Breast implants are widely used for both reconstructive and cosmetic purposes. There
is no evidence that breast implants increase the risk of breast cancer (Brinton et
al, 2000b; Mellemkjaer et al, 2000). On the contrary, several reports document that
women with cosmetic breast implants seem to be at a lower risk of developing breast
cancer (Berkel et al, 1992; Deapen et al, 1997; McLaughlin et al, 1998; Hoshaw et
al, 2001). However, the issue of potential delay in breast cancer diagnosis in the
augmented breast has been raised, since breast implants are radiopaque and this influences
the sensitivity of mammography (Eklund et al, 1988; Hayes et al, 1988; Silverstein
et al, 1992). Clinical reports have suggested a possible delay and difficulties in
the diagnosis of breast cancer (Leibman and Kruse, 1990; Silverstein et al, 1990a;
Carlson et al, 1993; Fajardo et al, 1995), but most epidemiological studies have not
supported a delay in diagnosis or impaired survival among women with breast implants
(Birdsell et al, 1993; Deapen et al, 2000).
We identified all subsequent incident cases of invasive breast cancer within a large
cohort of women with breast implants. The stage distribution at diagnosis, tumour
characteristics and overall survival of cohort women with breast cancer were compared
with those of a random sample of women with breast cancer from the general population
matched to the cohort on age and year of diagnosis. This study entails more detailed
and uniformly collected information about tumour stage and characteristics than previous
studies.
MATERIAL AND METHODS
We have previously identified 2740 women, who underwent cosmetic breast implantation
before the age of 55 years at private clinics and public hospitals in Denmark during
1973–1995 (Mellemkjaer et al, 2000). The women treated in the private clinics were
identified from the clinics' files, while the women treated in public hospitals were
identified through the National Register of Patients. For each woman, we obtained
the date of breast implantation and the Personal Identification number, a unique 10-digit
number, which encodes the date of birth and sex of all individuals in Denmark. An
additional 192 women who were treated in private clinics during 1996–1997, and 23
women who were over 55 years of age at implantation, were also included in the present
study, resulting in a final cohort of 2955 women with cosmetic breast implants.
The cohort was linked to the Danish Breast Cancer Cooperative Group (DBCG) register
using the Personal Identification number to identify women with invasive breast cancer
subsequent to breast implantation. The DBCG register is a clinical database, established
in 1977 and designed primarily to evaluate the programmes for adjuvant trials among
women with primary breast cancer. The register receives detailed information on primary
surgical procedure, histopathological examination, adjuvant treatment and clinical
follow-up. Based on tumour stage and menopause status, the patients are allocated
to groups with high or low risk of recurrence, and are treated in protocols accordingly.
Furthermore, the information on patients treated outside protocol programmes is recorded
(Andersen and Mouridsen, 1988; The DBCG Secretariat, 1998). A comparative study using
data from both the Danish Cancer Registry, which is the nationwide compulsory register
for all cancers established in 1943, based on reports from clinicians, pathologists
and also from death certificates (Storm et al, 1997), and the DBCG showed highly consistent
data for younger (98%) and middle-aged (95%) women diagnosed with breast cancer, whereas
the DBCG had 21% missing cases of breast cancer for the group over 70 years of age
(Rostgaard et al, 2000).
Women with breast implants were followed for invasive breast cancer from date of implantation
or 1 January 1977, whichever occurred last, until the age of 76 years, date of breast
cancer diagnosis, date of death, emigration, or 1 October 2001, whichever occurred
first. Computer linkage of the study cohort to the DBCG register identified 21 women
with cosmetic breast implants, who subsequently developed breast cancer.
We also linked the implant cohort with the Danish Cancer Registry using data available
until the end of 1998. We confirmed the 21 cases found in the DBCG and identified
additionally two women with cosmetic breast implants who were registered with subsequent
breast cancer, but who had not been reported to the DBCG. Their medical files were
obtained, and the relevant information for this study was abstracted. Both cases were
subsequently reported to the DBCG register.
