Risk of Invasive Breast Carcinoma Among Women
Diagnosed with Ductal Carcinoma In Situ and Lobular
Carcinoma In Situ, 1988-2001
Christopher I. Li, M.D., Ph.D.
Kathleen E. Malone, Ph.D.
Babette S. Saltzman, M.S.
Janet R. Daling, Ph.D.
Fred Hutchinson Cancer Research Center, Division
of Public Health Sciences, Epidemiology Program,
This study was supported by the National Cancer
Institute (NCI), through a contract with the Fred
Address for reprints: Christopher I. Li, M.D., Ph.D.,
1100 Fairview Avenue North, M4-C308, Seattle,
WA 98109-1024; Fax: (206) 667-5948; E-mail ad-
Received October7, 2005; revision received No-
vember 15, 2005; accepted December 19, 2005.
BACKGROUND. Incidence rates of ductal carcinoma in situ (DCIS) and lobular
carcinoma in situ (LCIS) have been rising, but little is known about which patients
will develop invasive breast cancer or what types of tumors these patients may
METHODS. By using Surveillance, Epidemiology and End Results (SEER) data, the
authors evaluated how types of invasive breast cancers diagnosed among 37,692
DCIS and 4490 LCIS patients differed and how clinical characteristics influenced
subsequent breast cancer risk.
RESULTS. Among DCIS patients, incidence rates of ipsilateral and contralateral
invasive breast cancer were 5.4/1000 person-years and 4.5/1000 person-years,
respectively; and among LCIS patients, incidence rates were 7.3/1000 person-years
and 5.2/1000 person-years, respectively. LCIS patients were 5.3-fold more likely
than DCIS patients to develop invasive lobular carcinomas. Women whose DCIS
had comedo histologic features or was poorly differentiated had 1.4-fold and
2.0-fold elevations in ipsilateral invasive breast cancer risk. Furthermore, among
DCIS patients, 20-49 year-olds and black women and Hispanic white women had
1.6, 2.7, and 2.3-fold elevated risks of Stage III/IV breast cancer compared with
50-59 year-olds and non-Hispanic whites, respectively.
CONCLUSIONS. Screening young DCIS patients more frequently and improving the
follow-up care of blacks and Hispanic whites with DCIS may reduce their risk of
advanced-stage breast cancer. In addition, LCIS may be a precursor rather than
just an ambiguous risk factor for invasive breast cancer, and, therefore, localized
treatment for LCIS may be warranted. Given that incidence rates of DCIS and LCIS
have been rising, investigations of these tumors should be continued to better
understand their etiology and appropriate clinical management. Cancer 2006;106:
2104–12. © 2006 American Cancer Society.
KEYWORDS: breast cancer, ductal carcinoma in situ, DCIS, lobular carcinoma in situ,
LCIS, second primary cancers.
spectively, from 1980-2001.1These trends have been attributed pri-
marily to the increasing numbers of mammograms and biopsies of
suspicious lesions that are being performed.2,3DCIS is generally
thought to be a precursor lesion of invasive breast cancer, and com-
pared with women in the general population, women diagnosed with
DCIS have a 2.0-fold to 8.6-fold higher risk of developing invasive
breast cancer.4–7Alternatively, lobular carcinoma in situ (LCIS) is
viewed as a marker of an increased risk of invasive breast cancer,
rather than as a true precursor lesion.8Compared with women in the
ncidence rates of both ductal carcinoma in situ (DCIS) and lobular
carcinoma in situ (LCIS) have increased 7.2-fold and 2.6-fold, re-
© 2006 American Cancer Society
Published online 10 April 2006 in Wiley InterScience (www.interscience.wiley.com).
general population, women with LCIS have a 3.0-fold
to 4.2-fold higher risk of invasive breast cancer.3–6
LCIS is a challenging disease to study because, unlike
DCIS, it lacks clinical signs and is almost always an
incidental finding in breast biopsies performed for
another reason, such as a suspicious mammogram.
