Breast Cancer Res Treat (2014) 147:389399
DOI 10.1007/s10549-014-3088-2
EPIDEMIOLOGY
Digital compared to screen-film mammography: breast cancer
prognostic features in an organized screening program
Maegan V. Prummel Susan J. Done Derek Muradali Vicky Majpruz
Patrick Brown Hedy Jiang Rene S. Shumak Martin J. Yaffe
Claire M. B. Holloway Anna M. Chiarelli
Received: 2 April 2014 / Accepted: 27 July 2014 / Published online: 10 August 2014
Springer Science+Business Media New York 2014
Abstract Our previous study found cancer detection rates
were equivalent for direct radiography compared to screen-
film mammography, while rates for computed radiography
were significantly lower. This study compares prognostic
features of invasive breast cancers by type of mammog-
raphy. Approved by the University of Toronto Research
Ethics Board, this study identified invasive breast cancers
diagnosed among concurrent cohorts of women aged 5074
screened by direct radiography, computed radiography, or
screen-film mammography from January 1, 2008 to
December 31, 2009. During the study period, 816,232
mammograms were performed on 668,418 women, and
3,323 invasive breast cancers were diagnosed. Of 2,642
eligible women contacted, 2,041 participated (77.3 %).
The final sample size for analysis included 1,405 screen-
detected and 418 interval cancers (diagnosed within
24 months of a negative screening mammogram). Polyt-
omous logistic regression was performed to evaluate the
M. V. Prummel (&)  D. Muradali  V. Majpruz  P. Brown 
H. Jiang  R. S. Shumak  A. M. Chiarelli
Prevention and Cancer Control, Cancer Care Ontario, 620
University Avenue, Toronto, ON M5G 2L7, Canada
e-mail: maeganvictoria.prummel@cancercare.on.ca
S. J. Done
Campbell Family Institute for Breast Cancer Research,
University Health Network, Toronto, Canada
S. J. Done  P. Brown  C. M. B. Holloway  A. M. Chiarelli
University of Toronto, Toronto, Canada
M. J. Yaffe
Imaging Research, Sunnybrook Health Sciences Centre,
Toronto, Canada
C. M. B. Holloway
Sunnybrook Health Sciences Centre, Toronto, Canada
association between tumour characteristics and type of
mammography, and between tumour characteristics and
detection method. Odds ratios (OR) and 95 % confidence
intervals (CI) were recorded. Cancers detected by com-
puted radiography compared to screen-film mammography
were significantly more likely to be lymph node positive
(OR 1.94, 95 %CI 1.013.73) and have higher stage (II:I,
OR 2.14, 95 %CI 1.114.13 and III/IV:I, OR 2.97, 95 %CI
1.028.59). Compared to screen-film mammography, sig-
nificantly more cancers detected by direct radiography (OR
1.64, 95 %CI 1.122.38) were lymph node positive.
Interval cancers had worse prognostic features compared to
screen-detected cancers, irrespective of mammography
type. Screening with computed radiography may lead to the
detection of cancers with a less favourable stage distribu-
tion compared to screen-film mammography that may
reflect a delayed diagnosis. Screening programs should re-
evaluate their use of computed radiography for breast
screening.
Keywords Digital mammography  Computed
radiography  Direct radiography  Prognostic features 
Stage  Tumour size  Grade  Hormone receptor status
Introduction
Early detection of breast cancer by screen-film mammog-
raphy has been shown to reduce mortality [1, 2]. Recently,
digital mammography has received attention as a poten-
tially improved imaging device compared to screen-film
mammography. There are two main types of digital mam-
mography: direct radiography, an on-line system with a
built in detector, and computed radiography, an off-line
system that uses a cassette-based detector and requires an
123
390
external reading device. Randomized trials and concurrent
cohort studies have shown that breast cancer detection rates
for direct radiography are equivalent to screen-film mam-
mography or significantly higher, particularly among young
women with dense breasts [316], while cancer detection
for computed radiography is significantly lower [16, 17].
A more complete investigation of the benefits of digital
compared to screen-film mammography is to examine the
prognostic features of invasive breast cancers detected by
each screening modality. Previous concurrent cohort
studies have shown that the characteristics of tumours
detected by direct radiography versus screen-film mam-
mography are equivalent [810, 15], or significantly more
favourable for direct radiography (e.g. more likely to
diagnose cancers at a lower grade [1113], with smaller
tumour size [13, 14, 18], and lymph node negative status
[13]). More recent concurrent cohort studies found direct
radiography was significantly more likely to diagnose
cancers that are high grade [17], and lymph node positive
[19] compared to screen-film mammography.
Our recent study [16] as well as another study [17]
found computed radiography had significantly lower cancer
detection compared to screen-film mammography. Only
two studies have examined prognostic features of cancers
detected by computed radiography, one found they were
similar in size compared to those detected by direct radi-
ography [20], the other found they were similar in size and
nodal status but more likely to detect cancers at higher
grade compared to screen-film mammography [17].
Given the lower cancer detection rate with computed
radiography [16, 17], it is likely that this technology may
be missing small early stage cancers, or may be associated
with a higher interval cancer rate. Only one study com-
pared the prognostic features of interval cancers following
direct radiography compared to screen-film mammography
and found the characteristics were similar [21]. No studies
to date have examined prognostic features of interval
cancers following computed radiography. This paper aims
to elucidate the impact of lower cancer detection rates on a
cohort of women screened with computed radiography
compared to screen-film. In particular, the objective is to
explore differences in prognostic features of invasive
screen-detected and interval breast cancers by type of
mammography among large concurrent cohorts of women
screened in the Ontario Breast Screening Program (OBSP).
Methods
Study population
This study, approved by the University of Toronto
Research Ethics Board, identified three concurrent cohorts
123
Breast Cancer Res Treat (2014) 147:389399
of women aged 5074 screened with screen-film mam-
mography, direct radiography or computed radiography
between January 1, 2008 and December 31, 2009, from
information routinely collected by the OBSP. Women were
followed prospectively until diagnosis of breast cancer or
their next screening exam. A complete description of the
methods used to identify the cohort of screened women
(n = 688,418) has been published [16]. In the previous
study, we compared screening performance measures by
type of mammography for the entire cohort. This study
examines the prognostic features among a subset of the
screening cohort (n = 3,323) who were diagnosed with
invasive breast cancer.
The OBSP has operated since 1990 to deliver a popu-
lation-based screening program and offers eligible women
biennial screening with mammography consisting of cra-
niocaudal and mediolateral oblique views performed by
