Contralateral breast cancer risk in patients with ductal carcinoma in situ and invasive breast cancer

Abstract

We aimed to assess contralateral breast cancer (CBC) risk in patients with ductal carcinoma in situ (DCIS) compared with invasive breast cancer (BC). Women diagnosed with DCIS (N = 28,003) or stage I–III BC (N = 275,836) between 1989 and 2017 were identified from the nationwide Netherlands Cancer Registry. Cumulative incidences were estimated, accounting for competing risks, and hazard ratios (HRs) for metachronous invasive CBC. To evaluate effects of adjuvant systemic therapy and screening, separate analyses were performed for stage I BC without adjuvant systemic therapy and by mode of first BC detection. Multivariable models including clinico-pathological and treatment data were created to assess CBC risk prediction performance in DCIS patients. The 10-year cumulative incidence of invasive CBC was 4.8% for DCIS patients (CBC = 1334). Invasive CBC risk was higher in DCIS patients compared with invasive BC overall (HR = 1.10, 95% confidence interval (CI) = 1.04–1.17), and lower compared with stage I BC without adjuvant systemic therapy (HR = 0.87; 95% CI = 0.82–0.92). In patients diagnosed ≥2011, the HR for invasive CBC was 1.38 (95% CI = 1.35–1.68) after screen-detected DCIS compared with screen-detected invasive BC, and was 2.14 (95% CI = 1.46–3.13) when not screen-detected. The C-index was 0.52 (95% CI = 0.50–0.54) for invasive CBC prediction in DCIS patients. In conclusion, CBC risks are low overall. DCIS patients had a slightly higher risk of invasive CBC compared with invasive BC, likely explained by the risk-reducing effect of (neo)adjuvant systemic therapy among BC patients. For support of clinical decision making more information is needed to differentiate CBC risks among DCIS patients.

Full text

ARTICLE OPEN
Contralateral breast cancer risk in patients with ductal
carcinoma in situ and invasive breast cancer
Daniele Giardiello
1,2,12
, Iris Kramer
1,12
, Maartje J. Hooning
3
, Michael Hauptmann
4,5
, Esther H. Lips
1
, Elinor Sawyer
6
,
Alastair M. Thompson
7
, Linda de Munck
8
, Sabine Siesling
8,9
, Jelle Wesseling
1,10
, Ewout W. Steyerberg
2,11
and Marjanka K. Schmidt
1
✉
We aimed to assess contralateral breast cancer (CBC) risk in patients with ductal carcinoma in situ (DCIS) compared with invasive
breast cancer (BC). Women diagnosed with DCIS (N=28,003) or stage I–III BC (N =275,836) between 1989 and 2017 were identified
from the nationwide Netherlands Cancer Registry. Cumulative incidences were estimated, accounting for competing risks, and
hazard ratios (HRs) for metachronous invasive CBC. To evaluate effects of adjuvant systemic therapy and screening, separate
analyses were performed for stage I BC without adjuvant systemic therapy and by mode of first BC detection. Multivariable models
including clinico-pathological and treatment data were created to assess CBC risk prediction performance in DCIS patients. The 10-
year cumulative incidence of invasive CBC was 4.8% for DCIS patients (CBC =1334). Invasive CBC risk was higher in DCIS patients
compared with invasive BC overall (HR =1.10, 95% confidence interval (CI) =1.04–1.17), and lower compared with stage I BC
without adjuvant systemic therapy (HR =0.87; 95% CI =0.82–0.92). In patients diagnosed ≥2011, the HR for invasive CBC was 1.38
(95% CI =1.35–1.68) after screen-detected DCIS compared with screen-detected invasive BC, and was 2.14 (95% CI =1.46–3.13)
when not screen-detected. The C-index was 0.52 (95% CI =0.50–0.54) for invasive CBC prediction in DCIS patients. In conclusion,
CBC risks are low overall. DCIS patients had a slightly higher risk of invasive CBC compared with invasive BC, likely explained by the
risk-reducing effect of (neo)adjuvant systemic therapy among BC patients. For support of clinical decision making more information
is needed to differentiate CBC risks among DCIS patients.
npj Breast Cancer (2020) 6:60 ; https://doi.org/10.1038/s41523-020-00202-8
INTRODUCTION
Contralateral breast cancer (CBC) is the most frequent second
cancer reported after first invasive breast cancer (BC)
1–3
. The
cumulative incidence of invasive CBC for women following
invasive BC is ~0.4% per year
4–6
. Several studies have shown a
decrease in CBC incidence as a result of (neo)adjuvant systemic
therapies
6–8
.
Ductal carcinoma in situ (DCIS) is a potential precursor of
invasive BC. The incidence of DCIS has increased substantially with
widespread introduction of population-based mammography
screening including digital mammography and represents
10–25% of all BC patients
9–11
. As DCIS has an excellent prognosis
with a disease-specific survival of >98% at 10 years
12–14
, a large
group of women is at risk of developing CBC.