Although LCIS has long been thought to not be asso-
ciated with any specific mammographic findings,
more recent data indicate that calcifications are seen
in 21% to 67% of LCIS cases.9–11Clinically, LCIS and
DCIS are viewed quite differently. Unlike DCIS, LCIS is
commonly viewed as a nonsurgical disease because
several small studies found that LCIS patients are just
as likely to develop invasive tumors in the breast ip-
silateral to their LCIS as they are in their contralateral
breast.12–16On the basis of these studies, it has been
argued that the only definitive surgical treatment for
LCIS is a bilateral mastectomy, an unnecessary oper-
ation for an estimated 75% of LCIS patients.17
Using data on DCIS and LCIS patients diagnosed
from 1988 to 2002 in 11 cancer registries that partici-
pate in the Surveillance, Epidemiology, and End Re-
sults (SEER) Program, we evaluated how types of in-
vasive breast cancers that women with DCIS and LCIS
develop differ and how characteristics of carcinomas
in situ influence risk of subsequent invasive breast
MATERIALS AND METHODS
Women diagnosed with unilateral DCIS or LCIS be-
tween January 1988 and December 2002 without a
prior history of any type of in situ or invasive cancer
were identified through 11 population-based cancer
registries in the United States that participate in the
National Cancer Institute’s SEER Program. January
1988 was chosen as the starting point for this analysis
because beginning in 1988, all of the SEER registries
began to uniformly record data on estrogen receptor
and progesterone receptor status. Patient medical
records are the principal source of data used by SEER.
It is estimated that over 95% of all incident cancer
cases in the populations under surveillance are ascer-
tained. Additional operational details and methods
used by the SEER Program are provided elsewhere.18
A total of 49,852 potentially eligible in situ carci-
noma cases were identified from SEER. In situ carci-
noma cases with less than 6 months of follow-up were
excluded (n ? 3981) to ensure that at least 6 months
separated a woman’s in situ carcinoma diagnosis from
her invasive carcinoma diagnosis. DCIS cases were
defined based on the following International Classifi-
cation of Diseases for Oncology (ICDO-3) codes: 8201,
8230, 8500, 8501, 8503, 8507, and 8523 (n ? 37,692);
LCIS cases were defined based on 1 of the following
ICDO-3 codes, 8520 and 8524 (n ? 5138). DCIS cases
were also grouped by subtype into the following 5
categories, DCISnot otherwise
ICDO-3 codes: 8500 and 8523), comedocarcinoma
(ICDO-3 code: 8501), papillary (ICDO-3 code: 8503,
8507), cribiform (ICDO-3 code: 8201), and solid
(ICDO-3 code: 8230). All of these categorizations are
based on a scheme that has been used previously.1
Women with other types of carcinoma in situ (CIS),
including tumors containing both DCIS and LCIS were
excluded from this analysis because there were too
few cases of these types of CIS to evaluate them sep-
arately (total n ? 3041). In addition, all LCIS cases
treated with a total mastectomy were excluded from
all analyses (n ? 648, 12.6% of the total). This exclu-
sion was made because data on whether or not
women were treated with a unilateral or a bilateral
mastectomy was available from SEER only from 1998-
2002. Data from 1998-2002 indicated that 65% of LCIS
patients treated with a total mastectomy received a
bilateral mastectomy. Thus, given the high proportion
of bilateral mastectomies occurring among LCIS pa-
tients and the finding that those receiving this treat-
ment have an extremely low risk of developing subse-
quent invasive breast cancer, we elected to exclude all
LCIS patients treated with a mastectomy. This same
criterion was not applied to DCIS patients because
only 11% of DCIS patients treated with a total mastec-
tomy received a bilateral mastectomy based on the
1998-2002 SEER data.
All cases of both DCIS and LCIS were followed for
diagnosis of a subsequent invasive breast cancer.
Cases of invasive breast cancer were defined as those
that were diagnosed 6 months or longer after a CIS
diagnosis. As a result, DCIS and LCIS cases with less
than 6 months of follow-up were excluded from anal-
ysis. Vital status and follow-up information are ascer-
tained annually through a variety of local, regional,
and national sources. Follow-up duration is calculated
in months using the date of diagnosis and whichever
of the following occurred first, 1) date of death, 2) date
last known to be alive, or 3) December 2002 (the
follow-up cutoff date used in our analysis). In our
analysis, subjects were censored as cases at the time
they were diagnosed with invasive breast cancer. The
remaining subjects were censored at 1) date of death,
2) date last known to be alive, 3) December 2002, or 4)
the date they were diagnosed with a second in situ
carcinoma (n ? 936), whichever occurred first.
