based�l ifestyle� cancer�

prevention�m essage,� and� may� enable�us �t o�de velop�dr ugs�t hat�m imic�t heir�e ffects�( ie�

energy�r estriction�m imetics).�

Breast�s creening��

What�do�w e� know?�

Breast�s creening�us ing�m ammography�r educes�m ortality�f rom�b reast�c ancer�i n�w omen�

older�t han�50�[ 100],�a nd�t here�i s�l imited�e vidence� among�w omen� at�hi gh�r isk�of �br east�

42�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

cancer�( lifetime�r isk� >�1: 6)�a ged�40�or �ol der�[ 101-103].�C ontrast-enhanced� magnetic�

resonance�i maging�( MRI)�i s�m ore�s ensitive�t han� mammography� for�de tecting�c ancer�i n�

high-risk�w omen�[ 104].�

What�ar e�t he�gaps ?�

We�do�not �know �t he�be nefits�of �s creening�w omen� younger�t han�40�or �w hether�M RI�

reduces�m ortality�f rom�br east�c ancer�a mong�hi gh-risk�w omen.�W e�a lso�ne ed�t o�de termine�

whether�t he�n ewer�3�T esla�M RI�m achines�a re�m ore�s ensitive�t han�t he�1.0–1 .5�T esla�M RI�

machines�t hat�w ere�us ed� in�e arlier�s tudies.�W e�ne ed�t o�c onduct�f urther�s tudies�t o�de fine�

the�be st�s urveillance�m ethod�f or�w omen�w ith�de nse�br easts,�w omen�a t�hi gh� risk�a nd�

women�w ho�ha ve�h ad�br east�c ancer,� and�c onsider�t he�pot ential�f or�us ing�ot her�t echniques,�

such�a s�ul trasound�or �i nfrared�i maging,�t o�s creen�t hese�w omen.�

What�ar e�t he�pr oblems?�

Research�n eeds�t o�ke ep�p ace�w ith�i mproving�i maging�t echnology.�

There� are� few�d ata�on�t he�upt ake�of �w omen�ol der�t han�70�t o�t he�N ational�B reast�

Screening�P rogramme.�T he�r ecent�de cline�i n� attendance�f or�s creening�i n�t he�ge neral�

(eligible)�popul ation�s uggests�w e�ne ed�t o� explore�w omen’s�he alth�be liefs�r egarding�br east�

screening.� For� example,�doe s�a ttending�s creening� negate�w omen’s�i nterest� in�pr evention�

strategies�be cause�m any� women�pe rceive�s creening�a s�p revention?�

Translational� implications�

Defining� optimum�s creening�m ethods�i n�di fferent� populations�m ay�s ave�l ives�a nd�e nsure�

more�e ffective�us e�of �l imited�r esources�w ithin�t he�N HS.�

The�i mportance�of �di et�an d�e xercise�af ter�a�di agnosis�of �e arly�br east�c ancer��

What�do�w e� know?�

Weight,�di et�a nd�e xercise�i mpact�on�out come�a fter�a �di agnosis�of �br east�c ancer.�M any�

breast�c ancer�pa tients�a re�ove rweight�a t�t he�t ime�o f�di agnosis,�w hile�m any� more�ga in�

weight� after�di agnosis,�w hich�m ay�i ncrease�t heir� risk�of �d ying�f rom�br east�c ancer�

[105,106]�or �f rom�w eight-related� co-morbidities�[ 107]�( eg�c ardiovascular�di sease�a nd�

43�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

other�c ancers).�R ecent�d ata�f rom�a �r andomised�c ontrolled�t rial�( the�W omen's� Intervention�

Nutrition�S tudy�[ WINS])�i n�t he�U SA�r eported� a�2 4%�i mproved�r elapse-free�s urvival�ove r�

five� years�a mong�pos t-menopausal�br east�c ancer� patients�f ollowing�a �l ow-fat�di et�

(commenced� within�t he�f irst� year�of �di agnosis),� compared�w ith�t he� group�r eceiving�us ual�

care�[ 108].�S ince�w eight�c ontrol�oc curred�a longside�t his�l ow-fat�di et�i t�i s�unc lear�w hether�

low�f at�or �w eight�c ontrol� was�l inked�w ith�i mproved�s urvival�i n�t his�s tudy.�

The�f easibility�o f�f ollowing�a �l ow-fat�di et� among� breast�c ancer�pa tients�ha s�be en�pi loted�

in�t he�W INS�U K�s tudy,� where�50 %�of �br east�c ancer�pa tients� achieved� a�l ow-fat�i ntake�

(less�t han�20% �e nergy�f rom�f at)�[ 108].�O bservational�da ta�l ink�e xercise�a fter�di agnosis�

(more�t han�t hree�hour s�p er�w eek)�w ith�i mproved�s urvival�[ 109].�A �r ecent�s ystematic�

review�l inked�e xercise�d uring�a nd�a fter�t reatment�t o�i mproved�ph ysical�f unction�a nd�

reduced� fatigue,�w hile�b enefits�i n�qua lity�of �l ife� were�m ainly�s een�i n�t he�po st-treatment�

phase�[ 110].��

What�ar e�t he�gaps ?�

The�da ta�on�w eight� and�o utcome�ha ve� come�f rom� historic�c ohorts.�T he�e ffect�of �w eight�

and�w eight� gain�on�out come�a longside� current�a djuvant�t herapies�n eeds�t o� be�de termined.�

We�ne ed�t o�de fine�d eliverable�di et�a nd� exercise�i nterventions�a fter�di agnosis,�a nd�t he�

optimum�t iming�a nd�m ode�of �de livery� for�i nterventions�ne ed�t o�be �de rived� from�hi gh-

quality�r andomised� controlled�t rials�bot h�dur ing�a nd�a fter�t reatment.�

Improved�br east�c ancer�s urvival�a mong� recent�c ohorts�s hifts�t he�f ocus�t o�c o-morbidities.�

However,�t here� are� few�d ata�on�t he�pr evalence�of � co-morbidities�or �t heir�e ffect�on�

outcome.��

What�ar e�t he�pr oblems?�

There�h as�be en� a�poor �up take�t o�di et�a nd�e xercise�t rials�pos t�di agnosis.�M ore�pa tient-

centred�qu alitative�s tudies�a re�ne eded�t o�e stablish� preferences�a long�w ith�b arriers� and�

motivators�t o�c hanging�b ehaviour�a fter�di agnosis.� The�f easibility�o f�de livering�di et�a nd�

exercise�i nterventions�po st�di agnosis�w ithin�t he�N HS�i s�a �pot ential�c oncern.�H ealthcare�

44�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

professionals�ne ed�t o�‘ buy� in’�a s�di et�a nd�e xercise� traditionally�a re�not �pr iorities�a mong�

breast�c ancer�t eams.��

We�a lso�ne ed�t o�c onsider�pot ential�f unding,�a ttitudes�a nd�w ork�p ressures�o f� healthcare�

professionals,�t o�de cide� who�i s�be st�pl aced�t o�de liver�i nterventions.�G ood�b iomarkers�of �

prognosis�a nd�m easurements�of �qua lity�of �l ife�a mong�br east�c ancer�pa tients�ne ed�t o�be �

defined�s o�w e� can� evaluate�t he�e ffect�of �di et� and�e xercise�i nterventions�i n�t rials.�

Translational� implications�

Optimum�di et�a nd�e xercise�i nterventions�m ay�i mprove�out comes�a nd�qu ality� of�l ife�f or�

people�w ith�br east� cancer.��

45�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

7.�P sychosocial�A spects� of�B reast�C ancer�( Table�7) �

Primary�pr evention�of �b reast�c ancer:�ps ychosocial�as pects�of �r isk�an d�pr evention�

Genetic�t esting�of fers�ps ychosocial�be nefits�f or�m any� women�a t�hi gh�r isk�o f�de veloping�

breast�c ancer,�but �pa tients’�pe rceptions�of �r isk�a re� often�i naccurate� and�w hile�m any�

methods�ha ve�be en�us ed� to�c ommunicate�i nformation�a bout�r isk,�t hey�do�no t�a lways�

improve�pa tients’�unde rstanding�[ 111].��

What�do�w e� know?�

Research�i nto�t he�ps ychosocial�i mpact�of �bi lateral�r isk-reducing�m astectomy� is�l imited,�

but�s uggests�t hat�w hile�w omen�m ay�b e�s atisfied�w ith�t heir�de cision�t o�unde rgo�s urgery,�

they�m ay� report�di ssatisfaction�w ith�t heir�bod y�i mage�a fterwards.�M ost�w omen�a re�l ess�

worried�a bout� cancer�a fter�s urgery,�but �t his�m ay�be �be cause�t hey�ove restimate�t heir�r isk�

of�de veloping�br east�c ancer.�T hey�ne ed�t o�und erstand�t heir�t rue�r isk�b efore� considering�

mastectomy�[ 112].�T here�i s�g ood�e vidence�t hat�c ounselling�c an�i mprove�t he�a ccuracy�of �

perceived�r isk,�but �t o�a �v aried�e xtent.��

Breast�s creening�pr ogrammes�f or�w omen�a t�i ncreased�r isk�do�not �i ncrease� anxiety�i n�

women�w ho�do�not �r equire�f urther�i nvestigation,�but �w omen�w ho�a re�r eferred�f or�f urther�

investigations�a re�e vidently�m ore� anxious�[ 113].� �

What�ar e�t he�gaps ?�

Exploring�i ssues�a round� cancer� genetics�i s�pa ramount,�s uch�a s�f ollow-up�s tudies�of �

carriers�w ho�ha ve�or �h ave�not �unde rgone� risk-reducing�s urgery,� and�t heir� partners.�

Research�i s�n eeded�i nto�t he�i mpact�of �di fferent�m odes�of �r isk�c ounselling�o n�pe rceived�

risk�a ccuracy,�h ealthcare� behaviour�a nd�upt ake�of � risk-management�opt ions.�W e�a lso�

need�t o�de velop� and�e valuate�de cision�a ids�f or�r isk�m anagement�a nd� choice�of �s urgery.�

Research� also�ne eds�t o�e xamine�f urther�t he�e ffect� of�c ommunicating� risk�a mong�pa rtners�

and�f amilies�of �w omen�di agnosed�or �i dentified� as� having� an�i ncreased� chance�of �

developing�t he�di sease. ��

46�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

After�di agnosis:�ps ychosocial�as pects�f or�pat ients�w ith�e arly�an d�adv anced�di sease�

What�do�w e� know?�

Areas� currently�w ell�s upported�i nclude�de scriptive�s tudies�of �t he�e xperiences�of �pa tients,�

carers,�f amily�a nd�p artners�[ 114,115];� the�c omparative�i mpact�of �m astectomy�ve rsus�

conservative�s urgery�[ 116],�a nd�of �br east�r econstruction�[ 117];�a spects�of �doc tor–patient�

communication�[ 118,119];�r ecognition�of �t he�ne ed�t o�i nclude�qua lity-of-life�e valuation�i n�

cancer�t reatment�t rials;�r eturn�t o�w ork�a fter�t reatment�[ 120]�a nd�pot ential�b enefits�of �

exercise�on�qua lity�o f�l ife�[ 121].�T his�r esearch�ha s� fruitfully�e mployed�bot h� quantitative�

and�qua litative�m ethods�t o�de monstrate�t hat�bi omedical�de velopments�a re�n ot�a �pa nacea�

for�t he�ps ychosocial�di stress�a ssociated�w ith�t he�di sease.�P sychosocial�i nterventions�ha ve�

been�s hown�t o�be nefit�di stressed�pa tients,�but �a re�o f�l ess�va lue�i n�pa tients�un selected�on�

grounds�o f�ps ychological�f unctioning�[ 122].�

What�ar e�t he�gaps ?�

It�i s�i mperative�t hat�ps ychosocial�r esearch�k eeps�p ace�w ith�de velopments�i n�bi omedical�

treatment�a nd�c are,�i ncluding�s urgical�a nd�a djuvant�opt ions�a vailable�( eg�n ew�s urgical�

procedures�f or� reconstructive�s urgery�a nd�d evelopments�i n�hor mone�t herapy),� ways�of �

effectively�c ommunicating�i nformation�a bout�t hese�opt ions�a nd�a iding�p atient�de cision�

making�w here� appropriate.�A n�e valuation�of �s elf-help�s trategies�i s�w arranted�a nd�w e�a lso�

need�t o�br oaden�t he�r esearch�a genda�be yond�ps ychological�di stress�t o�i nclude�

interventions�f or�bod y�i mage�a nd�s exual�pr oblems.�

Research�h as�i dentified�p atients’�pr iorities�f or�f uture�r esearch,�na mely�t he�i mpact�of �

cancer�on�l ife�( how�t o�l ive�w ith�c ancer),� risk�f actors�a nd�c auses,�e arly�de tection�a nd�

prevention�[ 123]. � Psychosocial�r esearch� currently� focuses�on�e arly�a nd� end-stage�b reast�

cancer,� yet�m ost�pa tients� are�not �unde r�t he�c are�o f� a�pa lliative�t eam�a nd�h ave�t o�l ive�w ith�

their�di sease�a nd�t he�s ymptoms�of �a djuvant�t reatment�( for�e xample�bone �p ain,�

neuropathy,�ph ysical� changes�t o�a ppearance)�a s� a� chronic�c ondition.�T he� experiences�of �

patients�i n�t his�s ituation�a re�a �s ignificant� gap�i n�our �know ledge.� Future� research�t herefore�

needs�t o�c onsider�b reast� cancer�i n�t erms�of �t hree�p eriods� –�e arly,� chronic� and�e nd�–�a nd�t o�

examine�t he�s pecific�ne eds�of �pa tients�a ssociated� with�e ach�s tage�[ 123].�T he�s pecific�

47�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

support�ne eds�of �bot h�br east�c ancer�pa tients�a nd�t heir�f amilies�f ollowing�di agnosis�of �

recurrence�a lso�w arrants�f urther�r esearch�[ 124]. �

There�i s�onl y�l imited�r esearch�i nto�c o-morbidities,� yet� cancer�i s�r arely�e xperienced�i n�

isolation�a nd�m any�pa tients�a re�f aced�w ith�t he� effects�of �t he�di sease�a longside�ot her,�of ten�

chronic,�he alth�c onditions.�W e�ne ed�t o�i nvestigate�how �t o�pr ovide�a ppropriate�

psychosocial�c are�f or�pa tients�i n�t his�s ituation.��

Topics�an d�i ssues�r elevant�t o�bot h�pr eventative�a nd�pos t-diagnosis�r esearch�

What�do�w e� know?�

There�i s�now � a�s ignificant�bod y�of �r esearch�i nto�t he�m any�ps ychosocial�i ssues�

surrounding�b reast� cancer.�T his�r esearch�h as�e mployed� a�r ange�of �r esearch� methods�t o�

explore�pa tients’�e xperiences�bot h�be fore�a nd� after�di agnosis.�A lthough�t he�ps ychosocial�

impact�of �br east�c ancer�d iagnosis�a nd�t reatment�ha s�be en�i ncreasingly� recognised�b y�

researchers�a nd�c linicians�i n�r ecent� years,�t here�i s� still�g reat�pot ential�f or�ps ychosocial�

research�t o�i nform�t he�p rovision�of �c are� and�i mprove�pa tients’�e xperiences.��

What�ar e�t he�gaps ?�

Existing�r esearch�i nto�bo th�pr eventative�a nd�pos t-diagnosis�i ssues�i s�pr edominantly�

focused�on�t he� experiences�of �w hite�w omen�i n�t he�U K�a nd�U SA�w ith�a �f luent�

understanding�of �E nglish.�W e�ur gently�ne ed�a dditional�r esearch�i nto�t he�e xperiences�of �

breast�c ancer�pa tients�f rom�a �br oad�r ange�of � ethnic�m inority�popul ations�a nd�of �t hose�w ho�

do�not �f ully�unde rstand� English�s o�t hat�t ailored�c are�c an�b e�pr ovided.�S imilarly,�t he�

experiences�of �ol der�w omen�a re�und er-represented.� �

While�w e�ha ve�i dentified�t he�na ture�of �m any�ps ychosocial�i ssues�f aced�b y� patients,�t here�

is�a �pr essing�n eed�t o�de velop�a nd�r igorously�e valuate�a ppropriate�ps ychosocial�

interventions.�T hese�s hould�i nclude�t ools�t o�he lp�pa tients�m ake�de cisions,� optimal�

methods�f or�c ommunicating�r isk,�w ays�o f�de aling� with�t he�e ffects�of �t reatment�a nd�r eturn�

to�w ork�a nd�s upport�f or�h ealthcare�s taff�a t�r isk�of �b urnout.�R esearch�i n�t his�a rea�c an�

identify�t he�m ost�e ffective�m eans�of �d elivering�c ost-effective,�a ccessible�i nterventions�( eg�

48�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

timing�of �i nterventions,�r oles�of �he althcare�p rofessionals�i n�de livering�i nterventions,�

comparing� group�a nd�i ndividual�i nterventions,�a nd�us ing�de velopments�i n�t echnology� for�

providing�i nformation�a nd�de cision�m aking).��

Cross-specialty�c ollaboration�i n�br east�c ancer�r esearch�t hat�i ncorporates�ps ychological�

theory�s hould�b e�a �pr iority.� For�e xample,�ps ychological�t heories�i n�r elation�t o�be haviour�

change� could�e nhance�r esearch�i nto�di et,�e xercise� and�c hemoprevention�i nterventions�s o�

that�f actors�i nfluencing�u ptake�a nd�a dherence� are� examined.��

What�ar e�t he�pr oblems?�

A�num ber�of �i ssues�r elating�t o�t he�m ethods�c urrently�e mployed�i n�ps ychosocial�r esearch�

should�be �a ddressed.� These�i nclude�a �ne ed�f or�l onger-term� follow-up�of �t he�i mpact�of �

surgical�pr ocedures� and�r isk�c ounselling,�t o�de velop�a ppropriate�v alid�a nd�r eliable�

measures,�t o�c onsult�pa tients�a bout�r esearch�p riorities�a nd�t o�i nvolve�a �w ider�r ange�of �

research�pa rticipants�( see�a bove).�T he�l imited�f unding�a vailable�f or�ps ychosocial�r esearch�

is�a �pr oblem�a nd�l imits�t he�dur ation�of �f ollow-up� and�pr ospective�s tudies,�e specially�f or�

trials�of �ps ychological�i nterventions.�

We�m ust�i dentify� and�a ddress�t he�ba rriers�t o�t he�u ptake�of �r esearch�f indings,�f or�e xample�

by�c ontinuing�t o�r aise� awareness�o f�t he�i mportance�of �ps ychosocial�r esearch�a nd�

interventions�a nd�t he�pot ential�r ole�t hat�a ll�he althcare�s taff�i n�bot h�pr imary� and�s econdary�

care� can�pl ay�i n�p roviding�ps ychosocial�c are�[ 125].�T his�i s�i mportant�be cause�t he�

essential�r ole�pl ayed�b y�s pecialist�nur ses�i n�pr oviding�ps ychosocial�c are�a nd�t he�

facilitation�of �r esearch�i n�t his�a rea�i s�of ten�und ervalued�i n�t he�N HS.�

Translational� implications�

Further� rigorous�r esearch�i n�t his�a rea�c ould�di rectly� improve�t he� experience�of �pa tients,�

their�f amilies�a nd�t hose�a t�i ncreased� risk�of �br east�c ancer�be cause�t heir�ps ychosocial�

needs�w ould�be �m ore�a ppropriately�a nd� effectively�m et�a t�a ll�s tages�of �t heir� cancer�

journey.��

49�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Conclusion�

Research�i nto�t he�p athophysiology,�de tection,�t reatment,�pr evention�a nd�ps ychosocial�

aspects�of �br east�c ancer�h as�pr oduced� a�w ealth�of � knowledge�a nd�h as�l ed�t o�s ubstantial�

improvements�i n�t he�c are�of �pe ople�w ith�br east�c ancer�or � at�hi gh� risk�of �de veloping�t he�

disease.��

This�a nalysis�ha s�i dentified�num erous� gaps�t hat,�i f�r esolved,�c ould�ha ve�a �s ubstantial�

impact�on�t he�di agnosis,�m anagement�a nd�p revention�of �br east�c ancer.�F or� progress�t o�

occur,�t he� gap�a nalysis�p anel�ha s�m ade�t hree�k ey�r ecommendations�f or� each�of �t he�s even�

research�a reas�( Table�8 ).� While�r ecognising�t he�b arriers�t o�a chieving�t hese� aims,�B reast�

Cancer�C ampaign�u rges�r esearchers� and�f unding�b odies�w orldwide�t o�t arget�t heir�

resources�a t�t hese�p riority� areas.�

50�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Abbreviations�

COX-2�= �c yclo-oxygenase-2��

DCIS�= �du ctal�c arcinoma�i n�s itu��

DDR�= �D NA�d amage�r esponse�

DNA�= �de oxyribonucleic�a cid�

EGFR�= �e pidermal� growth�f actor�r eceptor�

ER�= �oe strogen�r eceptor�

MRI�= �m agnetic�r esonance�i maging�

mRNA�= �m essenger� ribonucleic�a cid�

NHS�= �N ational�H ealth�S ervice�

RNA�= �r ibonucleic� acid�

RTK�= �r eceptor�t yrosine� kinase�

SNP�= �s ingle�nuc leotide� polymorphism��

TMA�= �t issue�m icroarray�

UK�= �U nited�K ingdom�

USA�= �U nited�S tates�of � America�

WINS�= �W omen's� Intervention�N utrition�S tudy�

Competing� interests�

AT,�J G,�D H,�M H�a nd� IH�a re�c urrent�m embers�of � Breast�C ancer�C ampaign’s�S cientific�

Advisory� Board.�A T,�K B,�A C,�J G,�D H,�M H,� IH� and�C S�a re�c urrent�B reast� Cancer�

Campaign� grant�hol ders.�

Authors’� contributions�

AT,�K B,�A C,�J G,�D H,�M H�a nd� IH�d esigned�t he�m eeting� format.�A ll�a uthors�r ead�a nd�

approved�t he� final�m anuscript.�

51�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Acknowledgements�

The�f ollowing�i ndividuals�pa rticipated�i n�t he� gap� analysis�m eeting� (*denotes�r ecipient�of �

current�or �p revious� Breast�C ancer�C ampaign�f unding,� +denotes�c urrent�o r�pr evious�B reast�

Cancer�C ampaign�S cientific�A dvisory�B oard�m embership).�

Dr� Liz�A nderson,�D r�J ohn�B artlett,�D r�S helia� Bingham,�D r�J eremy�B laydes*,�D r�S imon�

Boulton*,�P rofessor�N igel�B undred*+,�D r�R obert� Clarke*+,�P rofessor�R obert�C oleman*,�

Professor�C harles�C oombes,�P rofessor�J essica�C orner*,�P rofessor�J ack�C uzick,�P rofessor�

Trevor�D ale*,�D r� Amanda�D aley,�D r� Isabel�dos �S antos�S ilva*,�D r�A lison�D unning*,�D r�

Suzanne�E ccles*+,�D r�P aul�E dwards*,�P rofessor� Dylan�E dwards*,�P rofessor� Ian�E llis*,�

Dr�O livia�F letcher*,�D r� Thomas�F riedberg*,�P rofessor�W illiam�G ullick*,� Professor� Ian�

Hart*+,�D r�P enelope� Hopwood+,�P rofessor�W en�J iang*,� Dr�S tephen�J ohnston*+,�P rofessor�

Louise�J ones*+,�P rofessor�W illiam�M iller*+,�D r�S otiris�M issailidis*,�M s�B arbara�P arry,�

Professor�J ulian�P eto,�D r�S arah�P inder+,�D r�C olin�P urdie,�D r�E rik�S ahai*,� Dr�A ndrew�

Schofield*,�D r�M atthew� Smalley,�D r� Valerie�S peirs*+,�P rofessor�J oyce�T aylor-

Papadimitriou*,�P rofessor�G erry�T homas,�P rofessor�A shok�V enkitaraman*,�P rofessor�

Rosemary�W alker*+,�D r� Andrew�W ardley+,�D r�R uth�W arren*+�a nd�D r�C hristine�W atson*�

Rachel�W heeler� acted� as� scientific�e ditor�a nd�w as� funded�b y�B reast�C ancer� Campaign.��

Breast�C ancer�C ampaign�s taff�A rlene�W ilkie�a nd�D r� Lisa�W ilde�a ssisted�i n�t he�de sign�

and�i mplementation�of �t he�m eeting�f ormat� and�a cted�a s�f acilitators�t hroughout�t he�

process.�D r� Annabelle� Ballsdon�w as�r esponsible�f or�t he�m eeting�l ogistics�a nd�a cted�a s� a�

facilitator�a t�t he�m eeting.�A my�C aldwell,�P amela�G oldberg,�C laire� Learner�a nd�T anya�

Sadhwani�a cted� as�f acilitators�a t�t he�m eeting.�

The�ga p�a nalysis�m eeting�w as�he ld�a t�T he� Novartis�F oundation�a �r egistered�c harity�i n�

England� and�W ales�w hich�ha s�no�c ommercial�t ies.�

52�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

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Breast�C ancer�C ampaign�g ap� analysis�doc ument�

108.�C hlebowski�R T,�B lackburn�G L,�T homson�C A,�N ixon�D W,� Shapiro�A ,�H oy�M K,�

Goodman�M T,�G iuliano�A E,�K aranja�N ,�M cAndrew�P ,� et�al : �D ietary�f at�r eduction�an d�

breast�c ancer�ou tcome:� interim�e fficacy�r esults�f rom�t he�Wo men's�I ntervention�

Nutrition�S tudy. � J�N atl� Cancer�I nst �2006,� 98:1767-1776.�

109.�H olmes�M D,�C hen�W Y,�F eskanich�D ,� Kroenke�C H,�C olditz�G A:� Physical�ac tivity�

and�s urvival�a fter�b reast�c ancer�d iagnosis.� JAMA�2005,� 293:2479-2486.�

110.�M cNeely�M L,�C ampbell�K L,�R owe�B H,�K lassen�T P,�M ackey�J R,�C ourneya�K S:�

Effects�of �e xercise�on �b reast�c ancer�p atients�an d�s urvivors:�a�s ystematic�r eview�an d�

meta-analysis. �C MAJ�20 06,� 175:34-41.�

111.�J ulian-Reynier�C ,�W elkenhuysen�M ,�H agoel� L,�D ecruyenaere�M ,�H opwood�P ;�

CRISCOM�Wor king�G roup:�R isk�c ommunication�s trategies:�s tate�of �t he�ar t�an d�

effectiveness�i n�t he�c ontext�of �c ancer�g enetic�s ervices.� Eur�J �H um� Genet � 2003,� 11:725-

736.�

112.� Lostumbo� L,�C arbine�N ,�W allace�J ,�E zzo� J:� Prophylactic� mastectomy�f or�t he�

prevention�of �b reast�c ancer. � Cochrane�D atabase�Sy st�R ev�2004,� 4:CD002748.�

113.�B rett�J ,�B ankhead�C ,�H enderson� B,�W atson�E ,�A ustoker�J :� The�p sychological�

impact�of � mammographic�s creening.�A �s ystematic�r eview.� Psychooncology�2005,�

14:917-938.�

114.�B rennan�J ,�M oynihan,C:� Cancer�i n�C ontext:�A �P ractical�G uide�t o�Suppor tive�C are. �

Oxford:�O xford�U niversity�P ress;�2004.�

115.�W agner�C D,� Bigatti�S M,�S torniolo�A M:� Quality�of �l ife�of � husbands�o f�w omen�

with�b reast�c ancer. � Psychooncology� 2006,� 15:109-120.�

116.�M oyer�A :� Psychological�ou tcomes�of �b reast-conserving�s urgery�v ersus�

mastectomy:�a� meta-analytic�r eview. � Health�P sychol �1997,� 16:284-298.�

117.�H arcourt�D M,�R umsey� NJ,�A mbler�N R,�C awthorn�S J,� Reid�C D,�M addox�P R,�

Kenealy�J M,�R ainsbury� RM,�U mpleby�H C:� The�p sychological�i mpact�of �m astectomy�

with�or �w ithout�i mmediate�b reast� reconstruction:�a�p rospective,� multi-centred�

study. � Plast�R econstr�Sur g �2003,� 111:1060-1068.�

118.�S cott�J T,�H armsen�M ,�P rictor�M J,�E ntwistle�V A,�S owden�A J,�W att�I :� Recordings�or �

summaries�of �c onsultations�f or�p eople� with�c ancer. � Cochrane�D atabase� Syst�R ev�

2003,� 2:CD001539.�

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119.�F allowfield� L,�J enkins�V ,�F arewell�V ,�S olis-Trapala� I:� Enduring�i mpact�of �

communication�s kills�t raining:�r esults�of �a�12- month�f ollow-up. � Br�J �C ancer �2003,�

89:1445-1449.�

120.�M ain�D S,�N owels�C T,�C avender�T A,�E tschmaier�M ,�S teiner�J F:� A�q ualitative�s tudy�

of�w ork�a nd� work�r eturn�i n�c ancer�s urvivors. � Psychooncology�2005,� 14:992-1004.�

121.�M cNeely�M L,�C ampbell�K L,�R owe�B H,�K lassen�T P,�M ackey�J R,�C ourneya�K S:�

Effects�of �e xercise�on �b reast�c ancer�p atients�an d�s urvivors:�a�s ystematic�r eview�an d�

meta-analysis. � CMAJ�20 06,� 175:34-41.�

122.�S heard�T ,�M aguire� P:� The�e ffect�of �p sychological�i nterventions�on �an xiety�an d�

depression�i n�c ancer�p atients:�r esults�of �t wo�m eta-analyses. � Br�J �C ancer �1999,�

80:1770-1780.�

123.�C orner�J ,�W right�D ,�F oster�C ,�G unaratnam�Y ,�H opkinson�J ,�O kamoto�I :� The�

Macmillan�L istening�St udy:�L istening�t o�t he�V iews�of �P eople�A ffected�by �C ancer�about �

Cancer�R esearch.�P ublished�R eport.� London,�U K:�M acmillan�C ancer�S upport;�2006.� �

124.�S chofield�P ,�C arey� M,�B onevski�B ,�S anson-Fisher�R :� Barriers�t o�t he�p rovision�o f�

evidence-based�p sychosocial�c are�i n�on cology. � Psychooncology� 2006,� 15:863-872.�

125.�N orthouse� LL,�M ood�D ,�K ershaw�T ,�S chafenacker� A,�M ellon�S ,�W alker�J ,�G alvin�E ,�

Decker�V :� Quality�of �l ife�of �w omen�w ith�r ecurrent�b reast�c ancer�an d�t heir�f amily� m�

embers. � J�C lin�O ncol� 2002,�20 :4050-4064.�

65�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Table�1: �S ummary�of �G ap�A nalysis� for�G enetics�of �B reast�C ancer��What�do�w e�know :�

• Multiple�g enes�of �di fferent�pe netrance�a re�i nvolved�i n�t he�pr edisposition�t o� breast�

cancer�

• Genome�w ide�s creens�a nd�s omatic�g enetic�a pproaches�a re�i dentifying�f urther�

genes�i nvolved�i n�br east�c ancer�

Gaps�

• Detailed�unde rstanding�o f�t he�a ctions�of � BRCA1�a nd�B RCA2�

• Knowledge�of �l arge�s cale�g enetic�r earrangements�i n�t umour�c ells�

• The�i mportant�va riants,�e ffects�a nd�i nteractions�of �l ow�pe netrance� genes�

• Further�i dentification�of � point�m utations�a nd�e pigenetic�c hanges�

Problems�

• The�qua lity,�qu antity�a nd�a ccessibility�o f�m aterials�

• Funding� for�l arge�s cale�e xperiments�( such�a s�s equencing)�us ing�e xpensive�

equipment�

• Bioinformatic�a nalysis�s kills�

Translational�i mplications�

• Classifying�br east�t umours�a ccording�t o�t he�s ignalling�pa thways�t hat� are�di srupted�

to�pr edict�pr ognosis�a nd�r esponse�t o�t herapy�

• Determining�t he�r elevance�of �s omatic�e vents�t o�pr ognosis�a nd�r esponse�t o�t herapy�

• Generate�ne w,�t argeted�t herapies�b ased�on�t arget� discovery�

• Better� genetic�r isk� estimation�

Recommendations�

• Encourage�de velopment� of�r esearch�t echniques�t o� allow�i ntegrated�a nalysis�of �

sequence�l evel,�e pigenetic�a nd�l arge-scale�s omatic�c hanges�

• Engage�i n�na tional�i nitiatives�f or�a ctivities�s uch�a s�hi gh-throughput�r e-sequencing�

and�U K�c ontrols�

• Encourage�r esearch�i nvolving�i ntermediate�phe notypes�

66�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Table�2: �S ummary�of �G ap�A nalysis� for�t he�I nitiation�of �B reast�C ancer�

What�do�w e�know ?�

• Animal�m odels�ha ve� given�us �gr eat�i nsight�i nto�t he�m olecular�p athways�i nvolved�

in�br east�de velopment� and�d ysregulation�i n�c ancer�

What�a re�t he�G aps?�

• The�r elationship�of �s ignalling�pa thways�t o�duc tal� and�a cinar�br east�a rchitecture�

• The�ne ed� for�w idespread� use�of �m ore�a ppropriate�i n�vi vo�a nd�c ulture�m ethods�

• The�i mportance�o f�s troma�a nd�ot her� cell�t ypes,�c ell�a dhesion�a nd�t he�e xtracellular�

matrix.�

• Understanding�s tem�c ells�

• Understanding�m echanisms�of �e pithelial�a poptosis�

• Understanding�how �pr egnancy�a nd�f unctional�di fferentiation�i n�t he�br east�pr otect�

against�br east�c ancer�

Problems�

• The�br east�c ell�l ines�us ed�a nd�t heir�c ulture� conditions�

• A�w ider�va riety�of �pr omoters�w ith�s patial,�t emporal�a nd�di fferentiation�c ontrol�o f��

gene�e xpression�i s�ne eded�

• The�ne ed� for�m ouse�m odels�of �s pecific�b reast� cancer�t ypes� eg�t riple�ne gative�

breast�c ancer�

• The�i mplantation�m ethods�f or�s ingle� cells�i n�vi vo�

Translational�i mplications�

• Understanding�t he�c omplex�i nteractions�be tween� cell�t ypes�s hould�pr ovide� new�

opportunities�f or�i ntervention�

• Identifying�p reinvasive� changes�ha s�i mplications�f or�pa tient�t ailored�a pproaches�

Recommendations�

• Develop�t hree-dimensional�c ell�c ulture�m odels,�c ontaining�m ultiple�c ell�t ypes,�t hat�

reflect�t he�t issue�a rchitecture�of �t he�nor mal� and�di seased�br east�

• Generate�be tter�a nimal�m odels,�i n�w hich�ge ne�e xpression�c an�be �m anipulated�i n�e ach�

cell�t ype�of �t he�m ammary� gland� and�w ill�not �be �a ltered�b y�t ransdifferentiation�or �

dedifferentiation�

67�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

• Gain�a � greater�und erstanding�of �t he� genetic�c hanges�t hat�oc cur� within�a typias�a nd�

DCIS�

68�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Table�3: �S ummary�of �G ap�A nalysis� for�P rogression�of � Breast�C ancer�

What�do�w e�know ?�

• Oestrogen�r eceptor,�r eceptor�t yrosine�ki nase�( RTK)�a nd�D NA�r epair�pa thways�

have�be en�e xtensively�r esearched�

• Around�50% �of �D CIS�w ill�pr ogress�t o�i nvasive�di sease�i f�unt reated,�w ith�12 –20%�

recurring� at�10� years�de spite�a ppropriate�t reatment.�

What�a re�t he�G aps?�

• Understanding�t he�c omplexities�of �br east�c ancer�i ntracellular�s ignal�t ransduction�

pathways,�pa racrine�pa thways,�i nvasion,�a ngiogenesis�a nd�m etastasis�i ncluding�

relevance�of �t hese�m echanisms�t o�c linical�pr ogression��

• Whether�t here� are�i nherently�m igratory�s tem�c ells�or �i s�m etastatic�c apacity�

acquired�

• Understanding�t ime-dependent�pr ogression�e vents,�not ably�dor mancy�a nd�

reactivation�of �m icrometastasis,�a t�pa rticular�s econdary�s ites�

• Understanding�t he�e merging�r elationship�be tween� therapeutic� resistance� and�

metastasis��

• Causative�f actors�unde rlying�r ecurrence�of �D CIS�o r�pr ogression�t o�i nvasive�

disease�

• Understanding�i nterplay� between�s troma,�m yoepithelial�a nd�e pithelial�c omponents�

during�e arly�pr ogression� and�i nterplay�be tween�t umour�c ells,�s troma�a nd�i mmune�

system�i n�m etastasis�

• The�ne ed� for�i mproved�p reclinical�m odels�of �t he�i nfluences�of �t he�

microenvironment,�s ite�s pecific�m etastasis� and�do rmancy� �

• In�vi vo�i maging�t echnologies�t o�s tudy�t he�d ynamics�of �m etastasis�a nd�r elate�t his�

to�s ignalling�m echanisms,�a s�w ell�a s�m eans�t o�m anipulate�t hese�m echanisms�t o�

evaluate�t argeting�pot ential�

Problems�

• Appropriate� clinical�s amples�t o�e valuate�bi omarkers�a nd�c ellular�e ndpoints�

• Appropriate�p reclinical� models�a nd�i mproved�r esearch� reagents�

• Increasingly� complex�a nd�m ultidisciplinary� research�i nfrastructure���

Translational�i mplications�

69�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

• Identifying�p atients�a t�i ncreased�r isk�of �di ssemination��

• Effectively�p redict�t herapeutic�r esponse� with�g rowth�i nhibitors.��

• Improve�s election�of �pa tients�w ith�D CIS�f or� adjuvant�r adiotherapy�or �e ndocrine�

therapies,��

• Identify�c ellular�t argets�f or�de veloping�ne w� agents�t o�t arget�br east� cancer�

progression�e ffectively� and�s electively�

Recommendations�

• Improve�pr eclinical�m odels,�r esearch�r eagents�a nd�t echnologies�( including�i maging)�

• Enhance� access�t o�a ppropriate�c linical�m aterial,�n otably�m atched�s amples� during�

progression�a nd�s equential�s amples�obt ained�dur ing�t reatments�i ncluding�n ew�a gents� �

• Consider�t he�ge netic�s ignature/specific� genetic�l esions�w hen�e xploring�pr ogression�

biology�a nd�de signing�c linical�t rials�

70�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Table�4: �S ummary�of �G ap�A nalysis� for�T herapies�an d�T argets�i n�B reast�C ancer�

What�do�w e�know ?�

• The�s elective�us e�of �c ombinations�of �s urgery,�r adiotherapy,�c hemotherapy,� and�

biological�t herapies�ha s�i mproved�pa tient�s urvival�i n�r ecent� years.�

• Not�a ll�t herapies�us ed� are�e ffective�on�a ll�pa tients�

What�a re�t he�G aps?�

• There�i s�a n�i ncomplete�u nderstanding�of �t he�bi ology�of �b reast�c ancer�i ncluding�t he�

effects�of �c ompensatory� signalling�p athways�r esponsible�f or�dr ug�r esistance�

• We�c annot�de termine�w ho�g oes�on�t o�d evelop�m etastatic�di sease�o r�dr ug�r esistant�

cancers�

• Individualisation�of �t herapies�c ould�be �i mproved�

• The�opt imal�dur ation�of �t herapy�i s�unc lear�f or�m any� drugs�

Problems�

• There� are�i nsufficient�m odel�s ystems�f or�t he�c omplexity�a nd�di versity�of �b reast�

cancer�

• The�ne ed�t o�unde rstand�n ot�onl y�t he�c ancer�but �t he�t umour�m icroenvironment�a nd�

patient�c haracteristics�( including�dr ug�m etabolism�a nd�i mmune�m echanisms)�

• Availability�of �c linical�m aterial�i s�s carce,�p articularly�f rom�m etastatic�di sease�

tissues�

• The�ne oadjuvant�m odel� could�be �us ed�m ore�e ffectively��

Translational�i mplications�

• Patients�c ould�be �s elected�f or�a ppropriate�t herapy� more�e ffectively�

• Enhanced�und erstanding� of�t he�s equencing,� combinations�a nd�dur ation�of �

treatments�

Recommendations�

• Build�r esources�t hrough� high-quality,�uni form,�m ulticentre�c ollection�of � clinical�

material�f rom�br east�c ancer�pa tients�be fore� and�dur ing�t reatment�( including�

neoadjuvant�s tudies),�i ncluding�s amples�of �pr imary� tumours�a s�w ell�a s�m etastatic�

deposits�

• Develop�m ethods�f or� easy,�r eproducible�m onitoring�of � response�t o�a nd�

development�of �r esistance�t o�t herapy,�a s� well�a s�e arly�di sease�p rogression�

71�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

• Increase�r esearch� efforts� into�t he�r ole�of �t he�t umour�m icroenvironment�a nd�t he�

immune�s ystem�i n�t he�de velopment�a nd�t reatment� of�br east�c ancer�

72�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Table�5: �S ummary�of �G ap�A nalysis� for�D isease�M arkers�i n�B reast�C ancer�

What�do�w e�know ?�

• Patient�g roups�c an�be �s uccessfully�s tratified�i n�c linical�t rials�us ing�bi omarkers�

What�a re�t he�G aps?�

• Optimum�pr otocols�f or�pa thological�a ssessment�of �D CIS�a nd�s entinel�l ymph�

nodes�

• Combining�c linical,�r adiological,�p athological�a nd�g enomic�d ata�i n�t rial�

populations�

• No�r obust�va lidated�m arkers�ha ve� yet�be en�d eveloped�f or�pr edicting� response�t o�

chemotherapy�o r�r adiotherapy�

• There�i s�no�c onsensus�f or�m arkers�i ndicative�o f�r esistance�t o�t herapy�

• There�i s�a �n eed�f or�i mproved�pr ognostic�i ndices�ba sed�on�di sease�m arkers�

Problems�

• New�a ssays�m ust�be � robust�a nd�r eproducible�

• There�i s�a �n eed�f or�s tandardisation�of �t issue�ha ndling�

• The�i mpact�of �l egislation,�i ndustrial�i nvolvement�a nd�a cademic�pr essures�

• Networks�of � collaboration�e mploying�s ystems�bi ology�a re�r equired�

Translational�i mplications�

• Accurate�r ecognition�of �t he�di versity�o f�br east�c ancer�

• Identification�of �pa tients� most�l ikely�t o�be nefit�

• Identification�of �pa tients� least�l ikely�t o�be nefit�f rom�t herapy�a nd�he nce� able�t o�

avoid�t oxicity.�

Recommendations�

• Design�i nnovative�t rials�a nd�t ranslational�s tudies�t o�de velop�a nd�e valuate�

predictive�a nd�p rognostic�m arkers�

• Develop�c lose�m ultidisciplinary� collaboration�w ith�hi gh-quality�hi stopathology�

and�r igorous�s cientific� assessments�t o�va lidate�ne w�m arkers�i mportant�f or� patient�

outcome�

73�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

• Identify�r obust�m arkers�o f�r esistance�or �s ensitivity� to�t herapy�t hat�c an�b e�a pplied�

across�t he�s pectrum�of �br east�di sease� from�s creen-detected�t o�m etastatic�b reast�

cancer�

74�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

Table�6: �S ummary�of �G ap�A nalysis� for�P revention�of � Breast�C ancer�

What�do�w e�know ?�

• Endocrine�c hemoprevention�f or�oe strogen-responsive�t umours�w orks�

• Key�r isk�f actors�i nclude� mammographic�de nsity,� post-menopausal�w eight� gain,�

high�e nergy,�hi gh�f at�di ets�a nd�l ack�of � exercise��

• Breast�s creening�i s�e ffective.�M RI�s creening�i s�m ore�s ensitive��t han�

mammography� for�hi gh�r isk�w omen��

• Epidemiological�da ta�s uggest�w eight�c ontrol,�l ow� fat�di et�a nd�e xercise� after�

diagnosis�i mproves�out come�of �e arly�b reast� cancer�pa tients.��

What�a re�t he�G aps?�

• The�l ong�t erm�e ffects�of � chemoprevention�of �E R�pos itive�c ancers�a re�unkn own�

• Prevention�of �E R-negative�c ancers�r emains�a � challenge�

• There�i s�a �n eed�t o�unde rstand�t he�t arget�c ell�f or�br east�c ancer�p revention�

• Need��t o�i mprove��c urrent�r isk�pr ediction�m odels�by � �i ncluding��m odifiable�r isk�

factors����

• The�he alth�be liefs�o f�hi gh-risk�a nd�popul ation�r isk�w omen�r equire�e xploration�

• The�e ffects�of �b reast�s creening�out �w ith�c urrently�t argeted� groups�i s�not �know n�

• To�de fine�de liverable�di et�a nd�e xercise�i nterventions�f or�t he�pr imary� and�

secondary�p revention�of � breast�c ancer.�

• To�e lucidate�t he�m echanism��f or�br east� cancer�pr evention�w ith�e nergy�r estriction�

Problems�

• Accrual�a nd�r etention�of � women�i n�pr evention�t rials�

• Better�m odels�t o�r esearch�ne w�c hemoprevention�a gents�

• Breast�s creening�l ags�be hind�a dvances�i n�i maging� technology�

• Poor�upt ake�t o�di et�a nd�e xercise�t rials��a fter�di agnosis��

Translational�i mplications�

• Better�i dentification�of �hi gh�r isk�w omen� would�a llow�c hemoprevention�t o�be �

targeted�m ore�e ffectively�

• Defining� optimum�s creening�m ethods��w ill�e nsure� more�e ffective�us e�of �l imited�

NHS�r esources.�

75�

Breast�C ancer�C ampaign�g ap� analysis�doc ument�

• The�de velopment�of � energy�r estriction�m imetics�f or�br east�c ancer�pr evention�

Optimal�di et�a nd�e xercise�i nterventions�c ould�i mprove�qua lity�o f�l ife�a nd�o utcome�

for�w omen�w ith�br east�c ancer��

Recommendations�

• Improve�br east�c ancer� risk�pr ediction�m odels��

• Encourage�t ransdisciplinary�i nput�t o�pr evention�t rials�( eg� geneticists,�

epidemiologists,�nut ritionists,�ps ychologists�a nd�c linicians)�t o�s tudy�t he�

psychosocial,�c ompliance�a nd� genetic�a spects�of � prevention�

• Establish�t he�pot ential�be nefits�of �di et�a nd�e xercise�pos t�di agnosis�on�out come�a nd�

quality�of �l ife� for�br east�c ancer�p atients�

76�

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Table�7: �S ummary�of �G ap�A nalysis� for�P sychosocial�A spects�of �B reast� Cancer�

What�do�w e�know ?�

• There� are�ps ychosocial�e ffects��of � genetic�t esting,� prophylactic�m astectomy�a nd�

breast�s creening�

• Descriptive�s tudies�of �t he�e xperiences�of �b reast�c ancer�pa tients�us ing�qua ntitative�

and�qua litative�m ethods�s how�w omen�s till�e xperience�ps ychosocial�di stress�

despite�i mprovements�i n�t reatment�a nd�pr ognosis.� �

• Psychosocial�i nterventions�ha ve�be en�s hown�t o�be nefit�w omen,�i ncluding� those�

identified�a s�e xperiencing�hi gh�l evels�of �di stress.�

What�a re�t he�G aps?�

• Evaluation�of �de cision�a ids�f or�r isk�m anagement�a nd�c hoice�of �p reventative�

surgery�a mongst�hi gh�r isk�w omen.�

• Ways�of �e ffectively�c ommunicating�i nformation�a nd�a iding�pa tient�t reatment�

decision�m aking�

• Defining� patient�e xperiences�i n�e arly,� chronic� and� end�s tage�br east�c ancer� �

• Limited�r esearch�i nto�c o-morbidities�a mongst�br east�c ancer�pa tients��

• Experiences�of �e thnic�m inority�popul ations�a nd�ol der�w omen�

• The�ne ed�t o�de velop�a nd� evaluate� appropriate�ps ychosocial�i nterventions�f or�hi gh�

risk�w omen�a nd�t hose�di agnosed� as�ha ving�br east�c ancer��

• Use�of �ps ychological�t heories�i n�be haviour�c hange�t hat�c ould�e nhance�c ompliance�

to�l ifestyle�a nd� chemoprevention�t rials.�

Problems�

• The�ne ed� for�t he�l ong�t erm�f ollow�up�i n�ps ychosocial�r esearch�

• Barriers�t o�t he�upt ake�of � research�f indings�

Translational�i mplications�

• Direct�i mprovement�i n�t he�e xperience�o f�pa tients,� their�f amilies�a nd�t hose�a t�

increased�r isk�

Recommendations�

• Develop�a nd�r igorously� evaluate�a ppropriate�ps ychosocial�i nterventions�

• Encourage�c ross-speciality�c ollaboration�t o�i ncorporate�ps ychosocial�i ssues�a nd�

psychological�t heory�( eg� psychological�t heories�i n�r elation�t o�be haviour� change�

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are�r elevant�t o�t hose�r esearching�pr evention�w ith�di et�a nd�e xercise�or �

chemoprevention)�

• Ensure�r esearch� gives� greater� attention�t o�a ll�s tages�of �br east�c ancer� and�t hat�t he�

needs�of �ol der�w omen�a nd�t hose�f rom�a �r ange�of � ethnic�g roups� are�i ncluded�

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Table� 8:� � Gap� analysis� recommendations� and� future� directions�

Generic�ne eds:�

• Improved�pr eclinical�m odels�

• Access�t o�a ppropriate� and�a nnotated�c linical�m aterial�

• Cross�di sciplinary�w orking�

1.�G enetics�of �br east�c ancer�

• Encourage�de velopment� of�r esearch�t echniques�t o� allow�i ntegrated�a nalysis�of �

sequence�l evel,�e pigenetic�a nd�l arge-scale�s omatic�c hanges�

• Engage�i n�na tional�i nitiatives�f or�a ctivities�s uch�a s�hi gh-throughput�r e-sequencing�a nd�

UK�c ontrols�

• Encourage�r esearch�i nvolving�i ntermediate�phe notypes�

2.�I nitiation�of �br east�c ancer�

• Develop�t hree-dimensional�c ell�c ulture�m odels,�c ontaining�m ultiple�c ell�t ypes,�t hat�

reflect�t he�t issue�a rchitecture�of �t he�nor mal� and�di seased�br east�

• Generate�be tter�a nimal�m odels,�pa rticularly�f or�E R-positive�t umours,�i n�w hich�ge ne�

expression�c an�be �m anipulated�i n�a ll�c ell�t ypes�of � the�m ammary� gland�a nd� will�not �be �

altered�b y�t ransdifferentiation�or �de differentiation�

• Gain�a � greater�und erstanding�of �t he� genetic�c hanges�t hat�oc cur� within�a typias�a nd�

DCIS�

3.�P rogression�of �br east�c ancer�

• Improve�pr eclinical�m odels,�r esearch�r eagents�a nd�t echnologies�( including�i maging)�

• Enhance� access�t o�a ppropriate�c linical�m aterial,�i ncluding�s equential�s amples�

obtained�dur ing�t reatments�e xtending�t o�ne w�a gents� �

• Consider�ge netic�s ignature/specific� genetic�l esions�w hen�e xploring�pr ogression�

biology�a nd�de signing�c linical�t rials�

4.�T herapies�and�t argets�i n�br east�c ancer�

• Build�r esources�t hrough� high-quality,�uni form,�m ulticentre�c ollection�of � clinical�

material�f rom�br east�c ancer�pa tients�be fore� and�dur ing�t reatment�( including�

neoadjuvant�s tudies),�i ncluding�s amples�of �pr imary� tumours�a s�w ell�a s�m etastatic�

deposits�

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• Develop�m ethods�f or� easy,�r eproducible�m onitoring�of � response�t o�a nd�d evelopment�

of�r esistance�t o�t herapy,� as�w ell�a s�e arly�di sease�p rogression�

• Increase�r esearch� efforts� into�t he�r ole�of �t he�t umour�m icroenvironment�a nd�t he�

immune�s ystem�i n�t he�de velopment�a nd�t reatment� of�br east�c ancer�

5.�D isease�m arkers�i n�br east�c ancer�

• Design�i nnovative�t rials�a nd�t ranslational�s tudies�t o�de velop�a nd�e valuate�p redictive�

and�pr ognostic�m arkers�

• Develop�c lose�m ultidisciplinary� collaboration�w ith�hi gh-quality�hi stopathology�a nd�

rigorous�s cientific�a ssessments�t o�va lidate�ne w�m arkers�i mportant�f or�p atient�

outcome�

• Identify�r obust�m arkers�o f�r esistance�or �s ensitivity� to�t herapy�t hat�c an�b e�a pplied�

across�t he�s pectrum�of �br east�di sease� from�s creen-detected�t o�m etastatic�b reast�

cancer�

6.�P revention�of �br east�c ancer�

• Improve�br east�c ancer� risk�pr ediction�m odels� �

• Encourage�t ransdisciplinary�i nput�t o�pr evention�t rials�( for�e xample� geneticists,�

epidemiologists,�nut ritionists,�ps ychologists�a nd�c linicians)�t o�s tudy�t he�

psychosocial,�c ompliance�a nd� genetic�a spects�of � prevention�

• Establish�t he�pot ential�be nefits�of �di et�a nd�e xercise�pos t�di agnosis�on�out come�a nd�

quality�of �l ife� for�br east�c ancer�p atients�

7.�P sychosocial�as pects�o f�br east�c ancer�

• Develop�a nd�r igorously� evaluate�a ppropriate�ps ychosocial�i nterventions�

• Encourage�c ross-speciality�c ollaboration�t o�i ncorporate�ps ychosocial�i ssues�a nd�

psychological�t heory�( for�e xample�ps ychological�t heories�i n�r elation�t o�be haviour�

change� are� relevant�t o�t hose�r esearching�pr eventative�l ifestyles�i ncluding�di et�a nd�

exercise)�

• Ensure�r esearch� gives� greater� attention�t o�a ll�s tages�of �br east�c ancer� and�t hat�t he�

needs�of �ol der�w omen�a nd�t hose�f rom�a �r ange�of � ethnic�g roups� are�i ncluded�

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