For each of the 23 breast cancer cases with cosmetic breast implants (cases), we randomly
selected 11 controls with invasive breast cancer from the DBCG register, matched on
age and calendar year of breast cancer diagnosis 11 was the minimal number of available
individually matched controls, and consequently this number of controls was chosen
for each case, resulting in a total of 253 control subjects from the background population
(controls).
Information on the following variables was obtained from the DBCG register: date of
cancer diagnosis, place of operation, menopausal status, type of surgery and assessment
of whether the surgical margins were tumour free (side and deep margins). The histopathological
and staging variables were number of lymph nodes removed, number of involved lymph
nodes, size of tumour (macroscopic size, evaluated by the pathologist), oestrogen-
and/or progesterone-receptor status of tumour, histological diagnosis (WHO: ductal,
lobular, tubular and medullar carcinoma or other malignant tumours), malignancy grading
of ductal carcinomas (I–III according to mitosis activity, nuclear pleomorphy and
degree of tubule formation; I being the most benign and III the most aggressive) and
distant metastases at the time of surgery (evaluated by clinical examination in combination
with chest X-ray and blood tests, including blood cell count and liver enzymes). The
treatment-related variables were the intended adjuvant treatment according to trial
protocols (radiotherapy, chemotherapy and endocrine treatment).
The medical records for all the augmented breast cancer cases, with the exception
of one, which could not be found, and one randomly selected control per case were
retrieved to obtain information on how the cancer was diagnosed, and details on the
surgical procedure including implant status. We also compared the data reported to
the DBCG register with the medical records. Generally, there was a high level of concordance
in the reported data, but with regard to the variable ‘tumour cells in the surgical
margins’ four augmented breast cancer women were recategorised based on the medical
record information; in two cases, the biopsy specimen had been reported instead of
the final specimen, in one case, the parameter was missing in the DBCG, but was found
in the medical record, and in the last case, there were free margins, although narrow,
and the patient was recategorised as having free margins. None of the 23 control subjects
was recategorised regarding this variable, since there was complete agreement between
the medical records and the DBCG-data.
Statistical analyses
Frequencies were calculated for all variables. The differences between the women with
breast implants (cases) and women from the background population (controls) in binary
variables were evaluated with χ
2 tests, and crude odds ratios (OR) and corresponding 95% confidence intervals (CI)
were calculated. The difference in tumour size between the two groups was evaluated
by analysis of variance. In order to preserve power in the tests, the matching variables
were not included as covariates, because of the small number of breast cancer cases
with cosmetic breast implants and the large range of values of these matching variables.
All tests were performed with a 5% level of significance. Overall survival rates,
including death from all causes, were estimated by the Kaplan–Meier method and a log-rank
test was used for comparisons between the groups. Disease-free survival was not evaluated,
as information on first recurrence was unavailable for the seven cases and 52 controls
who did not participate in a postoperative treatment protocol.
RESULTS
In total, 23 of 2955 women (0.8%) with cosmetic breast implants developed breast cancer
after implantation. The mean age at the time of breast cancer diagnosis among these
women as well as controls was 47.2 years, range 35–75. The mean year of cancer diagnosis
was 1993, range 1986–2000. The women had undergone breast implantation at an average
age of 38 years (range 22–61 years), yielding an average interval from implantation
to breast cancer diagnosis of 9.3 years (range 0.3–17.9 years). A total of 21 women
had silicone breast implants, while implant type was unknown for the remaining two,
but they most likely also had silicone implants, since this was the preferred implant
in Denmark during the relevant period. The majority of women in the study were premenopausal
at the time of breast cancer diagnosis, which was to be expected in this relatively
young study population. Fewer of the cases were premenopausal compared to the controls,
although the difference was not significant (61 and 74%, respectively, OR=0.5; 95%
CI 0.2–1.3).
