Evaluation of breast cancer screening in the north of Portugal

MARIA JOSÉ AFONSO TEODÓSIO BENTO EVALUATION OF BREAST CANCER SCREENING IN THE NORTH OF PORTUGAL Tese de Candida u a ao g au de Dou o em Ciências Médicas subme ida ao Ins i u o de Ciências Biomédicas Abel Salaza da Uni e sidade do Po o. O ien ado – Dou o Ví o Rod igues Ca ego ia – P o esso Associado A iliação – Faculdade de Medicina da Uni e sidade de Coimb a Co-o ien ado – Dou o Guilhe me Gonçal es Ca ego ia – P o esso Associado com Ag egação A iliação – Ins i u o de Ciências Biomédicas Abel Salaza da Uni e sidade do Po o III De aco do com o dispos o no n.º 1 do a igo 34.º do Dec e o-Lei n.º 74/2006, publicado em Diá io da República, 1.ª sé ie, n.º 60 de 24 de Ma ço de 2006, e epublicado pelo Dec e o- Lei n.º 115/2013, publicado em Diá io da República, 1.ª sé ie, n.º 151 de 7 de Agos o de 2013, que p ocede à e cei a al e ação ao Dec e o-Lei n.º 74/2006, de 24 de ma ço de 2006, cons am nes a ese os a igos já publicados e os subme idos pa a publicação, que a segui se disc iminam: I. Cas o C, Ben o MJ, Lune N, Campos P. Assessing he comple eness o cance egis a ion using subop imal dea h ce i ica e in o ma ion. Eu J Cance P e 2012; 21(5):478-9. II. C oce i E, Calda ella A, Fe e i S, A danaz E, A eux P, Ba a S, Ba ios E, Ben o MJ, Bo doni A, Buzzoni C, Candela G, Colombani F, Dela osse P, Fede ico M, F anca J, Giacomin A, G osclaude P, Guiza d AV, Iza zugaza I, Konzelmann I, La Rosa F, Lapo e B, Leone N, Ligie K, Mangone L, Ma cos-G age a R, Ma inez R, Michelena MJ, Michia a M, Mi anda A, Molinié F, Muga za-Gomez C, Paci E, Pi e S, Puig-Vi es M, Sacche ini C, Sánchez MJ, T aina A, T e a e B, Tumino R, Van Vae enbe gh E, Vel en M, Wo ono AS. Consis ency and inconsis ency in es ing bioma ke s in b eas cance . A GRELL s udy in cu -o a iabili y in he Romance language coun ies. B eas . 2013:22(4):476-81. III. Gio dano L, on Ka sa L, Toma is M, Majek O, de Wol C, Lancucki L, Ho ind S, Nys öm L, Segnan N, Pon i A; Eunice Wo king G oup, Van Hal G, Ma ens P, Májek O, Danes J, on Eule -Chelpin M, Aasmaa A, An ila A, Becke N, Pén ek Z, Budai A, Mádai S, Fi zpa ick P, Mooney T, Zappa M, Ven u a L, Scha pan gen A, Ho ind S, Se oczynski P, Mo ais A, Rod igues V, Ben o MJ, Gomes de Ca alho J, Na al C, P ie o M, Sánchez-Con ado Escude o C, Zubiza e a Albe i R, Fe nández Llanes SB, Ascunce N, Ede a Sanza M, Sa iuga e I igoien G, Salas T ejo D, Ibáñez Cabanell J, Wiege M, Ohlsson G, Tö nbe g S, Ko zeniewska M, de Wol C, F acheboud J, Pa nick J J, Lancucki L, Duca oz S, Suonio E. Mammog aphic sc eening p og ammes in Eu ope: o ganiza ion, co e age and pa icipa ion. J Med Sc een. 2012;19 Suppl 1:72-82. IV IV. Ho ind S, Pon i A, Pa nick J, Ascunce N, Njo S, B oede s M, Gio dano L, F ige io A, Tö nbe g S; EUNICE P ojec and Eu osc een Wo king G oups, Van Hal G, Ma ens P, Májek O, Danes J, on Eule -Chelpin M, Aasmaa A, An ila A, Becke N, Pén ek Z, Budai A, Mádai S, Fi zpa ick P, Mooney T, Zappa M, Ven u a L, Scha pan gen A, Ho ind S, Se oczynski P, Mo ais A, Rod igues V, Ben o MJ, Gomes de Ca alho J, Na al C, P ie o M, Sánchez-Con ado Escude o C, Zubiza e a Albe i R, Fe nández Llanes SB, Ascunce N, Ede a Sanza M, Sa iuga e I igoien G, Salas T ejo D, Ibáñez Cabanell J, Wiege M, Ohlsson G, Tö nbe g S, Ko zeniewska M, de Wol C, F acheboud J, Pa nick J, Lancucki L, Duca oz S, Suonio E. False-posi i e esul s in mammog aphic sc eening o b eas cance in Eu ope: a li e a u e e iew and su ey o se ice sc eening p og ammes. J Med Sc een. 2012;19 Suppl 1:57-66. V. Ben o MJ, Gonçal es G, Aguia A, Cas o C, Veloso V, Rod igues V. Pe o mance indica o s e alua ion o he popula ion-based b eas cance sc eening p og amme in No he n Po ugal using he Eu opean Guidelines (submi ed). VI. Ben o MJ, Gonçal es G, Aguia A, An unes L, Veloso V, Rod igues V. Clinicopa hological di e ences be ween in e al and sc een-de ec ed b eas cance s diagnosed wi hin a sc eening p og amme in he No h o Po ugal. J Med Sc een 2014;21(2):104-109. VII. Ben o MJ, Gonçal es G, Aguia A, An unes L, Cas o C, Veloso V, Rod igues V. Clinicopa hological cha ac e is ics o in asi e b eas cance s diagnosed in pa icipan s, non-pa icipan s and no in i ed o he o ganized popula ion-based B eas Cance Sc eening, in he No h o Po ugal (submi ed). Table o con en s V C on en s Abs ac VII Resumo XI Abb e ia ions XV I – Backg ound 1 1. Epidemiology and clinicopa hogical cha ac e is ics o b eas cance 3 1.1 Incidence and mo ali y wo ldwide and in Po ugal 3 1.2 Incidence o b eas cance in he No he n Region o Po ugal 3 1.3 Risk ac o s o b eas cance 4 1.4 His opa hology and p ognosis 5 1.5 T ea men and su i al 6 2. B eas cance sc eening 6 2.1 P inciples o b eas cance sc eening 6 2.2 O ganiza ion and componen s o b eas cance sc eening 7 2.3 Po en ial bias in b eas cance sc eening 9 2.4 Quali y guidelines in b eas cance sc eening 9 2.4.1 Pe o mance indica o s 10 2.4.2 Impac indica o s 10 2.5 Moni o ing and e alua ion s udies 11 2.5.1 Pe o mance indica o s and ea ly su oga e indica o s o mo ali y 11 2.5.2 Randomized con olled ials 11 2.5.3 Obse a ional s udies 12 2.6 Po en ial ha ms associa ed wi h b eas cance sc eening 13 2.6.1 O e diagnosis (and o e ea men ) 13 2.6.2 In e al cance s 14 2.6.3 False-posi i e esul s 15 2.6.4 O he ha m ac o s associa ed wi h b eas cance sc eening 16 2.7 O ganized b eas cance sc eening p og ammes in he wo ld 16 Table o con en s VI 2.8 B eas cance sc eening p og ammes in Po ugal 16 2.9 Impo ance o popula ion-based cance egis ies in he planning and e alua ion o b eas cance sc eening p og ammes 18 2.9.1 No h Region Cance Regis y o Po ugal 19 II – Aims 21 III – Resul s 25 1. Impo an p econdi ions o b eas cance sc eening e alua ion 25 2. In e na ional compa ison o b eas cance sc eening p og ammes 37 3. Pe o mance indica o s e alua ion o he popula ion-based b eas cance sc eening p og amme in No he n Po ugal using he Eu opean Guidelines 63 4. Clinicopa hological di e ences be ween in e al and sc een-de ec ed b eas cance s diagnosed wi hin a sc eening p og amme in No he n Po ugal 87 5. Clinicopa hological cha ac e is ics o in asi e b eas cance s diagnosed in pa icipan s, non-pa icipan s and no in i ed o he o ganized popula ion- based B eas Cance Sc eening, in he No h o Po ugal 97 IV – Gene al discussion and conclusions 119 V – Fu u e s udies 125 VI – Re e ences 129 Acknowledgmen s 143 VII Abs ac Abs ac IX Abs ac The aim o a popula ion-based b eas cance sc eening p og amme (BCSP) is o lowe he bu den o he disease in a popula ion. As a public heal h in e en ion i needs o be e alua ed and when speci ic mo ali y analysis canno be used, he e alua ion o pe o mance and impac indica o s is an al e na i e, as hey can be e alua ed sho ly a e he sc eening implemen a ion. Pe o mance analyses include s a is ics o key moni o ing da a o cance sc eening (as co e age a e, pa icipa ion a e, and ecall a e) and ea ly impac indica o s include he analysis o he clinicopa hological cha ac e is ics o he de ec ed b eas cance s and in e al cance a e, among o he s. The aim o he esea ch epo ed in his hesis was o e alua e he popula ion-based BCSP implemen ed in he No he n Region o Po ugal. The exis ence o a popula ion-based cance egis y wi h high comple eness is an impo an p e-condi ion o an accu a e e alua ion o many indica o s o he sc eening p og amme. A speci ic s udy was conduc ed o assess he comple eness o he case asce ainmen a he No h Region Cance Regis y (RORENO). Resul s ob ained wa an ed he conclusion ha RORENO is a aluable sou ce o in o ma ion on he new cases o b eas cance diagnosed in he popula ion. Ano he impo an issue in he e alua ion o sc eening is ela ed o he molecula bioma ke s p o ile o he b eas cance cases. A s udy was conduc ed in Romance language coun ies, and al hough he e was high p e alence o bioma ke es ing, he a iabili y o ca ego ical labelling s essed he need o a mo e ex ensi e use o he exis ing guidelines. A i s insigh on he pe o mance o he BCSP o he No he n Region was done in he amewo k o wo in e na ional collabo a i e s udies, wi hin he p ojec o Eu opean Ne wo k o In o ma ion on Cance (EUNICE). Pa ame e s as o ganiza ion, co e age, pa icipa ion a e and alse-posi i e a e we e s udied. The BCSP showed simila co e age by in i a ion, highe co e age by examina ion and a lowe a e o u he assessmen , compa ed o he o e all esul s o he pa icipa ing sc eening p og ammes. The moni o ing o he BCSP o he No he n Region h ough compa ison o he pe o mance and impac indica o s wi h he s anda d Eu opean Guidelines assessed he quali y o sc eening and p o ided means o p edic he mo ali y ou come. The main esul s indica ed ha he BCSP was being highly accep ed by he popula ion, ha i was de ec ing he expec ed numbe o in asi e b eas cance s in he p e alen and subsequen ounds and was able o iden i y small size b eas cance s among he pa icipan s. Mos o he pe o mance and impac indica o s e alua ed we e consis en wi h he desi able le els o he Eu opean Guidelines and wi h o he in e na ional mammog aphy sc eening p og ammes. In e al b eas cance s a e an impo an indica o o he quali y o mammog aphy as well as o he p obable impac o he sc eening p og ammes on b eas cance . In his esea ch, 1 I – Backg ound Backg ound 3 I – Backg ound 1. Epidemiology and clinicopa hogical cha ac e is ics o b eas cance 1.1 Incidence and mo ali y wo ldwide and in Po ugal B eas cance is he mos common cance in women in many egions o he wo ld, including Aus alia, he wes e n pa o Asia, No h A ica, Wes e n Eu ope, No h Ame ica and pa s o Sou h Ame ica. In 2012, i is es ima ed ha 1,67 million new cases had occu ed, ep esen ing a s anda dized (wo ld s anda d popula ion) a e o 42.3/10 5 , a qua e o all cance s diagnosed in women. The highes a es we e epo ed in Swi ze land, he whi e popula ion o he USA, I aly and o he Eu opean coun ies and he lowes we e in A ica. 1-4 The e a e la ge di e ences be ween he incidence a es eco ded in de eloped coun ies (excep Japan) all abo e 80/10 5 and he a es ound in mos de eloping coun ies, wi h a es below 40/10 5 . B eas cance is also he leading cause o dea h in women wo ldwide. In 2012 a ound 522,000 women we e es ima ed o ha e died om his cause. The dis ibu ion pa e n o mo ali y is simila o he dis ibu ion o incidence, 1-3 howe e , he ange in mo ali y a es be ween de eloped egions and hose in de eloping coun ies, is less han ha o incidence (be ween 6-20/10 5 ). 