certified mammography technologists [22]. Women are not
eligible if they have a prior history of breast cancer or
augmentation mammoplasty or if they currently have
symptoms of breast disease. Equipment meets or exceeds
quality standards specified by the Canadian Association of
Radiologists Mammography Accreditation Program. All
radiologists in the OBSP (455 during the study period) are
accredited by this program, and must meet program stan-
dards by reading a minimum of 1,000 mammograms per
year. The monthly and annual volume of screens did not
differ by screening modality. Films are read once in batch
by a radiologist who can refer to previous film images.
Of the 146 OBSP screening centres during the study
period, 83 (56.8 %) provided screen-film mammography,
28 (19.9 %) digital mammography and 35 (23.3 %) centres
switched from screen-film to digital. Of the 63 centres that
offered digital, 44 operated direct radiography systems, 18
computed radiography and 1 both. Details on the types of
machines used by OBSP centres have been published [16].
Selection of breast cancer cases
All women diagnosed with primary invasive breast cancer
of any histological type in the Ontario Cancer Registry
were identified. Type of mammogram (screen-film, direct
radiography or computed radiography) was assigned based
on the screening examination by the OBSP centre pre-
ceding diagnosis of breast cancer. Women with an abnor-
mal digital or screen-film mammogram leading to
diagnostic assessment and a diagnosis of invasive breast
cancer within 12 months of their last screening examina-
tion were classified as having a screen-detected breast
cancer. Interval cancers were defined as breast cancers
diagnosed within 24 months of a benign mammogram
result. Cancers were further classified by whether the
Breast Cancer Res Treat (2014) 147:389399
cancer was detected or missed on the initial screen or on a
rescreen (subsequent screen).
Of 816,232 mammograms performed on 688,418 eligi-
ble women, 487,334 (59.7 %) were screen-film, 254,758
(31.2 %) direct radiography and 74,140 (9.1 %) computed
radiography. Of 3,323 women diagnosed with invasive
breast cancer from women screened during the study per-
iod, 2,642 (79.5 %) were alive and were able to be con-
tacted, of which, a total of 2,041 women (77.3 %)
consented to participate.
Definition of demographic and risk factor
characteristics
Demographic and risk factor information prior to diag-
nosis was collected by a telephone-administered ques-
tionnaire within 26 years of their last screening
examination. Approximately 2 weeks prior to being con-
tacted by phone, eligible women were sent a copy of the
questionnaire. Having the questionnaire in advance
allowed respondents time to recall dates and check
records, prior to being interviewed. Interviews were
conducted by specially trained interviewers and required
2030 min.
For calculation of body mass index, women were asked
to recall their height and weight at the time of their last
screening examination. Women were classified as having
benign breast disease if they answered yes to both of the
following questions, Has a doctor ever told you that you
had benign breast disease (non-cancerous cyst or breast
lump) that was not breast cancer, and Did you have a
breast biopsy to find your benign breast disease. If par-
ticipants reported at least one blood relative with breast or
ovarian cancer, they were classified as having a family
history. Women were classified as pre-menopausal if they
had a menstrual period within 12 months of their last
screening examination. For hormone therapy use, women
were asked, Have you ever taken hormone therapy pre-
scribed by a doctor for at least 3 months. If no, women
were classified as never users of hormone therapy. If
yes, the age that a woman started and stopped using
hormone therapy was recorded. Women were classified as
current users if they used hormone therapy within 1 year
of their last screening examination, and former users if they
stopped using hormone therapy more than 1 year prior to
their last screening examination. Time since former use of
hormone therapy was defined as the number of years
between last hormone therapy use and last screening
examination ([110 years, or [10 years). Women were
defined as current alcohol users if, at the time of the
interview, they were consuming alcohol at least once a
week, and current smokers if they were smoking at least
one cigarette per day.
391
Prognostic characteristics of invasive breast cancers
Tumour characteristics and age at diagnosis were collected
from surgical and pathological reports obtained from the
Ontario Cancer Registry. Reports were reviewed by a
specially trained abstractor and overseen by a reference
breast pathologist (S. J. Done). Tumour size was defined as
the diameter (in centimetres) of the largest invasive car-
cinoma. Lymph node status was defined as positive if at
least one sentinel or other lymph node contained malignant
cells. Cases with only isolated tumour cells were consid-
ered lymph node negative.
Stage was coded using the TNM classification scheme
[23]. T and N criteria were obtained directly from surgical
or pathological reports, while M was obtained from the
Ontario Cancer Registry. In a small proportion of cases
where M was missing from the Ontario Cancer Registry
(6 %), if the patient was lymph node negative or lymph
node positive with micrometastases or macrometastases in
13 axillary lymph nodes they were coded as having no
distant metastasis, otherwise M and overall stage of the
cancer was coded as missing. Tumours were graded using
the Nottingham combined histologic grading system [24].
Oestrogen, progesterone and HER2 protein receptors were
coded as positive or negative. If a patient was negative for
all three receptors they were coded as having a triple
negative breast cancer. Morphology was coded using the
International Classification of Diseases for Oncology ver-
sion 2.0 (ICD-O-2) [25].
Statistical analysis
Women screened with direct or computed radiography
were compared to women screened with screen-film on
tumour size (B2.0 versus [2.0), lymph nodes (positive
versus negative), stage (II and III/IV versus I), histologic
grade (2 and 3 versus 1), oestrogen, progesterone and
HER2 protein receptor (negative versus positive) and triple
negative status (yes versus no). Polytomous logistic
regression was performed to evaluate (i) the association
between tumour characteristic and type of mammography
stratified by detection method, and (ii) the association
between tumour characteristic and detection method strat-
ified by type of mammography. Analyses were adjusted for
age at last screen and tumour size (for models of grade,
hormone receptors, HER2 and triple negative). In the latter
analysis, only cancers detected after the initial screen were
examined to minimize over-diagnosis and length bias. As
additional analyses adjusting for benign breast disease to
evaluate its effect as a confounder did not alter the effect
estimates, final analyses are presented without adjustment
to increase study power and efficiency. Odds ratios (OR)
and corresponding 95 % confidence intervals (CI) were
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392 Breast Cancer Res Treat (2014) 147:389399

