Abstract. We investigated a cluster of three cases of inflam-
matory breast cancer (IBC) diagnosed within 10 months in an
office setting of 24 people. Information about medical history,
pregnancy history, family history of breast cancer, oral
contraceptive use/hormone replacement therapy, exposure to
possible oncogenic agents and tumor promoters were obtained
to determine whether there were differences in risk factors
for IBC between cases and controls. The physical environment
and location of the cases' office raised concern about air and
water quality as well as radiation as being contributory risk
factors for developing IBC. Of the three women with IBC,
two had high exposures to pesticides/herbicides, all three used
oral contraceptives and two used hormone replacement therapy
at the time of diagnosis, two had a family history of breast
cancer, and two were obese. Among fifteen controls four had
pesticide/herbicide exposure, one had a family history of breast
cancer, nine used oral contraceptives, seven used hormone
replacement therapy, and five were obese. No specific environ-
mental causes were established for this cluster. Several
promoting factors have been suggested that could result in
subclinical breast cancer emerging as IBC. Among them are
exogenous hormones and exposure to herbicides/pesticides.
Inflammatory breast cancer (IBC), a highly aggressive form
of breast cancer, is considered to be relatively rare (less than
4% of all breast cancers in the US) (1-4). Several studies
indicate that environmental factors may play an important
role in aggressive breast cancer (5-7). These studies document
the observation that the risk factors for aggressive breast
cancer, including IBC, are not the same as those for developing
breast cancer. For example one study found that organo-
chlorines do not increase incidence, but promote tumor
aggressiveness (7) and early age (20 or younger) at first preg-
nancy, a deterrent to developing breast cancer (8), is associated
with both aggressive disease as measured by tumor grade
(9) and the clinical manifestation of IBC (6).
Materials and methods
Study population. The three cases of IBC were diagnosed
within a 10-month period between May 1999 and March 2000
in an office of 24 long-term employees (23 females and 1 male)
in Castro Valley, California. All three of these cases worked
in a space on one side of the office with well documented
environmental health concerns.
The male and five of the females chose not to participate in
the study. The three cases and 15 controls were interviewed
to determine if specific risk factors for IBC could be identified.
The three cases moved into the second floor of the office
building in 1985, and they were the first to work in the space.
Environmental studies. Environmental surveys were conducted
for hazards in the office building as required by the California
Health Department (CHD). The office being studied was
located above a mammography and MRI imaging center.
Five measurements of air quality, a water sampling study,
three MRI surveys and evaluation of radiation leakage
between the mammography unit and the office were each
performed by contractors between February 1988 and April
2000. These environmental studies evaluate the office in its
entirety. All three cases had office spaces located on the side
of the office that had the worst air circulation according to
the employees and indoor air quality studies.
Interviews and questionnaires. The three cases were inter-
viewed in person by a researcher and detailed information on
ONCOLOGY REPORTS 24: 1277-1284, 2010
A cluster of inflammatory breast cancer (IBC) in an office
setting: Additional evidence of the importance of
environmental factors in IBC etiology
TINA J. DUKE1, NASREEN C. JAHED2, CARMELA C. VENEROSO2, RICARDO DA ROZA3, OWEN JOHNSON4,
DANIEL HOFFMAN2, SANFORD H. BARSKY5and PAUL H. LEVINE2
1Office of Water, U.S. Environmental Protection Agency, 1200 Pennsylvania Ave NW Washington, DC 20460;
2Department of Epidemiology and Biostatistics, The George Washington University School of Public Health and
Health Services; 3Eden Valley Medical Center; 4The Inflammatory Breast Cancer Foundation; 5Department
of Pathology, Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
Received May 12, 2010; Accepted July 5, 2010
Correspondence to: Dr Paul H. Levine, The George Washington
University School of Public Health and Health Services, 2100-W
Pennsylvania Ave NW, Suite 817 Washington, DC 20037, USA
Key words: inflammatory breast cancer, environmental factors,
oral contraceptives, hormone replacement therapy
history of any present illnesses, home and occupational
exposures, pregnancy history, and family history were
obtained. Subsequently, a trained interviewer conducted a
telephone interview of the two surviving cases and 15 controls
using a structured questionnaire developed for obtaining
demographic information about IBC risk factors. One of the
three cases died before the follow-up interview.