The risk of invasive CBC for DCIS patients has not been widely
investigated, but the annual risk is estimated between 0.4 and
0.6%
11,13,15,16
. Moreover, it is unclear if the risk of CBC is
comparable between patients diagnosed with invasive BC and
patients with DCIS. One study in the United States, using data
from the Surveillance, Epidemiology, and End Results (SEER)
database, found a similar relative CBC risk for DCIS patients
compared to patients with invasive BC
17
. On the other hand, an
indirect assessment between DCIS patients and invasive BC
patients has been provided by a CBC risk prediction model
developed and validated in the USA, showing a higher relative
CBC risk for DCIS compared with invasive BC (relative risk: 1.60,
95% confidence interval (CI) =1.42–1.93)
18,19
. The reason for a
potential higher CBC risk for DCIS patients is still unclear, but
might relate to the risk-reducing effect of adjuvant systemic
therapy among invasive BC patients
6,20,21
. In general, relatively few
DCIS patients receive adjuvant systemic therapy. In addition, CBC
risks may also differ based on the mode of detection of the first
BC. Previous research showed that screen-detected invasive breast
tumors have a better BC-specific survival than non-screened
tumors and hence receive less adjuvant systemic treatment
22
.
The aim of this study was to assess the risk of developing
invasive CBC in DCIS patients in direct comparison with patients
diagnosed with invasive BC using a large population-based cohort
of Dutch BC patients, taking age, mode of first BC detection, and
(neo)adjuvant systemic therapy into account. In addition, we
evaluated the CBC risk prediction performance in patients
diagnosed with DCIS.
RESULTS
Patient characteristics
The cohort comprised 28,003 DCIS patients (CBC =1334) and
275,836 patients with invasive BC (CBC =12,821), including 86,481
1
Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
2
Department of Biomedical Data Sciences, Leiden University Medical Center,
Leiden, the Netherlands.
3
Department of Medical Oncology-Cancer Epidemiology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.
4
Institute of Biostatistics and Registry
Research, Brandenburg Medical School, Neuruppin, Germany.
5
Department of Epidemiology and Biostatistics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
6
School of Cancer & Pharmaceutical Sciences, Kings College London, London, UK.
7
Department of Surgery, Dan L Duncan Comprehensive Cancer Center, Baylor College of
Medicine, Houston, USA.
8
Department of Research and Development, Netherlands Comprehensive Cancer Organisation, Utrecht, the Netherlands.
9
Department of Health
Technology and Services Research, Technical Medical Centre, University of Twente, Enschede, the Netherlands.
10
Department of Pathology, The Netherlands Cancer Institute,
Amsterdam, the Netherlands.
11
Department of Public Health, Erasmus MC, Rotterdam, the Netherlands.
12
These authors contributed equally: Daniele Giardiello, Iris Kramer.
✉email: mk.schmidt@nki.nl
www.nature.com/npjbcancer
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patients with stage I BC not receiving adjuvant systemic therapy;
i.e., no chemotherapy, endocrine therapy, nor trastuzumab (Table
1). The percentage of patients diagnosed with DCIS, of all BC
patients diagnosed in the Netherlands, was 5.7% in the
implementation phase of the mammography screening program
(1989–1998) and 10.5% in the period of full national coverage
(1999–2017). Median follow-up was 11.4 years.
CBC risk for patients diagnosed with DCIS and invasive BC
The 10-year cumulative incidence of invasive CBC was 4.8% (95%
CI =4.6–5.2%) for DCIS patients, 4.0% (95% CI =4.0–4.1%) for all
invasive BC patients, and 5.6% (95% CI =5.4–5.8%) for patients
with stage I BC not receiving adjuvant systemic therapy (Table 1,
Fig. 1
23
). For comparison, the 10-year cumulative incidence of
invasive CBC in patients diagnosed with stage I invasive BC treated
with adjuvant systemic therapy was 2.9% (95% CI =2.5–3.3%).
Being diagnosed with DCIS was associated with an increased risk
of invasive CBC compared with invasive BC overall (HR =1.10, 95%
CI =1.04–1.17), and with a lower risk when compared with stage I
BC without adjuvant systemic therapy (HR =0.87, 95% CI =
0.82–0.92, Table 2). Similar results were observed when using
competing risk regression (Table 2).
In sensitivity analyses using different time cutoffs for meta-
chronous CBC, results were similar. The HR for invasive CBC
developed at least six months after the first BC was 1.10 (95% CI =
1.04–1.17) for DCIS compared with invasive BC, and the HR was
1.09 (95% CI =1.03–1.16) using a 12-month cutoff.
The cumulative incidence of in situ CBC, death, and invasive
ipsilateral BC are shown in Supplementary Figs. 1–3
23
. The 10-year
cumulative incidence of in situ CBC was 1.6% (95% CI =1.5–1.8%)
for DCIS patients, 0.8% (95% CI =0.7–0.8%) for invasive BC
patients, and 1.1% (95% CI =1.0–1.2%) for patients with stage I BC
without adjuvant systemic therapy (Table 1). The risk of death was
lower in DCIS patients compared to invasive BC patients (HR =
0.47, 95% CI =0.45–0.49, Supplementary Table 1).
Results by age and screening (period)
Among patients who had their first BC diagnosis during the
implementation phase of the national screening program
(1989–1998), the risk of invasive CBC was similar in DCIS patients
compared with invasive BC patients (HR =0.93, 95% CI =
0.85–1.03, Table 3, Fig. 2a–c
23
). In the period of full nationwide
coverage of the screening program (1999–2017), the risk of
invasive CBC was higher for DCIS patients than for invasive BC
patients (HR =1.19, 95% CI =1.10–1.27, Table 3, Fig. 2b–d
23
). The
risk of invasive CBC was lower in DCIS patients compared with
patients with stage I BC not receiving adjuvant systemic therapy in
both periods (1989–1998: HR =0.90; 95% CI =0.81–1.00, and
1999–2017: HR =0.85, 95% CI: 0.79–0.91). The effects were similar
stratified by age group (<50 and ≥50 years) (Table 3). The
estimated 5- and 10-year cumulative incidences by age and period
are shown in Supplementary Table 2.
