ARTICLE
Epidemiology
Associa ion o symp oms and in e al b eas cance s in he
mammog aphy-sc eening p og amme: popula ion-based
ma ched coho s udy
Deepend a Singh
1,2
, Joonas Mie inen
1
, S ephen Du y
3
, Nea Malila
1,2
, Janne Pi käniemi
1
and Ah i An ila
1
BACKGROUND: We assessed he associa ion be ween symp oms epo ed a b eas cance sc eening isi s and in e al cance s
(ICs) in a p ospec i e manne .
METHODS: This popula ion-based ma ched coho s udy uses da a o he Finnish Na ional B eas Cance Sc eening P og amme
ha in i es women aged 50–69 yea s old du ing 1992–2012. Subjec s who a ended sc eening wi h symp oms we e ma ched wi h
asymp oma ic e e ence coho s based on age a sc eening isi , yea o in i a ion, numbe o in i ed isi s and municipali y o
in i a ion. The p ima y ou come was ICs.
RESULTS: Women wi h a lump had a h ee old (haza d a io 3.7, 95% confidence in e al (CI) 3.0–4.6) isk o ICs and a highe isk
(haza d a io 1.7, 95% CI 1.4 o 2.0) a he subsequen isi compa ed wi h hose wi hou a lump. The a al in e al cance isk
inc eased by 0.39 pe 1000 sc eens wi h a lump. The cumula i e incidences o in e al cance inc eased wi hin a mon h o a
mammog aphy-nega i e isi wi h a lump and a e abou 6 mon hs o he isi wi h e ac ion o nipple discha ge.
CONCLUSION: Women wi h b eas symp oms ha e a clea ly inc eased isk o in e al b eas cance a e he sc eening isi . Ou
findings indica e he need o di e en sc eening s a egies in symp oma ic women.
B i ish Jou nal o Cance (2018) 119:1428–1435; h ps://doi.o g/10.1038/s41416-018-0308-2
BACKGROUND
Beyond he andomised ial en i onmen , he e is some
unce ain y as o he unde lying incidence o b eas cance and
he a e o o e diagnosis in he sc eening popula ion.
1,2
Along
wi h sc eening pe o mance,
3–5
a es and p opo ions o in e al
cance s (ICs) a e impo an indica o s o assessing he e ec i e-
ness and quali y o sc eening.
2,6–8
The subs an ial p opo ion
(abou a hi d) o inciden b eas cance diagnosed ou side he
mammog aphy-sc eening p og amme
9,10
likely indica es ha
he e is oom o imp o emen in he de ec ion capabili y o he
mammog aphy-sc eening p og amme. Ea lie obse a ional s u-
dies
7,11–15
ha e highligh ed se e al easons o he inc eased
p opo ion o ICs in he sc eening p og amme. Howe e , in e ms
o equi y wi hin he sc eening popula ion, i is easonable o aim
o simila in e al cance a es o a leas simila p opo ions o
cance s a ising as in e al cases o he a ious he e ogeneous
g oups pa icipa ing in he sc eening. Fu he mo e, op ions o
modi y sc eening policies should be conside ed o high- isk
g oups. A sho e sc eening in e al may be jus ified, o ins ance,
i he in e al cance a e is significan ly high.
Based on he Eu opean Union (EU) guidelines, sc eening is
mean o unselec ed a ge popula ion.
7
Ea lie s udies om
Finland ha e indica ed ha a no iceable p opo ion (~ 2–3%) o
women ha e clinically significan symp oms when hey pa icipa e
in b eas cance sc eening.
16,17
Mos bu no all symp oma ic
women will ha e u he assessmen s wi h ul asound, addi ional
mammog ams o o he me hods; i hese e u n nega i e esul s,
he women e u n o he no mal, biennial sc eening in e al.
S udies on b eas symp oms (such as a lump, e ac ion o nipple
discha ge) indica e an inc eased isk o b eas cance
16–19
a he
cos o ise in alse-posi i e findings. The ela ions o symp oms
wi h in e al b eas cance s and sc een-de ec ed cance s (SDCs) a
he subsequen isi ha e ne e been s udied.
We in es iga ed whe he women epo ing b eas symp oms a
sc een a e a a highe isk o de eloping subsequen b eas
cance s (ICs and cance s diagnosed a he nex sc een) han hose
wi hou symp oms. To c ea e ounda ions o modi y he sc eening
policies in high- isk g oups, we es ima ed he cumula i e
incidence o ICs and a al in e al b eas cance s, and compa ed
he espec i e incidences in women wi h and wi hou symp oms.
The quali y measu es o sc eening mammog aphy we e compa ed
be ween isi s among subjec s wi h and wi hou symp oms o
ga he e idence o imp o ing p og amme pe o mance.
