The n e w e ng l a n d j o u r na l of m e dic i n e

case records of the massachusetts general hospital

Founded by Richard C. Cabot

Nancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate Editor
Jo-Anne O. Shepard, m.d., Associate Editor Alice M. Cort, m.d., Associate Editor
Sally H. Ebeling, Assistant Editor Christine C. Peters, Assistant Editor

Case 15-2010: An 85-Year-Old Woman with

Mammographically Detected Early Breast Cancer
Hyman B. Muss, M.D., Helen Anne DAlessandro, M.D., and Elena F. Brachtel, M.D.

Pr e sen tat ion of C a se

Dr. Lidia Schapira (Medical Oncology): An 85-year-old woman was seen in the multi- From the Division of Hematology and
disciplinary Breast-Evaluation Center of this hospital because of newly diagnosed Oncology, Department of Medicine, Uni-
versity of North Carolina at Chapel Hill;
carcinoma of the breast. and the Department of Medicine, Univer-
Four weeks earlier, a routine annual mammogram showed multiple microcalcifi- sity of North Carolina College of Medicine
cations in a clustered distribution in the anterior subareolar region of the right both in Chapel Hill (H.B.M.); and the
Departments of Radiology (H.A.D.) and
breast; they were new since a study the previous year. Two weeks later, a second Pathology (E.F.B.), Massachusetts General
mammogram confirmed the presence of microcalcifications in the subareolar Hospital; and the Departments of Radiol-
region of the right breast. Six days later, the patient saw a surgeon. ogy (H.A.D.) and Pathology (E.F.B.), Har-
vard Medical School both in Boston.
The patient reported no palpable breast masses or discharge. Specimens from
two previous breast biopsies, performed years earlier, had been benign. Menarche N Engl J Med 2010;362:1921-8.
had occurred at the age of 12 years and menopause at the age of 48. The patient was Copyright 2010 Massachusetts Medical Society.

nulliparous, with two adopted children. She had hypercholesterolemia, hypertension,

chronic obstructive pulmonary disease, hypothyroidism, nocturia and urinary fre-
quency, gastric esophageal reflux disease, arthritis, hearing loss, and anxiety.
Two years before this evaluation, the patient was admitted to this hospital be-
cause of pleural and pericardial effusions. The plasma level of rheumatoid factor
was 112 IU per milliliter (reference range, <30); testing for antinuclear antibodies
(ANA) was positive at dilutions of 1:40 and 1:160 (reference range, negative at 1:40
and 1:160), in a speckled pattern; and the level of IgA was 528 mg per deciliter
(reference range, 69 to 309). Test results for other immunoglobulins, immunofixa
tion, and protein electrophoresis were normal, and those for other autoantibodies
were negative. Flexible bronchoscopy and video-assisted thoracoscopic surgery were
performed. Results of pathological examination of pleural tissue and cytologic
examination of pleural fluid were benign; talc pleurodesis was performed.
Twenty months before evaluation, pathological examination of tissue from a
lesion in the midpole of the left kidney showed an oncocytoma. Fourteen months
before this presentation, a transthoracic echocardiogram was normal. Medications
included lisinopril, furosemide, simvastatin, acetylsalicylic acid, metoprolol, buspi
rone, omeprazole, levothyroxine, cholestyramine, calcium carbonatevitamin D, and a
fluticasone propionatesalmeterol metered-dose inhaler. The patient was allergic to
hydrochlorothiazide and hydroxyzine. She was a widow and retired factory worker,
with no known occupational exposures, and she lived with her adopted daughter.
She was on a low-salt diet, drank five to nine alcoholic beverages per week, exercised
regularly, and had stopped smoking 20 years earlier; she did not use illicit drugs.

