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19 - Han Metaplastic BC Clinical-Pathologic Study Analysis Response To NAC
19 - Han Metaplastic BC Clinical-Pathologic Study Analysis Response To NAC
https://doi.org/10.1038/s41379-019-0208-x
ARTICLE
Adam M. Brufsky4 Rachel C. Jankowitz4 Shannon L. Puhalla4 Ronald R. Johnson2 Atilla Soran2
● ● ● ● ●
Abstract
Metaplastic breast carcinoma is a rare heterogeneous category of breast cancer, often associated with a poor prognosis.
Clinical-pathologic studies with respect to varied morphologic subtypes are lacking. There is also a dearth of studies
assessing the response of metaplastic breast carcinoma to neoadjuvant chemotherapy. Cases of metaplastic breast carcinoma
diagnosed between 2007 and 2017 were identified. Various clinical-pathologic variables were tested for association with
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survival. Patients who underwent neoadjuvant chemotherapy were assessed for pathologic response. Median age at diagnosis
with metaplastic breast carcinoma was 64 years. With a median follow-up of 39 months, 26 patients (27%) recurred (24
distant and 2 loco-regional). The overall survival rate of the cohort was 66% (64/97). A number of variables were associated
with survival in univariable analysis; however, in multivariable analysis, only lymph node status and tumor size (pT3 vs.
pT1/2) were significantly associated with all survival endpoints: recurrence-free survival, distant recurrence-free survival,
overall survival and breast cancer-specific survival. Twenty-nine of 97 (30%) patients with metaplastic breast carcinoma
received neoadjuvant chemotherapy. Five (17%) patients achieved pathologic complete response. Matrix-producing
morphology was associated with higher probability of achieving pathologic complete response (p = 0.027). Similar to other
breast cancer subtypes, tumor size and lymph node status are prognostic in metaplastic carcinomas. The pathologic complete
response rate of metaplastic breast carcinoma in our cohort was 17%, higher than previously reported. Although the matrix-
producing subtype was associated with pathologic complete response, there was no survival difference with respect to tumor
subtypes.
Introduction
Cancer Center Database reported that metaplastic breast in the study. Consult cases were excluded. Slides for review
carcinomas are the histologic subtype associated with the were available for 84 cases (87%). Two pathologists (MH
worst overall survival [9, 10]. and RB) estimated the proportion of different tumor com-
Surgery (±radiation) is the standard treatment for most ponents. For patients receiving neoadjuvant chemotherapy,
metaplastic breast carcinomas. Metaplastic carcinoma is only core biopsy slides were reviewed for sub-classification.
often negative for estrogen receptor (ER) and human epi- The following case information was recorded: patient age,
dermal growth factor receptor 2 (HER2), limiting the use of tumor size, nuclear grade and receptor status (semi-quanti-
hormonal therapy and HER2 targeted therapy [9]. The use tative results), lymph node status, loco-regional treatment
of chemotherapy in metaplastic breast carcinoma is mostly (surgery and/or radiation), systemic therapy, recurrence-free
extrapolated from clinical trial results involving typical survival, distant recurrence-free survival, overall survival,
invasive ductal carcinomas. Published studies regarding and breast cancer-specific survival. For patients not treated
response of metaplastic breast carcinomas to chemotherapy, with neoadjuvant chemotherapy, the tumor size and nodal
particularly in the neoadjuvant setting, are either old or status was determined by standard pathology examination
small in sample size [6, 8]. Despite the traditional notion of the surgical specimen. For patients treated with neoad-
that metaplastic breast carcinomas are resistant to che- juvant chemotherapy, the radiographic or clinical pre-
motherapy, systemic chemotherapy is administered to therapy tumor size was taken for staging and the nodal
53.4–73.1% of patients with metaplastic carcinomas [1, 9]. status was considered positive if either metastatic tumor was
In recent years, neoadjuvant chemotherapy has been documented with percutaneous pre-therapy lymph node
increasingly used as part of the multidisciplinary manage- biopsy or if positive sentinel/axillary node(s) were identified
ment of breast cancer [11]. Historically administered to at definitive surgery.