METHODS
S udy design, da a sou ce and s udy popula ion
Ou ma ched coho s udy design was based on he ollow-up o
he ongoing Finnish Na ional B eas Cance Sc eening P og amme
ha began in 1987. Biennial sc eening isi s made by women
www.na u e.com/bjc
Recei ed: 10 July 2018 Re ised: 25 Sep embe 2018 Accep ed: 26 Sep embe 2018
Published online: 7 No embe 2018
1
Mass Sc eening Regis y, Finnish Cance Regis y, FI-00130 Helsinki, Finland;
2
Epidemiology g oup, Depa men o Heal h Sciences, Uni e si y o Tampe e, FI-33520 Tampe e,
Finland and
3
Wol son Ins i u e o P e en i e Medicine, Queen Ma y Uni e si y o London, Cha e house Squa e, London, England
Co espondence: Deepend a Singh (deepend a.singh@cance .fi)
©The Au ho (s) 2018 Published by Sp inge Na u e on behal o Cance Resea ch UK
aged 50–69 yea s be ween 1991 and 2012 we e selec ed. Th ee
egis ies, he Finnish Cance Regis y (1953–2014), he Mass
Sc eening Regis y (1992–2012) and he Cen al Popula ion
Regis y (1992–2014) we e used o ex ac in o ma ion on he
s udy pa icipan s a he indi idual le el. The Mass Sc eening
Regis y was used o ex ac in o ma ion on demog aphic,
symp oma ic and sc eening p ocedu e ac o s, including ecalls
and e e al da a ha ha e been shown o be alid and o high
quali y. All indi idual isi s we e linked o he Finnish Cance
Regis y da abase o e ie e in o ma ion on b eas cance s
(sc een-de ec ed and ICs). This included his ological findings and
po en ial dea h om inciden b eas cance . The Popula ion
Regis y was used o iden i y possible da es o dea h o
emig a ion, and whe e applicable, he cause o dea h was
e ie ed om S a is ics Finland. Fig. 1shows he flow diag am
o he s udy design.
Exposu e g oup (sc eening isi s wi h symp oms)
The exposed g oup is defined as isi s by women wi h b eas
symp oms (lump, e ac ion and nipple discha ge) epo ed a a
gi en sc eening ound. This g oup con ained all isi s wi h a leas
one symp om epo ed. Di e en symp oms (lump, e ac ion,
nipple discha ge) we e analysed sepa a ely, which in echnical
e ms assumes ha he fi s occu ence o any symp om was
independen gi en he co a ia es. Fo example, i mo e han one
symp om was epo ed a a single isi hen each symp om was
analysed sepa a ely. He e, he index isi mean any sc eening isi
wi h any gi en symp om.
Re e ence g oup (sc eening isi s wi hou symp oms)
The e e ence g oup is defined as isi s by women wi h no
epo ed b eas symp oms in he sc eening his o y be o e he
index isi . The women om he e e ence g oup can la e be he
pa o he exposed g oup i symp oms a e epo ed a u u e
sc eening isi s. Thus, symp oms a e ime-dependen co a ia es.
Indi idual se s o e e ence isi s o each symp om—al oge he
h ee se s—we e o med by ma ching.
Ma ching
The h ee exposed g oups we e equency ma ched o he
e e ence g oups by age a he sc eening isi (wi hin 2 yea s),
yea o in i a ion (2-yea band), numbe o isi s in he pas and
municipali y o in i a ion. Visi s wi h symp oms we e hen
agg ega ed based on ma ching a iables (and o he co a ia es).
Each symp om s a um was ma ched o he iable con ols
( e e ence isi s) by andom sampling. Random con ols we e
selec ed, based on he ma ching a iables abo e, as many imes
as he numbe o isi s in each s a um o symp oms by he
eplacemen sampling me hod. Hence, a single con ol had he
possibili y o be andomly selec ed mo e han once o he same
s a um. Based on ou assump ion o an e ec size and equi ed
powe o 0.80, he exposed- o- e e ence- isi s a io was 1:1 o
lump and e ac ion, and 1:2 o nipple discha ge.
Ou come assessmen
ICs we e defined as b eas cance s diagnosed in sc eened women
be o e he nex sc eening isi o wi hin a pe iod equal o a
sc eening in e al wi h (i) nega i e mammog aphy a he index
isi (i.e., es nega i e); (ii) posi i e mammog aphy a he index
isi , bu nega i e u he assessmen (i.e., episode nega i e); and
(iii) posi i e u he assessmen bu a da e o diagnosis > 6 mon hs
a e mammog aphy.
2
SDCs we e defined as p ima y b eas cance
diagnosed among he sc eening a endees wi hin 6 mon hs
ollowing an abno mal mammog am ( es posi i e). The subse-
quen ound SDCs we e analysed ollowing he index isi s wi h o
wi hou symp oms i he women a ended he subsequen ound.