816,232 Screening Examinations

688,418 Women
3323 Invasive Breast Cancers

81 Ineligible due to death (2.4)

Eligible
n=3242 (97.6%)

Contacted
n=2642 (81.5%)

Consented to Participate
173 (8.5%) Missing
n=2041 (77.3%) pathological/surgical report

45 (2.2%) Ductal carcinoma in

situ upon pathological review
Final Cohort for Analysis
n=1823 (89.3%)

Screen-Detected Cancer Interval Cancer

n=1,405 (77.1%) n=418 (22.9%)

Screen-film Direct Computed Screen-Film Direct Computed

Mammography Radiography Radiography Mammography Radiography Radiography
832 (59.2%) 477 (34.0%) 96 (6.8%) 228 (54.5%) 149 (35.7%) 41 (9.8%)

Fig. 1 Cohort of Invasive Breast Cancers among women screened between January 01, 2008 and December 31, 2009 within the Ontario Breast
Screening Program

reported. All analyses were performed using SAS version
9.2 [26]. A two-tailed 5 % significance level was used for
statistical tests.
Results
Of 2,041 women with invasive cancers who agreed to
participate, 173 (8.5 %) had missing pathological or sur-
gical reports and 45 (2.2 %) were found to be ductal car-
cinoma in situ (DCIS) upon review of the reports (Fig. 1).
Final sample size for analysis included 1,405 screen-
detected cancers (832 screened with screen-film, 477 direct
radiography and 96 computed radiography), and 418
interval cancers (228 screened with screen-film, 149 direct
radiography and 41 computed radiography).
Risk factors for interval and screen-detected cancers
between each of the cohorts were similarly distributed
(Table 1). However, significantly fewer women with can-
cer detected by computed radiography were diagnosed
with benign breast disease (9.5 %) compared to direct
radiography (23.2 %) or screen-film mammography
(21.0 %) (P = 0.01). Adjusting for benign breast disease
as a confounder did not alter the effect estimates.
Among screen-detected cancers, a significantly greater
proportion of lymph node positive cancers was detected by
direct radiography (OR 1.64, 95 %CI 1.122.38, P value =
0.01) and computed radiography (OR 1.94, 95 %CI
1.013.73, P value = 0.04) compared to screen-film
(Table 2). Computed radiography also detected signifi-
cantly more cancers at a higher stage compared to screen-
film (stage III/IV vs. stage I: OR 2.97, 95 %CI 1.028.59,
P value = 0.04), and there was a trend towards detection
of cancers with larger tumour size at computed radiography
versus screen-film, although the association was not sta-
tistically significant.
There were no significant differences in the prognostic
features of interval cancers by type of mammography
(Table 3).
Interval cancers were significantly more likely to be
larger compared to rescreen cancers, irrespective of
mammography type (screen-film: OR 2.83, 95 %CI