reduce the size of large tumors in order to pursue breast- Pathologic complete response was defined as absence of
conserving surgery, neoadjuvant chemotherapy is nowadays invasive carcinoma in the breast and lack of metastatic
frequently considered for smaller operable breast cancers. carcinoma in the lymph nodes at definitive surgery. Pre-
Although neoadjuvant chemotherapy confers no survival sence of residual ductal carcinoma in-situ was acceptable.
benefit over adjuvant chemotherapy, it allows evaluation of Recurrence-free survival was defined as the time from
tumor response to specific chemotherapy regimens. In diagnosis to development of any recurrence (distant or loco-
addition, pathologic complete response after neoadjuvant regional) or last follow-up. Distant recurrence-free survival
chemotherapy has been shown to be an independent pre- was defined as the time from diagnosis to development of
dictor for survival compared with cases that fail to achieve distant recurrence or last follow-up. Overall survival dura-
pathologic complete response [11–13]. However, there is a tion was defined as the time from diagnosis to death from
dearth of studies evaluating response to neoadjuvant che- any cause or last follow-up. Breast cancer-specific survival
motherapy in metaplastic breast carcinoma. duration was defined as the time from diagnosis to death
Clinical trials for metaplastic breast carcinomas are hard due to breast cancer or last follow-up.
to achieve due to the rarity of the diagnosis and hetero- Statistical analysis was performed using The R project
geneity of its morphologic subtypes. To gain further insight, for Statistical Computing (https://www.r-project.org/). For
we performed a retrospective review of metaplastic breast continuous variables, the p-value was obtained from two-
carcinoma diagnosed at a tertiary academic hospital. sided Wilcoxon rank sum test. For categorical variables, the
Approximately one-third of the study cases were treated p-value was obtained from the two-sided Fisher’s exact test.
with neoadjuvant chemotherapy, which allowed assessment Patients with missing/unknown information were excluded
of chemo-responsiveness of these tumors. The goals of this from the test. Confidence intervals were obtained from
study were to identify variables associated with survival and Wald normal approximation.
to determine the pathologic complete response rate to Kaplan–Meier survival curves (for recurrence-free, dis-
neoadjuvant chemotherapy in metaplastic breast carcinoma. tant recurrence free, overall and breast cancer-specific sur-
vival) were analyzed with respect to clinical-pathologic
variables (age, nodal status, tumor size, nuclear grade, ER
Methods status, PR status, HER2 status, Ki-67 labeling index, type of
surgery [lumpectomy versus mastectomy], administration
A 10-year (2007–2017) electronic data search was per- of radiation, administration of chemotherapy, administration
formed in the laboratory information system using the of endocrine therapy, neoadjuvant chemotherapy, tumor
keywords “metaplastic carcinoma” plus “breast” in the subtype [metaplastic only versus admixed], type of most
diagnostic line. Ninety-seven cases met the criteria based on prominent metaplastic component, and number of meta-
pathology reports and/or review of slides. Any case show- plastic component). p-values were obtained using the log-
ing unequivocal metaplastic tumor component was included rank test. The variables with statistically significant
Metaplastic breast carcinoma: a clinical-pathologic study of 97 cases with subset analysis of response. . .
associations were included in multivariable Cox propor- showed better differentiation toward no special type com-
tional hazard model. pared to the primary tumor.