Finnish na ional b eas cance sc eening p og am (FNBCSP)
Mass sc eening egis y
(1992-2012)
In o ma ion on he
mammog aphy
sc eening p ocess,
includes symp oms
in o ma ion
In o ma ion on
cance s, sc een-
de ec ed and in e al
cance s, and a al
b eas cance s
222848 isi s
excluded because o
missing in o ma ion
on symp oms s a us Visi s wi h symp oms
(exposu e g oup)
Lump = 51333
Re ac ion = 40917
Nipple discha ge = 9083
Visi s wi hou symp oms
( e e ence g oup)
No lump = 51332
No e ac ion = 40917
No nipple discha ge = 18166
Ma ching*
Exposu e g oup we e equency
ma ched o e e ence g oup
( isi s wi hou symp oms) by
co a ia es, selec ed by andom
sampling using eplacemen
me hod
Popula ion egis y
(1992-2014)
In i ed o sc eening
(4,594,335)
A ended (3,958,312)
*1:1 ma ching a io o lump and e ac ion, 1:2
a io o nipple discha ge
S udy popula ion
(3,735,464)
Cance egis y
(1992-2014)
Fig. 1 Flow diag am o s udy se ings
Associa ion o symp oms and in e al b eas cance s in he. . .
D Singh e al.
1429
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In addi ion, cance s we e sub-g ouped in o in si u ca cinomas and
non-localised b eas cance s. Fa al cance s we e defined as hose
b eas cance s ha esul ed in dea h du ing ollow-up.
Follow-up
The ollow-up ime s a ed om he index isi in 1 Janua y 1992
o 31 Decembe 2012 and ended a he da e o emig a ion o
dea h, upon diagnosis o in e al cance o a he end o he
ollow-up—i.e., 31 Decembe 2014—whiche e occu ed fi s .
Cance cases diagnosed among hose sc eened up o 31
Decembe 2012 and ollowed up o 31 Decembe 2014 ( o hose
sc eened in 2011 and 2012) we e di ided in o ICs and subsequen
SDCs using Finnish Cance Regis y da a. Conside ing possible
delays in he diagnosis da e a e posi i e mammog aphy findings,
a sc eening episode o 6-mon h in e als was used in he
defini ion o de ec ion mode. Thus, he ollow-up ime o ICs
s a ed a 7 mon hs o episode nega i e isi s and a 1 mon h o
es nega i e isi s and ended a he da e o he subsequen
sc eening isi a 23 mon hs.
S a is ical analysis
We compa ed b eas cance isk and he isk o b eas cance
dea h using Cox p opo ional haza d eg ession among women
wi h and wi hou epo ed symp oms a he index sc een.
Confidence in e als we e compu ed exac ly om pa ame e
likelihoods. The analyses we e adjus ed o age a he sc eening
isi . We calcula ed he incidence a e o in e al cance be ween
he sc eens ( om he index sc een and he 6-mon h episode o
he subsequen sc eening isi ) sepa a ely o es nega i es and
episode nega i es.
We also e alua ed he p og amme cha ac e is ics using basic
s a is ics. A es sensi i i y was es ima ed as he numbe o isi s
wi h a posi i e mammog aphy es and diagnosis o cance a
sc een di ided by he sum o SDCs plus ICs diagnosed a e
nega i e es esul s. Episode sensi i i y was calcula ed as he
numbe o isi s wi h a diagnosis o cance in a ull diagnos ic
p ocess in he sc eened popula ion di ided by all cance s
de ec ed in a sc eening ound among a ende s. Simila ly, he
posi i e p edic i e alue (PPV) was assessed as he numbe o
isi s wi h a posi i e mammog aphy es and diagnosis o cance
di ided by he numbe o es posi i es. The nega i e p edic i e
alue (NPV) was es ima ed as he numbe o isi s wi h a nega i e
es esul and no cance diagnosed di ided by he numbe o es
nega i es. All s a is ical analyses we e pe o med using R-3.4.0.
RESULTS
O e he s udy pe iod o 21 yea s, a lump was epo ed a 51,333
isi s and e ac ion a 40,917 isi s. These isi s we e ma ched o
an equal numbe o asymp oma ic isi s. The e we e 9083 isi s
wi h nipple discha ge, and hey we e ma ched wi h double he
numbe o e e ence isi s (i.e., 18,166 isi s) wi hou nipple
discha ge. De ailed numbe s o he po en ially eligible and he
confi med eligible popula ion included in he s udy a e shown in
Fig. 1.
The mean age a a sc eening isi did no di e be ween isi s
wi h and wi hou symp oms (mean age 55.7 s 56.1 yea s o isi s
wi h and wi hou a lump, espec i ely). Table 1shows he
cha ac e is ics o he final s udy coho . Abou one in h ee
women who epo ed a lump o nipple discha ge and one in eigh
women who epo ed e ac ion we e fi s - ime a endees. The
fi s and subsequen a endee’s p opo ions we e simila be ween
isi s wi h and wi hou symp oms. Mo e han 80% o ICs and he
subsequen ound’s SDCs, i espec i e o epo ed symp oms
s a us, we e no ecalled o u he assessmen a he index isi .