In a subgroup of patients diagnosed during or after 2011, with
information available on the mode of first BC detection, the HR of
invasive CBC was 1.53 (95% CI =1.29–1.82) for DCIS patients
compared with invasive BC patients, and 0.86 (95% CI =0.71–1.03)
compared with patients with stage I BC without adjuvant systemic
therapy (Table 4). Among all screen-detected first BCs, the HR of
invasive CBC was 1.38 (95% CI =1.35–1.68) for DCIS patients
compared with invasive BC patients and 0.81 (95% CI =0.66–1.00)
compared with stage I BC without adjuvant systemic therapy
(Table 4). When the first BC was not detected by screening, the HR
of invasive CBC was 2.14 (95% CI =1.46–3.13) for DCIS patients
compared to invasive BC patients and 1.04 (95% CI =0.68–1.59)
compared with stage I BC without adjuvant systemic therapy
(Table 4). The risk of death in patients with DCIS compared with
invasive BC and stage I BC without adjuvant systemic therapy
among screen-detected and not screen-detected is shown in
Supplementary Table 3.
Subtype-specific CBC risk
DCIS patients had a lower risk of stage IV CBC (HR =0.45, 95% CI
=0.22–0.92), and higher risks of grade I invasive CBC (HR =1.55,
95% CI =1.31–1.84) and ER-positive invasive CBC (HR =1.49, 95%
CI =1.33–1.66) compared with all invasive BC patients (Supple-
mentary Table 4). Overall, the subtype-specific CBC risk in DCIS
patients was comparable to patients with stage I BC not receiving
adjuvant systemic therapy (Supplementary Table 4).
Multivariable model
In the multivariable model, no strong predictors of CBC were
identified in DCIS patients (Table 5). The C-index of the
multivariable model of invasive CBC was 0.52 (standard deviation
(SD =0.01) for cause-specific Cox regression; when we considered
all CBC (in situ and invasive) the C-index was 0.51 (SD =0.01)
(Table 5). When we performed the analyses in a subgroup of
patients diagnosed during or after 2011, the C-index was 0.55
(SD =0.01) without information on the mode of first BC detection,
and 0.56 (SD =0.01) with information available on the mode of
first BC detection (data not shown).
DISCUSSION
In this large population-based study, the 10-year cumulative
incidence of invasive CBC was 4.8% for DCIS patients. The risk of
developing invasive CBC was lower for DCIS patients compared
with stage I BC patients not receiving adjuvant systemic therapy
(HR =0.87), but the risk was slightly higher compared with all
invasive BC patients (HR =1.10). A multivariable model, based on
the clinical information currently available, was unable to
differentiate risks of invasive CBC among DCIS patients.
The slightly higher invasive CBC risk in DCIS patients compared
with all invasive BC patients may be explained by the risk-
reducing effect of adjuvant systemic therapy among invasive BC
patients
6,20,21
. In our previous study using NCR data
6
we showed
that adjuvant endocrine therapy, chemotherapy, and trastuzumab
combined with chemotherapy were associated with overall 54%,
30%, and 43% risk reductions of CBC, respectively. In our study, a
large group (57%) of patients with invasive BC received (neo)
adjuvant systemic therapy. According to the Dutch guidelines,
DCIS patients are not offered treatment with adjuvant systemic
therapy
24
. The potential influence of adjuvant systemic therapy is
supported by the CBC risk evaluation in patients diagnosed with
stage I BC not receiving adjuvant systemic therapy, showing a
higher CBC risk in such patients than in patients diagnosed
with DCIS.
To our knowledge, only one previous study in the United States
investigated the risk of CBC in patients with DCIS in direct
comparison with patients diagnosed with invasive BC using SEER
data
17
. They found a similar CBC risk (including in situ and
invasive) for invasive ductal BC in comparison with DCIS, with a
relative risk of 0.98 (95% CI =0.90–1.06). However, that analysis
was based on an earlier, largely pre-screening, period (1973–1996),
and lacked information on adjuvant systemic therapy use.
Previous studies examining cohorts of DCIS patients have reported
a subsequent annual invasive CBC risk of 0.4–0.6%
13,15,16
,
comparable to our finding.
When analyses were restricted to patients with information
available on the mode of first BC detection, trends were similar
overall. However, the higher CBC risk for DCIS patients compared
with invasive BC was more pronounced within the not screen-
detected BC group compared with the screen-detected BC group.
Tumors not detected by screening could be interval tumors or
those arising in women not attending for screening. Certainly,
D. Giardiello et al.
2
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Table 1. Patient-, tumor-, and treatment characteristics of women diagnosed with ductal carcinoma in situ or invasive breast cancer.