All study participants were asked about their menstrual
history, pregnancy history, exogenous hormone use, family
history of breast cancer, surgical removal of their ovaries,
medical history, exposures to possible cancer-causing pollutants
in the environment such as herbicides and pesticides, and
details of the participant's breast cancer diagnosis (cases only).
Exogenous hormone use included information on the use of
oral contraceptives (OC), hormone replacement therapy, and
hormones taken to help become pregnant or to maintain a
pregnancy. Information was obtained on the estimated number
of years that the case used the hormone. Pregnancy history
included number of live births and the age when the case gave
birth to her first child. Women who reported a first-degree
relative (mother, daughter or sister) had been diagnosed with
breast cancer or women who reported a second degree relative
(grandmother, aunt, first cousin) had been diagnosed with
breast cancer at a young age (less than 35) or diagnosed with
breast and ovarian cancer were considered to have a family
history of breast cancer. A woman was considered to have
been pre-menopausal if her menstrual periods had not ended
before her date of diagnosis and post-menopausal if her
menstrual periods ended before her date of diagnosis due to
either natural menopause or surgical removal of her ovaries.
The cases' average weight was considered their weight as an
adult before the date of diagnosis. The diagnosis of IBC was
confirmed by biopsy from the physician of the 3 cases, who
provided the pathology reports.
Laboratory studies. Tissue samples from the three cases of
IBC were reviewed by standard light microscopy. Paraffin
embedded sections (5 μm) were stained with hematoxylin
and eosin and reviewed pathologically by the same research
pathologist. Details about the pathology of the cases are
provided later in this document. After lymphovascular tumor
emboli were documented, additional sections were studied
immunocytochemically with specific antibodies, which have
been shown in recent studies to further define the inflammatory
carcinoma phenotype (10-13).
The antibodies used for the immunocytochemistry included
monoclonal antibodies to E-cadherin (clone HECD-1) at a
concentration of 1-10 μg/ml (Zymed Laboratories, San
Francisco, CA); MUC-1, (clone HMPV, mouse IgG1) (Phar-
Mingen), at a concentration of 1-100 μg/ml; sialyl-Lewis X
(sLeX) (clone CSLEX-1) and sialyl-Lewis A (sLeA) (clone
CCOL-2) (UCLA Tissue Typing Laboratory, Los Angeles,
CA) each at concentrations of 10 μg/ml; and control mouse
IgG1 (Dako, Denmark) at a concentration of 50 μg/ml. Non-
IBC and normal breast tissues were used as controls.
Case 1, D.R. This 53 year old Caucasian woman had her
breast cancer diagnosed during a routine mammogram on
May 15, 1999. She routinely had been getting mammograms
but missed a year because her mother was ill. Between
January of 1997 and May of 1999 she had developed a focal
area of density with clustered microcalcifications and
architectural distortion in the upper aspect of the right breast.
She had a normal clinical breast examination in April 1999
and there were no obvious clinical symptoms of IBC prior to
early May when she noticed a small area of redness approxi-
mately 3x3 cm, which was still there the following day. Her
only additional symptom was a stabbing pain in her breast
that did not subside until chemotherapy was initiated.
In one week, her breast had changed dramatically and was
more red and firm. A lump could be felt on the right side but
the redness was more medially located around the nipple. At
no time did the redness involve more than half of the breast.
She saw her surgeon who noted mid periareolar swelling and
a small area of erythema and an orange-peel look to the skin
(peau d'orange). The surgeon also noted a suspicious enlarged
lymph node in the right axilliary tail. His initial diagnosis at
that time was IBC, although her physical findings never
involved more than half of her breast. A breast biopsy on
June 2, 1999 showed a moderately differentiated invasive
ductal carcinoma with a comedo pattern. Of the 15 sections
of skin, one contained two definite foci of dermal lymphatic
invasion. The tumor was ER (80%) and PR (20%) positive
and Her2-neu negative.