As presented in Table 1
Table 1
Breast cancer tumour characteristics of women with cosmetic silicone breast implants
prior to cancer diagnosis (cases) and breast cancer cases from the background population
(controls)
Cases (n=23)
Controls (n=253)
Characteristic of woman or tumour
n
%
n
%
OR (95% CI)a
Tumour histology (WHO)
Ductal
16
70
212
84
0.5 (0.2–1.6)b
Lobular
5
22
18
7
P=0.26
Other
0
0
18
7
Unknown
2
9
5
2
Tumour hormone-receptor status
Negative
6
26
52
21
1.7 (0.6–4.9)
Positive
10
43
148
59
P=0.32
Unknown
7
30
53
21
Tumour diameter (mm) (mean, range)
20.5
Range 9–50
25.2
Range 3–110
P=0.48
Unknown
3
13
10
4
Ductal carcinomas, malignancy grade (dedifferentiation)
Grade I
6
26
52
21
1.7 (0.6–5.0)c
Grade II
9
39
110
43
P=0.31
Grade III
1
4
40
16
Nonductal or unknown
7
30
51
20
Breast cancer operation
Mastectomy
15
65
184
73
0.6 (0.3–1.6)d
Lumpectomy
6
26
60
24
P=0.34
Lumpectomy followed by mastectomy
0
0
4
2
Biopsy only
2
9
5
2
Tumour cells in surgical margins (DBCG-data)
Yes
7
30
24
9
4.2 (1.5–11.4)
No
14
61
201
79
P=0.003
Unknown
2
9
28
11
Tumour cells in surgical margins (medical record information)
e
Yes
5
22
24
9
2.5 (0.8–7.3)
No
17
74
201
79
P=0.09
Unknown
1
4
28
11
Axillary surgery
Five or less lymph nodes removed
4
17
40
16
1.2 (0.4–3.6)
More than five lymph nodes removed
18
78
210
83
P=0.79
Unknown
1
4
3
1
Mean number of lymph nodes removed
11.4
Range 0–32
11.3
Range 0–31
P=0.16
Axillary lymph node metastases
Node-negative
11
48
130
51
0.9 (0.4–2.2)
Node-positive
11
48
120
47
P=0.86
Unknown
1
4
3
1
Mean number of lymph nodes affected
2.7
Range 0–20
2.2
Range 0–24
P=0.10
Women with distant metastases at time of diagnosis
1
4
4
2
P=0.36
a
Women with implants (cases) compared with women from the background population (controls).
Women with missing information with regard to the variable under study were excluded
from the analysis.
b
Ductal carcinomas vs all other cancers.
c
Malignancy grade I vs malignancy grade II and III grouped together.
d
Mastectomy vs lumpectomy. In case of conversion from lumpectomy to mastectomy, the
category was mastectomy. In cases of biopsy only, the category was lumpectomy.
e
Based on medical record information for 22 cases and 23 controls. For the remainder,
the DBCG-data were used.
, most of the tumours were ductal carcinomas, and either receptor positive or with
unknown receptor status, with no significant differences between the two groups. Tumour
diameter tended to be larger among controls than among cases, but the difference was
not significant. Tumour dedifferentiation, evaluated by grade of malignancy, did not
differ between the two groups. The majority of women among both cases and controls
were treated with mastectomy, which reflected the general treatment approach in Denmark
during the period. Based on the DBCG-data, the women with breast implants were four
times more likely than women in the control group to have tumour cells in the surgical
margins (OR=4.2; 95% CI 1.5–11.4). Using the medical record data on surgical margins
rather than the DBCG-data altered the statistical inference; the difference between
cases and controls diminished and became nonsignificant (OR=2.5; 95% CI 0.8–7.3).
Lymph node dissection was performed equally between implant women and controls. In
total, 48% of the women in both groups had regional lymph node involvement and also
to a similar extent. One patient in the implant group had distant metastases at the
time of diagnosis compared with four in the control group (P=0.36).