DCIS All invasive BC Stage I BC without adjuvant
systemic therapy
a
N%N%N%
Characteristics 28,003 9.2 275,836 90.8 86,481 31.4
Diagnosis, year
Median (range) 2009 (1989–2017) 2004 (1989–2017) 2004
(1989–2017)
Age, years
Median (range) 59 (21–95) 59 (18–102) 61 (18–99)
TNM stage
0 28,003 100.0 ––––
I––120,952 43.8 86,481 100.0
II ––124,883 45.3 ––
III ––30,001 10.9 ––
Tumor grade
I (well differentiated) 3729 16.1 44,690 20.9 27,566 41.9
II (moderately differentiated) 7864 33.8 95,251 44.6 28,159 42.8
III (poorly/undifferentiated) 11,639 50.1 73,581 34.5 10,036 15.3
Missing 4771 –62,314 –20,720 –
ER status
Positive ––133,761 82.7 41,883 90.1
Negative ––28,075 17.3 4598 9.9
Missing 28,003 –114,000 –40,000 –
HER2 status
Positive ––19,708 14.3 2324 6.1
Negative ––118,409 85.7 35,616 93.9
Missing 28,003 –137,719 –48,541 –
PR status
Positive ––106,786 67.5 33,862 74.8
Negative ––51,437 32.5 11,404 25.2
Missing 28,003 –117,613 –41,215 –
(Neo)adjuvant chemotherapy
Yes 17 0.1 91,844 33.3 ––
No 27,986 99.9 183,992 66.7 86,481 100.0
(Neo)adjuvant endocrine therapy
Yes 102 0.4 119,394 43.3 ––
No 27,901 99.6 156,442 56.7 86,481 100.0
(Neo)adjuvant trastuzumab
Yes 3 0.0 13,994 5.1 ––
No 28,000 100.0 261,842 94.9 86,481 100.0
Surgery to the breast
Breast conserving surgery 16,396 60.8 142,495 53.4 58,727 70.1
Mastectomy 10,571 39.2 124,530 46.6 25,023 29.9
Missing 1036 –881 –2731 –
Radiation to the breast
Yes 13,128 46.9 182,226 66.1 59,354 70.1
No 14,875 53.1 93,610 33.9 27,127 31.4
Follow-up, years
Median (IQR) 8.7 (8.5–8.8) 11.8 (11.7–11.8) 13.5 (13.4–13.6)
Cumulative incidence of invasive CBC, %
5-year (95% CI) 2.4 (2.2–2.6) 2.0 (2.0–2.1) 2.9 (2.8–3.0)
10-year (95% CI) 4.8 (4.6–5.2) 4.0 (4.0–4.1) 5.6 (5.4–5.8)
Number of invasive CBC 1334 12,821 5782
Cumulative incidence of death, %
5-year (95% CI) 3.8 (3.6–4.0) 15.0 (14.9–15.2) 7.8 (7.6–8.0)
10-year (95% CI) 9.8 (9.4–10.2) 29.4 (29.2–29.6) 19.2 (18.9–19.5)
Number of death 3340 91,797 23,899
D. Giardiello et al.
3
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invasive interval tumors tend to be more aggressive than screen-
detected BCs and hence receive more often adjuvant systemic
treatment
22
.
We observed that the invasive CBCs developed within the DCIS
group were less aggressive than the invasive CBCs developed after
invasive first BC, i.e., more estrogen receptor positive (ER-positive),
and lower tumor stage and grade. This may be explained by
underlying etiological factors and/or be related to the use of
adjuvant systemic therapy among invasive BC patients. Studies
have shown that adjuvant systemic therapy influences subtype-
specific CBC risk, e.g., endocrine therapy strongly reduces the risk
of developing ER-positive CBC, but not ER-negative CBC
6,21
. This is
supported by our subgroup analyses in patients with stage I BC
not receiving adjuvant systemic therapy, who tended to develop
similar CBC subtypes compared with DCIS patients.
The main strength of this study was the use of a large
population-based nationwide cohort of DCIS and invasive BC
patients, with complete follow-up on CBC over a long period. The
NCR did not have follow-up information on distant metastases for
all years included and therefore we could not take distant
metastasis as a competing event into account. However, in the
years where we had information on distant metastases
(2003–2006), the median survival was 1.1 years and the 5-year
overall survival after distant metastasis was fairly poor (6%). This
indicates that death could be used as a proxy for distant
metastasis. As we had complete information on death (as a
competing event), we do not expect that the lack of information
on distant metastases has led to an underestimation of the CBC
risk. We also did not have information available about contral-
ateral prophylactic mastectomy (CPM), which may have resulted in
an underestimation of the CBC risk and may not have had equal
uptake in all groups. According to Dutch guidelines
24
only women
carrying a BRCA1 or BRCA2 germline mutation are advised to
undergo a contralateral preventive mastectomy, as their CBC risk
is high with an estimated 10-year risk of ~10–20%
25,26
Unfortu-
nately, information about BRCA1 and BRCA2 mutation was lacking.
However, we do not expect that this missing information
importantly influenced the results since only 1–2% of the DCIS
population
27
, and 3–5% of the invasive BC population
25,28
will be
BRCA1 or BRCA2 mutation carriers. Finally, <1% of the DCIS
patients were not treated according to the Dutch guideline since
they received adjuvant chemotherapy, endocrine therapy, and/or
trastuzumab. However, since this number is low, we do not expect
that this affected our results.
