Original Article

Yonago Acta medica 2015;58:85–88

Microcalcification of Tumor is a Predictor of Response to Neoadjuvant		
Chemotherapy for Invasive Breast Carcinoma
Aya Murata,* Naoko Sannomiya,* Naoki, Miyamoto,* Naoyuki Ueda,* Akira Kamida,* Yuki Koyanagi,* Haruki Nagira,*
Eriko Matsuda,* Yuki Hashimoto,* Kengo Sato,* Yumi Hirooka,† Keiko Hosoya,† Yuzo Takagi,† Yuko Tanaka,† Kunio Araki,†
Kiyosuke Ishiguro† and Yasuaki Hirooka**Department of Pathobiological Science and Technology, School of Health Science, Tottori University Faculty of Medicine, Yonago 6838503, Japan and †Division of Breast and Endocrine Surgery, Tottori University Hospital, Yonago 683-8504, Japanshowing a pathological complete response (pCR).1–4
However, changes in medications or adjustments to thecourse of treatment (e.g., surgery) could be necessary if
a patient does not respond.
In this study, we investigated imaging findings ofinvasive breast carcinoma that could serve as a predictorof response to NAC with the aim of reducing the frequency of unnecessary treatment.

ABSTRACT
Background In recent years, neoadjuvant chemothera-py (NAC) is often performed for patients with unresectable breast carcinoma or without indication of breast
conserving therapy. However, it is currently difficult topredict response to NAC with diagnostic imaging ofbreast carcinoma. In this study, we investigated imaging
findings that could serve as a predictor of the response
to NAC for patients with invasive breast carcinoma.
Methods Twenty-six patients with invasive breast carcinoma who received NAC at the Division of Breast andEndocrine Surgery of Tottori University Hospital between January 2010 and May 2014 were retrospectively
investigated. Their imaging findings from mammograms
and ultrasonograms were reviewed. The association
between findings on mammograms and ultrasonograms
captured before NAC and response to treatment after
NAC was examined.
Results Of the 26 patients with invasive breast carcinoma, 19 (73%) responded well to treatment and 7(27%) did not. Most notably, all 10 patients who had
microcalcifications on mammogram responded well totreatment (53% of responders), and all patients who did
not respond to treatment had no microcalcifications (P <0.05). Of these 10 patients, 9 (90%) had microcalcifications of comedo type and one (10%) had non comedo
type. As a distribution, 8 of the 10 (80%) had a clusteredtype of microcalcifications and the remaining 2 (20%)
had a segmental type of them.
Conclusion
Microcalcifications of tumor observedin mammogram (particularly comedo type) could be a
predictor of response to NAC for patients with invasive
breast carcinoma.

SUBJECTS AND METHODS
Twenty-six patients with invasive breast carcinoma who
received NAC at the Division of Breast and Endocrine
Surgery of Tottori University Hospital between January2010 and May 2014 were retrospectively investigated.
Their imaging findings from mammograms and ultrasonograms were reviewed individually without patients
information by two medical breast cancer specialists
who had over 25 years experiences in breast examinations. When mutual evaluation of findings was notmatched, consensuses were got in each other. The association between findings on mammograms [tumor (size,
shape, and border/margin), microcalcifications (morphology and distribution)] and ultrasonograms [tumor
size, shape, border area, halo, internal echo, posterior
echo, and high echogenic foci] before NAC and response
to NAC was assessed.
Of the 26 patients, 14 received DTX (docetaxel hydrate) followed by FEC (F: fluorouracil, E: epirubicinhydrochloride, C: cyclophosphamide), 11 received DTX
plus trastuzumab followed FEC, and one received trastuzumab alone. The typical number of cycles was 4 of
FEC and 4 of DTX. Response to NAC was determined
Corresponding author: Yasuaki Hirooka, MD, PhD
yhirooka@med.tottori-u.ac.jp
Received 2015 March 26
Accepted 2015 April 24
Abbreviations: CT, computed tomography; DTX, docetaxel hydrate;
ER, estrogen receptor; FEC, (F: fluorouracil, E: epirubicin hydrochloride, C: cyclophosphamide); HER2, human epidermal growth
factor receptor type2; NAC, neoadjuvant chemotherapy; pCR,
pathological complete response; PD, progressive disease; PR, partial
response; RECIST, Response Evaluation Criteria in Solid Tumors;SD, stable disease

Key words

breast carcinoma; microcalcification; neoadjuvant chemotherapy
Neoadjuvant chemotherapy (NAC) is used to treat invasive breast carcinoma when the carcinoma is unresectable or when breast-conserving surgery is not indicated.
Some advantages of NAC include downstaging due
to tumor shrinkage and improved survival in patients85A. Murata et al.

according to the Response Evaluation Criteria in Solid
Tumors (RECIST)5 using contrast computed tomography (CT), and well response was defined as either a CRor partial response (PR). All patients besides one patient
who had progressive disease (PD) after NAC underwent
mastectomy or breast-conserving surgery. Fischer’s
exact test was used for statistical analysis and P < 0.05
was considered significant. This study was approved by
the ethics review board of Tottori University Faculty of
Medicine.

