R ev iew
Effectiveness of Breast Cancer Screening: Systematic Review and
Meta-analysis to Update the 2009 U.S. Preventive Services Task
Force Recommendation
Heidi D. Nelson, MD, MPH; Rochelle Fu, PhD; Amy Cantor, MD, MPH; Miranda Pappas, MA; Monica Daeges, BA;
and Linda Humphrey, MD, MPH
Background: In 2009, the U.S. Preventive Services Task Force
recommended biennial mammography screening for women
aged 50 to 74 years and selective screening for those aged 40 to
49 years.
Purpose: To review studies of the effectiveness of breast cancer
screening in average-risk women.
Data Sources: MEDLINE and Cochrane databases to 4 June
2015.
Study Selection: English-language randomized, controlled tri­
als and observational studies of screening with mammography,
magnetic resonance imaging, and ultrasonography that re­
ported breast cancer mortality, all-cause mortality, or advanced
breast cancer outcomes.
Data Extraction: Investigators extracted and confirmed data
and dual rated study quality; discrepancies were resolved
through consensus.
Data Synthesis: Fair-quality evidence from a meta-analysis of
mammography trials indicated relative risks (RRs) for breast can­
cer mortality of 0.92 for women aged 39 to 49 years (95% Cl,
0.75 to 1.02) (9 trials; 3 deaths prevented per 10 000 women
over 10 years); 0.86 for those aged 50 to 59 years (Cl, 0.68 to
0.97) (7 trials; 8 deaths prevented per 10 000 women over 10
years); 0.67 for those aged 60 to 69 years (Cl, 0.54 to 0.83) (5
trials; 21 deaths prevented per 10 000 women over 10 years);
n 2009, the U.S. Preventive Services Task Force
I (USPSTF) recom m ended biennial m am m ography
screening fo r w om en aged 50 to 74 years (1) on the basis
o f evidence o f benefits and harms (2). The USPSTF con­
cluded that screening decisions fo r w om en aged 40 to
49 years should be based on individual considerations,
and that evidence was insufficient to assess benefits
and harms fo r w om en aged 75 years or o ld e r (1).
M am m ography screening in the United States is
generally opportunistic, unlike many screening p ro ­
grams organized as p u b lic health services in other
countries. Despite changes in practice guidelines and
variation in clinical practices (3), overall screening rates
in the United States have rem ained relatively stable fo r
the past decade (4, 5). Data from the Healthcare Effec­
tiveness Data and Inform ation Set indicate that mam ­
See also:
Related articles . . . 205, 215, 226, 236, 256, 268, 279
Editorial comment ...................................................303
244 Annals of Internal Medicine • Vol. 164 No. 4 • 16 February 2016
Annals of Internal Medicine
and 0.80 for those aged 70 to 74 years (Cl, 0.51 to 1.28) (3 trials;
13 deaths prevented per 10 000 women over 10 years). Risk re­
duction was 25% to 31% for women aged 50 to 69 years in
observational studies of mammography screening. All-cause
mortality was not reduced with screening. Advanced breast can­
cer was reduced for women aged 50 years or older (RR, 0.62 [Cl,
0.46 to 0.83]) (3 trials) but not those aged 39 to 49 years (RR, 0.98
[Cl, 0.74 to 1.37]) (4 trials); less evidence supported this
outcome.
Limitations: Most trials used imaging technologies and treat­
ments that are now outdated, and definitions of advanced breast
cancer were heterogeneous. Studies of effectiveness based on
risk factors, intervals, or other modalities were unavailable or
methodologically limited.
Conclusion: Breast cancer mortality is generally reduced with
mammography screening, although estimates are not statisti­
cally significant at all ages and the magnitudes of effect are
small. Advanced cancer is reduced with screening for women
aged 50 years or older.
Primary Funding Source: Agency for Plealthcare Research and
Quality.
Ann Intern Med. 2016;164:244-255. doi:10.7326/M15-0969 www.annals.org
For author affiliations, see end o f text.
This article was published at www.annals.org on 12 January 2016.
m ography screening in 2014 in HMOs was perform ed
fo r 74% o f e lig ib le w om en covered by com m ercial
plans, 72% by M edicare, and 59% by M edicaid (6).
This systematic review updates evidence fo r the
USPSTF on the effectiveness o f m am m ography screen­
ing in reducing breast cancer m ortality, all-cause m or­
tality, and advanced breast cancer fo r w om en at aver­
age risk; and how effectiveness varies by age, risk
factors, screening intervals, and im aging m odalities.
Systematic reviews o f harms o f screening (7), p e rfo r­
mance characteristics o f screening m ethods (8), and ac­
curacy o f breast density determ ination and use o f sup­
plem ental screening technologies (9) are p rovided in
separate reports.
M ethods
Scope, Key Questions, and Analytic Framework
The USPSTF determ ined the scope and key ques­
tions fo r this review by using established m ethods (10,
11). A standard protocol was developed and p ublicly
posted on the USPSTF W eb site. A technical re p o rt fur-
www.annals.org
Effectiveness of Breast Cancer Screening R eview

t h e r d e s c r ib e s t h e m e t h o d s a n d in c lu d e s s e a rc h s tr a t e ­ m e e t i n g c r i t e r i a f o r h ig h q u a l i t y a n d t h o s e w i t h d e s i g n s
g ie s a n d a d d i t i o n a l i n f o r m a t i o n (7 ) . ra n k e d h i g h e r in t h e s t u d y d e s i g n - b a s e d h ie r a r c h y o f
I n v e s t ig a t o r s c r e a t e d a n a n a ly t ic f r a m e w o r k o u t l i n ­ e v i d e n c e w e r e e m p h a s i z e d b e c a u s e t h e y a r e le s s s u s ­
in g th e key q u e s tio n s , p a tie n t p o p u la t io n s , in te r v e n ­ c e p t i b l e t o b ia s ( e . g . , R C T s o v e r o b s e r v a t i o n a l s t u d ie s ) .
tio n s , and o u tc o m e s r e v ie w e d ( A p p e n d ix F ig u r e 1,
D ata E xtraction and Q uality A ssessm en t
a v a i l a b le a t w w w . a n n a l s . o r g ). K e y q u e s t i o n s i n c l u d e t h e
D e t a ils o f t h e s t u d y d e s i g n , p a t i e n t p o p u l a t i o n , s e t ­
e ffe c tiv e n e s s o f s c r e e n in g in r e d u c in g b re a s t c a n c e r
t i n g , s c r e e n i n g m e t h o d , i n t e r v e n t i o n s , a n a ly s is , f o l l o w ­
m o r t a l i t y , a ll- c a u s e m o r t a l i t y , a n d a d v a n c e d b r e a s t c a n ­
u p , a n d r e s u lt s w e r e a b s t r a c t e d b y o n e i n v e s t i g a t o r a n d
c e r, a n d how e f f e c t i v e n e s s d i f f e r s b y a g e , r is k f a c t o r s ,
c o n fir m e d by a second. Two in v e s tig a to r s in d e p e n ­
s c r e e n in g in t e r v a l s , and m o d a litie s (m a m m o g ra p h y
d e n tly a p p lie d c r it e r i a d e v e lo p e d b y th e U S P S TF (1 0 ,
[film , d ig it a l, to m o s y n th e s is ], m a g n e tic re s o n a n c e im ­
11) to ra te th e q u a l i t y o f e a c h s t u d y a s g o o d , f a ir , o r
a g i n g [ M R I], a n d u l t r a s o n o g r a p h y ) .
poor fo r s tu d ie s d e s ig n e d as R C Ts, c o h o rt s t u d ie s ,
T h e t a r g e t p o p u la t io n f o r t h e USPSTF re c o m m e n ­
c a s e - c o n t r o l s t u d ie s , a n d s y s t e m a t i c r e v ie w s ; c r it e r i a t o
d a tio n in c lu d e s w om en aged 4 0 y e a rs o r o ld e r , and