n engl j med 362;20 nejm.org may 20, 2010 1921

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 The n e w e ng l a n d j o u r na l
Figure 1. Mammogram.
A mammographic magnification view of the right breast
reveals pleomorphic calcifications in the subareolar region
(thick arrow) that were not present on the previous exam-
ination and are suggestive of carcinoma. Coarse calci
fications in the superior region (thin arrow) were pres-
ent on previous studies and represent a fibroadenoma.
She used a hearing aid and occasionally needed
assistance dressing because of shoulder pain but
was otherwise independent in activities of daily
living. There was no history of breast or ovarian
cancer or hereditary cancer syndromes.
On examination, the patient appeared well.
The height was 144.8 cm and the weight 66.7 kg.
Two masses, each approximately 8 mm in diam-
eter, were palpated in the right breast at approxi-
mately the 11 oclock position; one was at the
areolar edge, and the other, a hard mass, was
toward the axilla in the right outer quadrant.
There was no palpable axillary or supraclavicular
lymphadenopathy. The remainder of the exami-
nation was normal.
Fine-needle aspiration of both masses was
performed. Cytologic examination of the speci-
men from the areolar mass showed malignant
1922 n engl j med 362;20 nejm.org may 20, 2010
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of m e dic i n e
cells that were consistent with ductal carcinoma;
the tissue from the more distal lesion revealed
benign ductal cells, myoepithelial cells, and
stromal fragments, features consistent with a
fibroadenoma. A complete blood count was
normal, as were measurements of electrolytes,
calcium, glucose, total protein, albumin, and
globulin; tests of renal and liver function and
coagulation; and a Doppler ultrasonogram of the
kidneys and renal arteries. An electrocardiogram
revealed right bundle-branch block and nonspe-
cific ST-segment and T-wave abnormalities.
Ten days later, the patient was admitted to
this hospital. Both masses and part of the nipple
were excised. Pathological examination of the sub-
areolar mass revealed invasive ductal carcinoma,
1.2 cm by 1.0 cm by 1.0 cm, grade 3 of 3; ductal
carcinoma in situ, grade 3 of 3, both within and
adjacent to the invasive carcinoma; two smaller,
separate microscopical foci of invasive carcinoma,
0.6 cm and 0.9 cm in diameter; and a hyalinized
fibroadenoma. The tumor cells were positive for
estrogen-receptor protein and progesterone-
receptor protein, and there was strong overexpres-
sion of human epidermal growth factor receptor
type 2 (HER2), scored as 3+, indicating intense
immunostaining; there was no lymphatic or vas-
cular invasion, and final shaved margins of the
excision were negative for tumor.
A management decision was made.
Differ en t i a l Di agnosis
Dr. Hyman B. Muss: May we review the imaging
studies?
Dr. Helen Anne DAlessandro: An annual bilateral
screening mammogram revealed new calcifica-
tions in the subareolar right breast. The patient
was called back for magnification views of the
right breast (Fig. 1), which revealed new and
suspicious pleomorphic calcifications in the sub-
areolar region that were classified as category 4
(on a scale of 0 to 6) according to the Breast
Imaging Reporting and Data System (BI-RADS)
(in which 0 indicates a study that requires addi-
tional imaging evaluation; 1, a negative study; 2,
a benign finding; 3, a probably benign finding
requiring follow-up after a short interval; 4, a
suspicious abnormality for which biopsy is rec-
ommended; 5, a finding highly suggestive of a
malignant condition, for which biopsy is recom-
mended; and 6, a known, biopsy-proven carci-
 case records of the massachusetts gener al hospital
noma).1 Biopsy of the suspicious pleomorphic
calcifications was recommended. Coarse calcifi-
cations were noted in the superior right breast
that represented a fibroadenoma, a finding that
was unchanged from previous studies.
Pathol o gic a l Discussion
Dr. Elena F. Brachtel: The initial cytologic examina-
tion of the subareolar mass revealed malignant
cells that were consistent with ductal carcinoma
(Fig. 2A). Pathological examination of the subse-
quent excision showed invasive ductal carcinoma,
1.2 cm in greatest dimension, grade 3 of 3 (Fig.
