Increased Likelihood of Mastectomy in Human

Epidermal Growth Factor Receptor 2-positive

Ductal Carcinoma In Situ
ANNA WEISS, M.D., VIVI TRAN, JENNIFER BAKER, M.D., HASTEH FARNAZ, M.D., ANNE M. WALLACE, M.D., DAVID
CHANG, PH.D., M.P.H., M.B.A., HAYDEE OJEDA-FOURNIER, M.D., SARAH L. BLAIR, M.D.

From Moores UCSD Cancer Center, San Diego, California

Patients with human epidermal growth factor receptor 2 (HER2neu)-positive breast invasive
cancer are known to have larger, more aggressive tumors. Little research exists on the relationship
between HER2neu status and extent of ductal carcinoma in situ (DCIS). A retrospective review of
a single-institution database was performed for patients with DCIS between the years 2002 and
2011. A single blinded breast radiologist reviewed preoperative imaging. Pathology was reviewed
for extent of DCIS. Primary outcome was mastectomy. Multivariate logistic regression was used to
determine adjusted mastectomy risk. There were 166 cases, 34 HER2neu-positive. HER2neu
receptor-positive patients had larger lesions on imaging: 4.0 versus 2.7 cm, by 2.9 versus 1.5 cm (P 5
0.0499 and 0.0182). HER2neu-positive patients with DCIS were more likely than HER2neunegative to undergo mastectomy than lumpectomy (53 vs 28%, P 5 0.006). Pathology revealed
a trend toward larger lesions in HER2neu-positive patients (2.96 vs 2.22 cm, nonsignificant). Patients with HER2neu-positive disease were three times more likely to undergo mastectomy (odds
ratio, 2.9; 95% confidence interval, 1.23 to 6.78). Patients with HER2neu-positive DCIS had greater
extent of disease by imaging and were more likely to undergo mastectomy than HER2neunegative. These findings will help surgeons counsel patients on surgical treatment.

factor receptor 2
(HER2neu) is overexpressed in approximately 15
H
to 20 per cent of invasive breast carcinomas. Patients
UMAN

EPIDERMAL

GROWTH

with HER2neu-positive invasive carcinoma tend to have

more diffuse disease, larger tumors, higher grade lesions, and more aggressive tumor behavior including
higher recurrence2, 3 and poorer survival.4
Despite the known prognostic significance of
HER2neu in invasive carcinoma, the relationship in
ductal carcinoma in situ (DCIS) is unclear. Some literature reports that HER2neu-positive DCIS is more
likely to be high grade5 and more likely to have foci
of microinvasion.6 HER2neu has been shown to be
an independent predictor of recurrence.7 Conversely,
several studies indicate that patients with HER2neupositive DCIS have no difference in DCIS or invasive
recurrence.8, 9 Others report that a greater proportion
of DCIS will be HER2neu-positive compared with
invasive disease10 suggesting that HER2neu does not
Presented at the 25th Annual Scientific Meeting of the Southern
California Chapter of the American College of Surgeons, January
1719, 2014, in Santa Barbara, California.
Address correspondence and reprint requests to Sarah L. Blair
M.D., Moores UCSD Cancer Center, 3855 Health Science Drive,
MC 0987, San Diego, CA 92093-0987. E-mail: slblair@ucsd.edu.

play an important role in disease progression. Furthermore, HER2neu has also been linked to DCIS recurrence,
but not necessarily invasive recurrence after treatment,11 bringing its clinical importance into question.
Similar to invasive disease, mastectomy and lumpectomy with radiation both offer good local control.12
Studies have shown that multifocality is an independent
risk factor for the development of local recurrence after
breast-conserving surgery for DCIS13 and that patients
with multifocal DCIS are three times more likely to
undergo mastectomy than lumpectomy.14 Other factors
found to increase the mastectomy rate in DCIS are
younger age, higher grade, and larger tumors.15 To further clarify treatment recommendations for DCIS, this
studys objective is to investigate the correlation between HER2neu-positive status and more diffuse DCIS
by comparing preoperative imaging, tumor size, and rate
of mastectomy of HER2neu-positive versus -negative
patients.
Methods

Data were gathered on all patients undergoing

breast surgery at the University of California, San
Diego from 2002 to 2011. We queried this database
for all patients with DCIS. HER2neu information was

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Weiss et al.