r a t e o t h e r s t u d y d e s i g n s i n c l u d e d in t h i s r e v i e w a r e n o t
e x c lu d e s w o m e n w ith know n p h y s ic a l s ig n s o r s y m p ­
a v a i l a b le . D is c r e p a n c ie s w e re r e s o lv e d th ro u g h
t o m s o f b r e a s t a b n o r m a lit ie s a n d t h o s e a t h ig h - r is k f o r
consensus.
b r e a s t c a n c e r w h o s e s u r v e il l a n c e a n d m a n a g e m e n t a r e
beyond th e s c o p e o f th e U S P S T F 's r e c o m m e n d a t i o n s D ata S y n th esis
f o r p r e v e n tio n s e r v ic e s ( i.e ., p r e e x i s t i n g b re a s t c a n c e r W e c o n d u c t e d s e v e r a l m e t a - a n a ly s e s t o d e t e r m i n e
or h ig h - r is k b re a s t le s io n s , h e r e d ita r y g e n e tic syn­ m o r e p r e c is e s u m m a r y e s t i m a t e s w h e n a d e q u a t e d a t a
d ro m e s a s s o c ia te d w ith b re a s t c a n c e r, or p r e v io u s w e r e r e p o r t e d b y t r i a l s r a t e d a s f a i r - o r g o o d - q u a l i t y . In
la r g e doses o f c h e s t r a d ia tio n b e fo re age 3 0 y e a rs ). e a c h m e t a - a n a ly s is , t h e n u m b e r o f in c lu d e d tr ia ls w a s
R is k fa c to rs c o n s id e r e d in th is r e v ie w a re com m on c o u n te d as th e n u m b e r o f d is c r e t e d a ta s o u r c e s c o n ­
a m o n g w o m e n w h o a r e n o t a t h ig h r is k f o r b r e a s t c a n ­ t r i b u t i n g t o t h e s u m m a r y e s t i m a t e u s in g t h e i r m o s t r e ­
c e r (1 2 ) ( A p p e n d ix F ig u r e 1 , a v a i l a b le a t w w w . a n n a ls cent r e s u lt s . To d e te r m in e th e a p p r o p r ia te n e s s of
.o rg ). m e t a - a n a ly s is , w e c o n s i d e r e d c l i n i c a l a n d m e t h o d o l o g ­
ic a l d i v e r s i t y a n d a s s e s s e d s t a t is t ic a l h e t e r o g e n e i t y . A l l
D ata S o u rces and S earch es
o u tc o m e s w e re b in a r y (b re a s t cancer m o r ta lity , a ll­
A r e s e a r c h lib r a r ia n c o n d u c t e d e le c t r o n ic d a ta b a s e
cause m o r ta lity , and advanced cancer in c id e n c e de­
s e a rc h e s o f th e C o c h ra n e C e n tra l R e g is t e r of C on­
fin e d b y s ta g e and t u m o r s iz e ) . W e used a ra n d o m -
tr o lle d T r ia ls , C o c h ra n e D a ta b a s e of S y s t e m a t ic R e­
e ffe c ts m o d e l to c o m b in e r e l a t iv e r is k s (R R s ) a s t h e
v ie w s , a n d O v id M E D L IN E t o 4 June 2 0 1 5 . S e a rc h e s
e f f e c t m e a s u r e o f t h e m e t a - a n a ly s e s , w h i l e i n c o r p o r a t ­
w e r e s u p p le m e n t e d b y r e fe r e n c e s id e n t if ie d fr o m ad­
in g v a r i a t i o n a m o n g s t u d i e s . A p r o f i l e - l i k e l i h o o d m o d e l
d it io n a l s o u r c e s , in c lu d in g re fe re n c e lis ts a n d e x p e r t s .
w a s u s e d to c o m b in e s tu d ie s in t h e p r i m a r y a n a ly s e s
A d d it io n a l u n p u b lis h e d d a ta w e r e p r o v id e d b y th e in ­
(1 3 ). W e a s s e s s e d t h e p r e s e n c e o f s ta tis tic a l h e t e r o g e ­
v e s t i g a t o r s o f t h e C a n a d i a n N a t io n a l B r e a s t S c r e e n in g
n e i t y a m o n g t h e s t u d i e s b y u s in g t h e s t a n d a r d C o c h r a n
S t u d y ( C N B S S ) a n d S w e d is h T w o - C o u n t y T r ia l.
c h i- s q u a r e t e s t , a n d t h e m a g n i t u d e o f h e t e r o g e n e i t y b y
S tu dy S electio n u s in g t h e I 2 s t a t i s t i c ( 1 4 ) .
Two in v e s tig a to r s in d e p e n d e n tly e v a lu a te d each To a c c o u n t f o r c lin ic a l h e te r o g e n e ity and o b ta in
s tu d y to d e te r m in e i n c l u s io n e l i g i b i l i t y o n t h e b a s is o f c l i n i c a l l y m e a n i n g f u l e s t im a t e s , w e s t r a t i f i e d t h e a n a ly ­
p r e s p e c ifie d c r it e r ia . D is c r e p a n c ie s w e re r e s o lv e d s e s b y a g e g r o u p w h e n e v e r p o s s ib le (3 9 t o 4 9 y e a rs , 5 0
th ro u g h c o n s e n s u s . to 5 9 y e a rs , 6 0 to 6 9 y e a rs , 7 0 to 7 4 y e a rs , a n d >50
W e in c lu d e d r a n d o m i z e d , c o n t r o l l e d t r i a l s (R C T s ); y e a rs ). W e o b ta in e d a d d it io n a l a g e - s tr a tifie d d a ta f o r
o b s e r v a t io n a l s tu d ie s o f s c r e e n in g c o h o r ts ; a n d s y s te m ­ t h e m e t a - a n a ly s is f r o m th e in v e s tig a to r s o f 3 tr ia ls (1 5 ,
a tic r e v ie w s t h a t c o m p a r e d o u tc o m e s of w om en ex­ 1 6 ) ( T a b a r L. P e r s o n a l c o m m u n i c a t i o n ) .
p o s e d t o s c r e e n in g v e rs u s n o t s c r e e n in g . F o r a d v a n c e d F o r b r e a s t c a n c e r m o r ta lity , w e u s e d 2 m e th o d s o f
c a n c e r o u tc o m e s , s tu d ie s t h a t r e p o r t e d th e in c id e n c e in c lu d in g cases to h e lp c la r ify d is c r e p a n c ie s b e tw e e n
o f la t e - s t a g e d is e a s e a m o n g s c r e e n e d a n d u n s c r e e n e d e s t im a t e s . The lo n g case a c c ru a l m e th o d c o u n ts a ll
p o p u la t io n s w e re in c lu d e d , w h e re a s th o s e r e p o r tin g b re a s t cancer cases c o n tr ib u tin g to b re a s t cancer
c o m p a r is o n s o f d e t e c t io n m e th o d s t h a t d id n o t c a p tu r e d e a t h s . In t h i s m e t h o d , t h e c a s e a c c r u a l t i m e is e q u i v a ­
a w o m a n 's l o n g i t u d i n a l s c r e e n i n g e x p e r i e n c e w e r e n o t le n t t o o r c lo s e t o t h e f o llo w - u p tim e . T h e s h o r t c a s e
in c lu d e d (e .g ., ra te s o f s c r e e n - d e te c te d vs. n o n - s c r e e n - a c c ru a l m e th o d in c lu d e s o n ly d e a th s t h a t o c c u r a m o n g
d e te c te d c a n c e r). c a s e s o f b r e a s t c a n c e r d ia g n o s e d d u r in g t h e s c r e e n in g
S t u d ie s p r o v id in g o u tc o m e s s p e c ific to age, r is k i n t e r v e n t i o n p e r i o d , a n d in s o m e t r ia ls , w i t h i n a n a d d i ­
fa c to r s , s c r e e n in g i n t e r v a ls , a n d m o d a litie s w e r e p re ­ tio n a l d e fin e d case a c c ru a l p e r io d . The lo n g e s t
f e r r e d o v e r s tu d ie s p r o v id in g g e n e r a l o u tc o m e s , w h e n fo llo w - u p tim e s a v a i l a b le f o r e a c h t r i a l w e r e s e le c t e d
a v a i l a b le . S t u d ie s m o s t c l i n i c a l l y r e l e v a n t t o p r a c t i c e in f o r i n c l u s io n in t h e i n i t i a l m e t a - a n a ly s e s , a n d s e n s i t i v i t y
t h e U n i t e d S t a te s w e r e s e l e c t e d o v e r s t u d i e s t h a t w e r e a n a ly s e s w e r e c o n d u c t e d b y u s in g r e s u lt s o f s h o r t c a s e
le s s r e le v a n t. R e le v a n c e w as d e te r m in e d by p r a c tic e a c c ru a l m e th o d s .
s e ttin g , p o p u la t io n , d a te of p u b lic a tio n , and use of W e c a lc u l a t e d th e a b s o lu te ra te r e d u c tio n fo r
t e c h n o l o g i e s a n d t h e r a p i e s in c u r r e n t p r a c t i c e . S t u d ie s 1 0 0 0 0 0 w o m a n - y e a r s o f f o l l o w - u p ( i. e ., 1 0 0 0 0 w o m e n