She received neoadjuvant chemotherapy (four cycles of
adriamycin®and cyclophosphamide®) from June to August
1999 with a good response. Radiation therapy was given in
September and October of that year followed by seven cycles
of cyclophosphamide®, methotrexate®and 5-fluorouracil®
which ended in January 2000. In March 2000 she had a
right modified radical mastectomy plus a prophylactic left
mastectomy. No residual carcinoma was seen and there was
no evidence of tumor in the 12 lymph nodes removed. Three
cycles of Taxol®were given post operatively; a fourth course
was not given because of peripheral neuropathy. She has
remained free of disease since September 2000. (Last follow-
up: March 17, 2006).
Environmental data. She had taken oral contraceptives
for an eight year period but did not take hormone replacement
therapy because her sister had developed breast cancer. She
had been exposed to pesticides and herbicides as a result of
home use of these substances for 28 years.
Family history. She had a strong family history of breast
cancer; her mother died of breast cancer in her early 30's and
her sister died at 29 years old with breast cancer. Her maternal
and paternal grandmothers both had breast cancer, the former
at a young age.
Case 2, P.J. This 46-year old Caucasian female had her routine
mammogram in February, 1999 that was interpreted as being
normal with some calcifications. She was told to monitor them
for 6 months but she was concerned about the calcification
and saw her surgeon, the same surgeon who had seen Case 1.
He advised her to repeat the mammogram in three months.
At her follow up mammogram May, 1999 there were ‘little
She had a right breast biopsy June 24, 1999 using wire
localization technique. A follow-up mammography confirmed
DUKE et al: A CLUSTER OF INFLAMMATORY BREAST CANCER
that the lesion had been removed. The pathology report was
interpreted as showing benign, proliferative, fibrocystic changes
of the breast with calcification. No neoplastic component was
noted. On a follow-up visit she had mild breast soreness and
skin changes which were interpreted as dermatitis from the
Tegaderm®, which was the dressing used following her biopsy.
One week later, she felt that her breast was ‘hard as a rock’
but she attributed that to the biopsy. When she returned to the
surgeon July 21, 1999, reporting additional swelling with a
pressure sensation in the right breast, he noted visible swel-
ling with mild to moderate erythema, especially inferiorly.
He performed a direct aspiration near the incision to determine
if there was a hematoma, but no blood was aspirated.
The doctor's clinical impression was that the patient was
experiencing ‘diffuse soft-tissue infection cellulitis resulting
from the biopsy and wire technique’. An ultrasound on July
29, 1999 was interpreted as showing an irregular, amorphous
density in the outer aspect suggesting local inflammation but
no definite abscess and she was started on 500 mg Duricef®
po bid for two weeks. She did not respond and the dosage
was increased to 1 gm bid and Rifampicin®was added. An
ultrasound in late July showed no evidence of abscess. When
seen again by the surgeon August 12, 1999, she reported
improvement in her symptoms and was only taking Duricef.
On August 23, 1999 her breast was warm and red and in
September 1999 she saw an oncologist, who noted ‘an orange
peel look’ (peau d'orange), firmness of the entire right breast,
no tenderness, mild and diffuse erythema and enlarged right
axillary lymph nodes. Another ultrasound ruled out an abscess
and her surgeon asked the oncologist for a second opinion,
which led to a fine needle aspiration which was not diagnostic,
but revealed some atypical cells. Both doctors agreed on the
need for a biopsy and two new lumps were now noted for the
first time near the right axillary area. An open excisional
biopsy showed carcinoma and both dermal lymphatic and
perineural invasion were interpreted as IBC. The biopsy of an
axillary lump was interpreted as showing metastatic carcinoma.
The tumor was ER+(80%), PR+(50%) and Her2-neu-.
A whole body scan on September 23, 1999 was consistent
with metastatic disease in the skull, right scapula, posterior
ribs, multiple vertebrae, right sternoclavicular joint, posterior
iliac crests bilaterally, and right acetabulum. Chemotherapy
was initiated with Adriamycin®and Cytoxan®. After seven
cycles between October 1999 and January 2000 she responded
well. She was then given radiation therapy in February 2000
along with concomitant chemotherapy, methotrexate®and
5-fluorouracil®which was discontinued in April 2000. She was
treated with tamoxifen®and appeared to be in remission until
February 2001 when she developed skin nodules in her chest.