Bo h he es and episode sensi i i y o he mammog aphy was
highe o isi s wi h a lump o e ac ion compa ed wi h hose
wi hou such symp oms (82 and 75% s 64 and 63% o a lump s
no lump; 77 and 76% s 67 and 66% o e ac ion s no e ac ion;
Table 2). Likewise, he PPV o mammog aphy was highe o
e ac ion and a lump, compa ed wi h hose wi hou hese
symp oms. Howe e , he specifici y o mammog aphy was clea ly
lowe o isi s wi h a lump (88%) han hose wi hou (98%). Some
dec ease in specifici y was also seen o e ac ion and nipple
discha ge.
Incidence o sc een-de ec ed and ICs, subsequen SDCs and a al
ICs
In o al, 1440 (2.8%) SDCs and 387 (0.7%) ICs (ICs) we e diagnosed
in hose who epo ed a lump compa ed wi h 174 (0.3%) SDCs and
103 (0.2%) ICs in hose wi hou a lump, espec i ely (Table 3). The
p opo ions o SDCs and ICs we e highe also o e ac ion and
nipple discha ge compa ed wi h hose wi hou hese symp oms.
The age-adjus ed isk o SDCs was significan ly highe in hose
who epo ed a lump (adjus ed haza d a io 8.2, 95% CI 7.0–9.7),
e ac ion (adjus ed haza d a io 2.3, 95% CI 2.0–2.8) o nipple
discha ge (adjus ed haza d a io 1.5, 95% CI 1.1–2.3) compa ed
wi h hose wi hou symp oms. In addi ion, he age-adjus ed isk o
ICs was significan ly highe o a lump (adjus ed haza d a io 3.7,
95% CI 3.0–4.6), e ac ion (adjus ed haza d a io 1.5, 95% CI
1.1–1.9), and nipple discha ge (adjus ed haza d a io 2.4, 95% CI
1.6–3.7) compa ed wi h hose wi hou hese symp oms. The isk o
SDCs in he subsequen ound was significan ly highe only a e
isi s wi h a lump compa ed wi h hose wi hou a lump (adjus ed
haza d a io 1.6, 95% CI 1.3–2.0). The isk o in si u in e al
ca cinomas o subsequen sc een-de ec ed ca cinomas was also
highe in isi s wi h a lump and nipple discha ge compa ed wi h a
isi wi h no symp oms. The isk o non-localised in e al b eas
cance as well as SDCs in he subsequen ound we e also g ea e
o all h ee symp oms in compa ison wi h isi s wi hou
symp oms.
The age-adjus ed isk o dying om b eas cance was
significan ly highe in hose who epo ed a lump and we e
diagnosed wi h in asi e cance s (SDCs =adjus ed haza d a io 19,
95% CI 11–38; ICs =adjus ed haza d a io 2.0, 95% CI 1.1–3.4;
subsequen ound cance s =adjus ed haza d a io 2.7, 95% CI
1.6–4.1) compa ed wi h hose wi hou a lump (Table 3). In
addi ion, he isk o dying was highe in hose who epo ed
e ac ion and we e diagnosed wi h SDCs (adjus ed haza d a io
6.3, 95% CI 2.8–16) compa ed wi h hose wi hou e ac ion. Only
a ew dea hs occu ed du ing he ollow-up in hose who epo ed
nipple discha ge.
Cumula i e incidence o b eas cance s du ing he sc eening
in e al
The incidence o ICs a e a isi wi h a lump o nipple discha ge
inc eased a he apidly a e he isi in all he s udied
p og ession ypes (Fig. 2a–d). When using he cumula i e
incidence o he asymp oma ic o e he whole in e al as a
e e ence, he same le el o ICs was eached in only abou six
mon hs a e isi s wi h a lump and 12 mon hs a e isi s wi h
nipple discha ge. Rema kably, in mammog aphy-nega i e isi s
wi h a lump, he cumula i e incidence cu e de ached om he
no lump cu e immedia ely a e he fi s mon h o isi , whe eas
such a di e ence was no obse ed o he o he symp om ypes.
DISCUSSION
In his popula ion-based s udy wi h 21 yea s o sc eening ( he
ollow-up is es ic ed o 23 mon hs, al hough he s udy pe iod
was 21 yea s), we obse ed s ong associa ions be ween
symp oms and b eas cance isks. Women epo ing a lump a
a sc eening isi had a h ee old isk o ICs compa ed wi h hose
wi h no symp oms, also including subsequen SDCs. The
(cumula i e) incidence o in e al cance was highe in hose
who epo ed a lump i espec i e o he mammog aphy findings
Associa ion o symp oms and in e al b eas cance s in he. . .
D Singh e al.
1430
( es nega i es o episode nega i es) compa ed wi h hose
wi hou symp oms a he index isi . Likewise, e ac ion and
nipple discha ge we e significan ly associa ed wi h inc eased isks
o in e al b eas cance s. In absolu e e ms, pe 1000 women who
a ended and epo ed a lump, se en women we e diagnosed
wi h in asi e in e al b eas cance s, i.e., wi hin 24 mon hs
compa ed wi h abou wo cance s diagnosed wi hou symp oms.
The a al in e al cance isk inc eased by 0.39 pe 1000 sc eens
wi h a lump.