Despite low CBC risks, the use of CPM has increased in recent
years, both in patients diagnosed with invasive BC and in patients
diagnosed with DCIS, especially in the United States
14,29
. There-
fore, a need of individualized CBC risk prediction may be as
important for patients diagnosed with DCIS as for patients with
invasive BC. At present, CBC risk prediction models have been
developed and validated for patients with invasive BC, but these
models may not be appropriate for DCIS patients since most of the
information available for invasive BC is not routinely collected in
DCIS
18,19,30,31
. In our study, we had limited information on
biological characteristics of DCIS, e.g., no information on receptor
subtypes, and our multivariable model was therefore unable to
differentiate CBC risk among DCIS patients. So, based on the
clinical information currently available, CBC risk prediction in DCIS
patients is insufficiently robust to be clinically actionable. More
biological knowledge is needed to improve CBC prediction in DCIS
patients.
Based on the results of this study we do not suggest to start
treating DCIS patients with adjuvant systemic therapy to prevent
CBC as the absolute invasive CBC risk is low. To facilitate patients
and physicians in decision making, a comprehensive risk
prediction model specifically developed for patients with DCIS
would be desirable, including information on genetic, clinical, and
lifestyle factors.
Table 1 continued
DCIS All invasive BC Stage I BC without adjuvant
systemic therapy
a
N%N%N%
Characteristics 28,003 9.2 275,836 90.8 86,481 31.4
Cumulative incidence of ipsilateral invasive BC %
5-year (95% CI) 1.6 (1.5–1.8) 0.1 (0.1–0.1) 0.2 (0.1–0.2)
10-year (95% CI) 3.5 (3.3–3.8) 0.3 (0.2–0.3) 0.5 (0.4–0.6)
Number of ipsilateral invasive BC 920 1471 897
Cumulative incidence of in situ CBC, %
5-year (95% CI) 1.0 (1.0–1.1) 0.4 (0.4–0.5) 0.6 (0.6–0.7)
10-year (95% CI) 1.6 (1.5–1.8) 0.8 (0.7–0.8) 1.1 (1.0–1.2)
Number of in situ CBC 427 2278 1026
DCIS ductal carcinoma in situ, BC breast cancer, ER estrogen receptor, PR progesterone receptor, HER2 human epidermal growth factor receptor 2, IQR inter-
quartile range, CBC contralateral breast cancer, CI confidence interval.
a
The “stage I BC without adjuvant systemic therapy”group is a subset of the “all invasive BC”group.
Fig. 1 Cumulative incidences of invasive contralateral breast
cancer (CBC) in patients diagnosed with ductal carcinoma in situ
(DCIS), invasive breast cancer (BC) stage I–III, and stage I BC
without (neo)adjuvant systemic therapy. The xaxis represents the
time since first BC diagnosis (in years) and the yaxis the cumulative
CBC incidence.
D. Giardiello et al.
4
npj Breast Cancer (2020) 60 Published in partnership with the Breast Cancer Research Foundation

METHODS
Study population
We evaluated 323,285 patients diagnosed with in situ or invasive first BC in
1989–2017, who underwent surgery, from the Netherlands Cancer Registry
(NCR) (Supplementary Fig. 4). The NCR is an on-going nationwide
population-based data registry of all newly diagnosed cancer patients in
the Netherlands, with full coverage since 1989
32
. We excluded nine
patients with first diagnosis without cytological or histological confirma-
tion, 5785 with stage IV BC or with incomplete staging information, 66 with
squamous cell carcinoma, and 4145 with in situ BC that was not pure DCIS
(i.e., lobular, other subtype, or mixed with ductal). Follow-up for all patients
started 3 months after the first diagnosis; therefore, 9,441 patients who
had developed synchronous CBC (invasive or in situ), invasive ipsilateral
BC, or died within 3 months after the first diagnosis were excluded.
Patient and tumor characteristics
Clinico-pathological data were provided by the NCR. After notification by
the nationwide network and registry of histo- and cytopathology in the
Netherlands and the national hospital discharge database, registration
clerks of the NCR collect data directly from patients’records. Follow-up
information on vital status and second cancers was complete up to 31
January 2018.
Staging was coded according to the TNM Classification of Malignant
Tumors using the edition valid at the date of diagnosis, ranging from the
4th to the 8th edition
33
. If pathological stage was missing, clinical stage
was used
34
.
Receptor status was determined by immunohistochemistry (IHC), and
was included in the NCR since 2005. Tumors were defined as estrogen
receptor (ER) positive or progesterone receptor (PR) positive when >10% of
the tumor cells stained positive (from 2011 the threshold was ≥10%). A
tumor was defined human epidermal growth factor receptor 2/neu-
receptor (HER2) positive if IHC was 3+(strong and complete membranous
expression in >10% of tumor cells) or if IHC score 2+when additional
confirmation with in situ hybridization was available, but considered
unknown if in situ hybridization confirmation was missing.
The NCR did not record information on BRCA1 and BRCA2 germline
mutation status and family history.
From 2011, the NCR recorded the mode of first BC detection, i.e., if the
DCIS or invasive BC was screen-detected or not detected by screening. We
did not have detailed information available on the tumors not detected by
screening, but these may include interval tumors, non-screen attendant, or
screened outside the national program (e.g., owing to family history).
According to the Dutch guidelines, mammographic follow-up is similar for
DCIS and invasive BC
24
.
Data used in this study were included in the NCR under an opt-out
regime according to Dutch legislation and codes of conduct
34
. The NCR
Privacy Review Board approved this study under reference number
K18.245. Data were handled in accordance with privacy regulations for
medical research
34
.