Along with age and year of diagnosis, SEER also
provides information on race/ethnicity, laterality of
the tumor, American Joint Committee on Cancer
stage, tumor size, tumor grade, number of positive
lymph nodes, number of lymph nodes examined, his-
Invasive Breast Cancer After In Situ/Li et al. 2105
tology, estrogen-receptor status, and progesterone-re-
ceptor status. Information on surgical and radiation
treatments administered within 4 months of diagnosis
is available, but data on adjuvant hormonal therapy
are not. For this study, we divided information on
cancer-directed surgical treatment received for CIS
into 3 categories, 1) none, 2) partial or less than total
mastectomy (i.e., excisional biopsy, lumpectomy, seg-
mental mastectomy, quadrectomy, tylectomy, wedge
resection, nipple resection, and partial mastectomy,
NOS), and 3) total mastectomy (i.e., modified radical
mastectomy, radical mastectomy, and total mastec-
tomy, NOS). In addition, for women who received
either a partial or less than total mastectomy or a total
mastectomy, we created a variable indicating whether
or not lymph node resection was a part of the surgical
treatment based on the data available from SEER. In
our assessments of incidence rates of ipsilateral breast
cancer among DCIS patients, analyses were restricted
to women whose DCIS was not treated with a total
mastectomy, given the very low risk of ipsilateral in-
vasive breast cancer that these women have.
All statistical analyses were performed using Stata
SE for Windows (College Station, TX). Multivariate
adjusted hazard ratios (HR) and 95% confidence in-
tervals (95% CI)) were computed using the Cox pro-
portional hazard model.19Two sets of analyses were
performed. First, we compared the histologic types of
invasive breast cancers that women with DCIS devel-
oped to the types that women with LCIS developed (2
categories were evaluated, ductal [ICDO-3 code: 8500]
and lobular [ICDO-3 codes: 8520 and 8522]). Because
all LCIS patients treated with a mastectomy were ex-
cluded from our main analyses, for this analysis,
which compared DCIS patients to LCIS patients, we
also excluded DCIS patients treated with a total mas-
tectomy to make these 2 groups more comparable.
This analysis was adjusted for age and year of CIS
diagnosis, SEER registry, race/ethnicity, and whether
or not cancer-directed surgical treatment for the CIS
In our second set of analyses, we evaluated how
specific features of DCIS (such as age at diagnosis,
race/ethnicity, treatment, histologic subtype, tumor
size, and tumor grade) relate to risk of developing an
invasive breast cancer, and we evaluated how features
of LCIS relate to risk of developing an invasive breast
cancer. (Note: the relations between LCIS radiation
treatment, tumor size, and grade and risk of invasive
breast cancer could not be assessed because of miss-
ing data and the relatively small number of women
diagnosed with LCIS.) We also stratified these analyses
by the laterality of the invasive breast cancer. Again,
our analyses of factors associated with risk of ipsilat-
eral invasive breast cancer among DCIS patients were
restricted to patients whose DCIS was not treated with
a total mastectomy. All hazard ratios for risk of inva-
sive breast cancer after DCIS were adjusted for age
and year of DCIS diagnosis, race/ethnicity, SEER reg-
istry, and surgery/radiation treatments for DCIS. All
hazard ratios for risk of invasive breast cancer after
LCIS were adjusted for age and year of LCIS diagnosis,
race/ethnicity, SEER registry, and surgical treatments
for LCIS. In addition, hazard ratios for DCIS and LCIS
treatments were adjusted for whether or not lymph
node resection was a part of the surgical treatment.
LCIS cases had a slightly younger mean age at diag-
nosis compared with DCIS cases (54.3 ? 11.0 vs.
58.6 ? 12.9; Table 1). LCIS patients were much more
likely than DCIS patients not to have received cancer-
directed surgery (8.2% vs. 2.2%) or radiation therapy
(97.8% vs. 64.5%). Among patients treated with a par-
tial or less than total mastectomy, 97.6% (3951 of 4046)
of LCIS patients did not receive radiation, whereas
only 45.9% (10,883 of 23,687) of DCIS patients treated
with a partial or less than total mastectomy did not
receive radiation (data not shown).