2B and 2C). Two additional microscopical foci of
invasive ductal carcinoma, 0.6 and 0.9 cm in di-
ameter, were present in the vicinity of the main
mass. The invasive carcinoma invaded the smooth
muscle of the areolar skin, but lymphatic or
blood-vessel invasion was not identified. Also
present were a few foci of high-grade ductal carci-
noma in situ with comedonecrosis and calcifica-
tions (Fig. 2D). Final shaved margins of excision
were negative for tumor. On the basis of immuno-
histochemical staining, the tumor cells were posi-
tive for both estrogen-receptor protein and pro-
gesterone-receptor protein, and there was strong
overexpression of HER2 (3+) (Fig. 2E and 2F).2-6
Discussion of M a nagemen t
Dr. Muss: This 85-year-old widow has a mammo-
graphically detected, poorly differentiated inva-
sive ductal cancer that is positive for estrogen
receptors, progesterone receptors, and HER2 and
that has been resected, with negative margins;
she is clinically lymph-nodenegative. She has a
complex medical history but is highly functional,
exercises regularly, and is able to perform all ac-
tivities of daily living.
Detecting breast cancer in an 85-year-old is
not unusual. Breast-cancer incidence and mor-
tality dramatically increase with increasing age
(Fig. 3). Moreover, the population of the United
States continues to age, and in 2025, about 20%
of the population will be 65 years of age or
older; physicians should expect to see greater
numbers of older patients with all cancers. The
care of this patient raises several important is-
sues: the role of mammographic screening in
older women, the influence of a coexisting illness
on disease management, and most important
what other treatment should be offered.
n engl j med 362;20 nejm.org may 20, 2010
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Screening Mammography in Older Patients
Should this woman have been offered screening
mammography? Randomized trials have con-
firmed improved survival in women 40 to 70
years of age who undergo annual or biannual
screening mammography,7-9 but only sparse and
conflicting data are available pertaining to
women older than 70.10 The sensitivity, specificity,
and positive predictive value of mammography
for detecting breast cancer increase with age, be-
cause ductal tissue is replaced by fat, resulting
in an increase in the radiolucency of breast tissue.
One study of women 80 years of age or older who
underwent mammography on a regular basis
showed that breast cancer was detected at a low-
er stage and was associated with a higher rate of
breast-cancerspecific survival. In addition, how-
ever, deaths from other causes were lower in this
group, which suggests a bias for screening mam-
mography among healthier patients.11
Since the precise age at which to discontinue
screening mammography is uncertain and guide-
lines from major panels and organizations are
conflicting, using life expectancy and not age as
the basis for recommending screening appears
to be the most prudent approach. For example,
an 85-year-old woman in average health has an
estimated survival of about 5.9 years and a 1.2%
risk of dying of breast cancer in her remaining
lifetime, but to prevent one death from breast
cancer in this age group would require 2131
screening mammograms, as compared with 330
in patients 75 years of age and 133 in patients
50 years of age.12 Screening can also result in
complications from further imaging, treatment
of a breast cancer that is unlikely to become
clinically important, added psychological dis-
tress, and increased cost. Since prospective, con-
trolled trials are unlikely to be performed in elder
ly patients, a reasonable option would be to offer
yearly screening to women without severe coex-
isting conditions and with an estimated life ex-
pectancy of at least 5 years.13,14 I would have
estimated this patients remaining life expec-
tancy as about 5 years,15 and I would have dis-
cussed the pros and cons of screening with her
before offering mammography.
The Role of Coexisting illness in
the Treatment of Cancer in Older Patients
Coexisting illnesses increase in likelihood with
age and can have profound effects on cancer
treatment. In addition, functional assessment is
1923
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