Statistical analyses
The primary outcome was the development of metachronous CBC, defined
as an invasive BC in the contralateral breast diagnosed at least three
months after the first BC diagnosis (DCIS or invasive BC). Follow-up started
three months after the first BC diagnosis, and ended at date of in situ- or
invasive CBC, invasive ipsilateral BC, or last date of follow-up (owing to
death, lost to follow-up, or end of study), whichever occurred first.
Cox proportional hazard models were performed to investigate the
association of having DCIS compared with invasive BC as primary diagnosis
with the cause-specific hazard of invasive CBC. We also performed analyses
with in situ CBC, invasive ipsilateral BC, and death as the outcome.
According to the Dutch guideline, DCIS patients do not receive adjuvant
systemic therapy. We evaluated the impact of adjuvant systemic therapy
by comparing the invasive CBC risk between DCIS patients and patients
diagnosed with stage I BC not receiving adjuvant systemic therapy (no
chemotherapy, endocrine therapy, nor trastuzumab), i.e., a subgroup of
patients that resembles as much as possible the DCIS patient group in
terms of treatment conditions. As hazard ratios (HRs) based on Cox
regressions do not have a direct relationship with the cumulative incidence
of the event of interest, we also performed competing risks regression to
estimate the HRs for the subdistribution hazards of the Fine and Gray
model
35,36
. In situ CBC, invasive ipsilateral BC, and death were considered
as competing risks. We performed both univariable analyses and analyses
adjusted for age- and year of first BC diagnosis. Since 1989, women in the
Netherlands aged 50–70 have been invited for biannual screening by
mammography, which was extended to women aged 75 since 1998. Based
on this, we categorized age at first BC diagnosis into <50 years and ≥50
years. Based on the gradual implementation of the Dutch BC screening, we
categorized year at first BC diagnosis into two periods: 1989–1998
(implementation phase) and 1999–2017 (full nationwide coverage;
attendance rate is 78.8%
37
and detection rate of invasive BC 6.6 per
1000 in 2017
38
and for DCIS 0.94 per 1000 between 2004–2011
39
). We also
performed our analyses stratified by mode of first BC detection. These
analyses only included patients diagnosed during or after 2011 and aged
50–75 (eligible for screening).
Cumulative incidence curves of invasive CBC for DCIS patients, all
invasive BC patients, and patients with stage I BC not receiving adjuvant
systemic therapy were calculated considering in situ CBC, invasive
ipsilateral BC, and death as competing risks. These curves were stratified
by year of first BC diagnosis (1989–1998 and 1999–2017) and by age (<50
and ≥50 years).
We used joint Cox proportional hazard models
40
to investigate subtype-
specific CBC risk (according to stage, grade, ER, PR, and HER2 status) in
DCIS patients compared with patients with invasive BC and compared with
patients with stage I BC who did not receive adjuvant systemic therapy.
Each model included subtype-specific CBC (e.g., ER-positive CBC, ER-
negative CBC, ER unknown CBC), in situ CBC, ipsilateral invasive BC, and
death as possible outcomes. As the NCR actively registered receptor status
from 2005, these analyses only included patients diagnosed between
2005–2017.
Multivariable Cox regression was used to quantify the effect of clinico-
pathological and treatment characteristics on CBC risk (all CBC and invasive
CBC only) in DCIS patients. In addition, multivariable Fine and Gray
Table 2. Relative subsequent contralateral breast cancer risks (invasive and in situ) after diagnosis with ductal carcinoma in situ versus invasive
breast cancer using Cox and competing risk regression.
Cox regression Competing risks regression
Outcome(s) Type of first BC Unadjusted Adjusted
a
Unadjusted Adjusted
a
HR (95% CI) HR (95% CI) HR
b
(95% CI) HR
b
(95% CI)
Invasive CBC DCIS vs invasive BC 1.08 (1.01–1.14) 1.10 (1.04–1.17) 1.22 (1.15–1.28) 1.20 (1.14–1.27)
DCIS vs stage I BC without adjuvant systemic therapy 0.87 (0.82–0.92) 0.87 (0.82–0.92) 0.88 (0.83–0.94) 0.87 (0.82–0.93)
In situ CBC DCIS vs invasive BC 1.92 (1.72–2.13) 1.84 (1.66–2.04) 2.12 (1.92–2.38) 1.98 (1.79–2.20)
DCIS vs stage I BC without adjuvant systemic therapy 1.49 (1.33–1.67) 1.38 (1.22–1.55) 1.54 (1.37–1.72) 1.40 (1.25–1.58)
HR hazard ratio, CI confidence interval, CBC contralateral breast cancer, BC breast cancer, DCIS ductal carcinoma in situ.
a
Hazard ratios adjusted by age and year at first diagnosis.
b
Hazard ratios for the subdistribution hazards of the Fine and Gray model. Invasive CBC, in situ CBC, invasive ipsilateral BC, and death were taken into account
as competing risks.
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Table 3. Relative risk of invasive contralateral breast cancer after ductal carcinoma in situ versus invasive breast cancer by period and age at first
diagnosis using Cox and competing risks regression.