Of the 37,692 DCIS cases, 1504 (4.0%) were diag-
nosed with invasive breast cancer for an age-adjusted
incidence rate of 8.0/1000 person-years over the entire
study period (Table 2). Of the 4490 LCIS cases, 282
(6.2%) were diagnosed with invasive breast cancer for
an age-adjusted incidence rate of 12.5/1000 person-
years. Stratified by laterality, the incidence rate of
ipsilateral invasive breast cancer among women with
DCIS was 5.4/1000 person-years, and was 4.5/1000
person-years for contralateral breast cancer. LCIS pa-
tients had an incidence rate of ipsilateral invasive
breast cancer that was 35% higher than that of DCIS
patients (rate ? 7.3/1000 person-years), but a rate of
contralateral breast cancer that was only 16% higher
than that of DCIS patients (rate ? 5.2/1000 person-
In an analysis restricted to DCIS and LCIS patients
not treated with a total mastectomy, compared with
DCIS patients, LCIS patients were 0.8-fold (95% CI,
0.7-1.0) less likely to be diagnosed with invasive ductal
carcinoma, and 5.3-fold (95% CI, 4.1-6.9) more likely
to be diagnosed with invasive lobular carcinoma (Ta-
We examined the effects of DCIS features on the
risk of subsequent ipsilateral and contralateral breast
cancer separately. Compared with women diagnosed
with DCIS at age 50-59 years, women diagnosed at
20-49 years of age had an elevated risk of ipsilateral
invasive breast cancer (Table 4). With respect to race/
2106 CANCER May 15, 2006 / Volume 106 / Number 10
ethnicity, blacks with DCIS had increased risks of both
ipsilateral and contralateral breast cancer compared
with non-Hispanic whites. Women with comedo, pap-
illary, and solid DCIS had modest increased risks,
whereas women with cribiform DCIS had a reduced
risk of ipsilateral breast cancer compared with women
with DCIS NOS, though only the risk associated with
comedo DCIS was statistically significant. Women
with solid DCIS also had an elevated risk of contralat-
eral breast cancer, but, again, this risk was within the
limits of chance. Finally, compared with women with
well differentiated DCIS, women with poorly differen-
tiated DCIS had an elevated risk of ipsilateral, but not
of contralateral, invasive breast cancer.
With respect to age, women diagnosed with DCIS
between the ages of 20-49 years had 1.4-fold (95% CI,
1.1-1.9) and 1.6-fold (95% CI, 1.0-2.6) elevated risks of
Stage II and Stage III/IV invasive breast cancers, re-
spectively, compared with women diagnosed with
DCIS at age 50-59 years (Table 5). Compared with
non-Hispanic white women, black women had ele-
vated risks of Stage II (HR ? 1.7; 95% CI, 1.2-2.4) and
Characteristics of DCIS and LCIS Cases Diagnosed in 11 SEER Registries, 1988-2001
DCIS (n ? 37,692)LCIS (n ? 4490)
Age at in situ carcinoma diagnosis
Mean age, y (SD)
Year of in situ carcinoma diagnosis
American Indian/Alaska Native
Surgery for in situ carcinoma
Partial/less than total mastectomy
without axillary node dissection
with axillary node dissection
Radiation therapy for in situ carcinoma
Surgery and radiation therapy for in situ carcinoma
Partial/less than total mastectomy only
Total mastectomy only
Surgery (any type) and radiation
DCIS: ductal carcinoma in situ; LCIS: lobular carcinoma is situ; SEER: Surveillance, Epidemiology and End Results Program.
* NA: not applicable because 648 LCIS cases treated with a total mastectomy were excluded from all of our analyses.
Invasive Breast Cancer After In Situ/Li et al. 2107
Stage III/IV breast cancer (HR ? 2.6; 95% CI, 1.5-4.4),
and Hispanic white women had an elevated risk of
Stage III/IV breast cancer (HR ? 2.3; 95% CI, 1.1-4.8).
Age, race/ethnicity, and type of cancer-directed
surgery among LCIS patients were not related to risk
of invasive breast cancer (data not shown).
Before interpreting results of this study, it is important
to acknowledge its limitations. First, the histologic
categorizations used were based on diagnoses made
by pathologists from multiple institutions, and diag-
nostic criteria likely varied across pathologists, thus
resulting in a certain degree of misclassification error.