E F

Figure 2. Biopsy Specimens of the Right Breast.

Groups of pleomorphic tumor cells with mitotic figures (arrow) are seen on cytologic examination of a specimen from
a fine-needle aspiration biopsy (Panel A, Papanicolaou stain). The excised specimen (Panel B, hematoxylin and eosin)
shows invasive carcinoma (arrow) and a focus of ductal carcinoma in situ (arrowhead). The invasive carcinoma has
infiltrated the smooth muscle of areolar skin (asterisk), but no lymphatic invasion is seen. The invasive carcinoma is
poorly differentiated, with pleomorphic tumor cells in a diffuse pattern of growth (Panel C, hematoxylin and eosin).
A few foci of high-grade ductal carcinoma in situ with comedonecrosis and calcifications are seen (Panel D, hema-
toxylin and eosin). The invasive tumor cells are positive for estrogen-receptor protein, according to immunohisto-
chemical staining (Panel E, immunoperoxidase) and show strong overexpression of human epidermal growth factor
receptor type 2 (3+) (Panel F, immunoperoxidase).

a crucial part of managing a patients treatment,
and a comprehensive geriatric assessment
which includes a multidisciplinary evaluation of
functional status, cognition, social support, psy-
chological state, nutritional status, medication
1924 n engl j med 362;20
(polypharmacy), and coexisting medical condi-
tions can predict morbidity and mortality from
causes other than cancer.16 Functional assess-
ments of activities of daily living and instrumen-
tal activities of daily living can be performed
nejm.org may 20, 2010
 case records of the massachusetts gener al hospital

A Incidence B Mortality
500
200

400

Age-Specific Mortality Rate

150
Age-Specific Incidence
(per 100,000 per yr)

(per 100,000 per yr)

300

100
200

50
100

0 0
<1

<1
4
10 9
15 4
20 19
25 24
30 29
35 34
40 39
45 44
50 49
55 54
60 59
65 64
70 69
75 74
80 79
4
5

4
10 9
15 14
20 19
25 4
30 29
35 34
40 39
45 44
50 49
55 54
60 59
65 64
70 69
75 74
80 79
4
5
1

8
1

5
Age at Diagnosis (yr) Age at Death (yr)

Figure 3. Incidence of and Rates of Death from Breast Cancer among Women from the United States, According to Age Group.
Data on incidence (Panel A) are from the National Cancer Institutes Surveillance, Epidemiology, and End Results Project (http://seer
.cancer.gov/faststats/selections.php#Output). Data on mortality (Panel B) are from the National Center for Health Statistics.