Cox regression Competing risks
regression
Period Type of first BC NCBC events HR 95% CI HR
a
95% CI
All 1989–1998 DCIS vs invasive BC 81,105 6488 0.93 0.85–1.03 1.11 1.01–1.23
1999–2017 DCIS vs invasive BC 222,734 7667 1.19 1.10–1.27 1.32 1.23–1.41
1989–1998 DCIS vs stage I BC without systemic therapy 273,383 2696 0.90 0.81–1.00 0.93 0.85–1.04
1999–2017 DCIS vs stage I BC without systemic therapy 59,098 3086 0.85 0.79–0.91 0.88 0.81–0.94
Age <50 years at first diagnosis
b
1989–1998 DCIS vs invasive BC 22,084 2292 0.94 0.83–1.09 1.06 0.92–1.22
1999–2017 DCIS vs invasive BC 53,570 1838 1.20 1.06–1.37 1.26 1.11–1.45
1989–1998 DCIS vs stage I BC without systemic therapy 7192 870 0.90 0.78–1.04 0.89 0.78–1.04
1999–2017 DCIS vs stage I BC without systemic therapy 8162 472 0.85 0.74–0.97 0.82 0.71–0.94
Age ≥50 years at first diagnosis
b
1989–1998 DCIS vs invasive BC 59,021 4196 0.92 0.83–1.03 1.14 1.03–1.26
1999–2017 DCIS vs invasive BC 169,164 5829 1.18 1.10–1.26 1.35 1.26–1.47
1989–1998 DCIS vs stage I BC without systemic therapy 20,191 1826 0.89 0.80–1.00 0.96 0.86–1.08
1999–2017 DCIS vs stage I BC without systemic therapy 50,936 2614 0.85 0.78–0.92 0.88 0.81–0.95
HR hazard ratio, CI confidence interval, DCIS ductal carcinoma in situ, BC breast cancer.
a
Hazard ratios for the subdistribution hazards of the Fine and Gray model. Invasive CBC, in situ CBC, invasive ipsilateral BC, and death were taken into account
as competing risks.
b
Results were based on interaction analyses including the interaction term between age, period, and type of first BC (type of first BC+age+period+age×type
of first BC+period×type of first BC).
Fig. 2 Cumulative incidences of invasive contralateral breast cancer (CBC) in patients diagnosed with ductal carcinoma in situ (DCIS),
invasive breast cancer (BC) stage I–III, or stage I BC without (neo)adjuvant systemic therapy. a patients aged <50 years diagnosed between
1989 and 1998 (implementation phase Dutch mammography screening program); bpatients aged <50 years diagnosed between 1999 and
2017 (full national coverage of the Dutch mammography screening program); cpatients aged ≥50 years diagnosed between 1989 and 1998;
dpatients aged ≥50 years diagnosed between 1999 and 2017. The xaxis represents the time since first BC diagnosis (in years) and the yaxis
the cumulative CBC incidence.
D. Giardiello et al.
6
npj Breast Cancer (2020) 60 Published in partnership with the Breast Cancer Research Foundation

regressions were performed to assess the association between every factor
and the CBC cumulative incidence. Variables included in the models were
age at first DCIS diagnosis, tumor grade, type of surgery (mastectomy or
breast conserving surgery), and radiotherapy. The proportional hazard
assumption of the models was assessed by examining the Schoenfeld
residuals, and restricted cubic splines were used to verify whether linearity
of age at first DCIS diagnosis would hold
41
. The discrimination ability of the
models to identify patients developing CBC was calculated using the C-
index
42
. Missing data were multiply imputed by chained equations to
avoid loss of information owing to case-wise deletion causing bias and
reduction in efficiency
43,44
. Multiple imputation accounts for missing data
mechanisms assuming that the probability of missingness depends on the
observed data namely missing at random. For every predictor with missing
data, every imputation model selects predictors based on correlation
Table 4. Relative subsequent event risks after diagnosis with ductal carcinoma in situ versus invasive breast cancer by mode of first breast cancer
detection for patients diagnosed between 2011 and 2017
a
.
Overall By mode of first BC detection
b
Cox regression Competing risks
regression
Cox regression Competing risks
regression
Outcome Type of first BC HR (95% CI)
c
HR
c,d
(95% CI) HR
c
(95% CI) HR
c,d
(95% CI)
Invasive CBC DCIS vs invasive BC
(n=62,533, events=763)
1.53 (1.29–1.82) 1.55 (1.30–1.85) Screen-detected
e
1.38 (1.35–1.68) 1.38 (1.13–1.69)
Not screen-detected
e
2.14 (1.46–3.13) 2.20 (1.50–3.22)
DCIS vs stage I BC without
systemic therapy
(n=27,288, events =519)
0.86 (0.71–1.03) 0.86 (0.71–1.03) Screen-detected
e
0.81 (0.66–1.00) 0.81 (0.65–1.00)
Not screen-detected
e
1.04 (0.68–1.59) 1.05 (0.68–1.60)
In situ CBC DCIS vs invasive BC
(n=62,533, events =250)
1.99 (1.51–2.63) 2.00 (1.52–2.65) Screen-detected
e
1.75 (1.26–2.45) 1.75 (1.26–2.45)
Not screen-detected
e
3.41 (1.98–5.87) 3.46 (2.01–5.97)
DCIS vs stage I BC without
systemic therapy
(n=27,288, events =146)
1.51 (1.08–2.10) 1.51 (1.08–2.10) Screen-detected
e
1.40 (0.96–2.06) 1.41 (0.96–2.06)
Not screen-detected
e
2.23 (1.14–4.39) 2.25 (1.15–4.41)
BC breast cancer, HR hazard ratio, CI confidence interval, CBC contralateral breast cancer, DCIS ductal carcinoma in situ.