3 In Po ugal, he numbe o new cases o b eas cance in 2008 was es ima ed a 5,333 which co esponded o 27.6% o all cance s diagnosed in women, o jus o e 1 in 4 cases o cance we e a ibu ed o b eas cance . The age-s anda dized incidence a e s ood a 60.0/10 5 (Wo ld S anda d Popula ion). 3 The es ima ed p e alence o b eas cance cases a 5 yea s was 21,272. 5 Rega ding mo ali y om his cause, in Po ugal 1,661 women died in 2010 and he absolu e numbe s ha e inc eased since 1955, mainly due o inc eased li e expec ancy and aging o he emale popula ion, and changes in li es yle. 6 Howe e , he isk o dying om b eas cance o women aged 35-74 yea s inc eased 1.55%/yea be ween 1955 and 1992, and changed -2.20%/yea om 1992 o 2002. 7 1.2 Incidence o b eas cance in he No he n Region o Po ugal Acco ding o he No h Region Cance Regis y o Po ugal (Regis o Oncológico Regional do No e – RORENO) 1,764 new in asi e b eas cance cases we e diagnosed in 2008, co esponding o an incidence a e o 103.6/10 5 . This ep esen ed mo e han a qua e o all in asi e cance s diagnosed amongs women ha yea . 8 The age-s anda dized incidence a e (Wo ld S anda d Popula ion) in he No h Region was 66.4/10 5 , a highe alue han he one es ima ed o he whole coun y. 3 Backg ound 4 1.3 Risk ac o s o b eas cance Jus being a woman and ge ing olde a e he main isk ac o s o ha e b eas cance . 9 Men can also de elop b eas cance , bu i ep esen s app oxima ely 1% o he o al equency in women. 10 B eas cance ises sha ply wi h age. 9 Acco ding o da a om RORENO, in 2008, he o e all incidence a e o b eas cance was low a younge ages (3.8/10 5 in age g oup 20-24 yea s), a e which incidence a es mo e han double in he nex 5-yea age g oups ill age 44 (Figu e 1). In he ollowing ages, he inc ease was a enua ed and a peak a e was achie ed in he 60-64 age-g oup, wi h an incidence o 267.3/10 5 . Family his o y is a majo isk ac o , especially i he amily membe was diagnosed wi h he disease a a young age. A woman whose i s -deg ee ela i e had b eas cance be o e age 40, has 6 imes mo e isk o de eloping b eas cance be o e age 40, compa ed wi h a women o he same age bu wi h no amily his o y. 9 The BRCA1 and BRCA 2 genes ha e been ela ed o he occu ence o amilial b eas cance , mani es ing in p emenopausal women, bu on he whole hey don´ con ibu e o mo e han 10% o cases o b eas cance . O he isk ac o s we e linked o some benign b eas pa hologies, b eas densi y, li e s yle, die , ep oduc i e and ho monal ac o s. Al hough many isk ac o s a e al eady iden i ied, only a ew can be changed o p e en ed. Besides, mos women who do ge b eas cance don' ha e any signi ican isk ac o s (o he han being a woman and g owing olde ). 0 50 100 150 200 250 300 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85+ Ra e pe 100000 Figu e 1 B eas cance incidence in women esiden in he No he n Region o Po ugal, in 2008, by age-g oup Backg ound 5 1.4 His opa hology and p ognosis In gene al, he e a e h ee ca ego ies o b eas abno mali ies: benign condi ions, in-si u and in asi e cance . 11 Benign condi ions a e associa ed wi h a isk o b eas cance anging om one- o i e old, depending on he deg ee o epi helial p oli e a ion and a ypia. B eas cance is p obably an he e ogeneous g oup o diseases wi h mo e han one na u al his o y. 11 Mo e han 95% o b eas cance s o igina e om he epi helial elemen s o he mamma y gland, pa icula ly om he cells o he e minal duc al lobula uni s o he b eas . 12 The lobula ca cinoma in si u is associa ed wi h an inc eased isk o in asi e b eas cance bu is usually an inciden al inding and is no gene ally de ec ed by mammog aphy. Da a on he na u al his o y o duc al ca cinoma in si u (DCIS) a e limi ed, bu i is likely ha high-g ade ca cinomas a e associa ed wi h a signi ican ly highe isk o de elopmen o in asi e ca cinoma han low-g ade DCIS. Wea he DCIS is an obliga e p ecu so o in asi e duc al cance , o i bo h en i ies de i e om a common p ogeni o cell line is unclea . 13 In ela ion o in asi e ca cinomas, 75% o 80% a e in il a ing duc al ca cinomas and 5- 10% lobula ca cinomas. O he ypes o b eas cance include he medulla y, mucinous, ubula and o he less equen umou s. 12 The p ognosis o a pa ien wi h b eas cance is associa ed wi h ime-dependen a iables ( umou size, p esence and ex en o lymph nodes me as asis, and dis an me as asis, he h ee a iables de ining he TNM s age 14 ) and is also associa ed wi h a iables ela ed o he biology o he indi idual umou , as he his ological g ade 15 umou ype, ho mone ecep o s a us, among o he s. 11 These ea u es o b eas cance s a e undamen al o p edic ing esponse o ea men and o e all ou come. 12 Tumou size is one o he s onges p edic o s o b eas cance beha iou and s udies ha e shown ha sc eening leads o he de ec ion o smalle size umou s. 16-18 The 5-yea su i al o pa ien s wi h node-nega i e disease is 82.8%, bu he e is a di ec ela ionship be ween he numbe o in ol ed axilla y nodes and he isk o dis an ecu ence and sho e su i al. 18-20 G ade u ili y o s aging and p ognos ica ion became mo e ele an in he sc eening e a as a highe p opo ion o umou s a e T1N0M0 a diagnosis. 15 The 10-yea su i al o duc al ca cinomas was 76% o women wi h g ade 1 ca cinoma and 39% o hose wi h g ade 3 umou s. 21 Biological ma ke s became essen ial o p ognosis de ini ion and he apy. Pa ien s wi h ca cinomas wi h oes ogen (ER) and/o p oges e one ecep o (PR) posi i e ha e a be e su i al han ho mone ecep o nega i e umou s wi h a 5-yea o e all su i al (all s ages) o 83% in he ER+/PR+ g oup e sus 69% in he double nega i es. 22 Backg ound 6 1.5 T ea men and su i al T ea men o b eas cance commonly encompasses a combina ion o ea men s as su ge y, chemo he apy, adia ion he apy, and ho mone he apy. I depends on ac o s such as s age o he disease a diagnosis, his ological g ade, age, co-mo bidi ies and he women´s p e e ences. Some pa hological cha ac e is ics as ER and PR s a us and he human epide mal g ow h ac o ype 2 ecep o (HER2) in luence he use o a ge he apies. 23 B eas conse ing su ge y is he ea men o choice o he majo i y o small sized umou s. 24 Locally ad anced b eas cance s a e ea ed wi h a combined modali y including up on chemo he apy, su ge y and adia ion. 24 In he las decades, signi ican imp o emen s we e egis e ed in he su i al a es o women wi h b eas cance . 4 Fi e-yea su i al a es o e 80% we e e i ied in No h Ame ica, Eu ope and Aus alia. Nowadays, women wi h b eas cance ha e a highe su i al a e han o mos o he ypes o cance . 4,25 The 10-yea su i al a e o b eas cance in mos wes e n popula ions eached 70%. 26 2. B eas cance sc eening 2.1 P inciples o b eas cance sc eening The objec i e o sc eening o a disease is o disco e hose among he appa en ly well who a e in ac su e ing om he disease. 27 In 1968, Wilson and Junge 27 es ablished gene al p inciples o sc eening o he Wo ld Heal h O ganiza ion (WHO), ha a e s ill alid oday. 28 These p inciples o sc eening can be summa ized 28 as: - Sc eening should be di ec ed owa ds an impo an heal h p oblem - The e should be a simple, sa e, p ecise and alida ed sc eening es - T ea men s a ed a an ea ly s age should be o mo e bene i han ea men ini ia ed la e - The e should be e idence ha he sc eening es is e ec i e in educing mo ali y and mo bidi y - The bene i o sc eening should ou weigh he physical and psychological ha m caused by he es , diagnos ic p ocedu es and ea men - The oppo uni y cos o he sc eening p og amme should be economically balanced in ela ion o expendi u e on medical ca e as a whole - The e should be a plan o managing and moni o ing he sc eening p og amme and an ag eed se o quali y assu ance s anda ds - Po en ial sc eening pa icipan s should ecei e adequa e in o ma ion abou bene i s and disad an ages o pa icipa ion Backg ound 7 In gene al, b eas cance sc eening is consis en wi h hese p inciples: - B eas cance is he commones cause o dea h om cance in women in many egions o he wo ld. - B eas cance is a p og essi e pa hology and i s de elopmen can be hinde ed by ea ly de ec ion. 29,30 The impo ance o ea ly de ec ion is e iden upon examina ion o he s ong associa ion be ween s age a diagnosis and su i al. 30,31 - Sys ema ic examina ion wi h mammog aphy has he po en ial o lowe b eas cance mo ali y a es in app oxima ely 20% in women in i ed o sc eening 29,32 and o educe he bu den o he disease in he popula ion. 33 Mammog aphy sc eening is he only sc eening me hod ha has p o en o be e ec i e. 34 - Sensi i i y o he mammog aphic examina ion o de ec malignan lesions, as epo ed by IARC in 2002, 11 anged om 52% o 82% and speci ici y was highe han 90%; he p edic i e posi i e alue anged om 2%-22%, wi h mos s udies epo ing his alue as 12%. 11 - The e is su icien e idence 13 ha in i ing women 50-69 yea s o age o sc eening educes hei mo ali y om b eas cance . - T ea men is conside ed o be mo e e ec i e i cance is de ec ed a ea lie s ages. 35 - A e andomized ials sc eening p og ammes o women aged 50-69 a a 2- o 3- yea in e al a e expec ed o be cos -e ec i e in high-incidence coun ies wi h well o ganized p og ammes. 11 - The bene i s o b eas cance sc eening on mo ali y educ ion ou weigh he ha ms associa ed wi h sc eening, especially he isk o o e diagnosis. 29 Cu en da a indica e ha mammog aphic sc eening may no be e ec i e in all age g oups and he a io o bene i o cos a ies signi ican ly wi h age. 35,36 The sensi i i y o mammog aphy is in e sely p opo ional o b eas densi y, 37,38 and younge women end o ha e highe densi y. 36 Also he na u al his o y o he disease s ill has many unanswe ed ques ions, namely he malignan po en ial o DCIS o become in asi e, ie, o conside DCIS as a ma ke o malignancy equi ing ac i e ea men o a benign condi ion o no clinical signi icance. 29 2.2 O ganiza ion and componen s o b eas cance sc eening Acco ding o In e na ional Agency o Resea ch on Cance (IARC) an o ganized cance sc eening has 6 cha ac e is ics: 39 a w i en policy speci ying he a ge age ca ego ies, he me hod o sc eening and in e al; a de ined a ge popula ion; a managemen eam ha is esponsible o o e seeing acili ies whe e sc eening occu s and o ensu ing ha he a ge popula ion is sc eened; a clea decision s uc u e and esponsibili y o heal h ca e Backg ound 8 managemen ; a quali y assu ance s uc u e and a me hod o iden i ying cance occu ence in he a ge popula ion. 39 Popula ion-based b eas cance sc eening by mammog aphic examina ion is a mul i-s ep p ocess. 