w w w .a n n a ls .o rg Annuls of Internal Medicine • Vol. 164 No. 4 • 16 February 2016 245

R eview Effectiveness of Breast Cancer Screening

f o l l o w e d f o r 1 0 y e a r s ) f o r e a c h a g e g r o u p o n t h e b a s is ences b e tw e e n s c r e e n in g and c o n tro l g ro u p s on an

o f th e c o m b in e d RR a n d t h e c o m b i n e d c a n c e r ra te o f in t e n tio n - t o - s c r e e n b a s is . O t h e r i m p o r t a n t c h a r a c t e r is ­
th e c o n tro l g ro u p . W e e s tim a te d c o m b in e d cancer t i c s a r e d e s c r i b e d in t h e t e c h n i c a l r e p o r t (7 ).
ra te s f o r e a c h age g ro u p f o r c o n t r o ls w ith a ra n d o m
B reast C ancer M ortality O utcom es
e ffe c ts P o is s o n m odel u s in g d a ta fro m th e t r ia ls . A ll
S c re e n in g T ria ls
a n a ly s e s w e re p e rfo rm e d by u s in g S ta ta /IC , v e r s io n
The S w e d is h T w o -C o u n ty T r ia l (K o p p a rb e rg and
1 3 .1 ( S t a t a C o r p ) .
O s te r g o tla n d [2 6 ]), A g e tr ia l (2 7 ), G o t h e n b u r g tr ia l (2 5 ),
W e a s s e s s e d th e a g g r e g a te in te r n a l v a lid it y ( q u a l­
a n d C N B S S -1 a n d C N B S S - 2 ( 1 5 ) u s e d l o n g c a s e a c c r u a l
it y ) o f t h e b o d y o f e v id e n c e f o r e a c h k e y q u e s tio n as
m e th o d s t o r e p o r t b r e a s t c a n c e r m o r ta lity b y a g e . T h e
g o o d , f a ir , o r p o o r b y u s in g m e t h o d s d e v e l o p e d b y t h e
H IP t r i a l ( 2 9 ) , M M S T I, M M S T II, a n d S t o c k h o lm tr ia ls
U S P S T F t h a t a r e b a s e d o n t h e n u m b e r , q u a li t y , a n d s iz e
u s e d o n ly s h o r t c a s e a c c ru a l (3 0 ) t o r e p o r t b r e a s t c a n ­
o f s t u d i e s ; c o n s i s t e n c y o f r e s u lt s b e t w e e n s t u d i e s ; a n d
c e r m o r t a l i t y b y a g e . A c r o s s a ll t r i a l s , t h e m e a n o r m e ­
d ir e c t n e s s o f e v i d e n c e ( 1 0 , 1 1 ).
d ia n s c r e e n in g in t e r v e n tio n tim e ra n g e d fro m 3 .5 to
R ole o f th e F u nd in g S ou rce 1 4 .6 y e a r s , c a s e a c c r u a l t i m e fro m 7 .0 t o 1 7 .4 y e a rs ,
T h is r e s e a r c h w a s f u n d e d b y t h e A g e n c y f o r H e a l t h ­ a n d fo llo w - u p tim e fr o m 1 1 .2 t o 2 1 . 9 y e a r s .
c a re R e s e a rc h a n d Q u a lity (A H R Q ) u n d e r a c o n tr a c t to F o r w o m e n a g e d 3 9 t o 4 9 y e a r s , t h e c o m b i n e d RR
s u p p o rt th e w o rk o f th e USPSTF. The in v e s tig a to r s f o r b r e a s t c a n c e r m o r ta lity w a s 0 .9 2 ( 9 5 % C l, 0 . 7 5 t o
w o r k e d w ith U S P S TF m e m b e rs a n d A H R Q s ta ff to de­ 1 .0 2 ) ( 9 t r i a l s [ 1 5 , 2 5 - 2 7 , 2 9 , 3 0 ] ) ( F i g u r e 1 ). T h e c o m ­
v e l o p a n d r e f i n e t h e s c o p e , a n a ly t ic f r a m e w o r k , a n d k e y b i n e d RR f o r w o m e n a g e d 5 0 t o 5 9 y e a r s w a s 0 . 8 6 ( C l,
q u e s t i o n s ; r e s o lv e is s u e s d u r i n g t h e p r o j e c t ; a n d f i n a l ­ 0 .6 8 t o 0 . 9 7 ) (7 t r i a l s [1 5 , 2 5 , 2 6 , 2 9 , 3 0 ]); f o r th o s e
iz e t h e r e p o r t . T h e A H R Q h a d n o r o l e in s t u d y s e l e c t i o n , aged 6 0 to 6 9 y e a r s , it w a s 0 . 6 7 ( C l, 0 . 5 4 t o 0 . 8 3 ) (5
q u a l i t y a s s e s s m e n t , s y n t h e s is , o r d e v e l o p m e n t o f c o n ­ t r i a l s [ 2 6 , 2 9 , 3 0 ]) . C o m b i n i n g r e s u lt s f o r w o m e n a g e d
c lu s io n s . The AHRQ p r o v id e d p r o je c t o v e r s ig h t; re ­ 5 0 t o 6 9 y e a r s i n d i c a t e d a n RR o f 0 . 7 8 ( C l, 0 . 6 8 t o 0 . 9 0 ) .
v ie w e d th e d ra ft re p o rt; a n d d is t r ib u te d th e d ra ft fo r O n l y 3 S w e d is h t r i a l s ( O s t e r g o t l a n d , K o p p a r b e r g , a n d
peer r e v ie w , in c lu d in g to r e p r e s e n ta tiv e s of p ro fe s ­ M M S T I) p r o v i d e d o u t c o m e s f o r w o m e n a g e d 7 0 t o 7 4
s io n a l s o c ie t i e s a n d f e d e r a l a g e n c i e s . T h e A H R Q p e r­ y e a rs , a n d th e n u m b e r s o f e v e n t s in t h e s e t r i a l s w e r e
f o r m e d a fin a l r e v ie w o f th e m a n u s c r ip t t o e n s u r e t h a t m uch lo w e r th a n fo r o th e r a g e g r o u p s (2 6 ). A m e ta ­
t h e a n a ly s is m e t m e t h o d o l o g i c a l s t a n d a r d s . T h e i n v e s ­ a n a ly s is i n d i c a t e d a c o m b in e d RR o f 0 . 8 0 ( C l, 0 .5 1 to
t i g a t o r s a r e s o le l y r e s p o n s i b l e f o r t h e c o n t e n t a n d t h e 1 .2 8 ) (3 t r i a l s [ 2 6 ] ) .
d e c is io n t o s u b m it t h e m a n u s c r ip t f o r p u b lic a t io n . R e s u lts o f th e m e t a - a n a ly s is w e re used to d e te r­
m in e a b s o l u t e r a te s o f b r e a s t c a n c e r m o r t a l i t y r e d u c ­
t i o n p e r 1 0 0 0 0 w o m e n s c r e e n e d f o r 1 0 y e a r s ( T a b le 1 ).
R e s u l t s T h e n u m b e r o f d e a t h s r e d u c e d ( i.e ., p r e v e n t e d ) w a s 2 . 9
O f th e 12 0 7 0 a b s tra c ts id e n t if ie d by e le c t r o n ic ( C l, - 0 . 6 t o 8 .9 ) f o r w o m e n a g e d 3 9 t o 4 9 y e a r s ; 7 .7 ( C l,
s e a rc h e s a n d o t h e r s o u r c e s , 3 8 s t u d i e s m e t in c l u s io n 1 .6 t o 1 7 .2 ) f o r t h o s e a g e d 5 0 t o 5 9 y e a r s ; 2 1 . 3 ( C l, 1 0 .7
c r it e r i a f o r k e y q u e s t i o n s in t h i s r e p o r t , i n c l u d i n g 5 s y s ­ to 3 1 .7 ) f o r th o s e a g e d 6 0 to 6 9 y e a rs ; a n d 1 2 .5 ( C l,
t e m a t i c r e v ie w s o f 6 2 s t u d i e s ( A p p e n d i x F i g u r e 2 , a v a i l ­ -1 7 .2 t o 3 2 . 1 ) f o r t h o s e a g e d 7 0 t o 7 4 y e a r s . A b s o l u t e
a b l e a t w w w . a n n a l s . o r g ). r e d u c tio n f o r th e c o m b in e d g r o u p o f w o m e n a g e d 5 0
t o 6 9 y e a r s w a s 1 2 .5 ( C l, 5 .9 t o 1 9 .5 ) .
RCTs o f S creen in g
T h e e ffe c t o f s c r e e n in g w a s d im in is h e d , a lt h o u g h
E i g h t m a in t r i a l s o f m a m m o g r a p h y s c r e e n i n g m et
th e s t a t is t ic a l s ig n ific a n c e of th e e s tim a te s d id not
c r it e r ia fo r fa ir q u a lity : th e H e a lt h In s u ra n c e P la n of
c h a n g e , in o u r s e n s i t i v i t y a n a ly s is t h a t i n c l u d e d r e s u lt s
G r e a t e r N e w Y o r k ( H IP ) t r i a l (1 7 ); t h e C N B S S ( C a n a d ia n
o f a p u b l i s h e d c o m b i n e d a n a ly s is o f t h e S w e d is h t r i a l s
N a t io n a l B re a s t C ancer S c r e e n in g ) - 1 (1 8 , 19) and
( M M S T I, M M S T II, S t o c k h o l m , O s t e r g o t l a n d , G o t h e n ­
C N B S S -2 (2 0 , 2 1 ); th e Age tr ia l, p e rfo rm e d in th e
b u rg , and S to c k h o lm ) u s in g a lo n g case a c c ru a l
U n ite d K in g d o m (2 2 ); a n d 4 tr ia ls fr o m S w e d e n , w h ic h
( " f o l l o w - u p " ) m e t h o d ( 3 0 ) r a t h e r t h a n r e s u lt s o f i n d i v i d ­
w e re th e S t o c k h o lm tr ia l (2 3 ), M a lm o M a m m o g r a p h ic
u a l t r ia ls . In a s e p a r a t e s e n s i t i v i t y a n a ly s is , m e t a - a n a ly s is
S c r e e n in g T r ia l ( r e f e r r e d t o s e p a r a t e ly a s " M M S T I" a n d
e s tim a te s f r o m tr ia ls w ith s h o rt ca se a c c ru a l m e th o d s
"M M S T II" ) ( 2 4 ) , G o th e n b u rg tr ia l (2 5 ), and S w e d is h
d if f e r e d o n ly s lig h tly fr o m th o s e w ith lo n g c a s e a c c ru a l
T w o - C o u n t y T r ia l ( r e f e r r e d t o s e p a r a t e ly a s " O s t e r g o t -
( T a b le 1 ). A c r o s s a ll t r i a l s w i t h s h o r t c a s e a c c r u a l, t h e
la n d " a n d " K o p p a r b e r g " ) (2 6 ). U p d a te s o f th e C N B S S s ,
m ean o r m e d ia n s c r e e n in g in t e r v e n tio n tim e ra n g e d
t h e A g e t r i a l , a n d S w e d is h T w o - C o u n t y T r ia l p r o v i d e d
fro m 3 .5 t o 1 4 .6 y e a rs , c a s e a c c ru a l t im e fr o m 5 .0 t o
n e w d a ta f o r th is r e p o r t (1 5 , 1 6 , 2 7 ). T h e E d in b u r g h tr ia l
1 5 .5 y e a r s , a n d f o l l o w - u p t i m e f r o m 1 0 .7 t o 2 5 . 7 y e a r s .
(2 8 ) w a s n o t in c lu d e d because o f i m p o r t a n t b a s e li n e
d if fe r e n c e s b e tw e e n s c r e e n in g and c o n tro l g ro u p s ,
s u g g e s tin g in a d e q u a te r a n d o m iz a tio n . O b s e r v a tio n a l S tu d ie s
T r ia ls i n c l u d e d o v e r 6 0 0 0 0 0 w o m e n a n d v a r i e d in T h r e e g o o d - q u a l i t y s y s t e m a t i c r e v ie w s o f o b s e r v a ­
t h e ir r e c r u itm e n t, r a n d o m iz a tio n , s c r e e n in g p r o to c o ls , t io n a l s tu d ie s o f s c r e e n in g w e r e r e c e n tly c o n d u c t e d b y
c o n t r o l g r o u p s , a n d s iz e s ( A p p e n d i x T a b l e 1 , a v a i l a b le t h e E U R O S C R E E N W o r k in g G r o u p t o a s s e s s t h e e ffe c ­
a t w w w . a n n a l s . o r g ). B re a s t c a n c e r m o r ta lity w as th e tiv e n e s s o f m a m m o g r a p h y s c r e e n in g o n b r e a s t c a n c e r
m a in o u t c o m e m e a s u r e , a n d a ll t r i a l s e v a l u a t e d d i f f e r - m o r t a lit y ( 3 1 - 3 3 ) . A n a d d it io n a l r e v ie w in c lu d e d m any

246 Annals of internal Medicine • Vol. 164 No. 4 • 16 February 2016 w w w .a n n a ls .o r g

Effectiveness of Breast Cancer Screening R eview

Figure 1. Effects of screening on breast cancer mortality.

Author, Year (Reference) Trial Name Mean Relative Risk (95% Cl)
Follow-up, y
Women aged 39-49 y
Nystrom et al, 2002 (30)* MMST II 11.2 0.64 (0.39-1.06)
Tabar et al, 1995 (26) Kopparberg 12.5 0.73 (0.37-1.41)
Tabar et al, 1995 (26) Ostergotland 12.5 1.02 (0.52-1.99)
Moss et al, 2015(27) Age 17.5 0.93 (0.80-1.09)
Bjurstam et al, 2003 (25) Gothenburg 13.8 0.69 (0.45-1.05)
Habbema et al, 1986 (29) HIP 14.0 0.75 (0.53-1.05)
Nystrom et al, 2002 (30)* Stockholm 14.3 1.52 (0.80-2.88)
Nystrom et al, 2002 (30)* MMST I 18.2 0.74 (0.42-1.29)
M iller e ta l, 2014 (15) CNBSS-1 21.9 1.04 (0.87-1.24)
Overall (/2 = 25%; P = 0.230) 0.92 (0.75-1.02)

Women aged 50-59 y

Tabar et al, 1995 (26) Ostergotland 12.5 0.85 (0.52-1.38)
Tabar et al, 1995 (26) Kopparberg 12.5 0.48 (0.29-0.77)
Nystrom et al, 2002 (30)* Stockholm 13.7 0.56 (0.32-0.97)
Bjurstam et al,2003 (25) Gothenburg 13.8 0.83 (0.60-1.15)
Habbema et al, 1986 (29) HIP 14.0 0.83 (0.61-1.13)
Nystrom et al, 2002 (30)* MMST I 18.1 0.98 (0.75-1.29)
M iller et al, 2014(15) CNBSS-2 21.9 0.94 (0.78-1.13)
Overall (/2 = 38.0%; P = 0.139) 0.86 (0.68-0.97)

Women aged 60-69 y

Tabar et al, 1995 (26) Kopparberg 12.5 0.58 (0.35-0.96)
Tabar e ta l, 1995 (26) Ostergotland 12.5 0.62 (0.43-0.91)
Nystrom et al, 2002 (30)* Stockholm 13.1 0.94 (0.46-2.02)
Habbema et al, 1986 (29) HIP 14.0 0.85 (0.48-1.47)
Nystrom et al, 2002 (30)* MMST I 15.5 0.64 (0.45-0.92)
Overall (I2 = 0.0%; P = 0.739) 0.67 (0.54-0.83)

Women aged 70-74 y

Tabar et al, 1995 (26) Ostergotland 12.5 0.82 (0.43-1.58)
Tabar e ta l, 1995 (26) Kopparberg 12.5 0.76 (0.42-1.36)
Nystrom et al, 2002 (30)* MMST I 13.6 0.98 (0.15-6.60)
Overall (I2 = 0.0%; P = 0.962) 0.80 (0.51-1.28)

Favors Favors
Screening Control
Group Group

Meta-analysis of trials using the longest follow-up times available. CNBSS = Canadian National Breast Screening Study; HIP = Health Insurance Plan
of New York; MMST = Malmo Mammographic Screening Trial.
* Used short case accrual.