Women wi h symp oms had a clea ly inc eased ‘backg ound’
isk o b eas cance ; he con en ional sc eening pe o mance
measu es—such as sensi i i y, PPV and specifici y—did no ully
assess his aspec . The cumula i e incidence pa e ns as well as
he de ec ion o cance s du ing he subsequen ound p o ided
di ec e idence o he need o isk-adjus ed sc eening and a
be e diagnos ic wo k-up in he symp oma ic women. The
diagnos ic wo k-up could include de eloping be e eading and
ecall c i e ia in sc eening mammog ams, a mo e de ailed
Table 2 Pe o mance quali y measu es o sc eening mammog aphy in ela ion o symp oms s a us
Symp oms Sc eening episode Mammog aphy es
Sensi i i y % (95% CI) Sensi i i y % (95% CI) PPV % (95% CI) NPV % (95% CI) Specifici y % (95%CI)
Lump Yes 74 (71–78) 81 (80–83) 19 (19–20) 99 (99–99) 88 (88–88)
No 62 (56–68) 64 (58–70) 12 (11–13) 99 (99–99) 97 (97–97)
Re ac ion Yes 75 (72–79) 76 (73–80) 28 (26–29) 99 (99–99) 97 (96–97)
No 65 (59–70) 66 (60–72) 17 (16–19) 99 (99–99) 97 (97–98)
Nipple discha ge Yes 55 (46–65) 62 (52–71) 8.1 (6.9–9.4) 99 (99–99) 91 (91–92)
No 66 (57–75) 70 (61–78) 15 (13–17) 99 (99–99) 97 (97–97)
PPV posi i e p edic i e alue, NPV nega i e p edic i e alue, CI confidence in e al
Table 1 Coho cha ac e is ics
Cha ac e is ics Lump (n=51,333) Re ac ion (n=40,917) Nipple discha ge*
Yes (%) No (%) Yes (%) No (%) Yes (%)
(n=9083)
No (%)
(n=18,166)
Age a index isi (mean, SD) 55.7 (4.6) 56.1 (4.5) 57.7 (4.9) 56.6 (4.8) 54.9 (4.6) 56.1 (4.7)
A endance Fi s a endance 18,305 (35) 17,954 (35) 5012 (12) 4959 (12) 2904 (32) 5643 (31)
Subsequen a endance 33,028 (64) 33,379 (65) 35,905 (87) 35,958 (87) 6179 (68) 12,523 (68)
P e ious ound
a endance
Yes 31,571 (61) 32,228 (62) 34,168 (83) 34,263 (83) 5842 (64) 12,069 (66)
No 19,762 (38) 19,105 (37) 6749 (16) 6654 (16) 3241 (35) 6097 (33)
Pe iod o isi 1992–1997 15,478 (30) 15,520 (30) 0 0 1134 (12) 2298 (12)
1998–2002 7535 (14) 7493 (14) 3552 (8.7) 3552 (8.7) 1673 (18) 3316 (18)
2003–2007 11,791 (23) 11,804 (23) 12,996 (31) 13,190 (32) 2872 (31) 5671 (31)
2008–2012 16529 (32) 16,516 (32) 24,369 (59) 24,175 (59) 3404 (37) 6881 (37)
Recall ( es posi i es)
In asi e cance s Sc een-de ec ed cance s 1440 (2.8) 174 (0.34) 461 (1.1) 192 (0.47) 66 (0.73) 83 (0.46)
In e al cance s 70 (0.14) 7 (0.01) 16 (0.04) 5 (0.01) 12 (0.13) 6 (0.03)
Subsequen sc een a nex
ound
34 (0.07) 6 (0.01) 11 (0.03) 7 (0.02) 4 (0.04) 3 (0.01)
Fa al b eas cance s Sc een-de ec ed cance s 215 (0.41) 11 (0.02) 38 (0.09) 6 (0.01) 4 (0.04) 2 (0.01)
In e al cance s 8 (0.01) 2 (0.01) 2 2 0 0
Subsequen sc een a nex
ound
1 (0.01) 0 1 (0.01) 0 0 0
No ecall ( es nega i es)
In asi e cance s Sc een-de ec ed cance s 0 0 0 0 0 0
In e al cance s 317 (0.62) 96 (0.19) 138 (0.34) 96 (0.23) 40 (0.44) 35 (0.19)
Subsequen sc een a nex
ound
230 (0.45) 149 (0.29) 144 (0.35) 135 (0.33) 28 (0.31) 57 (0.31)
Fa al b eas cance s Sc een-de ec ed cance s 0 0 0 0 0 0
In e al cance s 32 (0.06) 18 (0.03) 13 (0.03) 5 (0.01) 5 (0.05) 2 (0.01)
Subsequen sc een a nex
ound
18 (0.03) 7 (0.01) 4 (0.01) 4 (0.01) 0 1 (0.01)
Values a e numbe s (pe cen age) unless s a ed o he wise
*Fo each isi s wi h nipple discha ge we e ma ched wi h wo isi s wi hou nipple discha ge
Associa ion o symp oms and in e al b eas cance s in he. . .