40 Hakama 41 p oposed ou main componen s o cance sc eening p og ammes ha can be applied o b eas cance sc eening: 1. Popula ion componen - de ini ion o a ge popula ion - iden i ica ion o indi iduals: unique pe sonal iden i ie s a e equi ed o compile he ull in o ma ion o a woman o e mul is ep sc eening episodes, and o link his in o ma ion o o he da a sou ces in heal h-ca e. 42 - measu es o achie e su icien co e age and a endance: use o an indi idual le e o in i a ion o sc een and eminde s o a end was ound o inc ease access and a endance. 39 In i a ion gi es each eligible pe son an equal chance o bene i om sc eening and he e o e educes heal h inequali ies. 43 2. Tes execu ion - es acili ies o mammog aphic examina ion and analysis - quali y con ol p og amme o ob aining mammog aphy and i s analysis: his componen ex ends om he echnical quali y con ol o he adiologic equipmen , p ocedu es, and he adiologis s pe o mance. Mammog aphic examina ion o he b eas wi h wo iews is likely o inc ease sensi i i y by app oxima ely 20%. 41 Double eading o he mammog aphy by wo expe ienced adiologis s compa ed o single eading inc eases he de ec ion a e by 10% bu lowe s speci ici y. 41 In case o disc epancy, consensus o a bi a ion by a hi d eade should be decided. 3. Clinical componen s - acili ies o diagnosis, ea men and ollow-up o pa ien s wi h sc een-de ec ed disease: a apid e e al and diagnos ic e alua ion by mul i-disciplina y eam o a oid unnecessa y delay should be p o ided 4. Coo dina ion - a e e al sys em linking he sc een, sc eening uni and clinical acili y - moni o ing, quali y con ol and e alua ion o he p og amme; ollow-up o incidence and mo ali y in he en i e a ge popula ion, and o bo h a ende s and non-a ende s. Majo o ganiza ional conside a ions a e he ages a which he p og amme s a s and s ops and he in e al a which he es is applied. 41,44 Women 50-69 yea s o age seem o be he ones ha bene i mos om sc eening mammog aphy. 45,46 Da a a e limi ed ega ding he e ec s o sc eening mammog aphy in women ha a e 70 yea s o age o olde 32 , and he e is unce ain y o e he alue o sc eening women be ween ages o 40 o 49. 32,47 Mos o he Backg ound 9 sc eening p og ammes ha e adop ed a 2-yea ly sc eening because o he high in e al cance a es seen in he hi d yea in ials. 11 B eas cance sc eening can be conduc ed ou side he o ganized p og amme when i is known as “oppo unis ic sc eening”. 39 This ype o sc eening e e s o ac i i ies ha in ol e e e al o mammog aphy acili ies by clinicians and sel - e e al by women hemsel es. 43 Compa ed o an o ganized sc eening p og amme, he oppo unis ic sc eening usually esul s in inc eased cos s as he e is no inbuil mechanism o p e en unnecessa ily equen sc eens and uncon olled ad e se e ec s. 44 2.3 Po en ial bias in b eas cance sc eening The e a e h ee main ypes o bias ha can sugges bene i om sc eening when he e is none. These biases a e he sel -selec ion, lead- ime, and leng h bias. 36 The sel -selec ion bias occu s when a g oup o indi iduals comes o wa d o be sc eened. 36 Volun ee s usually a e mo e heal h-conscious and hey a e mo e likely o ha e a be e ou come han he gene al popula ion. 36,48,49 Lead- ime bias is ela ed o he pe iod o ime be ween he de ec ion o he cance by sc eening and he ime when he cance would ha e been diagnosed clinically. 28 I cons i u es an a i icial addi ion o he su i al ime o sc een de ec ed cance cases. 49,50 Al hough a women diagnosed h ough sc eening may spend mo e ime awa e o he exis ence o he b eas cance , he da e o he dea h migh well emain unal e ed. 48 The leng h bias occu s when slow-g owing, less agg essi e cance s a e de ec ed du ing sc eening. 36 The p obabili y o a cance being de ec ed a sc eening depends on he leng h o ime he lesion is de ec able in a p eclinical phase, he so called sojou n ime. 11 The p obabili y o a cance o be sc een-de ec ed is g ea e when sojou n ime is longe . Wi hin a sc eening p og amme an unwa an ed p opo ion o cance s de ec ed will ha e a longe sojou n ime and p obably a be e p ognosis. 11,36,50 2.4 Quali y guidelines in b eas cance sc eening Acco ding wi h he Council o he Eu opean Union ecommenda ion launched in 2003, sc eening o cance should be based on a well-o ganized popula ion-based app oach using sys ema ic quali y assu ance a all app op ia e le els. 51 Implemen a ion o b eas cance sc eening o high quali y has he po en ial o no only lowe he bu den o disease in he popula ion a ending sc eening bu also on he quali y and e ec i eness o symp oma ic, ie, usual ca e. 43 E alua ion o b eas cance sc eening p og ammes in ol es analyses o pe o mance and impac . Pe o mance analyses include s a is ics o key moni o ing da a o cance Backg ound 16 and economic bu den o he women and heal hca e sys em, a e some easons o conce n a e a alse-posi i e esul . 45 The es ima ed cumula i e isk o a alse-posi i e ecall o assessmen in women aged 50-69 yea s unde going 10 biennial sc eening es s a ied be ween 8% and 21% (pooled es ima e 19.7%). 110 I ´s in e sely ela ed o age, as younge ages ha e a endency o mo e dense b eas s and lowe incidence o he disease. 45 A s udy in Spain ha included 762,506 women aged 45 o 69 yea s, obse ed an inc eased isk o cance de ec ion in women wi h a p e ious alse-posi i e es in mammog aphic sc eening. 111 2.6.4 O he ha m ac o s associa ed wi h b eas cance sc eening Risk o cance associa ed wi h adia ion, pain du ing p ocedu es, anxie y and o he psychological dis ess associa ed wi h a alse-posi i e sc eening esul 32,36 a e some addi ional side e ec s ela ed o sc eening wi h mammog aphy. 2.7 O ganized b eas cance sc eening p og ammes in he wo ld Sc eening p og ammes a e o ganized egionally o na ionally, and mos o hem a ge women 50 o 69 yea s old, wi h a 2-yea in e al be ween sc eening es s. 41 Acco ding o he O ganisa ion o Economic Co-ope a ion and De elopmen (OECD) 112 sc eening a es a ied widely ac oss coun ies in 2011, anging om less han 10% in Chile o o e 80% in Finland, he Ne he lands, he Uni es S a es and Aus ia - Fig 2. Some coun ies ha had high sc eening a es in he pas , expe ienced some educ ions o e he las decade, including Finland, he Uni ed S a es, he Uni ed Kingdom, No way, I eland and Canada. 2.8 B eas cance sc eening p og ammes in Po ugal In Po ugal, he o ganized popula ion-based b eas cance sc eening was ini ia ed in 1990 in he Cen e Region, conduc ed by he Po uguese Cance League (Liga Po uguesa Con a o Canc o – LPCC); women aged 45 yea s o o e we e in i ed o pa icipa e. 113 Sc eening p ocedu es included single- iew mammog ams, cen alized and independen ly ead by wo adiologis s, wi h a inal eading by a hi d independen and expe ienced adiologis , in case o disc epancy. Posi i e esul s we e assessed a he Po uguese Oncology Ins i u e o Coimb a and all diagnoses and cance ea men p ocedu es ollowed s anda dized he apeu ic p o ocols. Double iew mammog ams we e g adually in oduced un il he la e ‘90s, i s o age g oup 45-49 a ini ial sc eening, hen o all age g oups and a e wa ds, subsequen sc eening was also included; i was pe o med in e e y mobile and ixed uni . The age-g oup o in i a ion was se led a 45-69 yea s. Backg ound 17 In Po ugal he o ganized BCSP was implemen ed h oughou he coun y in a s agge ed way and o e a long pe iod o ime. A e he s a in he Cen e Region in 1990, i was implemen ed in he Sou he n Region in 1997, No he n Region and Madei a in 1999, Alga e in 2005 114 and in Aço es he p og amme s a ed in 2009. 115 Since he beginning o he sc eening p og amme, quali y assu ance was conside ed a p io i y, in acco dance wi h he Eu opean Guidelines. 24 In he No he n Region o Po ugal he popula ion-based BCSP is conduc ed by he no h b anch o LPCC and coo dina ed by he No h Regional Heal h Adminis a ion (Adminis ação Regional de Saúde do No e – ARS-N); 116 i s a ed in Oc obe 1999 in one municipali y and i g adually expanded o 65 municipali ies by he end o 2012 (76% o he Fig. 2 - Mammog aphy sc eening in women aged 50- 69, 2001 o 2011 (o nea es yea ) 1. P og amme. 2. Su ey. * Th ee-yea a e age. In o ma ion on da a o Is ael: h p://dx.doi.o g/10.1787/888932315602. Sou ce: OECD Heal h S a is ics 2013, h p://dx.doi.o g/10.1787/heal h-da a-en. 9,4 16,0 17,4 27,3 36,4 44,8 47,4 49,5 51,0 52,7 53,5 54,3 55,0 57,1 58,9 59,6 59,7 60,2 61,0 61,5 71,0 72,2 72,2 72,6 72,6 72,8 72,9 73,6 73,7 77,1 80,2 80,4 82,1 85,5 0 25 50 75 100 Chile ¹ Slo ak Rep. ¹ Mexico ¹ Tu key ¹ Japan 2 Swi ze land ² Hunga y ¹ G eece ² Es onia ¹ Czech Rep. ¹ F ance ¹ Ge many ¹ Aus alia ¹ Poland ² Ko ea ¹ I aly ¹ Iceland ¹* Luxembou g ¹* Belgium ¹ OECD20 New Zealand ¹ Canada ² I eland ¹ No way ¹ Uni ed Kingdom ¹ Slo enia ¹ Is ael ¹ Po ugal ² Denma k ¹ Spain ² Aus ia ² Uni ed S a es ² Ne he lands ¹ Finland ¹ % o women sc eened 2011 2001 Backg ound 18 Region). In ha yea , 90659 women we e submi ed o a mammog aphy, which ep esen s an o e all pa icipa ion a e o 61%. 117 The sc eening p og amme is o ganized wi h eigh mobile uni s and one ixed acili y (in 2012). The da abase/in o ma ion sys em om BCSP is se led a he LPCC and s o es da a elemen s on demog aphic cha ac e is ics, sc eening se ices and esul s, diagnos ic es s and cance in o ma ion. The p og amme includes a s uc u ed indi idual in i a ion o all esiden women aged 45- 69 yea s using he lis s o use s en olled in he Heal h Cen es. F om he beginning, sc eening p ocedu es included bila e al mammog aphy wi h wo- iew (c aniocaudal, mediola e al oblique), cen alized and independen ly ead by wo adiologis s, wi h a inal eading by a hi d independen and expe ienced adiologis , in case o disc epancy. The a ing scale applied o classi y he adiological indings ollows he Eu opean Guidelines; 116 his classi ica ion is widely used in Eu opean sc eening p og ammes. 