o f the same studies (34). The EUROSCREEN reviews
included studies from current population-based
screening program s in Europe and the United King­
dom ; included w om en aged 50 to 69 years; and were
designed as tim e-tren d, incidence-based m ortality, or
case-control studies. A lth ou g h quality criteria were not
prespecified, the studies were subjected to critical re­
view according to design-specific factors.
www.annals.org
O f 12 tim e-tren d studies reporting changes in
breast cancer m ortality in relation to the introduction o f
screening (32, 35-39, 4 0 -4 6 ), 3 with adequate
fo llo w -u p reported m ortality reductions ranging from
28% to 35% (41, 42, 45). A meta-analysis (33) o f
incidence-based m ortality studies estim ating breast
cancer m ortality from a co ho rt o f w om en not invited fo r
screening, or from historical and current control
Annals of'Internal Medium • Vol. 164 No. 4 • 16 February 2016 247
R eview Effectiveness of Breast Cancer Screening

T a b le 1. A g e -S p e c ific R ates o f B re ast C a n c e r M o rta lity R e d u c tio n W ith S c re e n in g

Age M ortality Rate in the Breast Cancer Deaths Prevented With

Control Group per 100 000 Mortality Reduction: Screening 10 0 0 0 Women
Person-Years (95% Cl)* Relative R is k (9 5 % C I)t Over 10 Years (95% Cl)
Long case accrual
39-49 y 36 (29 to 43) 0.92 (0.75 to 1.02) 2.9 (-0.6 to 8.9)
50-59 y 54 (50 to 58) 0.86 (0.68 to 0.97) 7.7 (1.6 to 17.2)
60-69 y 65 (52 to 81) 0.67 (0.54 to 0.83) 21.3 (10.7 to 31.7)
70-74 y 62 (48 to 80) 0.80(0.51 to 1.28) 12.5 (-17.2 to 32.1)
50-69 y 58 (55 to 62) 0.78 (0.68 to 0.90) 12.5 (5.9 to 19.5)

Short case accrual

39-49 y 22 (16 to 30) 0.87 (0.72 to 1.00) 2.9 (0.1 to 6.5)
50-59 y 31 (24 to 39) 0.86 (0.69 to 1.01) 4.5 (-0.2 to 9.8)
60-69 y 40 (28 to 56) 0.67 (0.55 to 0.91) 12.1 (3.4 to 20.7)
70-74 y 49 (36 to 64) 0.90 (0.46 to 1.78) 12.2 (-37.7 to 26.9)
50-69 y 32 (24 to 41) 0.81 (0.69 to 0.95) 6.1 (1.2 to 10.9)

* O n th e basis o f tria ls o f screening in c lu d e d in th e meta-analysis.

t From m eta-analyses o f screening tria ls using 2 d iffe re n t m e thod s o f case accrual. The long case accrual m e th o d counts all breast cancer cases
c o n trib u tin g to breast cancer deaths. In this m e thod , th e case accrual tim e is eq u iva le n t to o r close to th e fo llo w -u p tim e . The sho rt case accrual
m e thod includes o n ly deaths th a t o ccu r a m ong cases o f breast cancer d iag nose d d u rin g th e screening inte rventio n p e rio d , and in som e trials,
w ith in an a d d itio n a l d e fin e d case accrual p e riod.

groups, indicated a risk reduction o f 0.75 (Cl, 0.69 to
0.81) (7 studies [42, 47-52]) fo r w om en invited to
screening and 0.62 (Cl, 0.56 to 0.69) (7 studies [42,
47-52]) fo r those actually screened. A meta-analysis of
case-control studies (33) indicated an odds ratio of
0.69 (Cl, 0.57 to 0.83) (7 studies [53-58]) fo r wom en
invited to screening; and 0.52 (Cl, 0.42 to 0.65) (7 stud­
ies [53-58]) fo r those actually screened.
Six additional studies were not included in the p u b ­
lished systematic reviews because they were published
in 2011 or later (59 -6 3), included w om en in countries
outside Europe and the United Kingdom (63, 64), or
focused on ages o ld e r or younger than 50 to 69 years
(59, 64) (A p pe nd ix Table 2, available at www.annals
.org). These studies are generally consistent with the
EUROSCREEN results (61-63), including 2 observa­
tional studies o f w om en in th e ir 40s indicating a 26% to
44% reduction in breast cancer m ortality fo r w om en
invited to (59) or participating in screening (59, 63).
All-Cause Mortality
All included trials o f m am m ography screening re­
ported all-cause m ortality outcomes. However, not all
trials reported them according to age, and the 2 Cana­
dian trials reported com bined estimates. For all ages,
the com bined RR o f 0.99 (Cl, 0.97 to 1.002) (9 trials [15,
27, 30, 65]) was consistent with no reduction in all­
cause m ortality with screening. Results were sim ilar fo r
each age g ro u p (RR, 0.99 [Cl, 0.94 to 1.05] fo r wom en
aged 39 to 49 years [7 trials], 1.02 [Cl, 0.94 to 1.10] for
those aged 50 to 59 years [3 trials], 0.97 [Cl, 0.90 to
1.04] fo r those aged 60 to 69 years [2 trials], and 0.98
[Cl, 0.86 to 1.14] fo r those aged 70 to 74 years [2 trials])
and when short case accrual m ethods were used.
Mortality Outcomes by Risk Factors, Screening
Intervals, and Modalities
No trials reported m ortality outcom es fo r w om en
with specific risk factors besides age, and none com ­
pared different screening intervals or m odalities. Two
observational studies indicated no differences in breast
cancer m ortality after changing from annual to biennial
screening (66) or betw een annual and triennial screen­
ing (67) (A p pe nd ix Table 2).
Advanced Breast Cancer Outcomes
Screening Trials
Trials measured cancer severity in term s o f clinical
stage (0 to IV) (23, 24, 68, 69), n um ber o f involved
lymph nodes (0, 1 to 3, or >4) (18, 20, 25, 26, 70), and
tu m o r size (mm) (19, 21, 26), and these varied across
trials. A lthough "advanced" breast cancer is classified
as m etastatic disease (stage IV) by the Am erican Joint
C om m ittee on Cancer TNM system based on tu m o r
size, lymph node involvem ent, and presence o f metas­
tasis (71), m ost trials defined advanced breast cancer at
much lower thresholds (72).
To com bine results, the meta-analysis included the
m ost severe disease categories available from the tr i­
als, recognizing that these definitions do not represent
equivalent disease stages (A p pe nd ix Table 3, available
at w w w.annals.org). These include stage III and IV dis­
ease (i.e., regional and metastatic, respectively), size 40
to 50 mm or greater, or 4 or m ore positive lymph
nodes. C om bining results on the basis o f these d e fin i­
tions indicated no difference with screening fo r w om en
aged 39 to 49 years (RR, 0.98 [Cl, 0.74 to 1.37]) (4 trials
[19, 26, 68, 70]) but reduced risk fo r those aged 50
years or o ld e r (RR, 0.62 [Cl, 0.46 to 0.83]) (3 trials [21,
26, 68]) (Figure 2).
Observational Studies
Five case-series studies com pared breast cancer
diagnoses in populations o f w om en w ho had previous
screening versus none (73-77). However m ost studies
used thresholds indicating early stages o f disease (74,
77) or reported p ro po rtio ns rather than incidence rates
(73-77), pro vid ing inadequate data to determ ine the
effectiveness o f screening (A p pe nd ix Table 4, available
at w w w.annals.org).

248 Annals oflnternal Medicine • Vol. 164 No. 4 • 16 February 2016 www.annals.org
Effectiveness of Breast Cancer Screening R eview

T reatm en t-R elated M orbidity O utcom es p a re d b r e a s t c a n c e r d ia g n o s e s b y s c r e e n in g in t e r v a ls

S c re e n in g T ria ls ( 7 9 - 8 3 ) ( A p p e n d i x T a b l e 4 ) . S o m e a n a ly s e s i n d i c a t e d
A C o c h r a n e r e v ie w c o m p a r e d t r e a t m e n t s b e tw e e n n o d if fe r e n c e s b e tw e e n a n n u a l a n d b ie n n ia l s c r e e n in g
r a n d o m iz e d g r o u p s in 5 s c r e e n i n g t r i a l s : t h e C N B S S -1 in d e te c tin g advanced s ta g e d is e a s e (7 9 , 80, 8 3 ),
and C N B S S -2 , th e M M ST, and th e K o p p a rb e rg and w h e r e a s 2 a n a ly s e s i n d i c a t e d e a r l i e r s t a g e s o f d is e a s e
S t o c k h o l m t r i a l s ( 7 8 ) . In t h i s a n a ly s is , w o m e n r a n d o m l y a m o n g w o m e n a g e d 4 0 to 4 9 y e a rs w h o w e re s c re e n e d
a s s ig n e d t o s c r e e n i n g w e r e m o r e l i k e l y t o h a v e s u r g ic a l a n n u a ll y v e rs u s b ie n n ia lly (8 1 , 8 2 ); th is la tte r fin d in g
t h e r a p y , a n a ly z e d a s m a s t e c t o m i e s a n d lu m p e c to m ie s w a s c o n f i n e d t o w o m e n w i t h e x t r e m e b r e a s t d e n s i t y in
c o m b i n e d (R R , 1 .3 5 [ C l, 1 .2 6 t o 1 . 4 4 ] ) (5 t r i a l s ) o r m a s ­ o n e s tu d y (8 2 ). A r a n d o m iz e d tr ia l o f a n n u a l v e rs u s t r i ­
te c to m ie s a lo n e (R R , 1 .2 0 [C l, 1 .1 1 to 1 .3 0 ]) (5 tr ia ls ) e n n ia l s c r e e n i n g in d ic a te d d e te c tio n o f m o re tu m o rs
( 7 8 ) . T h e s e w o m e n w e r e a ls o m o r e l i k e l y t o h a v e r a d i ­ l a r g e r t h a n 2 0 m m in s iz e w i t h t r i e n n i a l s c r e e n i n g ; h o w ­
a t i o n t h e r a p y (R R , 1 .3 2 [C l, 1 . 1 6 t o 1 . 5 0 ] ) (2 t r ia ls ) , a n d e v e r, th is th r e s h o ld in d ic a te s e a r ly ra th e r th a n ad­
le s s l i k e l y t o h a v e h o r m o n e t h e r a p y (R R , 0 . 7 3 [ C l, 0 . 5 5 vanced d is e a s e (8 4 ). Two o b s e r v a tio n a l s tu d ie s of
t o 0 . 9 6 ] ) (2 t r ia ls ) . U s e o f c h e m o t h e r a p y w a s s i m i l a r b e ­ w om en r e c e iv i n g m a m m o g ra p h y v e rs u s m a m m o g ra ­
t w e e n g r o u p s (R R , 0 . 9 6 [C l, 0 . 7 8 t o 1 . 1 9 ] ) ( 2 t r i a l s ) ( 7 8 ) . p h y a n d t o m o s y n t h e s i s i n d i c a t e d n o d i f f e r e n c e s in c a n ­
c e r s iz e ( 8 5 ) o r n o d e s t a t u s ( 8 5 , 8 6 ) ( A p p e n d i x T a b l e 6 ,
a v a i l a b le a t w w w . a n n a l s . o r g ).
O b s e r v a tio n a l S tu d ie s
F o u r c a s e - s e r ie s s t u d i e s c o m p a re d b re a s t c a n c e r
t r e a t m e n t s in p o p u l a t i o n s o f w o m e n w h o h a d p r e v io u s
D is c u s s io n
s c r e e n in g v e rs u s none (7 3 -7 6 ) ( A p p e n d ix T a b le 5,
A s u m m a r y o f e v i d e n c e is p r o v i d e d in T a b l e 2 . T h e
a v a i l a b le at w w w . a n n a l s . o r g ). A l t h o u g h s tu d ie s in d i­
e ffe c tiv e n e s s o f m a m m o g r a p h y s c r e e n in g in r e d u c i n g
c a te d le s s e x t e n s i v e s u r g e r y , s u c h a s f e w e r t o t a l m a s ­
b r e a s t c a n c e r m o r t a lit y w a s e v a lu a te d b y R C T s a n d o b ­
te c to m ie s and m o re b re a s t c o n s e r v a tio n th e r a p ie s
s e r v a tio n a l s tu d ie s p r o v id in g f a ir - q u a lit y e v id e n c e . O u r
(7 3 -7 6 ), and le s s c h e m o th e ra p y (7 3 , 74, 76) am ong
m e t a - a n a ly s is of 8 r a n d o m iz e d tr ia ls in d ic a te s th a t
s c r e e n e d w o m e n , t h e d i a g n o s i s o f d u c t a l c a r c i n o m a in
b re a s t cancer m o r ta lity is g e n e r a lly re d u c e d w ith
s it u w a s i n c l u d e d in s o m e s t u d i e s ( 7 4 , 7 6 ) , r e s u l t i n g in
s c r e e n in g ; h o w e v e r , e s tim a te s a re n o t s ta tis tic a lly s ig ­
le s s i n t e n s i v e t h e r a p i e s o v e r a l l in s c r e e n e d w o m e n .
n if ic a n t f o r w o m e n a g e d 3 9 t o 4 9 y e a rs a n d th o s e a g e d
A d van ced B reast C ancer and T reatm en t-R elated 7 0 t o 7 4 y e a r s , t h e m a g n i t u d e s o f e f f e c t a r e s m a ll, a n d
M orbidity O u tcom es by R isk F actors, S creen in g r e s u lt s d i f f e r d e p e n d i n g o n h o w c a s e s w e r e a c c r u e d in
In terv a ls, an d M od alities t r ia ls . T h e s e r e s u lt s d i f f e r f r o m o u r p r e v io u s e s t i m a t e ( 2 )
F iv e o b s e r v a t i o n a l s t u d i e s b a s e d o n p o p u l a t i o n s in b e c a u s e th e y in c lu d e u p d a te d d a ta fr o m t h e C N B S S -1
th e U .S . B r e a s t C a n c e r S u r v e i l la n c e C o n s o r t i u m com ­ and C N B S S -2 , th e S w e d is h T w o - C o u n t y T r ia l, a n d t h e