Table 1 Patient and tumor characteristics and therapies received Table 1 (continued)
N % N %
Age group pN3 5 5
≤55 33 34 Unknown 6 6
>55 64 66 Tumor subtype
Median age (inter-quartile range) 64 (51–75) — Admixed with NST 49 51
pT Metaplastic only 48 49
pT1 25 26 Most prominent tumor component overall
pT2 43 44 Matrix producing 31 32
pT3/4 27 28 NST 24 25
Unknown 2 2 Squamous 21 22
Nuclear grade Spindle 18 18
G1 0 0 Other 3 3
G2 4 4 Most prominent metaplastic component when not
G3 81 84 admixed with NST (48 cases)
Unknown 12 12 Matrix producing 19 40
Estrogen Receptor (ER) Squamous 15 31
Positive 19 20 Spindle 14 29
Negative 78 80 Local treatment
H-score range for positive 1–150 — Lumpectomy + radiation 31 32
Median (IQR) for positive 10 (10–50) — Lumpectomy, no radiation 9 9
Progesterone receptor (PR) Mastectomy + radiation 15 16
Positive 11 11 Mastectomy, no radiation 40 41
Negative 86 89 Mastectomy, radiation scheduled 1 1
H-score range for positive 1–140 — No primary surgery 1 1
Median (IQR) for positive 6 (3–20) — Systemic therapy
HER2 Chemotherapy only 57 59
Positive 4 4 Chemo + endocrine therapy 6 6
Equivocal 4 4 Endocrine therapy only 3 3
Negative 89 92 Neither chemo nor endocrine therapy 31 32
Ki-67 Neoadjuvant chemotherapy
<50% 17 17 Yes 29 30
≥50% 55 57 No 68 70
Unknown 25 26 pT pathologic tumor stage, pN pathologic nodal stage, NST carcinoma
Median (inter-quartile range) 65 (50–80) — of no special type
Receptor profile
ER+/PR+ 3 3
ER−/PR− 70 72 p = 0.004), and smaller tumor size (pT1/2 rather than pT3,
ER+/PR− 16 17 p = 0.001, p < 0.001) were associated with improved
ER−/PR+ 8 8 recurrence-free and distant recurrence-free survival. For
ER+/HER2+ 2 2 overall survival, negative nodal status (p < 0.001), admin-
ER−/HER2− 76 78 istration of radiation (p = 0.042) and chemotherapy (p =
ER+/HER2− 17 18 0.003), and smaller tumor size (p < 0.001) were associated
ER−/HER2+ 2 2 with better survival. For breast cancer-specific survival,
pN negative nodal status (p < 0.001), lumpectomy as primary
pN0 62 64
surgery (p = 0.039), and smaller tumor size (p < 0.001)
pN1 21 22
were associated with better survival.
In multivariable analysis, lymph node status and tumor
pN2 3 3
size (pT3 vs. pT1/2) were the only two variables that were
associated with all survival endpoints, recurrence-free, dis-
tant recurrence free, overall, and breast cancer-specific
Metaplastic breast carcinoma: a clinical-pathologic study of 97 cases with subset analysis of response. . .
Fig. 1 Low-power view of representative cases showing metaplastic (a, c). High-power view of the same cases, showing abundant chon-
breast carcinoma with well-demarcated nodule(s) with central necrosis droid matrix with moderate to marked nuclear pleomorphism (b, d)
survival (Figs. 2 and 3, Table 3). More than one metaplastic a previous Mayo clinic study [8], reflecting the increased
component was associated with worse recurrence-free sur- awareness of this specific category of breast cancer after the
vival (hazard ratio of 7.21, p-value: 0.001, 95% CI: World Health Organization recognition in 2000 [5]. The
2.16–24.10) and breast cancer-specific survival (hazard patients in our cohort were slightly older at diagnosis
ratio: 5.42, p-value: 0.038, 95% CI: 1.10–26.60). Admin- (median age 64 years) than the typical age at presentation
istration of radiation therapy and chemotherapy were both for breast cancer. Previous literature has shown significantly
associated with improved overall survival (hazard ratio of worse recurrence-free and overall survival associated with
0.300 for radiation, p-value: 0.041, 95% CI: 0.095–0.950; metaplastic breast carcinoma than with classic triple-
hazard ratio of 0.397 for chemotherapy, p-value: 0.039, negative breast cancer [9, 15–17]. Our study did not
95% CI: 0.165–0.954) without a significant effect on include classic breast cancers, but our results showed that
recurrence-free survival (Table 3). metaplastic breast carcinoma patients had an overall survi-
val rate of 66% (with 39 months median follow-up), worse
than published data about classic triple-negative breast
Discussion cancer [10]. Squamous and spindle cell differentiation have
been shown to be associated with worse prognosis than
We identified 97 metaplastic breast carcinomas diagnosed other metaplastic components [16]. Our study did not reveal
and treated at our institution in the past 10 years (between any significant difference in overall or recurrence-free sur-
2007 and 2017). This number was much higher than the vival among different metaplastic breast carcinoma sub-
reported 27 cases over 21 years (between 1976 and 1997) in types. However, our results showed that the presence of