24 Assessmen o sc een posi i e mammog aphy is ca ied ou by a mul idisciplina y eam ( adiologis , su geon and pa hologis ) a a dedica ed clinical se ing ou side he hospi al, and cance ea men is es ablished acco ding o s anda dized hospi al he apeu ic p o ocols. Sc een ilm mammog aphy was used ill mid-2007, and he ea e , compu e -aided mammog aphy was pe o med in all sc eening uni s. The sc eening in e al is 24 mon hs. In he No he n Region, oppo unis ic b eas cance sc eening coexis s wi h he o ganized p og amme. The p ecise es ima i e o he ex en o oppo unis ic sc eening in he Region is unknown, bu acco ding o ARS-N in 2009, 54% o he women aged 45 o 69 yea s, using he p ima y heal h cen es had unde gone a mammog aphy. 115,118 In 2007 and 2008, 16% o he women ha we e e e ed o b eas sc eening ou side he o ganized p og amme had o epea he mammog aphy and 59% had an addi ional ul asound examina ion. 119 2.9 Impo ance o popula ion-based cance egis ies in he planning and e alua ion o b eas cance sc eening p og ammes The main objec i e o a b eas cance sc eening p og amme is o dec ease mo ali y om his cause. Howe e , as his bene i can only be assessed a e 7-10 yea s o p og amme ope a ion, sho e m indica o s we e de eloped ha allow an ea lie assessmen o he impac o sc eening. 81 In o de o pe o m his e alua ion, i is necessa y a close collabo a ion be ween he sc eening p og amme and he popula ion-based cance egis y. As i is clea om he conside a ions made in he ollowing pa ag aphs, quali y o a cance egis y is impo an o an app op ia e e alua ion o a sc eening p og amme. 120 The cance egis y co e s he en i e emale popula ion o a gi en egion, p o iding in o ma ion on all women ei he hey accep o no o pa icipa e in b eas cance sc eening; popula ion-based cance egis ies ha e an impo an ole in he e alua ion o he impac o sc eening on he en i e a ge popula ion. 24,92 Backg ound 19 The key unc ions o a popula ion-based cance egis y in he assessmen o b eas cance sc eening p og ammes a e he es ima ed b eas cance incidence, iden i ica ion o in e al cance s, moni o ing o umou cha ac e is ics and compa ison o su i al a es be ween g oups. 81,92 Popula ion-based cance egis ies p o ide in o ma ion on b eas cance incidence a es in a ce ain egion, suppo ing cance con ol planning ac i i ies. One o he mos impo an con ibu ions o a cance egis y o he sc eening e alua ion is o p o ide eliable da a o he analysis o incidence end o b eas cance a e he implemen a ion o a sc eening p og amme and he compa ison be ween he obse ed and he expec ed incidence a es. 81,121 The cance egis y is essen ial o iden i ying in e al cance s. 92 I is necessa y o ensu e ha he egis y has a high case asce ainmen and cases a e no missed, o bias migh be in oduced. Due o ime-lag in he eco ding o cance cases in a egis y, some unde es ima ion o in e al cance a es in he mos ecen yea s is una oidable. Howe e , i is ecommended o use only his sou ce o in o ma ion in o de o gua an ee he compa abili y o da a, namely s age o o he p ognos ic in o ma ion. 81,122 Tumou size, ype, g ade and lymph node s a us, ha e he g ea es impac on he p ognosis o b eas cance . I is e y impo an o compa e he s age o umou s diagnosed o e a sc eening cycle and hose diagnosed in an unsc eened popula ion as s age is ega ded as one o he ea ly indica o s o he e ec i eness o cance sc eening. 92 Un o una ely, s age compa ison o umou s epo ed om di e en ins i u ions and o e ime has been ound o a y signi ican ly so he use o his ological size as a p oxy o s age is ecommended. 81 In o de o con i m he e ec i eness o he sc een o de ec small, ea ly s age lesions, he di e en ca ego ies o de ec ion should be conside ed as sc een-de ec ed cance s, cance s in non-a ende s, in e al cance s, cance s in lapsed a ende s and cance s in women no ye in i ed. 92,104 2.9.1 No h Region Cance Regis y o Po ugal (RORENO) RORENO is a popula ion-based cance egis y, es ablished in 1988 by go e nmen al ini ia i e and loca ed a he Po uguese Oncology Ins i u e, in Po o. I cons i u es he main sou ce o in o ma ion on cance bu den o he No he n Po ugal and i co e s he a ea o i e dis ic s: B aga, B agança, Po o, Viana do Cas elo e Vila Real. In 2008, he es ima ed numbe o esiden s in he a ea was 3,294,709. New cases a e collec ed om he public and p i a e hospi als and pa hology labo a o ies. All in asi e cance s a e egis e ed. In o ma ion on he pa ien demog aphic da a and on cance is included in he egis y compu e ised da abase. Cance a iables include da e o Backg ound 20 diagnosis, opog aphy and mo phology, beha iou and g ade, s age and ea men . RORENO uses passi e and ac i e ollow-up ac i i ies o ob ain su i al. In o de o achie e high quali y o cance epo ing and comple eness, some ou ine audi s a e pe o med as well as compu e checks o consis ency, wa ning p og ammes, aining cou ses o egis a s and medical s a , and especially designed esea ch. In 2008, he numbe o ecei ed no i ica ions was 26,703 which co esponded o 16,935 new cance cases diagnosed in esiden s in he No he n Region. 21 II – Aims Aims 23 II – Aims E e y public heal h in e en ion should be e alua ed. 123 B eas cance sc eening is a public heal h in e en ion planned o lowe he bu den o he disease in a popula ion. 43 As explained be o e pe o mance and impac indica o s a e used o e alua e a popula ion-based B eas Cance Sc eening P og amme (BCSP). Though speci ic mo ali y is conside ed he bes impac indica o , i was explained ha o en i canno be used. Thus, ea ly su oga e impac and pe o mance indica o s a e o en used as an al e na i e. The aim o he esea ch epo ed in his hesis was o e alua e he popula ion-based BCSP implemen ed in he No he n Region o Po ugal. Fo ha pu pose, some a ailable su oga e impac and pe o mance indica o s we e used. Fu he mo e, some p econdi ions had o be analysed, in o de o assess he alidi y o da a used o build he abo e men ioned indica o s. Thus he speci ic objec i es o his esea ch we e: 1 – To e alua e he comple eness o cance egis y (RORENO) and bioma ke s classi ica ion, p econdi ions necessa y o he assessmen o popula ion-based b eas sc eening p og ammes. 2 – To e alua e pe o mance indica o s o he BCSP in compa ison wi h o he popula ion- based BCSP wi hin he Eu opean Ne wo k o In o ma ion on Cance p ojec . 3 – To e alua e he BCSP, using he s anda ds o pe o mance and impac indica o s, ecommended by he Eu opean Guidelines. 4 – To compa e he clinicopa hological cha ac e is ics o he in e al b eas cance s wi h he sc een-de ec ed cance s. 5 – To e alua e he clinicopa hological cha ac e is ics o b eas cance s de ec ed in a popula ion in i ed o an o ganized BCSP compa ed o he umou cha ac e is ics o a non- in i ed popula ion 25 III – Resul s 1. Impo an p econdi ions o b eas cance sc eening e alua ion Resul s – Pape II 32 Resul s – Pape II 33 Resul s – Pape II 34 Resul s – Pape II 35 Resul s – Pape II 36 37 III – Resul s 2. In e na ional compa ison o b eas cance sc eening p og ammes Resul s 39 III – Resul s 2. In e na ional compa ison o b eas cance sc eening p og ammes As i was desc ibed in poin 2.5 o he Backg ound sec ion, in e na ional collabo a i e wo k has he po en ial o imp o e and op imize sc eening p og ammes. 124,125 E o s ha e been done o s anda dize da a collec ion and de ini ions in o de o enable meaning ul compa isons ac oss coun ies. 124 Recen ly, he Po uguese sc eening p og ammes om he No he n and Cen e egions we e in i ed o join wo in e na ional s udies by pa icipa ion in he p ojec o Eu opean Ne wo k o In o ma ion on Cance (EUNICE), co- unded by he Eu opean Union. These wo s udies we e desc ibed in wo published pape s (III and IV). The i s s udy in ol ed 10 na ional and 16 egional sc eening p og ammes co e ing opics as o ganiza ion, co e age and pa icipa ion a es. F om esul s he e was an e iden wide ag eemen be ween p og ammes on he mammog aphy as he sc eening es , he a ge age ange 50-69 and he sc eening in e al ( wo yea s). Di e ences we e mo e no o ious a he o ganiza ion le el, olume concen a ion o se ices and he size o a ge popula ions. The sc eening p og amme om he No he n Region con ibu ed wi h 32122 examina ions egis e ed in 2005. Compa ed o he o he p og ammes, his BCSP showed simila co e age by in i a ion (80.2% e sus 79.3%) and highe co e age by examina ion (54.0% e sus 48.2%). The highes alues o co e age by examina ion we e ound in Spain (Na a a - 92.1% and Valencia - 73.9%) and Sweden (Väs manland – 82.5%). Conce ning he p oblem o he alse-posi i e cases (poin 2.6.3. o he Backg ound sec ion) in he second s udy men ioned abo e, a li e a u e e iew was pe o med on he alse-posi i e a e epo ed by ou o iginal esea ch pape s; addi ionally, da a collec ed in he EUNICE p ojec om 20 Eu opean b eas cance sc eening p og ammes we e used o calcula e c oss-sec ional a es o u he assessmen , wi h and wi hou needle biopsy and su ge y, and he posi i e p edic i e alue. Fo his s udy, he BCSP o he No he n Region con ibu ed wi h da a on 12299 ini ial and 12709 subsequen sc eening mammog aphic examina ions, pe o med in 2005. The o e all u he assessmen a e was 9.3% in ini ial and 4.0% in subsequen sc eenings, in women aged 50-69. Fo BCSP in he No he n Region hose alues we e 7.1% and 1.9%, espec i ely. Su gical in e en ion o cla i y p e ious indings using less in asi e echniques in BCSP was 0.7% in ini ial and 0.3% in subsequen examina ions, lowe alues han he ones e i ied o he o e all sc eening p og ammes s udied (1.0% and 0.7%, espec i ely). Compa ed o he Eu opean guidelines, 24 in he No he n Region BCSP he a e o u he assessmen a ini ial sc eening was e y close o he accep able alue (<7%) while he subsequen sc eening alue me he desi able le el (< 3%). Resul s – Pape III 41 Resul s – Pape III 48 Resul s – Pape III 49 Resul s – Pape III 50 Resul s – Pape III 51 Resul s – Pape IV 52 Resul s – Pape IV 53 Resul s – Pape IV 54 Resul s – Pape IV 55 Resul s – Pape IV 56 Resul s – Pape IV 57 Resul s 65 III – Resul s 3. Pe o mance indica o s e alua ion o he popula ion-based b eas cance sc eening p og amme in No he n Po ugal using he Eu opean Guidelines The moni o ing o he sc eening p og amme h ough compa ison o he pe o mance and impac indica o s wi h he s anda d Eu opean Guidelines assess he quali y o sc eening and p o ide means o p edic he mo ali y ou come in he ea ly yea s, 17 as i was e e ed in poin s 2.4.1 and 2.4.2 o he Backg ound sec ion. The objec i e o pape V was o e alua e he i s 10 yea s o ope a ion o he popula ion- based BCSP implemen ed in he No he n Region o Po ugal. A numbe o pe o mance and impac indica o s we e chosen and hey we e compa ed wi h he desi able and accep able le els epo ed in he Eu opean Guidelines. 