F ig u r e 2 . E ffe c ts o f s c r e e n in g o n a d v a n c e d c a n c e r o u tc o m e s .

A u th o r, Year (R eference) Trial N am e D e fin itio n o f E v e n ts /S c re e n in g E v e n ts /C o n tro l R e la tiv e Risk

A dvanced G ro u p , n / N G ro u p , n / N (9 5 % C l)
C ancer
W o m e n ag ed 3 9 - 4 9 y

Chu e t a l, 1 9 8 8 ( 6 8 ) HIP Stage III o r gre a te r 2 0 /1 3 7 4 0 2 3 /1 3 7 4 0 0 .8 7 ( 0 .4 8 - 1 .5 8 )

T a b a r e t al, 1 9 9 5 (2 6 ) S w edish T w o -C o u n try Size > 5 0 m m 1 4 /1 9 84 4 7 /1 5 60 4 1.5 7 ( 0 .6 3 - 3 .9 0 )

M ille r e t a l, 2 0 0 2 (1 9 ) CNBSS-1 Size > 4 0 m m 2 6 /2 5 2 1 4 2 2 /2 5 2 1 6 1 .1 8 ( 0 .6 7 - 2 .0 8 )

M o s s e t a l, 2 0 0 5 (9 7 ) A ge Size > 5 0 m m 3 3 /5 3 8 9 0 7 7 /1 0 6 971 0 .8 5 (0 .5 7 - 1 .2 8 )

O v e ra ll (I2 = 0 .0 % ; P = 0 .5 5 6 ) 9 3 /1 1 2 68 8 1 2 9 /1 6 1 531 0 .9 8 (0 .7 4 - 1 .3 7 )

W o m e n ag ed > 5 0 y

Chu e t a l, 1 9 8 8 (6 8 ) HIP Stage III o r g re a te r 2 2 /1 6 50 5 4 2 /1 6 50 5 0.5 2 (0 .3 1 -0 .8 8 )

T a b a r e t a l, 1 9 9 5 (2 6 ) S w edish T w o -C o u n try Size > 5 0 m m 6 2 /5 7 2 3 6 6 9 /4 0 381 0 .6 3 ( 0 .4 5 - 0 .8 9 )

M ille r e t a l, 2 0 0 0 (9 8 ) CNBSS-2 Size > 4 0 m m 1 5 /1 9 7 1 1 2 0 /1 9 69 4 0 .7 5 ( 0 .3 8 - 1 .4 6 )

O v e ra ll (I2 = 0.0 %; P = 0 .6 9 2 ) 9 9 /9 3 45 2 1 3 1 /7 6 5 8 0 0.6 2 ( 0 .4 6 - 0 .8 3 )

— i-------------

0.25 2 .0 0

Favors Favors
S creening C o n tro l
G ro u p G ro u p

Meta-analysis of trials reporting the most severe disease categories available. CNBSS = Canadian National Breast Screening Study; HIP = Health
Insurance Plan of New York.

w w w .a n n a ls .o r g Annals of Internal Medicine • Vol. 164 No. 4 • 16 February 2016 249

R eview Effectiveness of Breast Cancer Screening

Table 2. Summary o f Evidence: Effectiveness o f Breast Cancer Screening

Previous USPSTF Reviews Studies in Update Overall Quality Limitations

Effectiveness of screening in reducing breast
cancer-specific and all-cause mortality:
differences by age, risk factors, and
screening intervals
Mammography screening reduced breast
cancer mortality in RCTs for women aged
39-49 y (RR, 0.85 [95% Crl, 0.75-0.96]; 8
trials), those aged 50-59 y (RR, 0.86 [Crl,
0.75-0.99]; 6 trials), and those aged 60-69 y
(0.68 [Crl, 0.54-0.87]; 2 trials); data were
limited for women aged 70-74 y
3 RCTs provided updated data in Fair Trials have methodological limitations
addition to 5 previously Observational studies used various
published RCTs; 65 methods that introduce potential
observational studies (57 bias
included in 4 systematic
reviews, plus 8 additional
studies)

Effectiveness of screening in reducing the

incidence of advanced breast cancer and
treatment-related morbidity: differences by
age, risk factors, and screening intervals
Not included
5 RCTs of screening and cancer
stage; 1 Cochrane review of 5
RCTs of treatment; 1 RCT of
intervals; 14 observational
studies
Poor (observational Definitions of advanced breast cancer
studies) to fair were heterogeneous
(RCTs) Observational studies were not
designed to determine effectiveness

Effectiveness of screening in reducing breast

cancer-specific and all-cause mortality by
screening modality
Not included No studies evaluated this NA NA
question

Effectiveness of screening in reducing the

incidence of advanced breast cancer and
treatment-related morbidity by screening
modality
Not included 2 observational studies Poor No RCTs; comparability of groups not
known

BCSC = Breast Cancer Surveillance Consortium; CBE = clinical breast examination; Crl = credible interval; NA = not applicable; RCT = randomized,
controlled trial; RR = relative risk; USPSTF = U.S. Preventive Services Task Force.

Age trial and incorporate data by using the longest
case accrual m ethods available from each trial.
O bservational studies o f population-based m am ­
m ography screening, lim ited by inherent biases o f non-
random ized studies, reported a w ide range o f reduc­
tions in breast cancer m ortality. M ost studies were
conducted in Europe or the United Kingdom and in­
cluded w om en aged 50 to 69 years. Meta-analyses in­
dicated a 25% reduction based on 7 incidence-based
m ortality studies and a 31% reduction based on 7 case-
control studies. These results generally concur with our
meta-analysis o f trials fo r w om en aged 50 to 69 years
that indicated a statistically significant 22% reduction.
Evidence o f breast cancer m ortality reduction in
observational studies is inconsistent with random ized
trials o f w om en in th e ir 40s. Two observational studies
indicated 25% to 44% reductions with screening that
d iffer from the non-statistically significant reduction
from our meta-analysis o f trials. This difference may re-
fleet dissim ilarities between participants and n on pa rtic­
ipants o f screening program s in nonrandom ized
studies, as well as assum ptions underlying m ortality
estimates.
All-cause m ortality did not d iffer between random ­
ized groups in meta-analyses o f fair-quality trials, re­
gardless o f w hether trials were analyzed in com bined
or separate age groups.
Questions a bo ut the effectiveness o f screening in
reducing breast cancer-specific or all-cause m ortality
on the basis o f risk factors, screening intervals, and m o­
dalities remain largely unanswered by currently avail­
able research. No studies evaluated breast cancer-
specific or all-cause m ortality outcom es on the basis of
risk factors besides age. A lth ou g h there were no trials
o f the effectiveness o f d ifferen t screening intervals, 2
observational studies indicated no differences in breast
cancer m ortality after changing from annual to biennial
screening or between annual and triennial screening.

250 Annals of Internal Medicine • Vol. 164 No. 4 • 16 February 2016 www.annals.org
Effectiveness of Breast Cancer Screening R eview

Table 2 -C o n tin u e d

Consistency Applicability Summary o f Findings

Results are consistent across types o f studies
Most studies were conducted in Europe
RCTs were based on technologies and
treatments that have changed over
time
Breast cancer mortality is generally reduced with mammography
screening, although results o f RCTs varied by age: 39-49 y (RR,
0.92 [95% Cl, 0.75-1.02]; 9 trials), 50-59 y (RR, 0.86 [Cl,
0.68-0.97]; 7 trials), and 60-69 y (RR, 0.67 [Cl, 0.54-0.83];
5 trials); data were limited fo r women aged 70-74 y
Meta-analyses o f observational studies indicated 25%-31%
reduction in breast cancer m ortality for women aged 50-69 y
invited to screening
Two observational studies o f women in their 40s indicated
26%-44% reduction in breast cancer mortality
All-cause m ortality was not reduced with screening for any age
Studies of risk factors and screening intervals were not available
or were m ethodologically limited

Results are consistent across types o f studies
Most trials were conducted in Europe
RCTs were based on technologies and
treatments that have changed over
time
Mammography screening reduced cancer stage for women aged
>50 y (RR, 0.62 [Cl, 0.46-0.83]; 3 trials), but not fo r those aged
39-49 y
W omen randomly assigned to screening had more
mastectomies, lumpectomies, and radiation therapy, and less
hormone therapy, than controls
Observational studies were inconclusive
Studies of risk factors and screening intervals were not available
or were m ethodologically limited

NA NA NA

Results are consistent High clinical relevance No differences in cancer size or node status between screening
with mammography alone vs. mammography and
tomosynthesis