In particular, SEER captures data on DCIS but not on
atypical ductal hyperplasia, and distinguishing be-
tween these two lesions can be quite challenging given
the somewhat vague criteria used for their diagnoses.
This same problem is also present for the distinction
between LCIS and atypical lobular hyperplasias
(which are also not recorded by SEER).20Studies eval-
uating the concordance between tumors classified as
DCIS or LCIS by SEER and those classified through a
centralized pathology review are needed to quantify
the magnitude of this misclassification, as none have
been reported in the literature.
Age-adjusted Incidence Rates of Invasive Breast Cancer Diagnosed Among Women With DCIS and LCIS by Months of Follow-Up and Laterality
of the Invasive Breast Cancer
All Cases of Invasive Breast Cancer Ipsilateral vs. Contralateral Invasive Breast Cancer
No. of CasesTotal AAIR
Total Dx IBC
Cases* Total AAIR†,‡
Cases* Total AAIR
DCIS (n ? 37,692)
24-59(33.5)986 8.22.6 4335.2548 4.6
LCIS (n ? 4490)
(47.2)1504 8.04.0 6655.4 832 4.5
DCIS: ductal carcinoma in situ; LCIS: lobular carcinoma in situ; AAIR: age-adjusted incidence rate per 1000 person-years; Dx IBC: patients diagnosed with invasive breast cancer.
* Data on laterality of the invasive breast cancer diagnosed in 6 DCIS cases and 1 LCIS case are missing.
†Age-adjusted incidence rates for ipsilateral cases among DCIS patients reflect rates among women whose DCIS was not treated with a total mastectomy only.
‡Rates for all cases, ipsilateral cases, and contralateral cases among LCIS patients reflects rates among women whose LCIS was not treated with a total mastectomy.
Risk of Ductal and Lobular Invasive Breast Cancer Among Women Diagnosed With LCIS (n ? 4270; 21,582 Person-years at Risk) Compared With
Women Diagnosed With DCIS (n ? 24,187; 110,560 Person-years at Risk)*
Histology of the Invasive
Invasive Cancers Diagnosed Among Women With DCISInvasive Cancers Diagnosed Among Women With LCIS
* Excluding both DCIS and LCIS patients treated with a total mastectomy.
†All hazard ratios (HR) are adjusted for age, year, registry, race/ethnicity, and surgery.
‡P ? .05
2108CANCER May 15, 2006 / Volume 106 / Number 10
Another limitation of this study is that we lacked
data on factors that could influence the development
of invasive carcinomas, such as use of hormonal ther-
apy, mammography utilization, family history of
breast cancer, and body mass index. Similarly, some of
the differences in risk we observed across treatment
groups may have been due to confounding by indica-
tion, as characteristics of a woman’s initial in situ
carcinoma or personal history may have affected her
treatment choice. The impact of these unmeasured
confounders on both directions and magnitudes of the
risks that we observed is uncertain. However, it is
important to acknowledge that this is an observational
study, so results of this study should not influence
current clinical guidelines in the absence of support-
ive data from randomized trials.
Despite these limitations, strengths of this study
are that it is population-based, includes women diag-
nosed in multiple geographic regions, and includes a
large sample size. This study also confirms results of
various other studies, thus lending credence to the
current study’s findings. For example, we found that
4.0% (1504 of 37,692) of subjects in our DCIS cohort
developed invasive contralateral breast cancer, which
is within the range of 2% to 6% reported in 4 prior
studies.21–23In addition, the relation between comedo
DCIS and risk of subsequent ipsilateral breast cancer
has been noted in other studies.21,22,24
Risk of Invasive Breast Cancer Following DCIS by Age at In Situ Carcinoma Diagnosis, Race/Ethnicity, In Situ Carcinoma Treatments, and
Histologic Subtype in All Women and According to Laterality of Subsequent Invasive Breast Cancer
All Cases Ipsilateral Cases* Contralateral Cases
HR 95% CIHR 95% CIHR 95% CI
Age at diagnosis, y†
Cancer directed surgery/radiation**
Partial/less than total mastectomy only
Surgery (any type) and radiation
Tumor size, cm§,††
DCIS: ductal carcinoma in situ; CI: confidence interval; ref: reference category; NOS: not otherwise specified.