24 The selec ed indica o s we e also epo ed in mos o he in e na ional publica ions on his subjec . The de e mina ion o he backg ound incidence o he pe iod 2000-2009 in hose municipali ies co e ed by he sc eening p og amme was based on he end obse ed in 1995-1999 o he dis ic s whe e he sc eening was in oduced. Da a om RORENO was used o compu e obse ed incidence a es and o asce ain in e al in asi e b eas cance s. Excep o he ecall a e, mos o he pe o mance indica o s e alua ed we e consis en wi h he desi able le els o he Eu opean Guidelines: he sc eening p og amme was highly accep ed by he popula ion, i was de ec ing he expec ed numbe o in asi e b eas cance s, and i was able o de ec small size b eas cance s among he pa icipan s. Al hough no su icien , hese esul s a e conside ed necessa y o he expec ed u u e educ ion in mo ali y. 17,49 Resul s – Pape V 67 Ti le: Pe o mance indica o s e alua ion o he popula ion-based b eas cance sc eening p og amme in No he n Po ugal using he Eu opean Guidelines Au ho s names and a ilia ions: Ma ia José Ben o a,b , MD MSc a Ins i u e o Biomedical Sciences Abel Salaza , Uni e si y o Po o, b Epidemiology Uni , Po uguese Oncology Ins i u e, Guilhe me Gonçal es a , MD PhD a Ins i u e o Biomedical Sciences Abel Salaza , Uni e si y o Po o, Ana Aguia c , MD c Po uguese Cance League – No h B anch, Po o Cla a Cas o b , MSc b Epidemiology Uni , Po uguese Oncology Ins i u e, Vi o Veloso c , MD c Po uguese Cance League – No h B anch, Po o Ví o Rod igues, MD PhD e, e Facul y o Medicine, Uni e si y o Coimb a, Po uguese Cance League – Cen e B anch, Coimb a Co esponding au ho and eques s o ep in s Ma ia José Ben o, MD MSc Ins i u e o Biomedical Sciences Abel Salaza , Uni e si y o Po o, Rua de Jo ge Vi e bo, nº 228, 4050-313 Po o, Po ugal [email p o ec ed].p Telephone: 00 351 225084067 Fax: 00 351 225084004 Resul s – Pape V 68 Abs ac Objec i e: To e alua e he i s 10 yea s o ope a ion o he popula ion-based b eas cance sc eening p og amme implemen ed in he No he n Region o Po ugal, using selec ed ecommended s anda d pe o mance indica o s. Me hods: Da a om women aged 50-69 sc eened wi h wo- iew mammog aphy, biennially, in he pe iod 2000-2009, we e included. Main pe o mance indica o s we e compa ed wi h he ecommended le els o he Eu opean Guidelines. Resul s: A o al o 202,039 sc eening examina ions we e pe o med, 71731 (35.5%) in he p e alen sc eening and 130,308 (64.5%) in he subsequen sc eening. Co e age a e by examina ion eached 74.3% o he a ge popula ion, in he las pe iod e alua ed. Recall a es we e 8.1% and 2.4% and cance de ec ion a es we e 4.4/1000 and 2.9/1000 espec i ely, o p e alen and subsequen sc eenings The b eas de ec ion a e o in asi e cance , exp essed as a mul iple o he backg ound expec ed incidence was 3.1 in p e alen sc een and 2.2 in subsequen sc een. The incidence o in asi e in e al cance s me he desi able ecommended le els bo h he i s and second yea s since las sc eening examina ion, in he p e alen and subsequen sc eenings. In asi e umou s <15 mm we e 50.4% and 53.8% o he in asi e cance s de ec ed in p e alen and subsequen sc eenings. Less a ou able size, g ading and bioma ke s exp ession we e ound in in e al cance s compa ed o sc een-de ec ed cance s. Conclusions: B eas cance sc eening p og amme in he No he n Region o Po ugal was well accep ed by he popula ion. Mos o he pe o mance indica o s we e consis en wi h he desi able le els o he Eu opean Guidelines, which indica e an e ec i e sc eening p og amme. Fu u e esea ch should e i y he consis ency o some o hese esul s by using upda ed in o ma ion om a la ge popula ion. Keywo ds: b eas cance ; pe o mance indica o s; popula ion-based sc eening; mammog aphy Resul s – Pape V 69 1. In oduc ion The main objec i e o b eas cance sc eening is o educe mo ali y due o he disease. Tha is achie ed by iden i ying b eas cance a a s age when i is mo e cu able and he p obabili y o he disease being dissemina ed is smalle [1-4]. Because sc eening p og ammes mus be ope a ing o many yea s be o e b eas cance mo ali y educ ion can be e i ied, some ea ly su oga e measu es a e conside ed aluable indica o s o u u e changes in mo ali y a es [5]. In 2006, he Eu opean Union published he 4 h edi ion o he Eu opean Guidelines on Quali y Assu ance in B eas Cance Sc eening and Diagnosis [6] ha ha e been used in he e alua ion o speci ic Eu opean p og ammes [7, 8]. A good sc eening p og amme is a complex o ganisa ion wi h mul iple s eps encompassing he en i e sc eening p ocess and, o main ain a high-quali y se ice, i equi es con inuous supe ision and egula epo ing o igo ous scien i ic s udies [4, 9, 10]. These s udies, also con ibu e wi h e idence-based knowledge on he isks and bene i s o implemen ing b eas cance sc eening p og ammes in popula ions wi h di e se heal h sys ems and economic cons ain s [10]. In Po ugal, he o ganized popula ion-based b eas cance sc eening was ini ia ed in 1990 in he Cen e Region, conduc ed by he Po uguese Cance League (Liga Po uguesa Con a o Canc o – LPCC) a p i a e, non-p o i o ganiza ion; in he No he n Region an iden ical p og amme s a ed in Oc obe 1999 [11, 12]. The p og amme is inanced by he Na ional Heal h Se ice (NHS). I is co-o dina ed by he No h Regional Heal h Adminis a ion (o he NHS) and ope a ed by he no h b anch o LPCC. The o ganized p og amme coexis s wi h oppo unis ic b eas cance sc eening; da a on oppo unis ic sc eening is e y limi ed [13]. Since he beginning o he p og amme, quali y assu ance was conside ed a p io i y, in acco dance wi h he Eu opean Guidelines [6]. The objec i e o his s udy was o e alua e he b eas cance sc eening p og amme du ing he i s 10 yea s o ope a ion, in he No he n Region o Po ugal, using some o he s anda d pe o mance indica o s ecommended [6]. Resul s – Pape V 70 2. Ma e ial and me hods The popula ion-based b eas cance sc eening implemen ed om Oc obe 1999 o 2009 in he No he n Region o Po ugal s a ed in one municipali y and g adually expanded o 43 municipali ies (mos ly u al communi ies) by he end o 2009. The p og amme included a pe sonal in i a ion sen by mail wi h a p e-booked appoin men o esiden women aged 45- 69 yea s. Mos Po uguese people a e egis e ed in hei local Heal h Cen e s ( om NHS); hus he lis s o use s en olled in hese Heal h Cen e s a e e y good p oxies o a non- exis en compu e ized esiden s da abases [13]. Names and add esses o women egis e ed in he local Heal h Cen es we e p o ided o LPCC, who managed he in i a ion p ocess. Women no egis e ed in hese lis s we e also in i ed o pa icipa e h ough ad e ising, con ac s wi h heal h p o essionals and communi y s akeholde s. Mammog aphy was o e ed ee o cha ge and was pe o med a one o six mobile uni s o a one ixed acili y. F om he beginning sc eening p ocedu es included bila e al mammog aphy wi h wo- iew (c aniocaudal, mediola e al oblique), cen alized and independen ly ead by wo adiologis s, wi h a inal eading by a hi d independen and expe ienced adiologis , in case o disc epancy. Women wi h an abno mal sc een mammog aphy we e ecalled and eassessmen was ca ied ou by a mul idisciplina y eam ( adiologis , su geon and pa hologis ) a a dedica ed clinical se ing ou side he hospi al. Cance ea men was es ablished acco ding o s anda dized hospi al he apeu ic p o ocols. Sc een ilm mammog aphy was used ill mid-2007, and he ea e , compu ed adiog aphy was pe o med in all sc eening uni s. The sc eening in e al was 24 mon hs. Da a collec ed wi hin his p og amme, om he in i a ion p ocess ill he ollow-up o cance cases, we e ac i ely ga he ed and en e ed in a da abase cen alized a LPCC. In o ma ion on indi idual women was checked o accu acy and comple eness, be o e being in oduced in he compu e da abase. Da a we e o ganized by p e alen and subsequen sc eening; he la e includes egula and i egula sc eening [6]. Fo compa abili y wi h he Eu opean Guidelines, analysis shown he e was es ic ed o women aged 50-69. Women en olled in 1999 we e no included in his analysis due o e y low igu es. Resul s – Pape V 71 Co e age a e by examina ion was es ima ed using he a io be ween he numbe o examina ions wi hin he o ganized sc eening p og amme and he numbe o eligible women du ing a wo-yea pe iod [8]. Denomina o was de i ed om he census da a p o ided by he o ice o S a is ics Po ugal. In he las pe iod o he s udy, he me hodology o pe sonally in i e women o a end sc eening was de ini i ely es ablished and he pa icipa ion a e [6] was also calcula ed. Expec ed incidence a e in he absence o sc eening o he pe iod 2000-2009 was de ined as he p edic ed incidence a e o in asi e b eas cance based on he ends obse ed in 1995-1999, om he dis ic s whe e cance sc eening was implemen ed. Using he da abase om he popula ion-based No h Region Cance Regis y (Regis o Oncológico Regional do No e – RORENO), a Poisson eg ession model was used o calcula e he b eas cance incidence o women aged 50-69 and i was es ima ed as 1.23/1000, wi h an annual pe cen inc ease o 2.1% [6, 14]. In e al cance (IC) was de ined as b eas cance diagnosed in a woman who had a sc eening es , wi h/wi hou u he assessmen , which was nega i e ei he be o e he nex sc eening in i a ion o wi hin a ime pe iod equal o a sc een in e al o women who ha e eached he uppe age limi [6, 15]. To e alua e in e al cance s, sc eening da a we e linked o he RORENO da abase bu hei asce ainmen was limi ed o women pa icipa ing in he sc eening p og amme om 2000-2007 as he Cance Regis y only had comple e in o ma ion on b eas cance incidence ill 2009. The in e al cance a e was calcula ed as he numbe o in e al cance s di ided by he o al numbe o sc eens wi hin a speci ied ime. To e alua e he p opo ion o in e al cance s ela ed o he backg ound (expec ed) incidence, he es ima es we e made o he yea s 2000-2007 (es ima ed a e 1.20/1000). In e al cance s we e di ided in wo g oups acco ding o ime (in mon hs) since sc eening examina ion [6]: 0- 11 and 12-23. Radiological e iew o las sc eening/assessmen imaging and diagnos ic mammog aphy o he in e al cance was no pe o med. In o ma ion on he maximum dimension o in asi e umou and exp ession o bioma ke s as es ogen (ER) and Resul s – Pape V 72 p oges e one (PR) ecep o s and human epide mal g ow h ac o ecep o 2 (HER2) we e ga he ed om he pa hology epo s. Resul s a e gi en in numbe s, p opo ions and a es. Calcula ed pa ame e s a e displayed by wo-yea pe iods, om 2000 o 2009. As he implemen a ion o he p og amme was g adual, no all he municipali ies con ibu ed wi h he same numbe o sc eening ounds. In he 2000-2001 pe iod o e alua ion 8 municipali ies we e co e ed, and in he nex 4 pe iods 19, 32, 36 and 43 municipali ies we e included, espec i ely. Pe o mance indica o s used in his e alua ion we e: co e age a e by examina ion, ecall a e, cance de ec ion a e, posi i e p edic i e alue (PPV), a io benign/malignan , in e al cance a e, umou maximum dimension and umou g ade, which we e calcula ed using he ecommended s anda d de ini ions [6]. 