The effectiveness o f breast cancer screening in re­
ducing advanced breast cancer outcom es is supported
by less evidence than fo r m ortality. Studies provided
heterogeneous measures o f breast cancer severity and
generally reported early-stage disease. A meta-analysis
o f trials indicated a statistically significant reduction in
advanced disease fo r w om en aged 50 years or o ld er
w ho were random ly assigned to undergo screening,
b ut not fo r w om en aged 39 to 49 years. This reduction
in advanced cancer aligns with reductions in m ortality
outcom es fo r w om en o ld er than 50 years reported in
random ized trials and observational studies, but differs
from studies o f population trends th a t show no reduc­
tions in advanced breast cancer after the introduction
o f mass screening (87-89).
In a meta-analysis o f 5 trials, w om en random ly as­
signed to und ergo screening were m ore likely to have
surgical and radiation therapy and less likely to have
horm one therapy than controls; use o f chem otherapy
was sim ilar betw een groups. This fin d in g w ould be ex­
pected, because screening increases detection o f due-
w w w .a n n a ls .o rg
tal carcinoma in situ and early-stage disease that are
currently aggressively treated. Observational studies of
the im pact o f screening on diagnosis and treatm ent of
advanced cancer were inadequately designed to d ete r­
mine effectiveness because they generally provided
com parisons between screen-detected and non­
screen-detected cases and between p ro po rtio ns o f d if­
ferent cancer diagnoses fo r screened versus un­
screened wom en. C om parisons o f incidence rates
between screening versus nonscreening populations
w ould provide m ore a ppropriate measures.
The effectiveness o f screening in reducing ad­
vanced breast cancer and trea tm en t m o rb id ity on the
basis o f risk factors, screening intervals, and m odalities
was also unanswered by current research. The analysis
o f outcom es based on screening intervals in the U.S.
Breast Cancer Surveillance Consortium is lim ited by the
o p p ortu nistic nature o f screening in the United States.
W om en choosing short screening intervals p robably
d iffer in im portant ways from those choosing longer
intervals. Consequently, com parisons betw een out-
Annals of Internal Medicine • Vol. 164 No. 4 • 16 February 2016 2S1
R e v ie w
comes o f these 2 types o f w om en may not provide valid
measures o f effectiveness. O nly 2 observational studies
com pared im aging m odalities and found no d iffe r­
ences in cancer size or node status between wom en
receiving m am m ography alone versus m am m ography
and tomosynthesis.
O ur review has lim itations. First, we included only
English-language articles; this could result in language
bias, although we did not identify non-English-
language studies that otherwise m et inclusion criteria in
our searches. Second, we only included studies that
were applicable to current practice in the United States
in o rd e r to im prove clinical relevance fo r the USPSTF,
excluding studies and lim iting relevance to other p o p ­
ulations and settings. Third, studies used heteroge­
neous definitions fo r advanced breast cancer th a t did
not consider tu m o r subtypes, and m ost trials used im ­
aging technologies and treatm ents that are now o u t­
dated, lim iting th e ir applicability. Finally, studies were
not available fo r some key questions, specifically for
effectiveness based on risk factors, intervals, or other
m odalities; and the num ber, quality, and a pplicability
o f studies varied widely.
A d ditio na l research on the effectiveness o f mam ­
m ography screening with quality-of-life outcomes, as
well as m orbid ity and m ortality outcomes, and using
current im aging te chn olo gy and breast cancer trea t­
ments w ould provide further understanding o f the im ­
plications o f routine screening. Data fo r specific groups
o f w om en, particularly o ld e r w om en, or groups based
on racial and ethnic background, access to screening,
or existence o f com orbidities, fo r example, could fu r­
th er inform screening practices. New technologies,
such as tomosynthesis, are becom ing more w idely
used in the United States w ith o u t definitive studies o f
th e ir effects on screening outcomes. Studies on the
role o f additional im aging m odalities in screening are
required in o rd e r to app ro priate ly incorporate these
technologies in the screening process.
In conclusion, breast cancer m ortality is generally
reduced with m am m ography screening, although esti­
mates are not statistically significant at all ages and the
m agnitudes o f effect are small. Advanced cancer is re­
duced with screening fo r w om en aged 50 years or
older.
From the Pacific N orthw est Evidence-based Practice Center,
O rego n Health & Science University; Veterans Affairs Portland
Health Care System; and Providence Cancer Center, Provi­
dence Health & Services, Portland, O regon.
Disclaimer: The fin d in g s and conclusions in this article are
those o f the authors, w ho are responsible fo r its content, and
do not necessarily represent the views o f AHRQ. No statem ent
in this re p o rt should be construed as an official position of
AHRQ o r the U.S. D epartm ent o f Health and Human Services.
Acknowledgment: The authors thank A n d re w H am ilton, MLS,
MS, fo r con du cting literature searches and Spencer Dandy,
BS, fo r assisting w ith m anuscript preparation at the Pacific
N orthw est Evidence-based Practice C enter at O rego n Health
252 Annals of Internal Medicine • Vol. 164 No. 4 • 16 February 2016
Effectiveness of Breast Cancer Screening
& Science University; and Alison Conlin, MD, MPH, and M i­
chael Neuman, MD, at the Providence Cancer C enter at Prov­
idence Health and Services O regon, and Arpana Naik, MD, at
O regon Health & Science University fo r p ro vid in g m edical ex­
pertise. They also thank Jennifer Croswell, MD, MPH, at the
A gency fo r Healthcare Research and Q uality, and U.S. Preven­
tive Services Task Force m em bers Linda Baumann, PhD, RN;
Kirsten B ibbins-D om ingo, PhD, MD, MAS; Mark Ebell, MD,
MS; Jessica Herzstein, MD, MPH; M ichael LeFevre, MD, MSPH;
and D ouglas Owens, MD, MS.
Grant Support: By the AHRQ (contract 290-2012-00015-1, Task
O rd e r 2), Rockville, Maryland.
Disclosures: Drs. Nelson, Fu, Cantor, and Hum phrey; Ms. Pap­
pas; and Ms. Daeges re p o rt grants from AHRQ du rin g the
con du ct o f the study. A uthors not nam ed here have disclosed
no conflicts o f interest. Disclosures can also be view ed at www
.a cp o n lin e .o rg /a u th o rs/icm je /C o n flictO fln te re stF o rrn s.d o ? m s
N um =M 15-0969.
Requests for Single Reprints: Heidi D. Nelson, MD, MPH, O r­
egon Health & Science University, 3181 SW Sam Jackson Park
Road, Mail C ode BICC, Portland, OR 97239; e-mail, nelsonh
@ohsu.edu.
C urrent author addresses and author con tribu tions are avail­
able at w w w .annals.org.
R eferences
1. U.S. Preventive Services Task Force. Screening for breast cancer:
U.S. Preventive Services Task Force recommendation statement. Ann
Intern Med. 2009;151:716-26. [PMID: 19920272] doi:10.7326/0003
-4819-151-10-200911170-00008
2. Nelson HD, Tyne K, Naik A, Bougatsos C, Chan BK, Humphrey L;
U.S. Preventive Services Task Force. Screening for breast cancer: an
update for the U.S. Preventive Services Task Force. Ann Intern Med.
2009;151:727-37. [PMID: 19920273] doi:10.7326/0003-4819-151
-10-200911170-00009
3. Nelson HD, Weerasinghe R, Wang L, Grunkemeier G. Mammog­
raphy screening in a large health system following the U.S. Preven­
tive Services Task Force Recommendations and the Affordable Care
Act. PLoS One. 2015;10:e0131903. [PMID: 26121485] doi: 10.1371
/journal.pone.0131903.
4. National Center for Health Statistics. Tables 83 (page 1 of 3). Use
of mammography among women aged 40 and over, by selected
characteristics: United States, selected years 1987-2010. Accessed at
www.cdc.gov/nchs/data/hus/2013/083.pdf on November 23, 2015.
5. Block LD, Jarlenski MP, Wu AW, Bennett WL. Mammography use
among women ages 40-49 after the 2009 U.S. Preventive Services
Task Force recommendation. J Gen Intern Med. 2013;28:1447-53.
[PMID: 23674077] doi:10.1007/s11606-013-2482-5
6. National Committee for Quality Assurance. State of Health Care
Quality: Breast Cancer Screening.). Accessed atwww.ncqa.org
/ReportCards/HealthPlans/StateofHealthCareQuality/2015Tableof
Contents/BreastCancer.aspx on November 23, 2015.
7. Nelson HD, Cantor A, Humphrey L, Fu R, Pappas M, Daeges M,
et al. Screening for Breast Cancer: A Systematic Review to Update
the 2009 U.S. Preventive Services Task Force Recommendation. Ev­
idence Synthesis No. 124. AHRQ Publication No. 14-05201-EF-1.
Rockville, MD: Agency for Healthcare Research and Quality;
2015. Accessed at www.uspreventiveservicestaskforce.org/Page
/Document/draft-evidence-review-screening-for-breast-cancer/breast
-cancer-screeningl on 22 April 2014.
www.annals.org
Effectiveness of Breast Cancer Screening
8. M elnikow J, Fenton JJ, M ig lio retti D, W hitlo ck E, W eyrich M.
Screening for Breast Cancer W ith Digital Breast Tomosynthesis. Evi­
dence Synthesis No. 125. AHRQ Publication No. 14-05201-EF-2.
Rockville, MD: A gency fo r Healthcare Research and Quality; 2015.
9. M elniko w J, Fenton JJ, W hitlo ck E, M ig lio re tti D, W eyrich M,
Thom pson J, et al. Adjunctive Screening fo r Breast Cancer in
W om en W ith Dense Breasts: A Systematic Review fo r the U.S. Pre­
ventive Services Task Force. Evidence Synthesis No. 126. AHRQ Pub­
lication No. 14-05201-EF-2. Rockville, MD: Agency fo r Healthcare Re­
search and Quality; 2015.
10. Harris RP, Helfand M, W o o lf SH, Lohr KN, M ulrow CD, Teutsch
SM, et al; M ethods W ork Group, Third US Preventive Services Task