tions on mammogram, 9 (90%) had microcalcificationsof comedo type and one (10%) had non comedo type (Fig.
2). Eight of the 10 (80%) had a clustered distributionof microcalcifications and the remaining 2 (20%) had
a segmental distribution of them (Fig. 3). Additionally,
7 of the 10 patients with microcalcifications, including
6 of the 9 patients with microcalcifications of comedo
type, had overexpressed human epidermal growth factor receptor type2 (HER2). But there was no association
between microcalcifications and HER2 overexpression(Table 1). When the association between response totreatment and the regimen of NAC was examined, it was
found that all 11 patients who received trastuzumab in
combination therapy (all of them had HER2 overexpression) responded well to treatment. Furthermore, 7 of the
11 had microcalcifications and 6 of the 7 with microcalcifications were comedo type. The patient who received
trastuzumab alone did not respond well to treatment. No
other findings on mammograms or ultrasonograms wereassociated with response to treatment.

RESULTS
All patients were women and mean age was 55 years(range: 27–70 years). Of the 26 patients, 19 (73%; CR: 6,
PR: 13) responded well to treatment and 7 [27%; stabledisease (SD): 6, PD: 1] did not. All 10 patients who had
microcalcifications on mammogram responded well totreatment (53% of responders), and all patients who did
not respond to treatment had no microcalcifications (P <0.05) (Fig. 1). Of these 10 patients with microcalcifica-

Non-comedo type(10%)

Microcalcification (+)
Microcalcification (-)

(%)
100

75

n=9
n=7

50

25

0

Comedo type(90%)

n = 10

Response (+)

Fig. 2. Type of microcalcifications. Most microcalcifications werecomedo type.

Response (-)

Fig. 1. Microcalcifications and response to treatment. All breast
carcinomas with microcalcifications responded well to treatment(P < 0.05).

Segmental(20%)

Clustered(80%)

Fig. 3. Distribution of microcalcifications. Most microcalcifications had a clustered distribution.

86

A predictor of response to NAC
Table 1. Microcalcifications and HER2 overexpression
Microcalcifications (+)
HER2 (+)

Microcalcifications (−)

7

5

Total
12

HER2 (−)

3

11

14

Total

10

16

26

There was no association between microcalcifications and HER2 overexpression (P = 0.105).
Values within table indicate number of patients.
HER2, human epidermal growth factor receptor type2.

DISCUSSION
Few studies have discussed microcalcifications on mammogram in the context of NAC,6–8 and there is no consensus regarding the utility of microcalcifications as apredictor of response to NAC. Li et al. found that breast
carcinoma patients with microcalcifications were more
likely to exhibit an evaluable category of CR to neoadjuvant chemotherapy, although there was no significant
difference.7 In our study, all breast carcinoma patients
who had microcalcifications on mammogram responded
well to NAC (i.e., exhibited a CR or PR). Furthermore,
the fact that there was no association between HER2
overexpression and microcalcification, indicates thatbreast carcinoma with microcalcifications should exhibit
at least PR (tumor shrinkage of ≥ 30%) to NAC regardless of HER2 overexpression.
In contrast, Weiss et al. found that many of breast
carcinoma patients with microcalcifications exhibit SD
or PD after NAC, whereas breast carcinoma patients
without microcalcifications exhibit CR.8 In their study,
responses to NAC were evaluated to measuring thediameter of breast carcinoma by using mammograms.
They reported that the size of tumor with microcalcifications was 4.4 cm average in diameter evaluated bymammogram after NAC, while acutual histological sizeof tumor with microcalcifications was 2.3 cm average indiameter. Furthermore, the diameter of breast carcinoma
measured by mammogram was not correlated with histological tumor size. It was thought that overestimationof the tumor diameter causes poor evaluation of the responses to NAC.
Whereas we evaluated response using contrast CT.
Akashi-Tanaka et al. found that for all breast carcinomas
besides invasive lobular carcinoma and inflammatory
breast carcinoma, tumor diameter measured with contrast CT was most highly correlated with histologicaltumor diameter.9
In this study, characteristic feature of almost all microcalcifications on mammograms were comedo type.
Breast carcinoma with microcalcifications of comedo
type is considered to be highly proliferative activity.10
Furthermore, Brower et al. found that Ki-67 is highvalue in breast carcinoma with microcalcifications of
comedo type.11 As to association between Ki-67 andchemotherapy, Criscitiello et al. reported that the addition of chemotherapy to endocrine therapy is useful for
estrogen receptor (ER) positive, node positive breast carcinoma with high Ki-67 value.12 And, Petit et al. foundthat breast carcinoma patients with low ER expression
and high Ki-67, responded well to NAC.13 Moreover,
several studies have shown that patients with high Ki-67
are more likely to show a pathological CR.14, 15
The above findings demonstrate that microcalcifications of comedo type reflect the proliferative potential ofbreast carcinoma. Additionally, the fact that NAC is effective against breast carcinomas with highly proliferative activity, may explain that breast carcinoma patientswith microcalcifications on mammogram responded
well to treatment in this study.
In conclusion, the present study suggests that microcalcifications on mammogram (particularly comedotype) could be a predictor of response to NAC for patients with invasive breast carcinoma.
The authors declare no conflict of interest.

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