3. Resul s F om 2000 o 2009, a o al o 202,039 sc eening examina ions we e pe o med, 71731 (35.5%) in he p e alen sc eening and 130,308 (64.5%) in he subsequen sc eening. By he end o 2009, 43 municipali ies we e co e ed by he sc eening p og amme, co esponding o 50% o he o al numbe o municipali ies in he No he n Region bu comp ised only 17% o he women aged 50-69 and esiden in his egion. The co e age a e by examina ion was 47.2% a he s a o he p og amme and in he nex ou pe iods o sc eening i s alues we e 65.6%, 67.7%, 72.0% and 74.3%. Pa icipa ion a e in he pe iod 2008/2009 was 74.5%. Resul s om he e alua ion o he pe o mance indica o s acco ding o p e alen and subsequen sc eening a e shown in Tables 1 and 2. The ecall a e was 8.1% in p e alen sc eening, anging om 6.3% in 2000/2001 o 12.5% in 2008/2009. In subsequen sc eening he ecall a e was 2.4% wi h li le a ia ion along he 10 yea s. A ini ial sc eening, a o al o 312 b eas cance s we e diagnosed co esponding o a de ec ion a e o 4.4/1000 pa icipan s. In he subsequen sc eening a o al o 374 cance s we e de ec ed (de ec ion a e o 2.9/1000). The b eas de ec ion a e o in asi e cance , exp essed as a mul iple o he backg ound expec ed incidence was 3.1 in Resul s – Pape V 73 p e alen sc een (3.7/1.2) and 2.2 (2.6/1.2) in subsequen sc een (desi able le els in he Eu opean Guidelines a e >3 o p e alen sc een and >1.5 o subsequen sc een). The ecall a es dec eased wi h age and he de ec ion a es showed he opposi e pa e n, bo h in p e alen and subsequen sc eenings – ig 1 and 2. In he p e alen sc eening, he inc ease in ecall a es as he p og amme p og essed was ollowed by a pa allel inc ease in he a e o cance de ec ion, excep o he 2008/2009 pe iod ( able 1). In subsequen sc een, no pa e ns o endencies we e obse ed ( able 2). The in asi e umou s in he p e alen and subsequen sc eening comp ised 85.9% and 89.6% o he malignancies, espec i ely. A ini ial sc eening, he de ec ion a e o in asi e umou s inc eased o e ime excep o he las pe iod conside ed bu duc al ca cinoma in si u (DCIS) was ela i ely s able; o subsequen sc eening he e was li le a ia ion in he in asi e and DCIS a es. The posi i e p edic i e alue (PPV) was smalle a he p e alen sc eening compa ed wi h subsequen sc eening (5.6% s.12.5%). Wi h excep ion o he i s pe iod conside ed in bo h ypes o sc eening, ime ends showed ha as long as ecall a e was ge ing highe , he PPV alue was ge ing lowe . The a io o benign lesions o malignan lesions su gically emo ed me he desi able ecommenda ion om he Eu opean Guidelines, in bo h ypes o sc eening. In he p e alen sc eening smalle alues we e ound in mo e ecen yea s and o subsequen sc eening consis en low a ios we e e i ied in all pe iods o e alua ion. A o al o 112 in asi e in e al cance s we e iden i ied in he pe iod 2000-2007, ep esen ing 21.8% (51 cases) o he sc een de ec ed in asi e b eas cance s in he p e alen and 29.3% (61 cases) in he subsequen sc eens. Fo p e alen sc een, he in e al cance a e as a p opo ion o he expec ed b eas cance incidence was 18.3% wi hin he i s 0-11 mon hs and 49.2% o he 12-23 mon hs; o subsequen sc een, hese alues we e 15.0% and 49.6%, espec i ely (da a no shown). The Eu opean Guidelines desi able le el o his indica o was < 30% wi hin he i s 12 mon hs and < 50% o he second 12 mon hs. Resul s – Pape V 80 [23] B oede s M, Moss S, Nys om L, Njo S, Jonsson H, Paap E, e al. (2012). The impac o mammog aphic sc eening on b eas cance mo ali y in Eu ope: a e iew o obse a ional s udies. J Med Sc een. 19 (Suppl 1):14-25. [24] Segnan N, Rosso S,Pon i A. (2012). Is he b eas cance mo ali y dec ease in Sweden due o sc eening o ea men ? No he igh ques ion. J Na l Cance Ins . 104(14):1040- 1041. [25] Lynge E, Olsen AH, F acheboud J,Pa nick J. (2003). Repo ing o pe o mance indica o s o mammog aphy sc eening in Eu ope. Eu J Cance P e . 12(3):213-222. [26] Sa keala T, An ila A, Saa enmaa I,Hakama M. (2005). Validi y o p ocess indica o s o sc eening o b eas cance o p edic mo ali y educ ion. J Med Sc een. 12(1):33-37. [27] Ho ind S, Pon i A, Pa nick J, Ascunce N, Njo S, B oede s M, e al. (2012). False- posi i e esul s in mammog aphic sc eening o b eas cance in Eu ope: a li e a u e e iew and su ey o se ice sc eening p og ammes. J Med Sc een. 19 (Suppl 1):57-66. [28] Yankaskas BC, Klabunde CN, Ancelle-Pa k R, Renne G, Wang H, F acheboud J, e al. (2004). In e na ional compa ison o pe o mance measu es o sc eening mammog aphy: can i be done? J Med Sc een. 11(4):187-193. [29] Sa keala T, An ila A, Fo sman H, Luos a inen T, Saa enmaa I,Hakama M. (2004). P ocess indica o s om en cen es in he Finnish b eas cance sc eening p og amme om 1991 o 2000. Eu J Cance . 40(14):2116-2125. [30] Moskowi z M. (1996). Re ospec i e e iews o b eas cance sc eening: wha do we eally lea n om hem? Radiology. 199(3):615-620. [31] Vinnicombe S, Pin o Pe ei a SM, McCo mack VA, Shiel S, Pe y N,Dos San os Sil a IM. (2009). Full- ield digi al e sus sc een- ilm mammog aphy: compa ison wi hin he UK b eas sc eening p og am and sys ema ic e iew o published da a. Radiology. 251(2):347-358. [32] Nag egaal ID,Du y SW. (2013). Reduc ion in a e o node me as ases wi h b eas sc eening: consis ency o associa ion wi h umo size. B eas Cance Res T ea . 137(3):653-663. Resul s – Pape V 81 [33] Day NE, Williams DR,Khaw KT. (1989). 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Resul s – Pape V 82 Table 1 – Pe o mance indica o s and cha ac e is ics o cance s in p e alen sc een, in women aged 50-69 yea s, by 2-yea sc eening pe iod and compa ison wi h Eu opean guidelines Pa ame e s 2000-01 2002-03 2004-05 2006-07 2008-09 To al Eu opean guidelines a Sc eened women (n) 12910 15826 20573 13041 9381 71731 Recall a e (%) 6.3 7.1 7.4 8.8 12.5 8.1 <7 / < 5 Women e e ed o hospi al b (%) 0.5 0.7 0.7 0.8 0.7 0.7 Sc een cance s (n) 47 69 93 64 39 312 Sc een cance s (/1000) 3.6 4.4 4.6 5.0 4.6 4.4 in asi e (/1000) 2.9 3.7 4.0 4.4 3.6 3.7 duc al in si u (/1000) 0.8 0.7 0.5 0.5 0.5 0.6 In asi e (%) 78.7 84.1 88.2 89.1 87.2 85.9 90 / 80-90 Posi i e p edic i e alue c (%) 5.8 6.2 6.3 5.9 3.8 5.6 Ra io benign/malignan 0.23 0.33 0.35 0.16 0.03 0.24 ≤1:2 / ≤1:4 Tumou diame e d (n) 35 54 80 55 32 256 % ≤ 10 mm 31.4 40.7 33.8 41.8 18.8 34.8 NA / ≥25 % < 15 mm 45.7 51.9 47.5 58.2 46.9 50.4 50 / >50 % > 20 mm 34.3 24.1 27.5 16.4 15.6 23.8 Tumou g ade d (n) 36 52 76 52 31 247 % g ade 1 30.5 34.6 32.9 32.7 22.6 31.6 % g ade 2 55.6 46.2 56.6 51.9 61.3 53.9 % g ade 3 13.9 19.2 10.5 15.4 16.1 14.5 a Eu opean Guideline, accep able/desi able le el; b numbe o women e e ed o hospi al a e a posi i e assessmen as a p opo ion o he sc eened women; c numbe o cance s de ec ed as a p opo ion o he women wi h a posi i e sc eening es d In asi e umou s only; NA, no applicable Resul s – Pape V 83 Table 2 – Pe o mance indica o s and cha ac e is ics o cance s in subsequen sc een, in women aged 50-69 yea s, by 2-yea sc eening pe iod and compa ison wi h Eu opean guidelines Pa ame e s 2002-03 2004-05 2006-07 2008-09 To al Eu opean guidelines a Sc eened women (n) 9550 23773 45643 51342 130308 Recall a e (%) 2.2 2.0 2.4 2.6 2.4 <5 / <3 Women e e ed o hospi al b (%) 0.4 0.3 0.4 0.4 0.4 Sc een cance s (n) 33 63 133 145 374 Sc een cance s (/1000) 3.5 2.7 2.9 2.9 2.9 in asi e (/1000) 3.2 2.5 2.6 2.5 2.6 duc al in si u (/1000) 0.2 0.1 0.4 0.4 0.3 In asi e (%) 93.9 95.2 88.0 87.6 89.6 90 / 80-90 Posi i e p edic i e alue c (%) 15.7 13.8 12.5 11.5 12.5 Ra io benign/malignan 0.15 0.13 0.12 0.08 0.11 ≤1:2 / ≤1:4 Tumo diame e d (n) 30 58 112 125 325 % ≤ 10 mm 33.3 29.3 28.6 27.2 28.6 ≥25 / ≥30 % < 15 mm 53.3 60.3 50.9 53.6 53.8 50 / >50 % > 20 mm 30.0 15.5 20.5 21.6 20.9 Tumou g ade d (n) 31 57 114 124 326 % g ade 1 29.0 22.8 21.9 26.6 24.5 % g ade 2 51.6 52.6 57.9 48.4 52.8 % g ade 3 19.4 24.6 20.2 25.0 22.7 a Eu opean Guideline, accep able/desi able le el; b numbe o women e e ed o hospi al a e a posi i e assessmen as a p opo ion o he sc eened women; c numbe o cance s de ec ed as a p opo ion o he women wi h a posi i e sc eening es ; d In asi e umou s only; NA, no applicable Resul s – Pape V 84 Table 3 – Bioma ke exp ession in p e alen and subsequen sc een-cance s and in e al cance s Pa ame e s P e alen sc een cance s Subsequen sc een cance s In e al cance s ER s a us (n) 263 329 107 % Posi i e 87.1 87.8 71.0 % Nega i e 12.9 12.2 29.0 PR s a us (n) 263 329 107 % Posi i e 75.3 79.0 60.7 % Nega i e 24.7 21.0 39.3 HER2 s a us (n) 106 232 98 % Posi i e 13.2 14.7 21.4 % Nega i e 86.8 85.3 78.6 Resul s – Pape V 85 0 2 4 6 8 10 12 50 - 54 55 - 59 60 - 64 65 - 69 Recall a e (%) Age g oups (yea s) Fig. 1 Recall a e (%) by i e-yea age g oup and ype o sc een P e alen sc een Subsequen sc een 0 1 2 3 4 5 6 50 - 54 55 - 59 60 - 64 65 - 69 De ec ion a e (/1000) Age g oups (yea s) Fig.2 B eas cance de ec ion a e pe 1000 by i e-yea age g oup and ype o sc een P e alen sc een Subsequen sc een 87 III – Resul s 4. Clinicopa hological di e ences be ween in e al and sc een-de ec ed b eas cance s diagnosed wi hin a sc eening p og amme in No he n Po ugal Resul s 89 III – Resul s 4. Clinicopa hological di e ences be ween in e al and sc een-de ec ed b eas cance s diagnosed wi hin a sc eening p og amme in No he n Po ugal As s a ed in he Backg ound sec ion (poin 2.6.2) in e al cance s a e an impo an indica o o he quali y o mammog aphy as well as o he likely impac o he sc eening p og ammes on b eas cance . 81,82 The clinicopa hological cha ac e iza ion o in e al cance s is essen ial gi en i s ela ion wi h he mo ali y om he disease. 91 This was he subjec o pape VI. Moni o ing o in e al cance s occu ence is a c ucial pa o he e alua ion o a mammog aphy sc eening p og amme 24 o he eason ha i p o ides a mechanism o e alua e some o he echnical p ocesses in ol ed in he sc eening, as pe o mance and in e p e a ion o he mammog aphy, and i con ibu es o he e alua ion o he impac mammog aphy sc eening on b eas cance in he a ge popula ion. 100,126 The e ision o sc eening and diagnos ic mamog aphy necessa y o classi y he in e al cance s was no pe o med in his pape ; some au ho s conside ed his ask a necessa y ool o con inuous educa ion o adiologis s bu o ques ionable use ulness he e ospec i e e iews o sepa a e he in e al cance ca ego ies, as i is highly dependen on he adop ed me hodology. 