D Singh e al.
1431
Table 3 F equency (pe 1000 sc eening isi s) and age-adjus ed isk o cance ou comes in hose who epo ed symp oms compa ed wi h hose wi hou symp oms a sc een
Ou comes Lump (n=51,333) Re ac ion (n=
40,917)
Nipple discha ge*
Yes (pe
1000)
No (pe
1000)
Age-adjus ed haza d a io
(95% CI) wi h e e ence o
no lump
Yes (pe
1000)
No (pe
1000)
Age-adjus ed haza d a io
(95% CI) wi h e e ence o no
e ac ion
Yes (pe
1000) (n=
9083)
No (pe 1000)
(n=18,166)
Age-adjus ed haza d a io (95%
CI) wi h e e ence o no nipple
discha ge
In asi e cance s
Sc een-de ec ed
cance s
1440 (28) 174 (3.4) 8.3 (7.1–9.7) 461 (11) 192 (4.7) 2.4 (2–2.8) 66 (7.3) 83 (4.6) 1.7 (1.2–2.3)
In e al cance s 387 (7.5) 103 (2.0) 3.8 (3–4.7) 154 (3.8) 101 (2.5) 1.5 (1.2–1.9) 52 (5.7) 41 (2.3) 2.5 (1.7–3.8)
Subsequen sc een a
nex ound
264 (5.1) 157 (3.1) 1.7 (1.4–2.1) 156 (3.8) 158 (3.9) 1.1 (0.87–1.4) 32 (3.5) 72 (3.9) 1.0 (0.64–1.5)
In si u ca cinomas
Sc een-de ec ed
cance s
61 (1.2) 38 (0.74) 1.6 (1.1–2.4) 35 (0.86) 31 (0.76) 1.1 (0.70–1.8) 15 (1.7) 16 (0.88) 1.9 (0.92–3.8)
In e al cance s 35 (0.68) 9 (0.18) 3.9 (1.9–8.6) 7 (0.17) 6 (0.15) 1.2 (0.39–3.6) 9 (0.99) 4 (0.22) 4.0 (1.3–14)
Subsequen sc een a
nex ound
159 (3.1) 102 (1.9) 1.5 (1.2–1.9) 76 (1.9) 66 (1.6) 1.2 (0.83–1.6) 32 (3.5) 32 (1.8) 2.0 (1.2–3.3)
Non-localised cance s
Sc een-de ec ed
cance s
693 (13) 57 (1.1) 12 (9.2–16.0) 230 (5.6) 61 (1.5) 3.5 (2.6–4.7) 25 (2.8) 27 (1.5) 1.9 (1.1–3.2)
In e al cance s 178 (3.5) 57 (1.1) 3.4 (2.5–4.6) 79 (1.9) 48 (1.2) 1.7 (1.2–2.4) 20 (2.2) 18 (0.99) 2.2 (1.2–4.2)
Subsequen sc een a
nex ound
649 (12) 438 (8.5) 1.5 (1.3–1.7) 244 (5.9) 182 (4.5) 1.4 (1.1–1.7) 110 (12) 181 (9.9) 1.2 (0.96–1.6)
Fa al cance s
Sc een-de ec ed
cance s
215 (4.2) 11 (0.21) 19 (11–38) 38 (0.93) 6 (0.15) 6.3 (2.9–16) 4 (0.44) 2 (0.11) 4.0 (0.78–28)
In e al cance s 40 (0.78) 20 (0.39) 2 (1.2–3.5) 15 (0.36) 7 (0.17) 2.1 (0.90–5.6) 5 (0.55) 2 (0.11) 5.0 (1.1–34)
Subsequen sc een a
nex ound
19 (0.37) 7 (0.14) 2.7 (1.7–4.1) 5 (0.12) 4 (0.07) 1.3 (0.45–2.7) 0 1 (0.05) NA
*Fo each isi s wi h nipple discha ge we e ma ched wi h wo isi s wi hou nipple discha ge; CI confidence in e al, NA no a ailable
Associa ion o symp oms and in e al b eas cance s in he. . .
D Singh e al.
1432

indica ion o biopsies in he u he assessmen , and ea ly ecall
o hose wi h high- isk symp oms o whom he sc eening es o
u he assessmen p o es nega i e.
S eng hs and limi a ions o he s udy
To ou knowledge, his is he fi s popula ion-based s udy o
analyse he associa ion be ween symp oms and in e al and a al
b eas cance s. Ou s udy has se e al s eng hs. Fi s , we included
all sc eening isi s wi h symp oms om he s a o he
mammog aphy-sc eening p og amme (o e 21 yea s) and com-
pa ed hem wi h isi s wi hou symp oms. Since his was a
popula ion-based se ice-sc eening p og amme, he selec ion bias
was minimal. Second, we could use alida ed p ospec i ely
collec ed egis e da a wi h no ecall bias.