As shown in Table 2
Table 2
Adjuvant treatment according to DBCG-protocols of women with cosmetic silicone breast
implants prior to cancer diagnosis (cases) and women from the background population
(controls)
Cases (n=23)
Controls (n=253)
Adjuvant treatment according to protocola
n
%
n
%
OR (95% CI)b
Subsequent adjuvant treatment (any)
No
6
26
63
24
1.2 (0.4–3.2)
Yes
14
61
175
69
P=0.73
Unknown
3
13
15
6
Subsequent chemotherapy
No
11
48
98
39
2.3 (0.8–6.9)
Yes
5
22
103
41
P=0.12
Unknown
7
30
52
21
Subsequent endocrine therapy
No
11
48
157
62
0.6 (0.2–1.9)
Yes
5
22
44
17
P=0.39
Unknown
7
30
52
21
Subsequent radiotherapy
No
10
43
129
51
0.8 (0.3–1.8)
Yes
12
52
119
47
P=0.56
Unknown
1
4
5
2
a
See The DBCG Secretariat (1998).
b
Women with implants (cases) compared with women without implants (controls). Women
with missing information with regard to the variable under study were excluded from
the analysis.
, there was no difference in intended adjuvant treatment between the two groups. According
to standard adjuvant treatment protocols, 61% of the women with breast implants and
69% of the controls were allocated to adjuvant treatment (Table 2). Approximately
50% of all patients among both cases and controls were scheduled for radiotherapy,
including those with nonradical surgical margins. There were differences, although
not significant, in systemic adjuvant treatment, with more implant women receiving
endocrine therapy and more controls receiving chemotherapy. This pattern most likely
reflects the differences in menopausal status, which influence the choice of treatment,
since premenopausal women are more likely to receive chemotherapy.
In the survival analyses, the follow-up time was on average 6.4 years (range 0.3–15.7
years). Four women with breast implants died (17%), while 66 (26%) of the control
subjects died. As illustrated in a Kaplan–Meier plot (Figure 1
Figure 1
Overall survival after breast cancer in 23 women with cosmetic breast implants prior
to cancer diagnosis (cases) and 253 breast cancer cases from the background population
(controls).
), the 5-year survival estimate for implant women is 86% compared with 78% among the
controls (P=0.36). The medical records stated that in 13 (57%) of the 23 breast cancer
cases with implants, the implant was removed during the cancer surgery and in eight
women (35%) it was left in situ. In one case, the implant had been removed prior to
the cancer diagnosis, and in another case the medical records could not be traced.
All five of the implant women who, according to the medical records, had tumour cells
in the surgical margins were treated with mastectomy, and four of them also had explantation;
for the last case this information was not available. The nonradical margins were
found in the final mastectomy-specimen, and the women accordingly received postoperative
adjuvant radiotherapy. Two of the implant women were treated with skin-sparing mastectomy,
one kept her implant and the other was reconstructed with an immediate TRAM flap,
but neither of these patients was among those with nonradical margins.
From the medical records we ascertained that 16 (70%) of the implant women discovered
the tumour themselves. The remaining were diagnosed as follows: two were diagnosed
clinically by physicians during diagnostic work-up because of other diseases, one
was found by a plastic surgeon in a consultation related to capsular contracture,
two were diagnosed after a biopsy performed during an operation for a presumed breast
infection, and two were unknown. An equal proportion of the control subjects whose
medical records were retrieved had found the tumour themselves. None of the augmented
women with breast cancer and a potential maximum of five controls participated in
mammography screening for breast cancer, evaluated by knowledge of the mammography
screening centres active in the relevant areas and calendar period.
DISCUSSION
The results of our study of breast cancer among women with cosmetic breast implants
indicate that the cancer was not diagnosed later or at a more advanced stage than
in the normal population. The women with augmented breasts in our study did not differ
from controls with regard to relevant tumour characteristics at diagnosis. More of
the women with implants had tumour cells in the surgical margins, but we observed
no evidence of an unfavourable survival within our rather limited follow-up time.