85 Due o he ime lag be ween he diagnosis o he disease and egis a ion a RORENO, he e alua ion was es ic ed o he sc eening pe iod o 2000 o 2007, wi h da a om he egis y comple ed ill cance s diagnosed in 2009. The objec i e o pape VI was o compa e he clinicopa hological cha ac e is ics o in e al b eas cance s o he sc een-de ec ed cance s. O he esul s achie ed i was no ewo hy he highe size o in e al cance s, he highe g ade and less equen oes ogen ecep o posi i i y ound in hese cance s compa ed o sc een-de ec ed. This pa e n is also desc ibed in he majo i y o he in e na ional s udies. 94,100,127-132 This s udy was only possible hanks o he ex ensi e ne wo k o pa hologis s and hospi al cance egis ies ha collabo a ed wi h RORENO in p o iding quali y da a. Resul s – Pape VI 96 97 III – Resul s 5. Clinicopa hological cha ac e is ics o in asi e b eas cance s diagnosed in pa icipan s, non-pa icipan s and no in i ed o he o ganized popula ion-based B eas Cance Sc eening, in he No h o Po ugal Resul s 99 III – Resul s 5. Clinicopa hological cha ac e is ics o in asi e b eas cance s diagnosed in pa icipan s, non-pa icipan s and no in i ed o he o ganized popula ion-based B eas Cance Sc eening, in he No h o Po ugal F om he momen an o ganized sc eening p og amme has been in oduced o a coun y o egion i is necessa y o s udy he e ec i eness o he p og amme in ou ine heal h-ca e se ings and obse a ional s udies become he main con ibu o s o in o ma ion on he impac o sc eening. 66 Many s udies compa ed he b eas cance mo ali y among women in i ed and no in i ed o sc eening, o compa ed pa icipan s and non-pa icipan s. 120 O he s udies compa ed ea ly indica o s o e icacy as size and s age o b eas cance s diagnosed in in i ed and no in i ed popula ions ( he con ol g oup) o he sc eening p og amme. 121,133 As i was e e ed in he Backg ound sec ion (1.4 His opa hology and p ognosis) ad anced b eas cance s age is ela ed wi h highe mo ali y. I should be no iced ha his popula ion o no in i ed women can be subjec ed o mo e o less ma ked le el o oppo unis ic sc eening a he han wi h no sc eening a all, 57,134 leading o a possible educ ion in he BCSP epo ed bene i s. The phased implemen a ion o he sc eening p og amme in he No he n Region allowed he assessmen o he sc eening expe ience o he women esiden in he dis ic o B agança compa ed o a con empo aneous popula ion o women esiden in Vila Real and no exposed o he o ganized sc eening p og amme. In pape VII he objec i e was o know how di e en he clinicopa hological cha ac e is ics o he cance s we e, depending on he modali y o de ec ion. Al hough he size o he g oups may hampe ed some associa ions, in sc een-de ec ed b eas cance s he maximum dimension o he in asi e umou was smalle , and signi ican ly di e en om he cance s de ec ed in women non-pa icipan o no in i ed o he o ganized sc eening. The main limi a ion in his wo k de i ed om he impossibili y o assign o he no in i ed popula ion wha was he modali y o de ec ion o he b eas cance : i symp oma ic o h ough oppo unis ic sc eening. Resul s – Pape VII 101 Ti le: Clinicopa hological cha ac e is ics o in asi e b eas cance s diagnosed in pa icipan s, non- pa icipan s and no in i ed o he o ganized popula ion-based B eas Cance Sc eening, in he No h o Po ugal Sho i le: Clinicopa hological cha ac e is ics o b eas cance s in pa icipan s, non-pa icipan s and no in i ed o a sc eening p og amme Au ho s names, deg ees and a ilia ions: - Ma ia José Ben o, MD MSc, Ins i u e o Biomedical Sciences Abel Salaza , Uni e si y o Po o and Epidemiology Uni , Po uguese Oncology Ins i u e, Po o, Po ugal - Guilhe me Gonçal es, MD PhD, Ins i u e o Biomedical Sciences Abel Salaza , Uni e si y o Po o, Po ugal - Ana Aguia , MD, Po uguese Cance League – No h B anch, Po o, Po ugal - Luis An unes, MSc, Epidemiology Uni , Po uguese Oncology Ins i u e, Po o, Po ugal - Cla a Cas o, MSc, Epidemiology Uni , Po uguese Oncology Ins i u e, Po o, Po ugal - Vi o Veloso, MD, Po uguese Cance League – No h B anch, Po o, Po ugal - Vi o Rod igues, MD PhD, Facul y o Medicine, Uni e si y o Coimb a, and Po uguese Cance League – Cen e B anch, Coimb a, Po ugal Co esponding au ho and eques s o ep in s Ma ia José Ben o, MD MSc Ins i u e o Biomedical Sciences Abel Salaza , Uni e si y o Po o, Rua de Jo ge Vi e bo, nº 228, 4050-313 Po o, Po ugal [email p o ec ed].p Telephone: 00 351 225084067 Fax: 00 351 225084004 Resul s – Pape VII 102 Abs ac Objec i e The aim o his s udy was o e alua e he clinical and pa hological cha ac e is ics o he in asi e b eas cance s diagnosed in women pa icipan in b eas cance sc eening p og amme, compa ed o cance s de ec ed in non-pa icipan s and in no in i ed women. Se ing B eas Cance Sc eening P og amme (BCSP) o he no h egion o Po ugal. Me hods Da a was e ie ed om he popula ion-based No h Region Cance Regis y and om he o ganized popula ion-based BCSP, and eco ds we e ma ched o selec he h ee g oups o compa ison. Resul s In sc eening pa icipan s, 75.8% o in asi e b eas cance s we e ≤ 20 mm, 67.7% had no axilla y lymph nodes me as asis and 58.1% we e s age I. These cha ac e is ics we e signi ican ly mo e a ou able han hose ound in b eas cance s de ec ed in women non- pa icipan o no in i ed. A e mul i a iable analysis, size emained he only dis inguishing cha ac e is ic o b eas cance s de ec ed wi hin he sc eening p og amme compa ed o he o he wo s udied g oups. B eas cance s de ec ed in sc eening pa icipan s we e signi ican ly smalle , which is consis en wi h indings by o he au ho s. Conclusion The mo e a ou able p ognos ic cha ac e is ics o he b eas cance s de ec ed in a popula ion exposed o sc eening (including in e al cance s) indica e a possible mo ali y educ ion in he u u e. Keywo ds B eas cance ; o ganized sc eening; non-pa icipan s; mammog aphy; umou size Resul s – Pape VII 103 In oduc ion High-quali y popula ion-based b eas cance sc eening p og ammes, wi h pe iodic mammog aphic examina ion o asymp oma ic women became an impo an ool in cance con ol. 1,2 Fo logis ic easons he implemen a ion o a new popula ion-based sc eening p og amme in a ce ain coun y (o egion) can ake se e al yea s ill i is ully implemen ed in all he geog aphical a ea conside ed; o ha eason, du ing a ce ain ime pe iod, i happens ha e y simila neighbou ing popula ions a e being co e ed o no by he p og amme, c ea ing an oppo uni y o compa e likely ou comes be ween popula ions. 1 Compa isons o cha ac e is ics o he cance s diagnosed in women in i ed o no o an o ganized sc eening p og amme, and he analysis o di e ences be ween sc eened-de ec ed and symp oma ic b eas cance s, ha e been used as a u he app oach in he e alua ion o sc eening p og ammes. 3-8 The o ganized popula ion-based B eas Cance Sc eening P og amme (BCSP) implemen ed in he No he n Region o Po ugal, conduc ed by he no h b anch o he Po uguese Cance League (Liga Po uguesa Con a o Canc o – LPCC) s a ed in 1999 in one municipali y and g adually expanded i s co e age in he no h egion (5 dis ic s and 68 municipali ies). BCSP was implemen ed in he dis ic o B agança be ween 2003 and 2005 when ull co e age was eached; in 2005, he es ima ed numbe o women aged 50-69 yea s li ing in he dis ic was 19 554, ep esen ing 5.3% o he es ima ed 372 015 women o he same age li ing in he whole no he n egion. B agança and Vila Real a e neighbou ing dis ic s, wi h he same socioeconomical and cul u al ea u es and e y close backg ound b eas cance incidence. 9 In Vila Real he o ganized sc eening p og amme was only launched in 2009; in 2005, he es ima ed numbe o women aged 50-69 yea s li ing in his dis ic was 27 644, ep esen ing 7.4% o he women o he same age g oup in he no he n egion. We aimed a con ibu ing o he assessmen o BCSP. Fo ha pu pose, he speci ic objec i e o his s udy was o compa e he cha ac e is ics o he in asi e b eas cance s Resul s – Pape VII 104 de ec ed in popula ions wi h di e en sc eening exposu e/pa icipa ion s a us in ou o ganized sc eening p og amme. Me hods B ie ly, he me hods implemen ed a he BCSP we e he ollowing: e e y wo yea s women aged be ween 45 and 69 yea s we e sen a le e wi h an in i a ion o a wo- iew mammog aphy examina ion a one o he mobile o ixed uni s. A blind-double eading was sys ema ically pe o med a a dedica ed cen e by ained adiologis s wi h a inal eading by a hi d independen and expe ienced adiologis , in case o disc epancy. Since he beginning o he sc eening p og amme i has been ope a ing in acco dance wi h he Eu opean Guidelines 10 and p elimina y esul s ha e been published. 11 A speci ic da abase wi h indi idual eco ds o he sc eening p ocedu es and esul s was c ea ed in 1999 (BCSP da abase). In asi e b eas cance s diagnosed in women esiden in he no he n egion o Po ugal ha e been egis e ed since 1988, a he popula ion-based No h Region Cance Regis y (Regis o Oncológico Regional do No e – RORENO) which has high comple eness. 