Biopsy confirmed the presence of metastatic disease and she
was started on weekly Taxol®. Persistent thrombocytopenia led
to a bone marrow biopsy which confirmed bone marrow
involvement with the tumor. Taxotere®and Arimidex®led to
significant clinical improvement until August 2001 when she
developed a malignant pleural effusion. Gemzar®was unsuc-
cessful and she died in late 2001.
Environmental data. She reported taking oral contraceptives
(Orthonovum®) intermittently since she was married in 1976,
but discontinued them because of problems with hypertension.
She had taken no oral contraceptives since 1997. Between
April and September 1999 she took Prempro®for mood swings
and hot flashes; she was perimenopausal at the time. She took
one pill per day as prescribed by her physician. She was taking
this HRT until the time of her diagnosis.
Family history. She had a strong family history of breast
cancer. She had two paternal aunts with both breast cancer
and ovarian cancer. The daughter of one of these aunts
developed breast cancer in her 30's. Prior to being prescribed
Prempro®, she was asked if she had a family history of breast
cancer. She originally said no, because she did not believe
breast cancer on the paternal side was important.
Case 3, C.J. This 54 year old Caucasian woman's symptoms
began with ‘nerve pains’ in early 2000 which coincided with
her menstrual cycle. She had seen her primary physician
December 15, 1999 and everything appeared normal. She
noted an inverted nipple and enlargement of her left breast
followed by a green discharge in February 2000. She thought
she had mastitis and saw her gynecologist to request a
mammogram and he conducted a breast exam at that time.
The left mammogram obtained February 23, 2000 showed
‘an area of ill-defined density in the upper outer quadrant of
the left breast showing microcalcifications and adjacent skin
thickening’ which had not been present in the previous study
of January 1999. After the mammogram, her breast began to
feel warm but she could not feel a discrete lump. On March 1,
2000 she saw her surgeon, who had also seen Case 1 and
Case 2, and his initial diagnosis was IBC. A chest X-ray the
same day was unremarkable. She then developed redness of
the breast and within two weeks the entire breast was red.
A left breast and skin biopsy were obtained March 3, 2000
that revealed moderately differentiated infiltrating ductal
carcinoma. Adenocarcinoma was present in the dermal
lymphatics and the skin also showed vascular invasion. Her
cells were 60% ER+and 5% PR+. She was first treated with
neoadjuvant chemotherapy between February and August
2000; four cycles of Adriamycin®and Cytoxan®(cyclophos-
phamide) followed by four cycles of Taxol®. She had a
complete clinical response. This was followed by radiation
therapy and 20 mg tamoxifen®20 p.o daily. In January 2001
she had a mastectomy and remained in remission until
January 2002 when she was discovered to have enlarged
cervical lymph nodes. A fine needle aspirate biopsy confirmed
the presence of metastatic carcinoma and she was treated
with Taxotere®until April 2002, when she developed shortness
of breath due to a malignant pleural effusion. Her chemo-
therapy was switched to Gemzar®and she was placed on an
aromatase inhibitor, Femara®. The treatment was not effective
and she died in May of 2002.
Environmental data. She was raised in a house near rail-
road tracks and she lived with her mother (an avid gardener),
until she was 23 years old. Every summer insecticide bombs
were used to kill insects and spiders. Sprays were applied
every three months to attack ants. She was also an avid
gardener who applied herbicides/pesticides twice per year for
her adult life. She took oral contraceptives for 11 years until
she had a hysterectomy for metrorrhagia. Subsequently she
took Premarin®from 1979 to 2001, a 22 year exposure to
exogenous hormones. The HRT was taken until the time of
ONCOLOGY REPORTS 24: 1277-1284, 2010
Family history. Her mother was adopted and there was no
family history of breast cancer in any known family members.
Office setting. The 18 women who participated in the study
worked on the second floor of a California office building
(Fig. 1). All cases and controls were long-term clerical
employees. The average length of employment for the cases
was 14 years and one month and 14 years 9 months for the
From 1986 to 1999 there had been numerous cases of
illness involving upper respiratory problems as well as eye,
nose and throat irritation, headaches, fatigue and lethargy,
skin irritation and rashes. The workers reported concerns about
ventilation in their office. According to air quality studies
performed between 1989 and 2000, the vents in the ceiling
were not supplying air to one side of the office floor; this was
the side which housed the office spaces that the cases occupied.