quickly and provide independent information re-
lated to morbidity and mortality.17,18
This patient had several coexisting illnesses
that shorten life span: hypertension, chronic ob-
structive pulmonary disease, and arthritis. She also
had hypercholesterolemia, hypothyroidism, noc-
turia and urinary frequency, gastric esophageal
reflux disease, hearing loss, anxiety, an undefined
pulmonary illness, and a renal oncocytoma.15,19
At least several of these illnesses are likely to po-
tentiate toxic effects from adjuvant systemic breast
cancer therapy, especially from chemotherapy.
Worse, any therapy-related adverse effects that
might convert her from functionally independent
to dependent would also have a profound effect
on her quality of life. If she became dependent
on her adopted daughter for continued care, the
patient would most likely need to be cared for
outside the home. A comprehensive geriatric as-
sessment before the initiation of therapy should
be considered for patients such as this one.
Local and Regional Therapy
This patient had a successful lumpectomy and
was clinically node-negative. Additional options
for local and regional therapy include sentinel-
node biopsy and breast irradiation. In a large study
of patients who had no or minimal systemic
therapy before axillary dissection, cancers that
were 1 to 2 cm in diameter, and clinically nega-
n engl j med 362;20 nejm.org may 20, 2010
tive lymph nodes, 23% had one to three positive
nodes and 11% had four or more positive nodes.20
The corresponding 5-year survival rates were
87% and 66%, respectively. Taking into account
this patients expected survival, the small likeli-
hood of her having four or more positive nodes,
the rarity of axillary recurrence in older patients
with hormone-receptorpositive tumors, and the
fact that finding positive nodes is not likely to
have a dramatic effect on either her care or sur-
vival, I would not recommend biopsy of the sen-
tinel lymph node.
The role of breast radiation in older women
such as this one, with a small breast cancer that
has been removed surgically, is controversial.
Older women have a lower risk of ipsilateral re-
currence of breast cancer than younger women,
with21 or without22 radiation, especially women
with small, hormone-receptorpositive tumors.
A large, randomized trial involving older women
with small, hormone-receptorpositive, lymph-
nodenegative tumors treated with lumpectomy
and tamoxifen showed that the addition of breast
irradiation conferred no survival benefit22; 94%
of deaths in both groups were from nonbreast-
cancer causes. In a large meta-analysis, the ad-
dition of breast irradiation to lumpectomy did
not improve 15-year survival rates in patients
with breast cancer who were at low risk for local
or regional recurrence.23 On the basis of these
1925
 The n e w e ng l a n d j o u r na l
<40 yr 4049 yr 5059 yr 6069 yr
60
Decrease in Annual Risk (%)
50
51
44 45
40
39
34
30
29
20 24 24
10
0 newer, more intensive chemotherapy regimens.29
Recurrence Death
Figure 4. Decrease in the Annual Risk of Recurrence or Death Due to Breast
Cancer after 5 Years of Tamoxifen Treatment, at 15 Years of Follow-up.
The ages provided are for women at the time of diagnosis. Data are from
the Early Breast Cancer Trialists Collaborative Group.24
data and the patients low (<10%) risk of local
recurrence without radiation, radiation could be
safely omitted in this patient.
Systemic Adjuvant Therapy
Should this patient with a hormone-receptor
positive cancer receive endocrine therapy? The
most recent meta-analysis of trials of adjuvant
therapy by the Early Breast Cancer Trialists Col-
laborative Group showed that adjuvant tamoxifen
therapy, as compared with no tamoxifen treat-
ment, significantly improved both relapse-free
survival (decrease in the absolute annual risk of
recurrence, 51%) and overall survival (decrease in
the absolute annual risk of death, 37%) in women
70 years of age or older with early-stage, hor-
mone-receptorpositive breast cancer (Fig. 4).24
In postmenopausal women, adjuvant therapy with
aromatase inhibitors (anastrozole, letrozole, and
exemestane) has shown significant improvement
(approximately 3 to 5%), as compared with tamox-
ifen, in relapse-free survival but not in overall
survival.25 Unlike tamoxifen, aromatase inhibitors
are not associated with endometrial cancer or
thromboembolism, but their use does increase
the risk of fracture. I would choose an aromatase
inhibitor for this patient because of its more fa-
vorable toxic-effects profile, but I would also dis-
cuss with her the high cost of these agents as
compared with tamoxifen. If an endocrine agent
is recommended, it is important to query the pa-
tient about adherence,26 to ensure that she is tak-
ing her medication.
The use of adjuvant chemotherapy for this
patient is controversial because of the potential
1926 n engl j med 362;20 nejm.org may 20, 2010
of m e dic i n e
for increased adverse effects with the use of
70 yr
chemotherapy in elderly patients.27,28 The largest
meta-analysis of randomized trials of adjuvant
chemotherapy for early breast cancer24 included
an insufficient number of women 70 years of age
or older to clearly define the benefits of chemo-
35
37 therapy in this age group but suggested that the
benefits were similar to those in other postmeno-
pausal patients. An analysis of four randomized
trials showed that older patients and younger
patients had similar benefits when treated with
However, about 1% of older patients died of
treatment-related toxic effects.
What about trastuzumab for this patient? The
addition of trastuzumab to chemotherapy in pa-
tients with HER2-positive early breast cancer has
led to significant improvements in survival.30-32
A major question for this patient concerns the ef-
fect of her HER2 status on the risk of recurrence.
Data from patients with small HER2-positive, hor
mone-receptorpositive tumors are inconsistent,
with one study showing that HER2 status does not
have a major effect on the risk of recurrence.33
In addition, the use of trastuzumab has a risk of
congestive heart failure that is small but that in-
creases with advancing age.34 For these reasons, I
would not recommend the combination of che-
motherapy and trastuzumab for this patient. If a
biopsy specimen of a sentinel lymph node showed
positive lymph nodes, the risk of recurrence
would be increased but there would probably be
no major effect on her survival. The absolute ben-
efit of chemotherapy and trastuzumab would still
be small, and the risks of increased toxic effects
would be likely to negate the potential benefits.
Summary
This 85-year-old patient with important coexist-
ing conditions was found to have a small, high-
grade, clinically node-negative, hormone-recep-
torpositive, HER2-positive breast cancer. In
my opinion, her cancer would best be managed
with endocrine therapy with an aromatase in
hibitor alone. Tamoxifen could be considered
instead. Radiation therapy could be offered but
is not likely to result in any improvement in
survival. I would not recommend the combina-
tion of chemotherapy and trastuzumab because
the risks are likely to be greater than the ben
efits.
Dr. Nancy Lee Harris (Pathology): Are there any
questions?
 case records of the massachusetts gener al hospital