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Breast Cancer Res Treat (2014) 147:389399 393

Table 1 Breast cancer risk factors for women with invasive screen-detected and interval cancers by type of mammography (N = 1,823)
Characteristic Screen-detected cancers Interval cancers
Screen-film Direct Computed Screen-film Direct Computed
mammography radiography radiography mammography radiography radiography
(n = 832) (n = 477) (n = 96) (n = 228) (n = 149) (n = 41)
n (%) n (%) n (%) n (%) n (%) n (%)

Age at diagnosis (years)

5059 313 (37.6) 185 (38.8) 30 (31.3) 105 (46.1) 48 (32.2) 20 (48.8)
6069 405 (48.7) 226 (47.4) 53 (55.2) 96 (42.1) 84 (56.4) 16 (39.0)
C70 114 (13.7) 66 (13.8) 13 (13.5) 27 (11.8) 17 (11.4) 5 (12.2)
Body mass index (kg/m2)*
\25 264 (32.3) 148 (31.6) 27 (28.1) 99 (44.0) 54 (36.2) 17 (41.5)
2529.9 289 (35.3) 163 (34.8) 29 (30.2) 76 (33.8) 59 (39.6) 9 (21.9)
C30 265 (32.4) 158 (33.7) 40 (41.7) 50 (22.2) 36 (24.2) 15 (36.6)
Education level*
\High school 103 (12.4) 56 (11.8) 14 (14.6) 21 (9.3) 21 (14.1) 3 (7.3)
High school 218 (26.2) 121 (25.6) 28 (29.2) 59 (26.1) 40 (26.8) 10 (24.4)
[High school 510 (61.4) 296 (62.6) 54 (56.2) 148 (64.9) 88 (59.1) 28 (68.3)
Benign breast disease**
No 654 (79.0) 365 (76.8) 86 (90.5) 182 (80.2) 116 (78.4) 30 (73.2)
Yes 174 (21.0) 110 (23.2) 9 (9.5) 45 (19.8) 32 (21.6) 11 (26.8)
Family History
No 600 (72.1) 346 (72.5) 72 (75.0) 161 (70.6) 111 (74.5) 30 (73.2)
Yes 232 (27.9) 131 (27.5) 24 (25.0) 67 (29.4) 38 (25.5) 11 (26.8)
Age at first birth (years)
Nulliparous 96 (11.9) 58 (12.7) 11 (11.6) 17 (7.8) 12 (8.3) 2 (5.3)
\30 591 (73.0) 339 (74.0) 69 (72.6) 170 (78.0) 105 (72.9) 32 (84.2)
C30 122 (15.1) 61 (13.3) 15 (15.8) 31 (14.2) 27 (18.8) 4 (10.5)
Age at menarche (years)
B11 149 (18.3) 102 (21.8) 23 (24.2) 39 (17.4) 29 (19.6) 11 (26.8)
[11 666 (81.7) 367 (78.2) 72 (75.8) 185 (82.6) 119 (80.4) 30 (73.2)
Menopausal Status*
Pre-menopausal 85 (10.2) 53 (11.1) 7 (7.3) 24 (10.6) 11 (7.4) 5 (12.5)
Peri/Post-menopausal 746 (89.8) 424 (88.9) 89 (92.7) 203 (89.4) 138 (92.6) 35 (87.5)
Hormone therapy
Never 488 (67.5) 273 (67.1) 55 (66.3) 131 (64.2) 73 (55.3) 21 (56.8)
Current 84 (11.6) 43 (10.6) 6 (7.2) 29 (14.2) 15 (11.4) 3 (8.1)
Former 151 (20.9) 91 (22.4) 22 (26.5) 44 (21.6) 44 (33.3) 13 (35.1)
Time Since using HRTa
Never 488 (76.4) 273 (75.0) 55 (71.4) 131 (74.9) 73 (62.4) 21 (61.8)
[1 year to 10 years 100 (15.7) 66 (18.1) 15 (19.5) 34 (19.4) 34 (29.1) 10 (29.4)
[10 years 51 (8.0) 25 (6.9) 7 (9.1) 10 (5.7) 10 (8.5) 3 (8.8)
Alcohol use
Never 427 (51.4) 241 (51.0) 43 (44.8) 116 (50.9) 65 (43.9) 21 (51.2)
Current 333 (40.1) 196 (41.4) 45 (46.9) 105 (46.0) 70 (47.3) 19 (46.3)
Former 70 (8.4) 36 (7.6) 8 (8.3) 7 (3.1) 13 (8.8) 1 (2.5)
Smoking
Never 411 (49.4) 234 (49.1) 49 (51.0) 130 (57.0) 73 (49.0) 19 (46.3)
Current 121 (14.5) 56 (11.7) 13 (13.5) 26 (11.4) 24 (16.1) 5 (12.2)