937

TABLE 1. Overall Demographics and Demographics of Mastectomy versus umpectomy Populations

166 Total
Patients

No. (percent)
Age (median, years)
Race
White
Black
Hispanic
Asian
Married
DCIS grade
Low
Intermediate
High
ER/PR-positive

54

Mastectomy 54
(32.53)

Lumpectomy 112
(67.47)

51

56

122 (73.49)
5 (3.01)
23 (13.86)
16 (9.64)
107 (64.46)

41 (75.93)
1 (1.85)
6 (11.11)
6 (11.11)
39 (72.22)

81 (72.32)
4 (3.57)
17 (15.18)
10 (8.93)
68 (60.71)

32 (19.28)
62 (37.35)
72 (43.37)
141 (84.94)

3 (5.56)
18 (33.33)
33 (61.11)
39 (72.22)

29 (25.89)
44 (39.29)
39 (34.82)
102 (91.07)

P Value
0.868
0.792

0.147
0.001

0.001

DCIS, ductal carcinoma in situ; ER/PR, estrogen receptor/progesterone receptor.

collected prospectively on all patients with DCIS while

the institution was enrolling for a national randomized controlled trial. Exclusion criteria were unknown
HER2neu status and invasive carcinoma on final pathology. Primary outcome was mastectomy. Secondary
outcomes were the two largest size dimensions on final
pathology named length and width. Our primary independent variable was HER2neu status. Our covariates included age, race, and marital status.
Chi-squared analyses were performed comparing demographic information and outcomes between HER2neupositive and -negative patients as well as mastectomy
and lumpectomy patients. A single breast radiologist
who was blinded to the HER2neu status of the patients
reviewed all imaging, and a two-dimensional size was
given for all lesions. Pathology was reviewed for final
size of the lesion. Multivariate analyses were then
performed to control for covariates determining odds
ratio of mastectomy, controlling for age, race, and
marital status. Statistical analysis was performed in Stata
Special Edition 11.2. Statistical significance is defined
as P < 0.05. This study was approved by our Institutional
Review Board, IRB Project No. 130073.
Results

There were 406 total patients with DCIS treated

between 2002 and 2011. Two hundred twenty-eight
cases were excluded for unknown HER2neu status; 11
patients (12 cases) were excluded for invasive cancer
on final pathology. Thirty-two of these 166 cases were
HER2neu-positive (19%). Fifty-three total patients (32%)
underwent mastectomy. HER2neu-positive patients
tend to be younger than HER2neu-negative, but this is
not significant (P 4 0.422); there is no significant
difference in race (P 4 0.694). HER2neu-positive
patients have significantly higher grade DCIS (87.5%
are high grade vs 32.84% of HER2neu-negative patients, P < 0.001). There is a significant difference in

TABLE 2.

Odds Ratio of Mastectomy by Demographics

HER2neu-positive
disease
Age (years)
039
4049
5059
6069
7079
$80
Race
White
Black
Hispanic
Asian
Married

Odds Ratio
of Mastectomy

95% Confidence
Interval

2.89

1.236.78

Reference
0.69
0.38
0.81
0.26
(sample size
too small)

Reference
0.153.21
0.081.77
0.164.01
0.371.77

Reference
0.63
0.59
1.12
1.46

Reference
0.066.62
0.211.68
0.353.59
0.683.10

HER2neu, human epidermal growth factor receptor 2.

rates of estrogen receptor/progesterone receptor (ER/PR)positive disease: HER2neu-negative disease is 85 per

cent ER/PR-positive, whereas HER2neu-positive disease is only 59 per cent ER/PR-positive (P < 0.001).
Demographics for patients undergoing mastectomy
and lumpectomy are presented in Table 1. There is no
significant difference in age, race, or marital status
between patients who undergo mastectomy or lumpectomy. Patients who undergo mastectomy have higher
grade DCIS and are more often ER/PR-negative.
Table 2 represents the odds ratio of mastectomy by
HER2neu status and patient demographics. Patients
with HER2neu-positive disease were three times more
likely to undergo mastectomy (odds ratio, 2.9; 95%
confidence interval, 1.23 to 6.78); age, race, and
gender made no difference. Table 3 presents lesion
size on imaging, mastectomy rate, and actual size on
final pathology. On preoperative imaging, HER2neupositive tumors appeared larger (4 3 2.9 cm vs 2.74 3
1.5 cm, P 4 0.05 length and 0.02 width). On final