The ventilation system was turned off at night.
The office contained stored billing records printed on
carbonless copy paper (CCP). The CCP billing records were
stored on shelving at a temperature above 68 degrees Fahren-
heit in the same area where the cases and controls worked.
File boxes were stacked in front of windows that did not open
in an area where ventilation did not operate adequately when
A magnetic resonance imaging (MRI) center and mammo-
graphy center were both located on the first floor of the office
building (Fig. 1). The imaging center had occupied the
building for 10 years and the mammography center for seven
years. There was no shielding between the mammography
and MRI center on the first floor and the workspace on the
second floor. In January 1999 the mammography center
replaced their existing mammography machine with a new one
and in September 1999 the imaging center closed its business.
The office staff worked on a flexi-time schedule, and the
three cases were among the first employees to arrive at work
each day between 5:30 a.m. and 6:30 a.m. Two of the three
cases had workspaces above the mammography center
(Fig. 1). Their workspaces were also on the side of the
second floor where air quality studies performed between
1989 and 2000 determined insufficient air supply distribution.
The third case had an assigned desk directly above the MRI
center, but in the morning she would sit at a desk near the
other cases above the mammography center to socialize with
Environmental surveys. As mentioned earlier, the employees
expressed considerable concern about their working environ-
ment and potential exposures. The California Health Depart-
ment (CHD) required the employer to conduct a survey of the
environment for radiation and other environmental hazards in
the office building. Contractors conducted surveys and assess-
ments between January 1989 and April 2000. A summary of
their findings is presented in the paragraphs below.
In March of 1999 surveys of the static magnetic field
from the MRI on the second floor of the building were below
the lowest health guideline of 5.0 Gauss. These surveys were
conducted after the installation of new equipment. A 1999
radiation leakage survey was performed and the report stated
that no radiation could be detected on the second floor, despite
the absence of concrete between the two floors. As with the
MRI equipment, however, the old mammography equipment
had been replaced and the survey was conducted with new
equipment present. Only one water sampling study was
performed and the results indicated that the only organic
compounds detected were present at allowable California
maximum contaminant levels and were lower than typical
levels supplied by East Bay Municipal Utility District.
DUKE et al: A CLUSTER OF INFLAMMATORY BREAST CANCER
Figure 1. Castro valley office building.
There were five air quality studies performed. The first air
study in 1989 indicated that the levels of CO2and CO were
above the levels indicated by the American Society of Heating,
Refrigerating, and Air Conditioning Engineers (ASHRAE)
(14). Additional studies showed an unacceptable air exchange
in cubic feet per minute (CFM). Later indoor air quality studies
showed successful remediation of the ventilation problem
and compliance with ASHRAE guidelines.
Questionnaire results. The average age of the cases was
52.9 years and 54.4 years for the controls. The three cases
were Caucasians. The 15 controls included eleven Caucasians,
two Asians, one African American, and one Hispanic. The
three cases did not live in the same residential area, and
therefore did not share a common residential water supply or
other residential environmental factors. The average Body
Mass Index (BMI) (BMI was calculated with the following
formula: [Weight in pounds ÷ Height in inches] x 703 =
BMI kg/m2) of the cases was 32.3 kg/m2and for the controls
29.3 kg/m2. The one case that had children gave birth at age
19 and seven of the 15 controls (46.7%) had their first full
term pregnancy at age 20 or younger. The case did not
breastfeed any of her children and the controls breastfed an
average of 3.7 months. Two cases (66.7%) and 12 controls
(80%) were post-menopausal. Oral contraceptives were used
an average of 8.0 years for the cases and 4.9 years for controls.
Hormone replacement therapy was used an average of 6.7 years
for cases (who took HRT until diagnosis) and 2.1 years for
controls. Two of three cases (66.7%) had a positive family
history of breast cancer (the mother of the third case was
adopted and no data were available on the maternal side).
Only one of the fifteen controls (6.7%) had a family history
of breast cancer. The mother and sister of one case were
diagnosed with breast cancer. The second case had two aunts
and a cousin diagnosed with breast cancer at a young age and
the aunts both also developed ovarian cancer. The control
had two first-degree relatives diagnosed with breast cancer,
mother and sister respectively. Cigarettes were smoked 11 years
for one case and an average of 27.6 years for 5 controls. Pesti-
cides and herbicides were used an average of 27.5 years for
2 cases and 10.4 years for 5 controls.