M. Han et al.
Table 2 Association of clinical and pathologic variables with pathologic complete response (pCR) to neoadjuvant chemotherapy
Total (N = 29) Residual tumor/negative pCR (N = 5, 17%) p-value
for pCR (N = 24, 83%)
more than one metaplastic component was associated with lymph node status and smaller tumor size were predictors
worse recurrence-free and breast cancer-specific survival. for better recurrence-free and breast cancer-specific survival
This is plausible because increased plasticity, a stem-cell- in metaplastic breast carcinoma. Nevertheless, caution is
like feature, often implies poor differentiation. Similar to urged with respect to survival analysis, given that the
typical breast carcinomas, our results indicated that negative patients were not treated uniformly as part of a clinical trial.
Metaplastic breast carcinoma: a clinical-pathologic study of 97 cases with subset analysis of response. . .
OS
0.50 ++ + + + + + 0.50
++
+ + + + +
0.25 0.25
p = 0.00077 p < 0.0001
0.00 0.00
0 10 20 30 40 50 60 70 80 90 100 110 120 0 10 20 30 40 50 60 70 80 90 100 110 120
Month Month
Number at risk Number at risk
Strata
Strata
pT1/2 68 61 50 43 38 35 30 27 18 14 10 9 4 pT1/2 68 64 52 46 42 37 32 29 21 17 11 9 4
pT3 27 14 8 5 4 3 2 2 2 1 1 1 1 pT3 27 17 9 6 4 3 2 2 2 1 1 1 1
0 10 20 30 40 50 60 70 80 90 100 110 120 0 10 20 30 40 50 60 70 80 90 100 110 120
Month Month
1.00
++ +++ 1.00 +++ ++++ +
++ + +++ ++ +++
+ ++ ++ + ++++ ++++ +++++++ ++
++ + + ++++ ++ + + + ++
0.75 ++++++ +++ ++ ++ +++++ + ++++ 0.75 ++ +++++ + ++++
+ ++
++
+
DRFS
BCSS
0.50 ++ + + + + + 0.50 ++
+ + + + +
0.25 0.25
p = 4e 04 p < 0.0001
0.00 0.00
0 10 20 30 40 50 60 70 80 90 100 110 120 0 10 20 30 40 50 60 70 80 90 100 110 120
Month Month
Number at risk Number at risk
Strata
Strata
pT1/2 68 61 50 43 38 36 31 28 19 16 11 9 4 pT1/2 68 64 52 46 42 37 32 29 21 17 11 9 4
pT3 27 15 8 5 4 3 2 2 2 1 1 1 1 pT3 24 15 9 6 4 3 2 2 2 1 1 1 1
0 10 20 30 40 50 60 70 80 90 100 110 120 0 10 20 30 40 50 60 70 80 90 100 110 120
Month Month
In this study, we reported the largest number (29 of 97) patients achieved pathologic complete response [11].
of patients with metaplastic breast carcinoma undergoing Although National Cancer Database study applied slightly
neoadjuvant chemotherapy at a single institution and the more strict criteria for pathologic complete response by
highest rate of pathologic complete response (17.2%) for excluding cases with ductal carcinoma in-situ in the resec-
metaplastic breast carcinoma. In a previous MD Anderson tion specimen, the overall pathologic complete response
study, only 2 (10%) patients with metaplastic breast carci- rate in our study is similar to the pathologic complete
noma treated with neoadjuvant chemotherapy achieved response rate reported in the National Cancer Database
pathologic complete response [6]. A recent Johns Hopkins study [11].