123
394
Table 1 continued
Characteristic Screen-detected cancers
Screen-film Direct
mammography radiography
(n = 832) (n = 477)
n (%) n (%)
Former 300 (36.1) 187 (39.2)
* At last screening examination
** P = 0.011 for screen-detected cancers
a
Among former users
1.844.36, P value \0.001; direct radiography: OR 3.78,
95 %CI 2.017.11, P value \0.001; computed radiogra-
phy: OR 4.29, 95 %CI 1.2814.40, P value = 0.02)
(Table 4). While there was a trend towards interval cancers
having a greater stage and grade at diagnosis compared to
rescreen cancers for all mammography types, the associa-
tion was only statistically significant for screen-film (stage
III/IV vs. I: OR 5.42, 95 %CI 2.5911.34, P value \0.001;
grade 3 versus 1: OR 1.96, 95 %CI 1.093.51,
P value = 0.02). For screen-film, interval cancers were
also significantly more likely than rescreen cancers to be
lymph node positive (OR 2.62, 95 %CI 1.684.09, P value
\0.001), while no trend was observed for direct or com-
puted radiography. For direct radiography, interval cancers
were significantly more likely than rescreen cancers to be
oestrogen receptor negative (OR 3.89, 95 %CI 1.768.61,
P value \0.001), progesterone receptor negative (OR 2.43,
95 %CI 1.254.74, P value = 0.01) and triple negative
(OR 5.49, 95 %CI 2.0814.49, P value \0.001). The same
trends were observed for screen-film and computed radi-
ography; however, the associations were not statistically
significant.
Discussion
Overall, this study found cancers detected by direct radi-
ography had equivalent stage, grade, hormone and HER2
receptor status, however, were more likely to be lymph
node positive compared to cancers detected by screen-film
mammography. Screening with computed radiography led
to the detection of a significantly higher proportion of stage
II or greater cancers compared to screen-film mammogra-
phy. This is an important finding and may suggest a
delayed diagnosis for these women.
Tumour size, stage, grade, hormone receptor, HER2
receptor and triple negative status were found to be similar
for cancers detected with direct radiography and screen-
film mammography. Consistently, other studies found
equivalent tumour size [810], grade [10] and triple
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Breast Cancer Res Treat (2014) 147:389399
Interval cancers
Computed Screen-film Direct Computed
radiography mammography radiography radiography
(n = 96) (n = 228) (n = 149) (n = 41)
n (%) n (%) n (%) n (%)
34 (35.4) 72 (31.6) 52 (34.9) 17 (41.5)
negative receptor status [13] for cancers detected by direct
radiography versus screen-film mammography. One study
found direct radiography detected significantly more grade
3 cancers versus 2 compared to screen-film [17], while two
others found more favourable prognostic features for can-
cers detected by direct radiography compared to screen-
film (e.g. higher proportion of low-grade oestrogen/pro-
gesterone receptor positive and HER2 receptor negative
cancers) [11, 13]. We found a similar trend as the latter two
for histologic grade; although not statistically significant.
Our study found that direct radiography detected sig-
nificantly more lymph node positive cancers compared to
screen-film mammography. A recent concurrent cohort
study had a similar finding, which was attributed in part to
a change in the methodology of recruitment of patients
[19]. Two other studies have reported this finding [27, 28];
both compared a current digital mammography cohort with
a historic screen-film mammography cohort and are
therefore limited by differences in radiologist experience
and/or technology over time. As tumour size and distri-
bution of stage were comparable for direct radiography and
screen-film mammography, this result warrants further
investigation.
There were no significant associations for grade, hor-
mone receptor, HER2 receptor and triple negative status
among cancers detected by computed radiography and
screen-film mammography; however, computed radiogra-
phy detected slightly more cancers with larger tumour size,
and a significantly greater proportion was lymph node
positive with greater stage at diagnosis. Ours is the first
study, to our knowledge, to examine stage distribution of
cancers among women screened by computed radiography
compared to screen-film mammography. This result may
be explained by the significantly lower cancer detection
rate reported in our earlier study, comparing performance
measures of computed radiography to screen-film mam-
mography [16]. This lower cancer detection rate was most
likely attributed to the substantially lower physical imaging
performance metrics found for computed radiography
compared to direct radiography [29]. It is plausible that
Breast Cancer Res Treat (2014) 147:389399 395