Pathology. All three cases exhibited a histopathological
phenotype of florid lymphovascular invasion (tumor emboli
ONCOLOGY REPORTS 24: 1277-1284, 2010
Figure 2. Lymphovascular emboli. (A) Lymphovascular emboli display intense E-cadherin plasma membrane immunoreactivity. Similar observations were made
with MUC-1 immunoreactivity. (B) Lymphovascular emboli display absent sialyl-Lewis A immunoreactivity (left) compared to strong sialyl-Lewis A
immunoreactivity (right) exhibited by normal acini. Similar results were observed for sialyl-Lewis X. (C) Lymphovascular emboli are observed within dermal
lymphatics. Note the clear space which exists around the compact tumor embolus indicative of its retraction away from the vessel wall.
within lymphovascular spaces). Lymphovascular emboli within
dermal lymphatics were especially prominent (Fig. 2C).
These emboli appeared as compact clusters of tumor cells in
the central portions of the vascular lumens with apparent
retraction away from the vascular endothelial cells (Fig. 2C).
E-cadherin membrane immunoreactivity was present in
these lymphovascular emboli in all three cases (Fig. 2A). The
lymphovascular tumor emboli in all three cases exhibited
strong MUC-1 immunoreactivity but weak to absent sialyl-
Lewis X/A immunoreactivity (Fig. 2B). Adjacent normal
ducts and acini showed markedly decreased E-cadherin and
MUC-1 immunoreactivity but increased sialyl-Lewis X/A
immunoreactivity (Fig. 2B).
The occurrence of three cases of IBC in an office setting in
less than a year has not, to the best of our knowledge, been
previously reported. IBC was documented by both clinical
and pathologic evaluation with all three cases having invasion
of the dermal lymphatics and immunopathologic features of
IBC. IBC is characterized by tumor emboli within lympho-
vascular spaces termed lymphovascular invasion.
Cancer clusters are a notoriously difficult subject to inter-
pret (15). The long latent period between initiation and clinical
presentation for most cancers means a cluster is likely to be of
biological significance if it occurs in an occupational situation
(16). Other biological links can be noted when relatively rare
tumors and/or malignancies with a very rapid doubling time
appear. IBC is relatively rare and has a rapid doubling time.
Many clusters go unresolved perhaps because they are statis-
tical anomalies rather than biological. A cluster study,
however can lead to the development of hypotheses that can be
tested in more systematic studies, such as case control studies.
A possible link between the environment and development
of IBC is documented in a study of 581 Tunisian women with
aggressive breast cancer, 45% meeting the AJCC criteria for
IBC, where the ratio of IBC to non-IBC breast cancer was
markedly higher in the rural population than the urban
population (6). Other findings indicate that there is a possible
association between hormonal stimulation and the develop-
ment of IBC, but the authors were only able to collect
information on the time period for the first births in a small
subset of the population (6). Chang et al showed that obesity,
which is associated with increased estrogen production, may
serve as a contributor to IBC development (17). Another
potential factor includes insulin-like growth factor-1 because
it is involved in carcinogenesis and associated with obesity.
It is reasonable to assume that a high BMI sets the stage for the
rapid proliferation of malignant cells once a critical point in the
carcinogenic process has been reached.
One study has shown that exposure to organochlorines is
associated with more aggressive tumor behavior (7); several
organochlorines have been shown to elicit responses that may
mimic or antagonize the effects of endogenous sex hormones
(7) which could possibly influence the growth or aggressive-
ness of breast cancer. This is important for IBC, because it is
a cancer that presents itself and grows rapidly.
Concern has arisen in the scientific community regarding
the potentially adverse health effect that can develop from
MRI exposure. The positioning of the Eden Valley office
above the East Bay MRI Imaging Center provided an oppor-
tunity for long term employee exposure due to possible
radiation leakage. Studies have attempted to show a correlation
between electromagnetic field exposure and breast cancer,
but the current literature is mixed and inconclusive (18-24). No
surveys of the mammography center were performed during
the operation of old equipment, which was replaced in 1999.