Force. Current m ethods o f the US Preventive Services Task Force: a
review o f the process. Am J Prev Med. 2001;20:21-35. [PMID:
11306229]
11. U.S. Preventive Services Task Force. Procedure Manual. Rock­
ville, MD: Agency fo r Healthcare Research and Quality; 2011.
12. Nelson HD, Zakher B, Cantor A, Fu R, G riffin J, O 'M eara ES, et al.
Risk factors fo r breast cancer fo r w om en aged 40 to 49 years: a
systematic review and meta-analysis. Ann Intern Med. 2012; 156:635-
48. [PMID: 22547473] d o i:1 0.7326/0003-4819-156-9-201205010
-00006
13. Hardy RJ, Thom pson SG. A likelihood approach to meta-analysis
with random effects. Stat Med. 1996;15:619-29. [PMID: 8731004]
14. H iggins JP, Thom pson SG, Deeks JJ, Altm an DG. Measuring
inconsistency in meta-analyses. BMJ. 2003;327:557-60. [PMID:
12958120]
15. M iller AB, W all C, Baines CJ, Sun P, To T, Narod SA. Twenty five
year fo llo w -u p fo r breast cancer incidence and m ortality o f the Ca­
nadian National Breast Screening Study: random ised screening trial.
BMJ. 2014;348:g366. [PMID: 24519768] do i:1 0.1136/bm j.g366
16. Tabar L, Vitak B, Chen TH, Yen AM , Cohen A, T ot T, et al. Swed­
ish tw o-county trial: im pact o f m am m ographic screening on breast
cancer m ortality during 3 decades. Radiology. 2011;260:658-63.
[PMID: 21712474] d o i:1 0.114 8 /ra d io l.1 1110469
17. Shapiro S, Venet W, Strax P, Venet L, Roeser R. Ten- to fourteen-
year effect o f screening on breast cancer mortality. J Natl Cancer
Inst. 1982;69:349-55. [PMID: 6955542]
18. M iller AB, Baines CJ, To T, W all C. Canadian National Breast
Screening Study: 1. Breast cancer detection and death rates am ong
w om en aged 40 to 49 years. CMAJ. 1992;147:1459-76. [PMID:
1423087]
19. M iller AB, To T, Baines CJ, W all C. The Canadian National Breast
Screening Study-1: breast cancer m ortality after 11 to 16 years of
follow -up. A random ized screening trial o f m am m ography in wom en
age 40 to 49 years. Ann Intern Med. 2002;137:305-12. [PMID:
12204013]
20. M iller AB, Baines CJ, To T, W all C. Canadian National Breast
Screening Study: 2. Breast cancer detection and death rates am ong
w om en aged 50 to 59 years. CMAJ. 1992;147:1477-88. [PMID:
1423088]
21. M iller AB, To T, Baines CJ, W all C. Canadian National Breast
Screening Study-2: 13-year results o f a random ized trial in wom en
aged 50-59 years. J Natl Cancer Inst. 2000;92:1490-9. [PMID:
10995804]
22. Moss SM, Cuckle H, Evans A, Johns L, W aller M, B obrow L; Trial
M anagem ent Group. Effect o f m am m ographic screening from age
40 years on breast cancer m ortality at 10 years' follow -up: a
random ised controlled trial. Lancet. 2006;368:2053-60. [PMID:
17161727]
23. Frisell J, Lidbrink E, Hellstrom L, Rutqvist LE. Followup after 11
y e a rs -u p d a te o f m ortality results in the Stockholm m am m ographic
screening trial. Breast Cancer Res Treat. 1997;45:263-70. [PMID:
9386870]
24. Andersson I, Aspegren K, Janzon L, Landberg T, Lindholm K,
Linell F, et al. M am m ographic screening and m ortality from breast
cancer: the M alm o m am m ographic screening trial. BMJ. 1988;297:
943-8. [PMID: 3142562]
w w w .a n n a ls .o rg
R eview
25. Bjurstam N, Bjorneld L, W arwick J, Sala E, Duffy SW, Nystrom L,
et al. The G othenburg Breast Screening Trial. Cancer. 2003;97:2387-
96. [PMID: 12733136]
26. Tabar L, Fagerberg G, Chen HH, Duffy SW, Smart CR, Gad A,
et al. Efficacy o f breast cancer screening by age. New results from
th e Swedish Two-C ounty Trial. Cancer. 1995;75:2507-17. [PMID:
7736395]
27. Moss SM, W ale C, Smith R, Evans A, Cuckle H, Duffy SW. Effect of
m am m ographic screening from age 40 years on breast cancer m or­
tality in the UK A ge trial at 17 years' follow -up: a random ised con­
tro lle d trial. Lancet Oncol. 2015; 16:1123-32. [PMID: 26206144] doi:
10.1016/S1470-2045(15)00128-X.
28. Alexander FE, Anderson TJ, Brown HK, Forrest AP, Hepburn W,
Kirkpatrick AE, et al. 14 years o f follow -up from the Edinburgh ran­
dom ised trial o f breast-cancer screening. Lancet. 1999;353:1903-8.
[PMID: 10371567]
29. Habbem a JD, van Oortmarssen GJ, van Putten DJ, Lubbe JT,
van d e r Maas PJ. Age-specific reduction in breast cancer m ortality
by screening: an analysis o f the results o f the Health Insurance Plan
o f G reater New York study. J Natl Cancer Inst. 1986;77:317-20.
[PMID: 3461193]
30. Nystrom L, Andersson I, Bjurstam N, Frisell J, N ordenskjold B,
Rutqvist LE. Long-term effects o f m am m ography screening: updated
overview o f the Swedish random ised trials. Lancet. 2002;359:909-19.
[PMID: 11918907]
31. N jor S, Nystrom L, Moss S, Paci E, Broeders M, Segnan N, et al;
Euroscreen W orkin g Group. Breast cancer m ortality in m am m o­
graphic screening in Europe: a review o f incidence-based m ortality
studies. J Med Screen. 2012;19 Suppl 1:33-41. [PMID: 22972809]
32. Moss SM, Nystrom L, Jonsson H, Paci E, Lynge E, N jor S, et al;
Euroscreen W orking Group. The im pact o f m am m ographic screen­
ing on breast cancer m ortality in Europe: a review o f trend studies.
J Med Screen. 2012;19 Suppl 1:26-32. [PMID: 22972808]
33. Broeders M, Moss S, Nystrom L, N jor S, Jonsson H, Paap E, et al;
EUROSCREEN W orkin g Group. The im pact o f m am m ographic
screening on breast cancer m ortality in Europe: a review o f observa­
tional studies. J M ed Screen. 2012; 19 Suppl 1:14-25. [PMID:
22972807]
34. Harris R, Yeatts J, Kinsinger L. Breast cancer screening for
wom en ages 50 to 69 years a systematic review o f observational
evidence. Prev Med. 2011 ;53:108-14. [PMID: 21820465] d o i:1 0.1016/j
.ypm ed.2011.07.004
35. Jorgensen KJ, Zahl PH, Gotzsche PC. Breast cancer m ortality in
organised m am m ography screening in Denmark: com parative
study. BMJ. 2010;340:c1241. [PMID: 20332505] do i:10.1136/bm j
,c1241
36. O tto SJ, Fracheboud J, Looman CW, Broeders MJ, Boer R, Hen­
driks JH, et al; National Evaluation Team fo r Breast Cancer Screen­
ing. Initiation o f population-based m am m ography screening in
Dutch municipalities and effect on breast-cancer mortality: a system­
atic review. Lancet. 2003;361:1411-7. [PMID: 12727393]
37. O tten JD, Broeders MJ, Fracheboud J, O tto SJ, de Koning HJ,
Verbeek AL. Impressive tim e-related influence o f the Dutch screen­
ing program m e on breast cancer incidence and m ortality, 1975-
2006. Int J Cancer. 2008;123:1929-34. [PMID: 18688863] doi:10
.1002/ijc.23736
38. Pons-Vigues M, Puigpinos R, Cano-Serral G, M ari-D ell'O lm o M,
Borrell C. Breast cancer m ortality in Barcelona follow ing im plem en­
tation o f a city breast cancer-screening program . Cancer Detect Prev.
2008;32:162-7. [PMID: 18639990] doi:10.1016/j.cdp.2008.05.002
39. Cabanes A, Vidal E, Perez-Gomez B, Aragones N, Lopez-Abente
G, Pollan M. Age-specific breast, uterine and ovarian cancer m ortal­
ity trends in Spain: changes from 1980 to 2006. Cancer Epidemiol.
2009;33:169-75. [PMID: 19766076] doi:10.1016/j.canep.2009.08
.010
40. Barchielli A, Paci E. Trends in breast cancer mortality, incidence,
and survival, and m am m ographic screening in Tuscany, Italy. Cancer
Causes Control. 2001; 12:249-55. [PMID: 11405330]
41. G orini G, Zappa M, Miccinesi G, Paci E, Costantini AS. Breast
cancer m ortality trends in tw o areas o f the province o f Florence, Italy,
Annals of Internal Medicine • Vol. 164 No. 4 • 16 February 2016 253
 R ev ie w
where screening programmes started in the 1970s and 1990s.
Br J Cancer. 2004;90:1780-3. [PMID: 15150601]
42. Ascunce EN, Moreno-lribas C, Barcos Urtiaga A, Ardanaz E, Ed-
erra Sanz M, Castilla J, et al. Changes in breast cancer mortality in
Navarre (Spain) after introduction of a screening programme. J Med
Screen. 2007;14:14-20. [PMID: 17362566]
43. Haukka J, Byrnes G, Boniol M, Autier P. Trends in breast cancer
mortality in Sweden before and after implementation of mammog­
raphy screening. PLoS One. 2011 ;6:e22422. [PMID: 21966354] doi:
10.1371/journal.pone.0022422
44. Blanks RG, Moss SM, McGahan CE, Quinn MJ, Babb PJ. Effect of
NHS breast screening programme on mortality from breast cancer in
England and Wales, 1990-8: comparison of observed with predicted
mortality. BMJ. 2000;321:665-9. [PMID: 10987769]
45. Duffy SW, Tabar L, Olsen AH, Vitak B, Allgood PC, Chen TH,
et al. Absolute numbers of lives saved and overdiagnosis in breast
cancer screening, from a randomized trial and from the Breast
Screening Programme in England. J Med Screen. 2010;17:25-30.
[PMID: 20356942] doi:10.1258/jms.2009.009094
46. Autier P, Boniol M, Gavin A, Vatten LJ. Breast cancer mortality in
neighbouring European countries with different levels of screening
but similar access to treatment: trend analysis of WHO mortality da­
tabase. BMJ. 2011 ;343:d4411. [PMID: 21798968] doi:10.1136/bmj
,d4411
47. Hakama M, Pukkala E, Heikkila M, Kallio M. Effectiveness of the
public health policy for breast cancer screening in Finland: popula­
tion based cohort study. BMJ. 1997;314:864-7. [PMID: 9093096]
48. Olsen AH, Njor SH, Vejborg I, Schwartz W, Dalgaard P, Jensen
MB, et al. Breast cancer mortality in Copenhagen after introduction
of mammography screening: cohort study. BMJ. 2005:330:220.
[PMID: 15649904]
49. Sarkeala T, Heinavaara S, Anttila A. Breast cancer mortality with
varying invitational policies in organised mammography. Br J Can­
cer. 2008;98:641-5. [PMID: 18231108] doi:10.1038/sj.bjc.6604203
50. Paci E, Giorgi D, Bianchi S, Vezzosi V, Zappa M, Crocetti E, et al.
Assessment of the early impact of the population-based breast can­
cer screening programme in Florence (Italy) using mortality and sur­
rogate measures. Eur J Cancer. 2002;38:568-73. [PMID: 11872351]
51. Kalager M, Zelen M, Langmark F, Adami HO. Effect of screening
mammography on breast-cancer mortality in Norway. N Engl J Med.
2010;363:1203-10. [PMID: 20860502] doi:10.1056/NEJMoa1000727
52. Swedish Organised Service Screening Evaluation Group. Reduc­