12 Da a was e ie ed om RORENO using he ollowing c i e ia: in asi e b eas cance s diagnosed be ween 2003 and 2008, in women aged 50-69 yea s a diagnosis ( o be in acco dance wi h age g oup conside ed in he Eu opean Guidelines) 10 and esiden in he dis ic s o Vila Real and B agança. Then, in o ma ion on he sc eening his o y o b eas cance s in women esiden in B agança was e ie ed om he BCSP da abase. Va iables as name, da e o bi h and na ional heal h numbe we e used o ma ching. Simila o he “sc eening exposu e” 4 and “pa icipa ion” 6 s a us classi ica ions used by o he au ho s, he abo e desc ibed in o ma ion was used o selec h ee g oups o compa ison: • women in i ed and pa icipa ing in he sc eening, including sc een-de ec ed cance s and in e al cance s ( esiden s in B agança) named pa icipan s in his analysis; Resul s – Pape VII 105 • women in i ed bu no pa icipa ing in sc eening, including women who ne e a ended o ganized sc eening p ocedu es, and hose whose las pa icipa ion had been mo e han 2 yea s be o e ( esiden s in B agança), named non-pa icipan s; • women no in i ed o sc eening, which includes wo subg oups: hose esiden in Vila Real dis ic , who we e no in i ed o sc eening in he s udy pe iod, and women esiden in B agança dis ic wi h b eas cance diagnosed p io o an in i a ion o pa icipa e in he sc eening p og amme, named no in i ed. Da a collec ed om he BCSP and RORENO da abases included he pa ien da e o bi h, da e and ound o las mammog aphy, ou come o sc eening, sc eening exposu e/pa icipa ion s a us (pa icipan s, non-pa icipan s, no in i ed), municipali y o esidence, da e o diagnosis o b eas cance , age a diagnosis, umou size in mm (wi h u he di ision in 3 g oups, acco ding o he cu -o s o he Eu opean Guidelines) 10 , his ological ype using he In e na ional Classi ica ion o Diseases o Oncology-3 d edi ion (8500, 8521 coded as duc al; 8520, 8522, 8524 coded as lobula ; 8211, 8480, 8510, 8530, 8540 coded as o he ), his ological g ade acco ding o No ingham G ading Sys em 13 , lymph node s a us, umou s age (TNM classi ica ion – AJCC 14 ), i s ea men (mas ec omy, b eas conse ing su ge y, chemo he apy). In cases wi h up on chemo he apy, a clinical T and N we e assigned. In o ma ion on bioma ke s as oes ogen (ER) and p oges e one (PR) ecep o s s a us, and de ec ion o o e exp ession and/o ampli ica ion o he human epide mal g ow h ac o ecep o 2 (HER2) we e egis e ed acco ding o he pa hology epo s. B eas cance s de ec ed in women pa icipa ing in sc eening, in non-pa icipan s and in women no in i ed o sc eening we e compa ed o each o he a o emen ioned a iables. Compa isons we e made pai wise. P opo ions we e compa ed using he Pea son χ 2 es o Fishe ’s exac es when χ 2 es was no applicable, and one-way analysis o a iance was used o compa e he means o he con inuous a iables. Uncondi ional mul i a iable logis ic eg ession was used o assess he associa ion be ween sc eening exposu e/pa icipa ion s a us and clinicopa hological cha ac e is ics o Resul s – Pape VII 112 Re e ences 1. Lynge E, To nbe g S, on Ka sa L, Segnan N, an Delden JJ. De e minan s o success ul implemen a ion o popula ion-based cance sc eening p og ammes. Eu J Cance 2012;48:743-8. 2. 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B eas sc eening, p ognos ic ac o s and su i al- - esul s om he Swedish wo coun y s udy. B J Cance 1991;64:1133-8. 29. McCann J, S ock on D, Day N. B eas cance in Eas Anglia: he impac o he b eas sc eening p og amme on s age a diagnosis. J Med Sc een 1998;5:42-8. 30. S ock on D, McCann J. Cance egis ies in moni o ing, e alua ing and planning b eas cance sc eening p og ammes. In: Sankila R, Déma e E, Hakama M, Lynge E, Shou en LJ, Pa kin DM, eds. E alua ion and Moni o ing o Sc eening P og ammes. Luxembou g: O ice o O icial Publica ions o he Eu opean Communi ies, 2001:181-94 Resul s – Pape VII 115 31. Nag egaal ID, Allgood PC, Du y SW, e al. P ognosis and pa hology o sc een-de ec ed ca cinomas: how di e en a e hey? Cance 2011;117:1360-8. 32. Day NE, Williams DR, Khaw KT. B eas cance sc eening p og ammes: he de elopmen o a moni o ing and e alua ion sys em. B J Cance 1989;59:954-8. 33. Ho ind S, So um R, Tho esen S. 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Resul s – Pape VII 116 Table 1 – Dis ibu ion o clinicopa hological cha ac e is ics o in asi e b eas cance s diagnosed in women pa icipan , in non- pa icipan and no in i ed o he o ganized popula ion-based B eas Cance Sc eening P og amme in 2003-2008 Clinicopa hological cha ac e is ics Exposu e/pa icipa ion s a us Signi icance le el Va iable alue Pa icipan s (P) n = 125 (%*) Non-pa icipan s (NP) n = 57 (%*) No in i ed (NI) n = 314 (%*) P alue P/NP P alue P/NI P alue NP/NI His ology Duc al Lobula O he 109 (87.2) 13 (10.4) 3 (2.4) 49 (86.0) 4 (7.0) 4 (7.0) 271 (86.3) 29 (9.2) 14 (4.5) 0.27 0.57 0.63 Tumou size ≤10 mm >10 Missing 37 (30.1) 86 (69.9) 2 3 (5.6) 51 (94.4) 3 30 (11.2) 239 (88.8) 45 <0.001 <0.001 0.22 Tumou size <15 mm ≥15 mm Missing 63 (52.1) 58 (47.9) 4 8 (19.0) 34 (81.0) 3 55 (24.2) 172 (75.8) 87 <0.001 <0.001 0.47 Tumou size ≤20 mm >20 mm Missing 94 (75.8) 30 (24.2) 1 18 (33.3) 36 (66.7) 3 142 (50.5) 139 (49.5) 33 <0.001 <0.001 0.02 Tumou g ade G ade 1 G ade 2 G ade 3 Missing 27 (23.1) 75 (64.1) 15 (12.8) 8 8 (16.3) 23 (46.9) 18 (36.7) 8 48 (19.4) 141 (57.1) 58 (23.5) 67 0.002 0.06 0.15 Lymph nodes nega i e posi i e Missing 84 (67.7) 40 (32.3) 1 24 (45.3) 29 (54.7) 4 143 (53.0) 127 (47.0) 44 0.005 0.006 0.31 Dis an me as asis Nega i e Posi i e Missing 124 (100) 0 (0) 1 53 (98.1) 1 (1.9) 3 271 (95.8) 12 (4.2) 31 0.30 0.02 0.40 S age I II III IV Missing 72 (58.1) 40 (32.3) 12 (9.7) 0 1 12 (22.2) 23 (42.6) 18 (33.3) 1 (1.9) 3 106 (37.5) 94 (33.2) 71 (25.1) 12 (4.2) 31 <0.001 <0.001 0.11 ER s a us Posi i e Nega i e Missing 108 (87.8) 15 (12.2) 2 43 (84.3) 8 (15.7) 6 206 (78.9) 55 (21.1) 53 0.54 0.036 0.38 PR s a us Posi i e Nega i e Missing 96 (78.0) 27 (22.0) 2 38 (74.5) 12 (25.5) 6 167 (64.7) 91 (35.3) 56 0.61 0.009 0.18 Resul s – Pape VII 117 HER2 s a us Nega i e Posi i e Missing 56 (87.5) 8 (12.5) 61 25 (67.6) 12 (32.4) 20 126 (73.7) 45 (26.3) 143 0.015 0.024 0.25 T iple nega i e no yes Missing 57 (89.1) 7 (10.9) 61 35 (94.6) 2 (5.4) 20 151 (88.3) 20 (11.7) 143 0.35 0.87 0.26 * he pe cen s we e calcula ed excluding hose cance s wi h alue unknown; P/NP, sc een pa icipan s compa ed o non- pa icipan s; P/NI, sc een pa icipan s compa ed o no in i ed; NP/NI, non-pa icipan s compa ed o no in i ed; ER, oes ogen ecep o ; PR, p oges e one ecep o ; HER2, epide mal g ow h ac o ecep o 2 Resul s – Pape VII 118 Table 2 – Mul i a iable logis ic eg ession o he associa ion be ween clinicopa hological cha ac e is ics o b eas cance and mode o pa icipa ion (sc eening pa icipan s e sus non-pa icipan s o no in i ed) Pa ame e s OR adjus ed o co a ia es 95% Con idence In e al P alue Pa icipan s/Non pa icipan s (n = 163) Tumou size ≤20 mm >20 mm 1 4.36 2.00 – 9.71 <0.001 Lymph nodes nega i e posi i e 1 1.28 0.58 – 2.83 0.54 Tumou g ade g ade 1 g ade 2 g ade 3 1 0.78 2.30 0.28 – 2.19 0.71 – 7.45 0.64 0.17 Pa icipan s/ No in i ed (n = 370) Tumou size ≤20 mm >20 mm 1 2.39 1.38 – 4.13 0.002 Lymph nodes nega i e posi i e 1 1.28 0.77 – 2.14 0.34 ER s a us Posi i e Nega i e 1 1.12 0.47 – 2.69 0.79 PR s a us Posi i e Nega i e 1 1.37 0.67 – 2.77 0.39 OR, odds a io; ER, oes ogen ecep o ; PR, p oges e one ecep o 119 IV – Gene al discussion and conclusions Discussion and conclusions 121 IV – Gene al discussion and conclusions This hesis ul ils he deside a um o all public heal h in e en ions need o be assessed. 123 The esea ch conduc ed wi hin his hesis indica es ha he popula ion-based BCSP o he No he n Region o Po ugal achie ed high quali y s anda ds whe he compa ed wi h he Eu opean Guidelines o compa ed o o he Eu opean sc eening p og ammes, and should be expanded o co e all eligible women in he No he n Region. This conclusion is suppo ed by he alid s udies included in his hesis. S eng hs and limi a ions we e ex ensi ely discussed in de ail o each indi idual s udy. Many indica o s o he sc eening e alua ion depend on he exis ence o a popula ion- based cance egis y wi h high comple eness; his was e alua ed in pape I. Resul s ob ained wa an ed he conclusion ha RORENO is a aluable sou ce o in o ma ion on he new cases o b eas cance diagnosed in he emale popula ion. RORENO also pa icipa ed in an in e na ional collabo a i e s udy o e alua e he c i e ia o he emale b eas cance bioma ke posi i i y used in di e en coun ies; his was add essed in pape II showing he need o a mo e ex ensi e use o he exis ing guidelines. Pape s III and IV p o ided in o ma ion on he cha ac e is ics and pe o mance o b eas cance sc eening p og ammes ac oss Eu ope. The BCSP o he No he n Region pa icipa ed in his collabo a i e p ojec o he EUNICE wi h da a om 2005; i showed simila co e age by in i a ion, highe co e age by examina ion and a lowe a e o u he assessmen , compa ed o he o e all esul s o he pa icipa ing sc eening p og ammes. These wo pape s demons a ed he easibili y and use ulness o compa ing Eu opean-wide sc eening moni o ing indica o s. Fu he mo e, esul s conce ning he BCSP in he No he n Region p o ided a i s insigh on he sc eening p og amme pe o mance and we e in line wi h he majo i y o he Eu opean sc eenings e alua ed. In pape V, pe o mance and ea ly su oga e impac indica o s o he sc eening p og amme we e e alua ed by compa ing hem o he Eu opean Guidelines. The main esul s indica ed ha he sc eening p og amme conduc ed in he No he n Region o Po ugal was highly accep ed by he popula ion, i was de ec ing he expec ed numbe o in asi e b eas cance s and in his g oup o umou s, i was able o de ec small size b eas cance s among he pa icipan s. These esul s a e consis en wi h an e ec i e sc eening p og amme and mo ali y educ ion is o be expec ed in he u u e. 17,120 In pape s IV and V i was obse ed ha he ecall a e in he p e alen ound exceeded he alue ecommended in he Eu opean Guidelines and he highes alues we e e i ied in he las yea s o e alua ion. Ne e heless, his high ecall a e was lowe han alues obse ed in o he Eu opean p og ammes, as s a ed be o e (pape IV). High ecall a e is posi i ely co ela ed wi h alse-posi i e esul s 110 ha a e conside ed a cause o needless psychological dis ess in addi ion o incu ing in in asi e in es iga ions. 120 Possible Fu u e s udies 128 no e alua ion has been done in he g oup 45-49 yea s in e ms o pe o mance and impac indica o s, in compa ison o o he in e na ional s udies. Besides, he e ec i eness o he sc eening p og amme in hese younge ages has been unde in ense discussions among expe s on sc eening. 13,46 The me hodology desc ibed in pape s III, IV, V should be used ou inely and an annual w i en epo should be p oduced as a esul om he con inuous moni o ing o he p og amme. Besides, new ways o epo ing as e and signi ican epidemiological and clinical in o ma ion on cance diagnosis should be essayed, in o de o p o ide up- o-da e in o ma ion o he sc eening p og amme; his in o ma ion is i al o e alua e i a emedial ac ion has o be igge ed and/o o alida e he e ec i eness o he p og amme. 67 Re iew o cu en e idence and con o e sy on he p ocedu es, e icacy and cos - e ec i eness o such sc eening p og ammes is also a ne e ending ask, as i is illus a ed in ecen con o e sial discussions. 29,57,63,147-151 129 VI – Re e ences Re e ences 131 VI – Re e ences 1. Jemal A, Cen e MM, DeSan is C, Wa d EM. Global pa e ns o cance incidence and mo ali y a es and ends. Cance Epidemiol Bioma ke s P e 2010;19:1893-907 2. Fe lay J, Shin HR, B ay F, Fo man D, Ma he s C, Pa kin DM. Es ima es o wo ldwide bu den o cance in 2008: GLOBOCAN 2008. In J Cance 2010;127:2893-917 3. Fe lay J, Shin H, B ay F, Fo man D, Ma he s C, Pa kin D. 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