Table 2 Tumour characteristics and adjusted odds ratios with 95 % confidence intervals for invasive screen-detected cancers (n = 1,405)
Characteristics Screen-film mammography Direct radiography Adjusted OR Computed radiography Adjusted OR
N = 832 N = 477 (95 % CI) N = 96 (95 % CI)
n (%) n (%) n (%)

Tumour size at diagnosis, cma

B2.0 625 (75.5) 365 (77.5) 1.00 (reference) 64 (66.7) 1.00 (reference)
[2.0 203 (24.5) 106 (22.5) 0.91 (0.611.35) 32 (33.3) 1.71 (0.893.27)
Missing 4 6 0
Lymph nodesa
Negativea 627 (77.7) 324 (73.1) 1.00 (reference) 65 (68.4) 1.00 (reference)
Positive 179 (22.3) 119 (26.9) 1.64 (1.122.38)* 30 (31.6) 1.94 (1.013.73)
Missing 30 34 1
Stage at diagnosisa
I 533 (64.8) 289 (61.1) 1.00 (reference) 48 (50.5) 1.00 (reference)
II 240 (29.2) 144 (30.4) 1.22 (0.841.76) 38 (40.0) 2.14 (1.114.13)
III or IV 50 (6.1) 40 (8.5) 1.77 (0.923.40) 9 (9.5) 2.97 (1.028.59)
Missing 9 4 1
Histologic gradea
1 249 (30.7) 129 (28.2) 1.00 (reference) 29 (30.5) 1.00 (reference)
2 394 (48.6) 220 (48.1) 1.49 (0.972.22) 43 (45.3) 0.85 (0.411.77)
3 168 (20.7) 108 (23.6) 1.22 (0.742.00) 23 (24.2) 0.85 (0.352.03)
Missing 21 20 1
Oestrogen receptorb
Positive 527 (87.0) 275 (88.7) 1.00 (reference) 48 (85.7) 1.00 (reference)
Negative 79 (13.0) 35 (11.3) 0.78 (0.461.31) 8 (14.3) 1.09 (0.462.57)
Missing 226 167 40
Progesterone receptorb
Positive 474 (78.3) 240 (77.9) 1.00 (reference) 47 (83.9) 1.00 (reference)
Negative 131 (21.7) 68 (22.1) 0.84 (0.561.28) 9 (16.1) 0.64 (0.281.47)
Missing 227 169 40
HER2b
Positive 62 (12.6) 28 (11.8) 1.00 (reference) 11 (22.0) 1.00 (reference)
Negative 429 (87.4) 209 (88.2) 0.89 (0.531.52) 39 (78.0) 1.63 (0.743.62)
Missing 341 240 46
b
Triple negative
No 559 (93.8) 288 (95.4) 1.00 (reference) 53 (93.0) 1.00 (reference)
Yes 37 (6.2) 14 (4.6) 1.32 (0.672.60) 4 (7.0) 0.87 (0.292.59)
Missing 236 175 39
*
P value = 0.01; P value = 0.04; P value = 0.02
a
Adjusted for age at last screen (continuous), and whether the cancer was detected on an initial or rescreen
b
Adjusted for age at last screen (continuous), whether the cancer was detected on an initial or rescreen and tumour size (continuous)
a
lymph node negative includes cases with only isolated tumour cells

these cancers had a delayed diagnosis and were detected in
a subsequent screen. Two studies have examined pathology
of cancers detected by computed radiography, one com-
pared them only to direct radiography and found no dif-
ference in tumour size [20], no other tumour characteristics
were compared. The other study found computed radiog-
raphy detected cancers of similar size and nodal status;
however, significantly more were grade 3 versus 2 com-
pared to screen-film [17].
Consistent with a previous population-based study from
the Netherlands [21], there were no significant differences
in prognostic characteristics of interval cancers for women
screened with direct radiography compared to screen-film.
We also found no differences in the pathology of interval

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396 Breast Cancer Res Treat (2014) 147:389399

Table 3 Tumour Characteristics Screen-film Direct Adjusted OR Computed Adjusted OR