study reported 13% (6 of 45) of patients diagnosed with Although metaplastic breast carcinoma is often regarded
metaplastic breast carcinoma received neoadjuvant che- as having a triple-negative phenotype, they actually show
motherapy, among whom only 1 patient achieved patholo- various immunoprofiles. Only 70.3% of the 2451 meta-
gic complete response [18]. None of the patients with plastic breast carcinoma cases in the National Cancer
metaplastic breast carcinoma who received neoadjuvant Database study were truly negative for ER, PR, and HER2;
chemotherapy in a recent Turkish study (n = 8) [15] or in a HER2 was positive in 118 (4.8%) [10]. Our study showed
Japanese study (n = 14) [17] achieved pathologic complete similar results, with 67% (65 of 97) of metaplastic breast
response. In a recent review of the National Cancer Data- carcinoma being triple negative. Weakly to moderately ER
base from 2010 to 2014, 33,162 patients with breast cancers positive metaplastic breast carcinoma constituted 20% of
underwent neoadjuvant chemotherapy, of whom 19.2% of our cases. Interestingly, the ER−/PR+ group represented a
M. Han et al.
1.00
++ +++++++ + 1.00 ++ +
++++++ +
+++ ++ + +++ + +
++ + + + ++ +++ + + ++ ++++
+ ++
++++ + ++
++++ ++
0.75
+ ++ +++ ++ + +++ 0.75 + +++ +++ + +++
+
+
RFS
OS
0.50 0.50
+ + +
+ + ++ ++
++
0.25 0.25 + ++ ++
p = 0.00021 p < 0.0001
0.00 0.00
0 10 20 30 40 50 60 70 80 90 100 110 120 0 10 20 30 40 50 60 70 80 90 100 110 120
Month Month
Number at risk Number at risk
Strata
Strata
pN0 62 53 41 36 30 27 22 20 14 9 6 6 3 pN0 62 55 41 37 33 29 24 22 16 11 7 6 3
pN1/2/3 29 19 14 9 9 8 8 7 5 5 4 4 2 pN1/2/3 29 23 17 12 10 8 8 7 6 6 4 4 2
0 10 20 30 40 50 60 70 80 90 100 110 120 0 10 20 30 40 50 60 70 80 90 100 110 120
Month Month
1.00
++ +++++++ + 1.00 ++++
+ ++
+++ ++ +++ + +++ +++ + + ++ +++++ ++
++++ ++
++ + + + ++ +++ + ++ + +++ +++ + +++
++++ +++ +++ +++ + +++ +
0.75 + 0.75
+
+ +
DRFS
BCSS
0.50 0.50
+ + + + ++
+ + ++ ++ + ++ ++
0.25 0.25
p < 0.0001 p < 0.0001
0.00 0.00
0 10 20 30 40 50 60 70 80 90 100 110 120 0 10 20 30 40 50 60 70 80 90 100 110 120
Month Month
Number at risk Number at risk
Strata
Strata
pN0 62 53 41 36 30 28 23 21 15 11 7 6 3 pN0 61 55 41 37 33 29 24 22 16 11 7 6 3
pN1/2/3 29 20 14 9 9 8 8 7 5 5 4 4 2 pN1/2/3 27 21 17 12 10 8 8 7 6 6 4 4 2
0 10 20 30 40 50 60 70 80 90 100 110 120 0 10 20 30 40 50 60 70 80 90 100 110 120
Month Month
higher number of cases than we expected (8%). Wright and [9] 72 (11.3%) patients with known hormonal receptor
colleagues studied the influence of hormonal status on the status showed ER positivity but only 57 (6.4%) patients
prognosis of metaplastic breast carcinoma using the Sur- received hormonal therapy [9]. The authors did not com-
veillance, Epidemiology, and End Results data from 2000 to ment on tumor response to hormonal therapy, which may be
2010 [19]. The authors showed that 79% (1632 of 2066) of of interest in future studies. In our current study, 6 of the 19
metaplastic breast carcinomas in the Surveillance, Epide- ER+ patients received endocrine therapy. ER+ status was
miology, and End Results database were negative for both associated with worse distant recurrence-free and breast
ER and PR. The rest of the cases were ER+/PR+ (8.8%), cancer-specific survival (Table 3), but the administration of
ER+/PR− (7.6%) and ER−/PR+(4.6%). The authors endocrine therapy did not have any significant impact on
concluded that hormonal status does not affect the 5-year survival. However, it is to be noted that the total number of
overall survival (65.7 vs. 63.5%, p = 0.70) [19]. However, ER+ patients in the current study is rather small and the
the author did acknowledge that the lack of information impact of ER status on survival should be confirmed using
about the anti-hormonal therapy and the HER2 status of the larger datasets.