tion in breast cancer mortality from organized service screening with
mammography: 1. Further confirmation with extended data. Cancer
Epidemiol Biomarkers Prev. 2006;15:45-51. [PMID: 16434585]
53. Gabe R, Tryggvadottir L, Sigfusson BF, Olafsdottir GH, Sig-
urdsson K, Duffy SW. A case-control study to estimate the impact of
the Icelandic population-based mammography screening program
on breast cancer death. Acta Radiol. 2007;48:948-55. [PMID:
18080359]
54. Puliti D, Miccinesi G, Collina N, De Lisi V, Federico M, Ferretti S,
et al; IMPACT Working Group. Effectiveness of service screening: a
case-control study to assess breast cancer mortality reduction. Br
J Cancer. 2008;99:423-7. [PMID: 18665188] doi:10.1038/sj.bjc
.6604532
55. Otto SJ, Fracheboud J, Verbeek AL, Boer R, Reijerink-Verheij JC,
Otten JD, et al; National Evaluation Team for Breast Cancer Screen­
ing. Mammography screening and risk of breast cancer death: a
population-based case-control study. Cancer Epidemiol Biomarkers
Prev. 2012;21:66-73. [PMID: 22147362] doi:10.1158/1055-9965.EPI
-11-0476
56. van Schoor G, Moss SM, Otten JD, Donders R, Paap E, den
Heeten GJ, et al. Increasingly strong reduction in breast cancer mor­
tality due to screening. Br J Cancer. 2011;104:910-4. [PMID:
21343930] doi: 10.1038/bjc.2011.44
57. Allgood PC, Warwick J, Warren RM, Day NE, Duffy SW. A case-
control study of the impact of the East Anglian breast screening pro­
gramme on breast cancer mortality. Br J Cancer. 2008;98:206-9.
[PMID: 18059396]
254 Annals of'Intemal Medicine • Vol. 164 No. 4 • 16 F e b ru a ry 2016
Effectiveness of Breast Cancer Screening
58. Fielder HM, Warwick J, Brook D, Gower-Thomas K, Cuzick J,
Monypenny I, et al. A case-control study to estimate the impact on
breast cancer death of the breast screening programme in Wales.
J Med Screen. 2004;11:194-8. [PMID: 15563774]
59. Hellquist BN, Duffy SW, Abdsaleh S, Bjorneld L, Bordas P, Tabar
L, et al. Effectiveness of population-based service screening with
mammography for women ages 40 to 49 years: evaluation of the
Swedish Mammography Screening in Young Women (SCRY) cohort.
Cancer. 2011;117:714-22. [PMID: 20882563] doi:10.1002/cncr
.25650
60. Hofvind S, Skaane P. Stage distribution of breast cancer diag­
nosed before and after implementation of population-based mam-
mographicscreening. Rofo. 2012;184:437-42. [PMID: 22426937] doi:
10.1055/s-0031-1299352
61. Hofvind S, Ursin G, Tretli S, Sebuodegard S, Mailer B. Breast
cancer mortality in participants of the Norwegian Breast Cancer
Screening Program. Cancer. 2013;119:3106-12. [PMID: 23720226]
doi: 10.1002/cncr.28174
62. Mook S, Van't Veer LJ, Rutgers EJ, Ravdin PM, van de Velde AO,
van Leeuwen FE, et al. Independent prognostic value of screen de­
tection in invasive breast cancer. J Natl Cancer Inst. 2011; 103:585-
97. [PMID: 21350218] doi: 10.1093/jnci/djr043
63. Coldman A, Phillips N, Wilson C, Decker K, Chiarelli AM, Brisson
J, et al. Pan-Canadian study of mammography screening and mor­
tality from breast cancer. J Natl Cancer Inst. 2014; 106. [PMID:
25274578] doi: 10.1093/jnci/dju261
64. Schonberg MA, Silliman RA, Marcantonio ER. Weighing the ben­
efits and burdens of mammography screening among women age
80 years or older. J Clin Oncol. 2009;27:1774-80. [PMID: 19255318]
doi:10.1200/JC0.2008.19.9877
65. Aron JL, Prorok PC. An analysis of the mortality effect in a breast
cancer screening study. Int J Epidemiol. 1986;15:36-43. [PMID:
3957541]
66. Coldman AJ, Phillips N, Olivotto IA, Gordon P, Warren L, Kan L.
Impact of changing from annual to biennial mammographic screen­
ing on breast cancer outcomes in women aged 50-79 in British Co­
lumbia. J Med Screen. 2008;15:182-7. [PMID: 19106258] doi:10
.1258/jms.2008.008064
67. Parvinen I, Chiu S, Pylkkanen L, Klemi P, Immonen-Raiha P,
Kauhava L, et al. Effects of annual vs triennial mammography interval
on breast cancer incidence and mortality in ages 40-49 in Finland.
Br J Cancer. 2011;105:1388-91. [PMID: 21934688] doi:10.1038/bjc
.2011.372
68. Chu KC, Smart CR, Tarone RE. Analysis of breast cancer mortality
and stage distribution by age for the Health Insurance Plan clinical
trial. J Natl Cancer Inst. 1988;80:1125-32. [PMID: 3411625]
69. Duffy SW, Tabar L, Vitak B, Yen MF, Warwick J, Smith RA, et al.
The Swedish Two-County Trial of mammographic screening: cluster
randomisation and end point evaluation. Ann Oncol. 2003; 14:
1196-8. [PMID: 12881376]
70. Moss S, Thomas I, Evans A, Thomas B, Johns L; Trial Manage­
ment Group. Randomised controlled trial of mammographic screen­
ing in women from age 40: results of screening in the first 10 years.
Br J Cancer. 2005;92:949-54. [PMID: 15726102]
71. Edge S, Byrd DR, Compton C, Fritz AG, Greene FL, Trotti A.
AJCC Cancer Staging Manual. 7th ed. New York: Springer Publish­
ing; 2010.
72. Autier P, Hery C, Haukka J, Boniol M, Byrnes G. Advanced breast
cancer and breast cancer mortality in randomized controlled trials on
mammography screening. J Clin Oncol. 2009;27:5919-23. [PMID:
19884547] doi: 10.1200/JC0.2009.22.7041
73. Buseman S, Mouchawar J, Calonge N, Byers T. Mammography
screening matters for young women with breast carcinoma: evi­
dence of downstaging among 42-49-year-old women with a history
of previous mammography screening. Cancer. 2003;97:352-8.
[PMID: 12518359]
74. Garcia Fernandez A, Chabrera C, Garcia Font M, Fraile M, Lain
JM, Gonzalez S, et al. Mortality and recurrence patterns of breast
cancer patients diagnosed under a screening programme versus
comparable non-screened breast cancer patients from the same
w w w .a n n a ls .o rg
Effectiveness of Breast Cancer Screening
population: analytical survey from 2002 to 2012. T um our Biol. 2014;
35:1945-53. [PMID: 24114015] doi: 10.1007/s13277-013-1260-7
75. Jensen AR, G am e JP, Storm HH, Ewertz M, Cold S, Alvegaard T,
et al. Stage and survival in breast cancer patients in screened and
non-screened Danish and Swedish populations. Acta Oncol. 2003;
42:701-9. [PMID: 14690155]
76. O liv o tto IA, Mates D, Kan L, Fung J, Samant R, Burhenne LJ.
Prognosis, treatm ent, and recurrence o f breast cancer fo r wom en
attending or not attending the Screening M am m ography Program
o f British Colum bia. Breast Cancer Res Treat. 1999;54:73-81. [PMID:
10369083]
77. Olsson A, G am e JP, T engrup I, Zackrisson S, M anjer J. O ver­
w e ig h t in relation to tu m o u r size and axillary lym ph node involve­
m ent in postmenopausal breast cancer patients-differences between
w om en invited to vs. not invited to m am m ography in a random ized
screening trial. Cancer Epidem iol. 2009;33:9-15. [PMID: 19679041]
doi: 10.1016/j.canep.2009.04.008
78. Gotzsche PC, Jorgensen KJ. Screening fo r breast cancer with
m am m ography. Cochrane Database Syst Rev. 2013;6:CD001877.
[PMID: 23737396] d o i:1 0.1002/14651858.CD001877.pub5
79. Dittus K, G eller B, W eaver DL, Kerlikowske K, Zhu W, Plubbard R,
et al; Breast Cancer Surveillance Consortium . Im pact o f m am m ogra­
phy screening interval on breast cancer diagnosis by menopausal
status and BMI. J Gen Intern Med. 2013;28:1454-62. [PMID:
23760741 ] do i:1 0.1007/s11606-013-2507-0
80. Goel A, Littenberg B, Burack RC. The association between the
pre-diagnosis m am m ography screening interval and advanced
breast cancer. Breast Cancer Res Treat. 2007;102:339-45. [PMID:
16927175]
81. Plubbard RA, Kerlikowske K, Flowers Cl, Yankaskas BC, Zhu W,
M ig lio re tti DL. Cumulative pro ba bility o f false-positive recall or b i­
opsy recom m endation after 10 years o f screening m am m ography: a
coh ort study. Ann Intern Med. 2011;155:481-92. [PMID: 22007042]
doi: 10.7326/0003-4819-155-8-201110180-00004
www.annals.org
R eview
82. Kerlikowske K, Zhu W, Hubbard RA, Geller B, Dittus K, Braith-
w aite D, et al; Breast Cancer Surveillance Consortium . O utcom es o f
screening m am m ography by frequency, breast density, and post­
menopausal horm one therapy. JAM A Intern Med. 2013;173:807-16.
[PMID: 23552817] doi:10.1001/jam ainternm ed.2013.307
83. W hite E, M ig lio retti DL, Yankaskas BC, G eller BM, Rosenberg
RD, Kerlikowske K, et al. Biennial versus annual m am m ography and
the risk o f late-stage breast cancer. J Natl Cancer Inst. 2004;96:
1832-9. [PMID: 15601639]
84. Breast Screening Frequency Trial Group. The frequency o f breast
cancer screening: results from the UKCCCR Randomised Trial.
United Kingdom Co-ordinating C om m ittee on Cancer Research. Eur
J Cancer. 2002;38:1458-64. [PMID: 12110490]
85. Skaane P, Bandos Al, G ullien R, Eben EB, Ekseth U, Haakenaasen
U, et al. Com parison o f digital m am m ography alone and digital
m am m ography plus tomosynthesis in a population-based screening
program . Radiology. 2013;267:47-56. [PMID: 23297332] doi:10
.1148/radiol. 12121373
86. Rose SL, Tidw ell AL, Bujnoch LJ, Kushwaha AC, N ordm ann
AS, Sexton R Jr. Im plem entation o f breast tomosynthesis in a
routine screening practice: an observational study. AJR Am J
Roentgenol. 2013;200:1401-8. [PMID: 23701081] doi:10.2214/AJR
.12.9672
87. Bleyer A, W elch HG. Effect o f three decades o f screening m am ­
m ography on breast-cancer incidence. N Engl J Med. 2012;367:
1998-2005. [PMID: 23171096] doi:10.1056/NEJM oa1206809
88. Lousdal ML, Kristiansen IS, M oller B, Stovring H. Trends in breast
cancer stage distribution before, during and after introduction o f a
screening program m e in Norway. Eur J Public Health. 2014;24:
1017-22. [PMID: 24596400] doi:10.1093/eurpub/cku015
89. A utie r P, Boniol M, M id dle ton R, Dore JF, Hery C, Zheng T, et al.
Advanced breast cancer incidence follow ing population-based
m am m ographic screening. Ann Oncol. 2011;22:1726-35. [PMID:
21252058] do i:1 0.1093/annonc/m dq633
Annals of Internal Medicine • Vol. 164 No. 4 • 16 February 2016 255
Copyright © American College of Physicians 2016.