* Hazard ratios (HR) for ipsilateral cases are restricted to women with DCIS whose DCIS was not treated with a total mastectomy.
†HRs for age at diagnosis are adjusted for year, registry, race/ethnicity, and surgery/radiation.
‡P ? .05
§HRs for race/ethnicity, subtype, tumor size, and grade are adjusted for age, year, registry, and surgery/radiation.
** HRs for surgery/radiation are adjusted for age, registry, race/ethnicity, and lymph node removal.
††Data on tumor size and grade are missing for 32% and 49% of cases, respectively.
Invasive Breast Cancer After In Situ/Li et al. 2109
Four potential implications of this study, when
considered in the context of other available evidence,
are as follows: 1) Because young women diagnosed
with DCIS had elevated risks of advanced stage breast
cancer, screening them more frequently may reduce
these risks; 2) Compared with non-Hispanic white
women, black women and Hispanic white women
with DCIS also have an elevated risk of advanced stage
breast cancer, suggesting that efforts to improve fol-
low-up care for black and Hispanic white women with
a history of DCIS are needed to reduce this health
disparity; 3) Rather than simply a marker of risk for
invasive breast cancer, LCIS may be a precursor lesion
of ILC; and 4) Given that rates of ipsilateral invasive
cancer are higher than rates of contralateral cancer
among women with LCIS, the treatment of LCIS as a
nonsurgical disease may need to be reconsidered.
Each of these implications is discussed in detail below.
We noted that women diagnosed with DCIS be-
tween the ages of 20-49 years had elevated risks of
advanced stage breast cancers compared with older
women. The reason for this is unclear, but it may be
related to differences in the biologic aggressiveness of
invasive tumors by age because younger women tend
to be diagnosed with more biologically aggressive tu-
mors. Thus, they may grow and spread more quickly
during the time between their follow-up mammo-
grams compared with the less aggressive tumors that
older women develop. So our findings suggest that
shorter screening intervals for women diagnosed with
DCIS at a young age, or perhaps screening them with
additional modalities, may be potential means of re-
ducing their risk of advanced stage breast cancer,
though these approaches require further study.
We also observed that black women and Hispanic
white women with DCIS had elevated risks of ad-
vanced stage breast cancer. These findings are consis-
tent with several studies indicating that black women
in the general population have higher risks of ad-
vanced stage breast cancer and of mortality after their
diagnosis than do white women.25,26These studies
suggest that these disparities are primarily related to
socioeconomic status and access to appropriate care
rather than to differences in tumor biology or genetic
susceptibility. A recent study observed that compared
with non-African American DCIS patients, African
American DCIS patients were significantly less likely
to receive radiation after their lumpectomy.27Two
previous studies have also evaluated risk of second
breast cancers by race. One found that black women
did not have an increased risk of a second primary in
situ or invasive contralateral breast cancer, though its
analyses were limited by a small sample size.7Consis-
tent with our results, the second study observed that
among women with localized invasive or in situ breast
cancer, black women had an increased risk of
contralateral breast cancer compared with white
women.28Thus, efforts to improve follow-up care for
black women and Hispanic white women diagnosed
with DCIS may be an important means of lowering
their risk of subsequent invasive breast cancer.
DCIS is generally considered to be a precursor
lesion for invasive breast cancer, whereas LCIS is typ-
ically thought of as a nonsurgical disease that is
viewed as a risk factor for, but not a precursor of,
invasive breast cancer. Our observation that women
with LCIS are 5.3-fold more likely to develop invasive
lobular cancer (ILC) and 0.8-fold less likely to develop
Risk of Invasive Breast Cancer Following DCIS by Age at DCIS Diagnosis and Race/Ethnicity Stratified by Invasive Breast Cancer Stage
Stage I Stage II Stage III/IV
HR 95% CI HR95% CI HR95% CI
Age at diagnosis, y*
DCIS: ductal carcinoma in situ; CI: confidence interval; ref: reference category.
* Hazard ratios (HR) for age at diagnosis are adjusted for diagnosis year, registry, race/ethnicity, and surgery/radiation.
†P ? .05
‡HRs for race/ethnicity are adjusted for age, year, registry, race/ethnicity, and surgery/radiation.