The lack of measurements with the original mammography
machine prevents estimation of the true exposures experienced
by the employees.
Additionally, for workers who handle CCP, the most
common exposures are formaldehyde and kerosene or its
components (25). Regarding the risk of cancer, formaldehyde
has been noted to be etiologically related to sino-nasal carci-
noma (26). While elevations in risks have been noted in other
cancer types also, no linkage has been identified in breast
Studies on OC use and breast cancer prognosis have
yielded contradictory results. A number of studies showed no
association with OC use on prognosis (27-31), a number found
that OC users had smaller tumors and were less advanced
clinically (32,33), and a number found that OC users had a
worse prognosis (9,34-37). It is difficult to compare the studies
because many of the studies have not investigated dose and
composition and these have changed over time (38).
Extensive epidemiologic studies have determined that
breast cancer is in part hormonally mediated, but the connec-
tion between breast cancer and hormonal therapy is not clear.
Two of the cases in this cluster were taking hormone replace-
ment therapy at the time of their diagnosis. There is little
information on the association of HRT exposure with IBC,
but the risk of breast cancer diagnosis increases in women
using hormone replacement therapy as the duration of use
The possibility that agricultural pesticides and herbicides
could have an influence not only on breast cancer incidence,
but also aggressiveness warrants attention. Organochlorines,
although structurally unrelated to estrogen, have the ability to
evoke estrogenic responses and thus to interfere with estrogen-
controlled pathways (7). These compounds include poly-
chlorinated biphenyls (PCBs), dioxins, triazine herbicides,
and pesticides such as dieldrin, dicophane (DDT), and the
DDT metabolite dichloroethene (DDE) (41).
Although we were unable to identify a specific etiology
for this unusual time-space cluster of IBC, its occurrence lends
support to the hypothesis that environmental factors may be
important contributors to IBC etiology. Studies of clusters
can lead to knowledge regarding etiologic agents. Tumor
promotion appears to be an important factor in this cluster
and further studies may help in understanding IBC. The
cases' previous exposures to pesticides/herbicides, oral
contraceptives and hormone replacement therapy, pregnancy
history and family history of breast cancer are strong and
when coupled with the documented environmental exposures
in the work place may have led to the accelerated development
of aggressive IBC breast tumors.
In conclusion, the data indicate that oral contraceptives
and hormone replacement therapy use, obesity, and exposure
to pesticides and herbicides, may have contributed to this
DUKE et al: A CLUSTER OF INFLAMMATORY BREAST CANCER
unusual cluster of IBC cases. It is not possible to explain
how the combinations of environmental factors affected
these 3 women. However, each woman had strong exposures
to agents and/or factors that may be associated with tumor
progression. The compromised conditions in their work
space over a long duration may well have contributed to the
aggressive developments of their breast cancer.
It is important to note that while most cluster studies do
not lead to the determination of the cause of the clusters, we
undertook this study in order to develop hypotheses for IBC
risk factors. Even when there is a potential environment,
condition, or combination of conditions with a biologically
plausible hypothesis of how it might contribute to cancer,
trying to trace cancer cases to a specific cause poses unique
challenges. Unlike outbreaks of infectious diseases, which can
be linked to some recent exposure, a cluster of cancer cases
might have its roots in an exposure that occurred 10 to 20 years
earlier (42); conversely, however, IBC is a rapidly growing
tumor like Burkitt's lymphoma (BL), which has a doubling
time of 24 h, and a time-space clustering is more likely to
indicate a proximate cause. The objective was to use this
observation to look for etiologic clues in IBC and highlight
areas where additional documentation and research are
necessary. The findings from this apparent cluster, although
inconclusive, should be tested out on larger case-control studies
under development at large institutions.
We thank Ms. Barbara Severini who was instrumental in
facilitating collection of environmental data and recruitment
of controls. We also would like to thank all of the study
participants and funding agencies for contributing to the
work of this study. The opinions in this manuscript are those
of the authors and do not necessarily represent the opinions
and/or policies of the U.S. Environmental Protection Agency.
Supported in part by Grant no. DAMD 17-01-1-0244 with
the Department of Defense and the Inflammatory Breast
Cancer Research Foundation.
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DUKE et al: A CLUSTER OF INFLAMMATORY BREAST CANCER