Clinical case series have reported a tendency towards a delayed breast cancer diagnosis
among women with breast implants (Gottlieb et al, 1984; Leibman and Kruse, 1990; Silverstein
et al, 1990a; Carlson et al, 1993; Fajardo et al, 1995). Overall, epidemiological
studies have not been able to confirm such reports. Two large cohort studies (Birdsell
et al, 1993; Deapen et al, 2000), which compared breast implant women with breast
cancer to breast cancer cases in the background population, reported findings similar
to ours. There were no significant differences with regard to stage of disease at
diagnosis or survival. Information on the cases and controls was obtained from medical
records and cancer registers, respectively, so information bias cannot be ruled out.
Also in concordance with our findings, a clinical study (Cahan et al, 1995) comparing
22 augmented breast cancer patients with all other breast cancer patients in the same
surgical clinic found no differences in stage of disease at diagnosis. It was concluded
that nonpalpable and preinvasive breast cancer can be detected in the augmented patient.
A similar study (Clark et al, 1993) of all breast cancer cases in augmented women
diagnosed at the study clinic found that augmented women tended to have smaller tumours
and more often their tumours were diagnosed at physical examination (by themselves
or their physician) than other breast cancer patients diagnosed at the clinic. Significantly
fewer of the augmented women had nodal involvement (19 vs 41% in the comparison group).
However, in both the above studies, it was not stated how the patients were referred
to the clinic, and selection bias may have influenced the results. In another cohort
study (Brinton et al, 2000b), 78 cases of breast cancer in women with breast implants
were compared with breast cancer cases in a control cohort of women who had undergone
other kinds of cosmetic surgery. A tendency towards more advanced stages in cases
compared with controls was reported. However, the differences were not statistically
significant. As in our study, no differences in overall survival were noted.
The presence of breast implants, silicone or saline, makes mammography more difficult
(Gumucio et al, 1989). The implant obscures some of the parenchyma, and breasts with
subglandular positioned implants with capsular contracture are the most difficult
to examine (Carlson et al, 1993). Specific techniques have been developed to increase
the efficacy of mammography among augmented women (Eklund et al, 1988). A methodological
study (Silverstein et al, 1990b) compared preoperative mammograms with postaugmentation
mammograms in 62 healthy women, and found that the implants obscured from 9 to 44%
of the glandular tissue, depending on implant location, mammography view and technique.
Obtaining a baseline mammography prior to and perhaps even after implantation has
been recommended (Leibman and Kruse, 1990; Silverstein et al, 1992).
Overall, the results of the above mammographic and epidemiological studies point in
different directions regarding delayed breast cancer diagnosis among implanted women.
Since most of the women in our study found the tumour themselves, a potential impairment
of mammography could not be evaluated. It is possible that in a population of women
undergoing regular breast cancer screening with mammography, women with breast implants
could be diagnosed at a later state than women without implants. None of the studies
to date has sufficient data to answer this question. However, the presence of breast
implants, especially submuscularly positioned implants, often makes both clinical
examination and self-examination of the breast tissue easier, since the glandular
tissue can be palpated against a firm background, and this may account for the lack
of delay in diagnosis (Clark et al, 1993). Women who receive breast implants tend
to focus on health issues and be self-attentive (Anderson, 1998), and to have less
breast tissue, thus probably making them more likely to find a breast tumour even
at an early stage.
Both cases and controls in our study received on average the same surgical and adjuvant
treatment. However, more implant women had residual tumour cells in the surgical margins,
even though this excess was not statistically significant when based on information
from the medical records. Medical record information is likely to be more complete
than the DBCG register data, but was only obtained for a small subset of the controls,
and this could introduce selection bias. If we had reviewed the medical records from
all the background controls, which was not feasible because of problems with the availability
of the records, we may have encountered controls who would qualify for reclassification,
and this could have affected our calculations in an unknown direction.
We had an a priori expectation that women with implants would be more likely to request
breast preservation than other women and speculated that this could account for the
excess of women with nonradical margins. However, similar proportions of women in
the two groups were treated with mastectomy, including all the women with nonradical
margins. Free surgical margins are a strong predictor of both local control of the
disease and survival (Clemons et al, 2001; Medina-Franco et al, 2002); however, cases
did not have a poorer survival than controls. The average follow-up time of 6.4 years
is limited with respect to evaluating survival, since death from breast cancer can
occur several years after the cancer diagnosis, and the study population is small,
so the results should be interpreted with caution. To our knowledge, no other study
has reported on the risk of nonradical tumour resection among women with breast implants,
and this issue needs further attention.