a
The analyses were performed in all patients diagnosed between 2011–2017, since from 2011 we had virtually complete information on the mode of first BC
detection.
b
Results were based on interaction analyses including the interaction term between mode of first BC detection and type of first BC (type of first BC+mode of
first BC detection+mode of first BC detection×type of first BC).
c
Adjusted for age at first BC diagnosis.
d
Hazard ratios for the subdistribution hazards of the Fine and Gray model. Invasive CBC, in situ CBC, invasive ipsilateral BC, and death were taken into account
as competing risks.
e
Not screen-detected includes interval tumors, non-screen attendant, or screened outside the national program.
Table 5. Relative risks of invasive and in situ contralateral breast cancer after diagnosis with ductal carcinoma in situ or invasive breast cancer using
multivariable Cox and competing risk regression models.
Outcome Invasive CBC Invasive and in situ CBC
Cox regression Competing risk
regression
Cox regression Competing risk
regression
HR 95% CI HR
a
95% CI HR 95% CI HR
a
95% CI
Age (years) 1.01
b
0.93–1.10 0.78
c
0.69–0.89 0.93
b
0.87–1.00 0.71
c
0.63–0.81
Tumor grade
Moderately differentiated versus well
differentiated
0.93 0.78–1.12 0.94 0.79–1.12 0.99 0.85–1.16 0.99 0.85–1.16
Poorly differentiated versus well differentiated 0.92 0.76–1.10 0.93 0.77–1.11 0.94 0.81–1.09 0.94 0.81–1.09
Surgery (Mastectomy versus BCS) 0.96 0.80–1.16 1.00 0.83–1.21 1.08 0.92–1.26 1.13 0.96–1.32
Radiotherapy to the breast (yes versus no) 1.11 0.94–1.32 1.12 0.94–1.33 1.12 0.97–1.30 1.14 0.98–1.32
Baseline failure-free probability at 10 years
d
0.949 0.956
e
0.932 0.943
e
C-index (SD) 0.520 (0.01) 0.515 (0.01) 0.513 (0.01) 0.526 (0.01)
CBC contralateral breast cancer, HR hazard ratio, CI confidence interval, BCS breast conservative surgery, SD standard deviation.
a
Hazard ratios for the subdistribution hazards of the Fine and Gray model.
b
Parameterized per decade.
c
Parameterized as a restricted cubic spline with three knots.
d
The baseline failure-free probabilty function is calculated for baseline values of the predictors included in the multivariable models.
e
Baseline failure-free probability function for the subdistribution hazard of the Fine and Gray model.
D. Giardiello et al.
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Published in partnership with the Breast Cancer Research Foundation npj Breast Cancer (2020) 60

structure underlying the data. Details about the imputation model are
provided in Supplementary Methods.
Analyses were performed using STATA version 16.0, SAS (SAS Institute
Inc., Cary, NC, USA) version 9.4, and R software version 3.5.3
45
.
Reporting summary
Further information on research design is available in the Nature Research
Reporting Summary linked to this article.
DATA AVAILABILITY
The data sets generated and/or analyzed during the current study are not publicly
available, as the study has used external data from the Netherlands Cancer Registry.
The data sets will be made available from the Netherlands Cancer Registry upon
reasonable request (data request study number K18.245). To apply for data access,
please visit https://www.iknl.nl/en/ncr/apply-for-data. The data sets that support Figs.
1 and 2, and supplementary figs. 1–3, are publicly available in the figshare repository,
in the following data record: https://doi.org/10.6084/m9.figshare.12982424
23
.
CODE AVAILABILITY
The codes developed during this study are available upon reasonable request.
Analyses were performed using STATA version 16.0, SAS (SAS Institute Inc., Cary, NC,
USA) version 9.4, and R software version 3.5.3.
Received: 11 June 2020; Accepted: 1 October 2020;
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ACKNOWLEDGEMENTS
The authors thank the registration team of the Netherlands Comprehensive Cancer
Organization (IKNL) for the collection of data for the Netherlands Cancer Registry
(NCR) as well as IKNL staff for scientific advice. We thank all patients whose data we
used for this study and the clinicians who treated these patients. This work was
supported by the Alpe d’HuZes/Dutch Cancer Society (KWF Kankerbestrijding) [grant
number A6C/6253] and by Cancer Research UK/KWF Kankerbestrijding [grant
numbers C38317, A24043]. The funders had no role in the design of the study, the
statistical analyses, interpretation of the data, and writing of the manuscript.
AUTHOR CONTRIBUTIONS
The data used for this study were derived from by the Netherlands Cancer Registry.
M.K.S. designed the study; I.K. prepared and coded the data for analysis; D.G.
performed the statistical analyses; I.K., D.G., M.K.S. interpreted the results and drafted
the first version of the manuscript; all other authors contributed to the interpretation
of the results and revisions of the manuscript. D.G. and I.K. shared co-first authorship.
All authors approved the final manuscript.
COMPETING INTERESTS
The authors declare no competing interests.
ADDITIONAL INFORMATION
Supplementary information is available for this paper at https://doi.org/10.1038/
s41523-020-00202-8.
Correspondence and requests for materials should be addressed to M.K.S.
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