characteristics and adjusted mammography radiography (95 % CI) radiography (95 % CI)
odds ratios with 95 % N = 228 N = 149 N = 41
confidence intervals for invasive n (%) n (%) n(%)
interval cancers (n = 418)
Tumour size at diagnosis, cma
B2.0 111 (50.2) 62 (44.6) 1.00 (reference) 16 (40.0) 1.00 (reference)
[2.0 110 (49.8) 77 (55.4) 1.23 (0.662.30) 24 (60.0) 1.98 (0.715.52)
Missing 7 10 1
Lymph nodesa
Negativea 123 (56.4) 85 (59.9) 1.00 (reference) 22 (55.0) 1.00 (reference)
Positive 95 (43.6) 57 (40.1) 1.07 (0.571.99) 18 (45.0) 0.39 (0.121.28)
Missing 10 7 1
Stage at diagnosisa
I 84 (39.4) 52 (37.7) 1.00 (reference) 13 (33.3) 1.00 (reference)
II 98 (46.0) 67 (48.6) 1.61 (0.813.19) 20 (51.3) 2.21 (0.766.47)
III or IV 31 (14.6) 19 (13.8) 0.99 (0.382.61) 6 (15.4)
Missing 15 11 2
Histologic gradeb
1 44 (19.9) 25 (17.6) 1.00 (reference) 9 (22.5) 1.00 (reference)
2 93 (42.1) 54 (38.0) 1.80 (0.684.74) 15 (37.5) 3.82 (0.4532.44)
3 84 (38.0) 63 (44.4) 1.94 (0.755.02) 16 (40.0) 4.06 (0.4833.97)
Missing 7 7 1
Oestrogen receptorb
Positive 134 (75.3) 66 (73.3) 1.00 (reference) 16 (66.7) 1.00 (reference)
Negative 44 (24.7) 24 (26.7) 1.71 (0.853.41) 8 (33.3) 1.10 (0.333.68)
Missing 50 59 17
Progesterone receptorb
Positive 120 (66.7) 58 (64.4) 1.00 (reference) 14 (58.3) 1.00 (reference)
a Negative 60 (33.3) 32 (35.6) 1.58 (0.842.97) 10 (41.7) 0.89 (0.302.66)
Adjusted for age at last screen
(continuous), and whether the Missing 48 59 17
cancer was detected on an initial HER2b
or rescreen Positive 30 (19.5) 14 (17.3) 1.00 (reference) 1 (4.4) 1.00 (reference)
b
Adjusted for age at last screen Negative 124 (80.5) 67 (82.7) 0.86 (0.381.93) 22 (95.6) 0.26 (0.032.03)
(continuous), whether the
Missing 74 68 18
cancer was detected on an initial
or rescreen and tumour size Triple negativeb
(continuous) No 148 (86.5) 74 (81.3) 1.00 (reference) 17 (77.3) 1.00 (reference)
a
lymph node negative includes Yes 23 (13.5) 17 (18.7) 1.77 (0.813.85) 5 (22.7) 1.23 (0.324.73)
cases with only isolated tumour Missing 57 58 19
cells

cancers for computed radiography versus screen-film;
however, this may have been due to limited power. An
interval cancer may be missed for technical or interpretive
reasons (missed interval), or the cancer may not have been
mammographically detectable at screening (true interval)
[30]. The same study from the Netherlands found tumour
size was similar for missed and true intervals between
groups of women screened with screen-film mammography
and direct radiography [21]. One other study found sig-
nificantly smaller tumour size for missed interval cancers
following direct radiography compared to screen-film [14];
however, this study measured tumour size on imaging
rather than the surgical specimen and combined DCIS and
invasive cancers, therefore results may not be comparable.
While there was a trend towards poorer prognostic
features for interval versus screen-detected cancers for all
mammography types, the effect estimates were strongest
for time-dependent factors, such as stage, among women
screened with screen-film mammography. This suggests
digital mammography may detect cancers earlier. Mean-
while, risk estimates for hormone receptor negative and
triple negative cancers were strongest among women
screened with direct radiography. This is the first study to
examine interval compared to screen-detected cancers by

123
 Table 4 Tumour characteristics of invasive cancers detected on a rescreen and interval cancers stratified by type of mammography (n = 1,304)
Screen-film mammography Direct radiography Computed radiography
Characteristic Rescreen Interval Adjusted OR Rescreen Interval Adjusted OR Rescreen Interval Adjusted OR
N = 603 N = 228 (95 % CI) N = 333 N = 149 (95 % CI) N = 64 N = 41 (95 % CI)
n (%) n (%) n(%) n(%) n (%) n (%)

Tumour size at diagnosis, cma

B2.0 462 (77.0) 111 (50.2) 1.00 (reference) 259 (78.5) 62 (44.6) 1.00 (reference) 43 (67.2) 16 (40.0) 1.00 (reference)
[2.0 138 (23.0) 110 (49.8) 2.83 (1.844.36)* 71 (21.5) 77 (55.4) 3.78 (2.017.11)* 21 (32.8) 24 (60.0) 4.29 (1.2814.40)
Lymph nodesa
Negativea 459 (79.4) 123 (56.4) 1.00 (reference) 228 (75.0) 85 (59.9) 1.00 (reference) 44 (69.8) 22 (55.0) 1.00 (reference)
Positive 119 (20.6) 95 (43.6) 2.62 (1.684.09)* 76 (25.0) 57 (40.1) 1.62 (0.883.01) 19 (30.2) 18 (45.0) 0.94 (0.293.02)
Stage at diagnosisa
Breast Cancer Res Treat (2014) 147:389399