We found few cases of breast cancer in the cohort of women with cosmetic breast implants.
Previous findings based on the same cohort (Mellemkjaer et al, 2000) identified 16
cases of breast cancer among 2740 women with cosmetic breast implants under 55 years
of age. Compared to the 17.3 expected cases, this yielded a standardised incidence
ratio (SIR) of 0.9 (95% CI 0.5–1.5). Others have reported similar findings and concluded
that women with cosmetic breast implants are not at increased risk of subsequent breast
cancer (Berkel et al, 1992; Deapen et al, 1997; McLaughlin et al, 1998; Brinton et
al, 2000b); on the contrary, a recent meta-analysis reported a 30% reduction of breast
cancer risk among women with breast implants (RR=0.72; 95% CI 0.61–0.85) and it was
concluded that breast implants may confer a protective effect against breast cancer
(Hoshaw et al, 2001). Several explanations for this protective effect have been put
forward: activation of the immune response as result of foreign body reaction may
enhance detection and degradation of precancerous lesions; compression of the glandular
tissue from the implant may diminish blood perfusion, which may alter cellular metabolism,
and a local decrease in body temperature caused by the implant could diminish cellular
metabolism (Deapen et al, 1997; Brinton et al, 2000b; Hoshaw et al, 2001). However,
different preoperative characteristics among women seeking breast implantation compared
with other women could perhaps more likely account for the decreased breast cancer
risk among implant women. This includes less use of oral contraception (Kjøller et
al, 2003), less alchohol use (Fryzek et al, 2000; Kjøller et al, 2003), lower age
at first birth, higher parity, and lower BMI (Cook et al, 1997; Brinton et al, 2000a;
Fryzek et al, 2000; Kjøller et al, 2003). Amount of glandular tissue may also play
a role although this has been highly debated, mostly because of the problems of evaluating
the true glandular mass of the breast (Hsieh and Trichopoulos, 1991; Tavani et al,
1996; Thurfjell et al, 1996; Egan et al, 1999) However, in both Swedish and Danish
investigations of women who underwent breast reduction surgery, large statistically
significant reduction in breast cancer incidence of 30–50% were observed, respectively
(Boice et al, 1997,2000). In a recent study based on the same Swedish cohort of women
with breast hypertrophy, a reduction in breast cancer risk proportionate to the amount
of resected breast tissue was reported (Brinton et al, 2001). These studies support
the concept of the amount of breast tissue being a risk factor in breast cancer.
The primary limitations of our study are the small number of breast cancer cases among
augmented women and the relatively short follow-up time, which suggest that survival
estimates be interpreted with caution. Potential bias exists, since more augmented
breast cancer cases were treated outside adjuvant protocols, and there may be differences
in the quality of information between the two groups, which thus may not be as comparable
as intended. However, since information was sampled from the same registries, this
potential bias is less of a concern than in other studies in which different data
sources were used. The strengths of this study include the ability to have virtually
complete follow-up of a well-defined cohort of women with cosmetic breast implants
and to obtain highly detailed clinical and staging information for both cases and
controls from the DBCG-register, which permitted evaluation of numerous important
tumour- and treatment-related parameters. In addition, linkage with the Danish Cancer
Register allowed complete ascertainment of all breast cancer cases.
In conclusion, the present study suggests, consistent with several other epidemiological
studies, that the stage of breast cancer at diagnosis in breast-implanted woman does
not appear to be more advanced compared with age- and calendar-matched controls, indicating
that the diagnosis is not meaningfully delayed because of the implants, and that overall
survival appears not to be influenced by the presence of implants. We suggest that
the issue of nonradical surgical margins be investigated in future studies.