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TABLE 3. Lesion Size on Imaging, Mastectomy Rates, and Pathology Measurements

Size on imaging (cm)
Length
Width
Mastectomy rate, no. (%)
Pathology (cm)

HER2neu-positive

HER2neu-negative

P Value

4.02
2.88
17/32 (53.13)
2.96

2.74
1.5
37/134 (27.61)
2.22

0.0499
0.0182
0.006
0.115

HER2neu, human epidermal growth factor receptor 2.

pathology, there was a trend of HER2neu-positive to be

larger, but this was not significant.
Discussion

The results of this study indicate that HER2neupositive DCIS lesions are more diffuse on imaging and
more frequently treated with mastectomy. This may be
explained by more multifocal disease in HER2neupositive DCIS.11 The rate of HER2neu-positive DCIS
in this study is 19 per cent, which is consistent with
previously reported rates of approximately 25 per cent.5, 10
The rate of mastectomy in this study is 32 per cent,
which is similar to other groups.15 Also consistent is
the inverse relationship of HER2neu positivity and
hormone receptor status.5, 10, 16 The current study found
that HER2neu-positive tumors were associated with
larger appearance on imaging than HER2neu-negative;
many groups report that larger tumors should be treated
with mastectomy.15 This study as well as Rakovitch
et al.14 report that patients who are HER2neu-positive
are three times more likely to undergo mastectomy than
HER2neu-negative patients.
Although the importance of HER2neu tumor biology in DCIS is unknown, the surgical treatment algorithms for DCIS in general are widely accepted and
similar to invasive disease. Surgical options include
mastectomy, lumpectomy, and lumpectomy plus radiation. Surgeons have used the used various models to
try to predict preoperatively which patients will be
good candidates for lumpectomy versus mastectomy.
The best known model, the Van Nuys Prognostic Index
(VNPI), is a simple scoring method that has been used
in the United States for more than 10 years to stratify
patients with different risks of local recurrence to decide which patients are good candidates for breast
conservation radiation. The index is based on patient
age, grade, tumor size, presence or absence of comedo
necrosis, and margin width.17 The current study shows
that breast conservation is more difficult in patients
with HER2neu-positive tumors; therefore, future research could study the use of incorporating HER2neu
status as an adjunct to the VNPI.
A strength of this study is detailed and accurate data
collection. Very few data sets collect HER2neu information on DCIS. Another strength is the single,

blinded breast radiologist and pathologist who

reviewed all imaging and tumor specimens. Limitations include a relatively small sample size and singleinstitution study. This study is retrospective, which
introduces selection bias. Lastly, the study is unable
to provide definitive explanation of why Her2neupositive tumors are significantly more extensive,
whether it is actual lesion size or detectability on
mammogram. An alternative explanation is that imaging overestimates the size of HER2neu-positive disease.
However, the sample size is limiting; a study with
a larger sample size would likely reveal that the mammographic size difference actually correlates with greater
pathologic extent of DCIS in HER2neu-positive patients.
This study highlights many areas of investigation. A
large multicenter trial incorporating HER2neu into
VNPI and tracking recurrence and survival could be
a future direction. Another potential future avenue of
research could be neoadjuvant anti-HER targeting.
Several groups have been investigating chemotherapeutic agents targeting HER/epidermal growth factor
receptor/ErbB family receptors (i.e., trastuzumab).18, 19
This would be interesting in the neoadjuvant breast
conservation setting as well.
In conclusion, patients with HER2-positive DCIS had
greater extent of disease by imaging and were more
likely to undergo mastectomy than HER2neu-negative.
A study with a larger sample size may reveal that
HER2neu-positive DCIS is more diffuse and multifocal,
a question that deserves further investigation.
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