2110 CANCER May 15, 2006 / Volume 106 / Number 10
invasive ductal carcinoma (IDC) compared with
women with DCIS, may lead one to question the latter
description. These results are also consistent with a
previous report indicating that LCIS is often followed
by ILC,29and suggest that LCIS may be a precursor of
ILC specifically, as one might expect based on its
histopathologic characteristics. There is laboratory ev-
idence to support this. E-cadherin is a cell adhesion
molecule that is not expressed by almost all ILCs, but
this molecule is expressed by almost all IDCs. Acs et
al.30found that 96 of 100 (96%) IDCs expressed e-
cadherin, whereas 41 of 42 (98%) ILCs showed com-
plete loss of e-cadherin expression. Similarly, 128 of
131 DCIS (98%) cases expressed e-cadherin, whereas
50 of 53 LCIS (94%) cases had complete loss of e-
cadherin expression. Thus, e-cadherin not only distin-
guishes lobular from ductal carcinomas, but also loss
of its expression appears to be an early event in the
development of lobular carcinomas. So there is grow-
ing evidence suggesting that LCIS may be a precursor
of ILC, rather than just a marker of invasive breast
One of the reasons for our observation that
women with LCIS have a higher incidence rate of
invasive breast cancer, and particularly of ipsilateral
invasive breast cancer, may be because LCIS has been
historically viewed as a nonsurgical disease and, thus,
often not treated definitively. This is largely due to
results of several studies published from 1974 to 1991
that were based on cohorts of LCIS ranging in size
from 34 to 258 cases, with 6 to 54 incident invasive
breast cancers. These studies found that women with
LCIS were equally likely to be diagnosed with ipsilat-
eral and contralateral invasive breast cancers. Thus, it
has been argued that the only logical operation for
LCIS would be a bilateral mastectomy, which would
be unnecessary approximately 75% of the time.17Our
results challenge this notion, as we actually found that
incidence rates of ipsilateral invasive breast cancer
were higher among LCIS patients compared with DCIS
patients (7.3/1000 vs. 5.4/1000, respectively), whereas
rates of contralateral invasive breast cancer were more
similar between LCIS and DCIS patients (5.2/1000 vs.
4.5/1000, respectively). The reason for these differ-
ences may be that DCIS patients are more likely to
have definitive local surgical treatment than are LCIS
patients. Specifically, it is striking that only 95 of 4046
(2%) LCIS patients in this study who received a partial
or less than total mastectomy also received radiation,
whereas 12,804 of 23,687 (54%) DCIS patients who
received a partial mastectomy were treated with radi-
ation. Clearly, LCIS patients are routinely not receiv-
ing definitive local treatment, but, based on our study,
it appears that these women have a higher incidence
rate of ipsilateral invasive breast cancer than of con-
tralateral breast cancer, contrary to what has been
reported previously. Thus, local treatment for women
with LCIS may be warranted, although further studies
are needed to evaluate this.
In summary, this study provides greater insight
into the clinical significance of DCIS and LCIS over a
recent time period in which the incidence rates of
these two lesions has increased dramatically.1With
respect to DCIS, our results suggest that screening
women diagnosed with DCIS at a young age more
frequently may be one way to reduce their risk of
subsequent advanced-stage breast cancers. Further-
more, improving follow-up and screening of black
women and Hispanic white women with DCIS may be
an important means of reducing their risks of ad-
vanced-stage invasive breast cancer. With respect to
LCIS, our data indicate that LCIS may be a precursor
lesion of ILC rather than just an ambiguous risk factor
for invasive breast cancer and that localized treatment
for LCIS may be warranted given that these women
have much higher rates of ipsilateral invasive breast
cancer, but much more similar rates of contralateral
breast cancer, compared with DCIS patients. Given
that there are a growing number of women who have
been diagnosed with DCIS and LCIS, continued inves-
tigations of these tumors are needed to better under-
stand their etiology and to determine what treatments
may be most effective for improving overall and dis-
ease-free survivals of these women.
1. Li CI, Daling JR, Malone KE. Age-specific incidence rates of
in situ breast carcinomas by histologic type, 1980 to 2001.
Cancer Epidemiol Biomarkers Prev. 2005;14:1008-1011.
2.Ernster VL, Barclay J, Kerlikowske K, Grady D, Henderson C.
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2112 CANCER May 15, 2006 / Volume 106 / Number 10