A Physician: How do you predict the effect of
coexisting conditions on survival?
Dr. Muss: Several investigators have described
age-related coexisting conditions in patients with
breast cancer35 as well as scales that relate func-
tional status to survival.36 A patient the age of this
one has on average four or five coexisting condi-
tions. A major goal of many oncologists and
geriatricians is to devise a coexisting-conditions
scale or functional scale that is easy to use, is Web-
based, and would allow a busy clinician to easily
estimate the effects of coexisting illnesses and
decreased function on survival. The cooperative
trials group Cancer and Leukemia Group B is cur-
rently evaluating a short, mostly self-administered
geriatric assessment as a tool to predict outcomes
for and toxic effects on older patients37 and hopes
that in several years it will have a usable scale
that will accurately estimate survival in older pa-
tients with cancer.
Dr. Eric P. Winer (Medical Oncology, Dana
Farber Cancer Institute): After the diagnosis was
made, with the use of fine-needle aspiration,
this patient could have been treated with endo-
crine therapy alone in view of her relatively short
life expectancy; if her breast cancer progressed,
then she could have surgery. It is unlikely that
she would die from her cancer.
Dr. Muss: There is extensive experience in man-
aging breast cancer in older women with endo-
crine therapy alone after confirming the diagno-
sis with a tissue biopsy. The literature suggests
that survival among patients treated this way is
similar to that among patients treated initially
with surgery; however, most patients treated with
endocrine therapy alone will have tumor progres-
sion requiring surgery within 5 years.38 There-
fore, in a patient with an estimated survival of
5 years or more, it is probably best to resect the
primary tumor, as was done in this patient.
A Physician: Are you concerned about the increased
risk of osteoporosis and fracture in this patient
in association with aromatase-inhibitor therapy?
Dr. Muss: There are 40,000 deaths per year
from breast cancer and a similar number from
fractures. I think oncologists have become quite
knowledgeable about bone loss in patients such
as this one. I would perform a baseline bone-
density evaluation in this patient, and if the re-
sults showed osteopenia (or osteoporosis), I would
consider therapy with oral bisphosphonates and
continue supplementation with oral calcium and
vitamin D.39 Oral bisphosphonates can be effec-
tive in preventing or minimizing further bone
loss in women treated with aromatase inhibi-
tors. Alternatively, tamoxifen might improve this
patients bone density but would increase her risk
of endometrial cancer and thromboembolism.
Dr. Harris: Dr. Schapira, would you tell us how
you managed this patients cancer and how she
is doing?
Dr. Schapira: We discussed whether to complete
her staging with a sentinel-node biopsy, and we
discussed the role of both radiation and adjuvant
endocrine therapy. After a multidisciplinary dis-
cussion, we recommended that she avoid further
surgery and complete local treatment with ra-
diation, followed by endocrine therapy with the
aromatase inhibitor anastrozole. The treatment
was associated with an acceptable adverse-event
profile, and the patient remains in clinical remis-
sion 18 months after her initial presentation.
Her bone mineral density is normal, and we have
not initiated bisphosphonate therapy. We plan to
continue the anastrozole and see her annually.
A nat omic a l Di agnosis
Invasive ductal carcinoma of the breast, grade 3
of 3, positive for estrogen receptors, progesterone
receptors, and HER2.
This case was presented at the postgraduate course Breast
Cancer: Current Controversies and New Horizons, July 10, 2009,
sponsored by the Department of Continuing Medical Education,
Harvard Medical School.
Dr. Muss reports receiving consulting fees from Pfizer, Amgen,
Roche, Bristol-Myers Squibb, Sandoz, Abraxis, and Boehringer-
Ingelheim. No other potential conflict of interest relevant to this
article was reported. Disclosure forms provided by the authors
are available with the full text of this article at NEJM.org.

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