20
Valida ion o he
cance diagnosis (sc een-de ec ed and ICs) and dea h om cance
using na ional and co e ing da a sou ces (Finnish Cance Regis y
and S a is ics Finland) and he use o unique pe sonal iden ifie o
indi idual-le el linkage elimina es he possibili y o selec i e
misclassifica ion. Thi d, we ma ched he symp oma ic isi s o
asymp oma ic isi s by possible con ounding baseline cha ac e -
is ics o minimise bias in he isk es ima es. As a esul , we ound
no significan di e ence in he backg ound a iables be ween
isi s wi h and wi hou symp oms. Finally, he p og amme p ocess
and ou come indica o defini ions used in his s udy adhe e o
hose defined by WHO-IARC and men ioned in EU guidelines on
b eas cance sc eening and diagnosis,
7,21
including he p o ision
o ele an in o ma ion desc ibing he pe o mance and also
ailu es du ing he a ious s eps o he sc eening p ocess.
Ou s udy also has po en ial limi a ions. The symp om in o ma-
ion was based on he women’s epo ing in he pas 2 o
6 mon hs and a check by a adiog aphe a he isi . The
adiog aphe ’s inspec ion is likely o be less comp ehensi e han a
ull clinical examina ion. The collec ion o symp om in o ma ion
is mainly done in o de o suppo he in e p e a ion o he
mammog ams. Howe e , in almos e e y case—i no all— he
adiog aphe o nu se examines he b eas o confi m
he p esence o symp oms (mainly a lump and e ac ion) be o e
he mammog aphy is pe o med. Thus, he e a e easons o
conside he collec ed symp om in o ma ion o be alid, albei no
pe ec . A second po en ial limi a ion is ha ou es ima es could
ha e been con ounded, because symp oma ic women a e mo e
likely o a end han asymp oma ic women. Howe e , because o
he high a endance a e in he Finnish mammog aphy-sc eening
p og amme (84% among he in i ed, he highes among any
2.0
1.5
1.0
Cumula i e p obabili y (pe 10,000)
Cumula i e p obabili y (pe 10,000)
Cumula i e p obabili y (pe 10,000)Cumula i e p obabili y (pe 10,000)
Cumula i e p obabili y (pe 10,000) Cumula i e p obabili y (pe 10,000)
Cumula i e p obabili y (pe 10,000) Cumula i e p obabili y (pe 10,000)
Cumula i e p obabili y (pe 10,000)Cumula i e p obabili y (pe 10,000)Cumula i e p obabili y (pe 10,000)
Cumula i e p obabili y (pe 10,000)
0.5
0.0
2.0
1.5
1.0
0.5
0.0
2.0
1.5
1.0
0.5
0.0
8
6
4
2
0
8
6
4
2
0
8
6
4
2
0
4
3
2
1
0
4
3
2
1
0
4
3
2
1
0
1.5
1.0
0.5
0.0
1.5
1.0
0.5
0.0
1.5
1.0
0.5
0.0
05
Follow up (mon hs) Follow up (mon hs) Follow up (mon hs) Follow up (mon hs)
Follow up (mon hs) Follow up (mon hs) Follow up (mon hs) Follow up (mon hs)
Follow up (mon hs) Follow up (mon hs) Follow up (mon hs) Follow up (mon hs)
10 15 20 0 510 15 20 0 510 15 20 0 510 15 20
0 5 10 15 20 0 5 10 15 20 0 5 10 15 20 0 5 10 15 20
0510
15 20 0510
15 20 0510
15 20 0510
15 20
abc d
Fig. 2 a–dCumula i e incidence o in asi e (pe 1000): a ecalled ICs; bno ecalled ICs; cnon-localised ICs; d a al in e al cance s. No e: he
confidence in e als lines o cumula i e incidence a e indica ed by ligh do ed lines in symp oma ic and asymp oma ic g oups
Associa ion o symp oms and in e al b eas cance s in he. . .
D Singh e al.
1433
exis ing mammog aphy-sc eening p og amme), and as 97% o
a endees a e asymp oma ic, he a endance bias caused by
symp oms is likely o be small. Thi d, we did no use he
backg ound incidence o b eas cance o es ima e he in e al
cance a e in he absence o sc eening, bu ins ead used a
de ec ion me hod
22
ha akes in o accoun cance s om he
sc eening p og amme; hus, es ima es a e sensi i e o o e -
diagnosis and lead ime bias. Gi en he high co e age and
a endance a e in he Finnish sc eening p og amme, i was no
possible o find a compa able non-sc eened g oup o es ima e he
backg ound incidence o b eas cance . In addi ion, he e was no
possibili y o es ima e backg ound incidence o b eas cance in
women wi h symp oms. We did no find any di e ence in he PPV
o mammog aphy, wi h and wi hou symp oms, be ween he fi s
and subsequen sc eening ounds (no shown in esul s); hus, he
lead ime bias because o p e alen sc eens is negligible.
Fu he mo e, we used in asi e b eas cance s—and also
ad anced and a al b eas cance s, which would be less a ec ed
by o e diagnosis— o es ima e he incidence a es and haza d
a ios. Only 5% o all ca cinomas in hose wi h symp oms we e
in si u ca cinomas.