I 394 (66.2) 84 (39.4) 1.00 (reference) 210 (63.6) 52 (37.7) 1.00 (reference) 34 (54.0) 13 (33.3) 1.00 (reference)
b
II 173 (29.1) 98 (46.0) 2.12 (1.363.32)* 96 (29.1) 67 (48.6) 2.83 (1.485.42) 22 (34.9) 20 (51.3) 2.74 (0.799.48)
III or IV 28 (4.7) 31 (14.6) 5.42 (2.5911.34)* 24 (7.3) 19 (13.8) 2.67 (0.957.51) 7 (11.1) 6 (15.4) 0.79 (0.096.85)
Histologic gradeb
1 179 (30.7) 44 (19.9) 1.00 (reference) 83 (26.0) 25 (17.6) 1.00 (reference) 20 (31.3) 9 (22.5) 1.00 (reference)
2 291 (49.7) 93 (42.1) 0.955 (0.541.68) 152 (47.7) 54 (38.0) 1.19 (0.483.02) 33 (51.6) 15 (37.5) 3.94 (0.4038.51)
3 115 (19.7) 84 (38.0) 1.96 (1.093.51) 84 (26.3) 63 (44.4) 2.58 (1.006.66) 11 (17.2) 16 (40.0) 10.63 (0.91124.42)
b
Oestrogen receptor
Positive 375 (86.8) 134 (75.3) 1.00 (reference) 191 (89.7) 66 (73.3) 1.00 (reference) 33 (89.2) 16 (66.7) 1.00 (reference)
Negative 57 (13.2) 44 (24.7) 1.44 (0.842.48) 22 (10.3) 24 (26.7) 3.89 (1.768.61)* 4 (10.8) 8 (33.3) 1.95 (0.409.46)
Progesterone receptorb
Positive 335 (77.5) 120 (66.7) 1.00 (reference) 160 (75.1) 58 (64.4) 1.00 (reference) 32 (86.5) 14 (58.3) 1.00 (reference)
k
Negative 97 (22.5) 60 (33.3) 1.42 (0.892.26) 53 (24.9) 32 (35.6) 2.43 (1.254.74) 5 (13.5) 10 (41.7) 2.02 (0.468.92)
HER2b
Positive 46 (13.4) 30 (19.5) 1.00 (reference) 19 (11.7) 14 (17.3) 1.00 (reference) 5 (13.4) 1 (4.4) 1.00 (reference)
Negative 298 (86.6) 124 (80.5) 1.29 (0.732.29) 143 (88.3) 67 (82.7) 1.22 (0.512.96) 27 (86.6) 22 (95.6) 0.44 (0.045.23)
Triple negativeb
No 399 (94.1) 148 (86.5) 1.00 (reference) 198 (95.6) 74 (81.3) 1.00 (reference) 36 (94.7) 17 (77.3) 1.00 (reference)
Yes 25 (5.9) 23 (13.5) 1.91 (0.993.72) 9 (4.4) 17 (18.7) 5.49 (2.0814.49)* 2 (5.3) 5 (22.7) 2.36 (0.3316.70)
k b
* P value \0.001; P value = 0.02; P = 0.04; P = 0.01; P = 0.002
a
Adjusted for age at last screen (continuous)
b
Adjusted for age at last screen (continuous) and tumour size (continuous)
a
lymph node negative includes cases with only isolated tumour cells
397

123
398
type of mammography. Further evaluation is necessary to
corroborate these observations.
The strengths of this study include the use of large
concurrent cohorts within an organized breast screening
program. The population-based design enhances the gen-
eralizability of the results. Additionally, we were able to
adjust for potential confounders, such as age and whether
the screen was an initial screen or a rescreen. There are also
some limitations. Information on type of interval cancer,
true or missed, was unavailable for this study; however,
evidence suggests both are comparable by type of mam-
mography [21]. The computed radiography cohort may
have had limited power to detect associations in our
stratified analyses. We did not have specific information on
radiologists, such as number of years of experience or
annual volumes of mammograms read.
Overall, this study found cancers detected by direct
radiography and screen-film mammography had equivalent
prognostic features, while cancers detected by computed
radiography were two times more likely to be stage II, and
three times more likely to be stage III/IV compared to stage
I. This suggests that computed radiography may be missing
early stage cancers. These results corroborate our earlier
findings that computed radiography had a significantly
lower cancer detection rate than screen-film mammography
[16], and therefore, may reflect a delayed diagnosis for
these women. Screening programs should re-evaluate their
use of computed radiography for breast screening.
Acknowledgments The authors thank the study staff, Anjana Aery
and Amanda Veglia, the women who participated in the study, and
Cancer Care Ontario for the use of its data.
Conflict of interest There are no conflicts of interest to disclose.
Funding This work was supported by the Canadian Breast Cancer
Research Alliance and the Canadian Institutes of Health Research
(Grant #102603). These agencies had no involvement in the study or
the decision to approve for publication.
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