cases was a significant drawback of the study. The response HER2 positivity is even rarer and no study evaluating the
of ER-positive metaplastic breast carcinoma to anti- effectiveness of anti-HER2 therapy in metaplastic breast
hormonal therapy is largely unknown. In fact, not all hor- carcinoma is available. In the current study, HER2 was
mone receptor-positive metaplastic breast carcinoma in the positive (immunohistochemical score of 3+) in 4 (4.1%)
National Cancer Database study received hormonal therapy; cases, including 2 squamous cell, 1 spindle cell, and 1
Metaplastic breast carcinoma: a clinical-pathologic study of 97 cases with subset analysis of response. . .
matrix-producing type of metaplastic breast carcinoma. differences among different subtypes of metaplastic breast
HER2 positivity was identified in the metaplastic tumor carcinoma and their different sensitivity to the commonly
component. An additional four cases showed equivocal used chemotherapeutic regimens. However, this finding
HER2 results (IHC score 2+ and fluorescence in-situ should be further confirmed in larger multi-institutional stu-
hybridization [FISH] equivocal by 2013 HER2 guideline dies. Nevertheless, it is important to accurately diagnose/
criteria). Three of the four HER2 positive metaplastic breast recognize matrix-producing metaplastic breast carcinoma,
carcinoma patients in our study received targeted therapy, which is characterized by abundant myxoid or chondroid
two in the neoadjuvant setting and another one post surgery. stroma with a large area of central necrosis and a rim of viable
One of the two neoadjuvant patients receiving trastuzumab- tumor cells with moderate to severe nuclear pleomorphism.
based chemotherapy achieved pathologic complete Although matrix-producing subtype was predictive of a
response. Regardless of pathologic complete response or higher likelihood of achieving pathologic complete response
administration of targeted therapy, all four HER2+ patients in this cohort, no survival benefit was associated with either
were alive during follow-up period. It is difficult to assess pathologic complete response status or matrix-producing type
the effect of targeted therapy in this anecdotal experience. histology. The literature regarding metaplastic breast carci-
Metaplastic breast carcinoma has been shown to be noma histologic sub-types and pathologic complete response
extremely heterogeneous in morphology and in molecular is limited; only a case report about pathologic complete
analysis [3, 20]. Matrix-producing type metaplastic breast response in primary breast squamous cell carcinoma is
carcinoma was the most common type of metaplastic carci- available [21]. None of the 11 metaplastic breast carcinoma
noma in our study. Interestingly, the matrix producing variant with squamous differentiation in the current study achieved
was also the only histo-morphologic feature associated with pathologic complete response after neoadjuvant chemother-
higher probability of achieving pathologic complete response apy. Given the limited data in this study and in the literature,
(p < 0.05). This most likely represents the biological caution is urged in over-interpretation of the associations of
M. Han et al.
the morphologic features and achieving a pathologic complete cancer: a National Cancer Centre Database analysis. Eur J Cancer.
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10. Ong CT, Campbell BM, Thomas SM, Greenup RA, Plichta JK,
The pathologic complete response rate of metaplastic
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