P e ious s udies on he associa ion be ween symp oms and he
isk o b eas cance a e limi ed because o ac o s such as s udy
design, size, ollow-up ime and assessmen o he possible
ou come measu es o b eas cance . None heless, a ew s udies
ha e ound ha he p esence o a palpable lump is associa ed
wi h a highe isk o SDCs.
18,19
We a e no awa e o any s udies
ha ha e assessed he ela ionship o symp oms wi h o he
ou come measu es.
Clinical and public heal h implica ions
Bo h he sc eening es and episode sensi i i ies ended o be
highe in symp oma ic women compa ed wi h he asymp oma ic.
Co espondingly, he sc eening specifici y was lowe in he
symp oma ic women. O no e, pa icula ly in women wi h a lump,
we e he (episode) sensi i i y losses in he u he assessmen du ing
he index isi s. Mo eo e , highe in e al cance incidence wi hin six
mon hs a e a nega i e mammog aphy wi h a lump is a clea
conce n o he p og amme. This indica es ha u he assessmen is
needed mo e equen ly (albei wi h a po en ial loss o specifici y),
and he e needs o be highly s ingen diagnos ic e idence o a
decision no o ca y ou a ull u he assessmen including a co e
biopsy in hese cases. As mos isi s (~ 97%) we e asymp oma ic, he
numbe o addi ional se ices would be a he small as well as he
imp o emen o p og amme’s o e all pe o mance and ou come.
Bu s ill, high-quali y and clinically app op ia e se ices a e
impo an o women ha ing symp oms a a sc eening isi . One
op ion is o ecall all women wi h symp oms e en i he
mammog aphy esul is nega i e, as p ac ised in No way (< 0.3%
o all hose sc eened we e ecalled wi h symp oms).
23
Doing his in
Finnish p og amme would significan ly lowe he PPV o ecall, as
2.5% o all sc eens had symp oms and only ~ 1 ou o 10 symp o-
ma ic isi s ha e been ecalled.
17
Taking in o accoun he high incidence o ad anced and a al
in e al b eas cance s in symp oma ic women, i is likely ha
p o ec ion by biennial sc eening isi would clea ly no be
su ficien e en a e po en ial imp o emen s in u he assess-
men s. We a e no awa e o ecommenda ions o su eillance o
ollow-up o symp oma ic women in he p og amme. Hence, we
ecommend a sho e sc eening in e al o he symp oma ic
g oup so ha he cumula i e incidences o in e al and a al
in e al cance would possibly become mo e equi able. Fo wo o
he s udied symp oms (lump and nipple discha ge), he in e al
cance incidence inc eased so apidly ha he fi s ollow-up isi
could ake place e y sho ly a e he index isi . Finally, aking
in o accoun he p obabili y o a al sc een-de ec ed b eas cance
is highe in women wi h a symp om al eady a he index isi ,
women need o be be e in o med abou symp oms and made
awa e ha i a symp om occu s, i is no a good idea o wai un il
he nex in i a ion o he p og amme. Guidelines o u he
assessmen in pa ien s p esen ing wi h symp oms be o e ha ing a
scheduled in i a ion acco ding o he p og amme—as de eloped
by Na ional Heal h Se ice in he UK
24
—could be use ul also in
o he se ings.
CONCLUDING REMARKS
Women wi h b eas symp oms a isi s wi hin he popula ion-
based b eas cance sc eening p og amme ha e a clea ly
inc eased isk o b eas cance . The cumula i e incidence o
in asi e, ad anced and a al b eas cance s, as well as he
de ec ion o hem a he nex sc een, p o ide di ec e idence o
he need o isk-adjus ed sc eening in symp oma ic women—
e.g., ailo ing he managemen p ocedu es a index isi s and
sho ening he sc eening in e als o hese women. This s udy
p o ides clea e idence o upda e and suppo he EU guidelines
7
ecommenda ion ha ensu es su ficien a en ion being paid o
symp oma ic de ails p o ided by women. Ou findings he e o e
ha e impo an implica ions o sc eening-aged women, adiolo-
gis s, nu ses and mammog aphy-sc eening p og ammes o e all.
ACKNOWLEDGEMENTS
This wo k was suppo ed by he Cance Founda ion G an o Finland. The unde had
no ole in he design, he conduc o he s udy and finalisa ion o he manusc ip .
AUTHOR CONTRIBUTIONS
DS and AA designed he s udy. JM and DS did he s a is ical analysis and ake
esponsibili y o he accu acy o he da a analysis. DS, AA, JM, SD, NM and JP
in e p e ed he da a and edi ed he manusc ip .
ADDITIONAL INFORMATION
Compe ing in e es s: The au ho s ha e no conflic o in e es o disclosu es. All
au ho s decla e no financial o o he ela ionships o ac i i ies ha could appea o
ha e influenced he submi ed wo k.
E hical app o al: This s udy comply wi h e hical s anda ds.
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Associa ion o symp oms and in e al b eas cance s in he. . .
D Singh e al.
1435