Comparison of invasive micropapillary and triple negative invasive ductal carcinoma of the breast

The Breast xxx (2015) 1e9

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Original article

Comparison of invasive micropapillary and triple negative invasive ductal carcinoma of the breast Hong-liang Chen, Ang Ding* Department of Breast Surgery, Obstetrics and Gynecology Hospital of Fudan University, 419 Fangxie Road, Huangpu District, Shanghai 200011, China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 10 March 2015 Received in revised form 15 July 2015 Accepted 1 September 2015 Available online xxx

Background: Invasive micropapillary carcinoma (IMPC) of the breast and triple negative breast cancer (TNBC) are both aggressive subtypes, but little information is available on their comparison. Patients and methods: Retrospective analysis of 95 IMPC and 200 TNBC-IDC (invasive ductal carcinoma) was conducted to compare the clinicopathologic characteristics and survivals. Results: For IMPC, pN was the independent prognostic factor of local-regional recurrence free survival (LRRFS) (P ¼ 0.045) and metastasis free survival (MFS) (P ¼ 0.048), but not of overall survival (OS) (P ¼ 0.165). For TNBC, pT and lymphovascular invasion (LVI) were both independent prognostic factors of MFS (pT: P ¼ 0.006, LVI: P ¼ 0.010) and OS (pT: P ¼ 0.006, LVI: P ¼ 0.001), but not for LRRFS (pT: P ¼ 0.060, LVI: P ¼ 0.503). IMPC exhibited more aggressive features than TNBC, including larger tumor size, a greater proportion of nodal involvement, and an increased incidence of LVI. After a median followup duration of 61 months, 5y-LRRFS rate was lower in IMPC than in TNBC, in entire cohort (71.4 ± 4.8% vs. 89.8 ± 2.2%, P < 0.001) and in node positive cases (64.2 ± 5.9% vs. 81.7 ± 4.4%, P ¼ 0.048). A tendency of lower 5y-MFS rate was observed in TNBC compared with in IMPC, in node positive cases (63.8 ± 5.5% vs. 74.8 ± 5.5%, P ¼ 0.053) and in node negative cases (80.1 ± 3.6% vs. 96.2 ± 3.8%, P ¼ 0.052), but it did not reach significance. 5y-OS was similar between IMPC and TNBC (81.9 ± 4.7% vs. 79.8 ± 3.1%, P ¼ 0.475). Conclusions: IMPC is featured with high rate of lymph node involvement which is strongly associated with high rate of LRR. TNBC is featured with high rate of early distant metastasis without increase of nodal metastases. The survival is still relatively poor even in node negative cases. © 2015 Elsevier Ltd. All rights reserved.

Keywords: Invasive micropapillary carcinoma of breast Triple negative breast cancer Clinicopathologic characteristic Prognosis

Introduction Invasive micropapillary carcinoma (IMPC) of the breast is an uncommon and distinct variant of invasive breast carcinoma, with the rate of incidence ranging from 1.0 to 8.4% [1e6]. Since the relatively recent identification of IMPC in the mid 1990s [7,8], researchers have been quick to note the importance of this entity given its apparent greater risk of lymphovascular invasion (LVI), lymph node metastasis, local recurrence and distant metastasis at relatively high frequencies, thus exhibiting a more aggressive behavior than invasive ductal carcinomas of non special type (IDC NST) [9,10]. Recently, gene expression profiling studies established a widely applied molecular classification of breast cancers distinguishing three major subtypes, luminal, HER2þ and triple negative breast cancer (TNBC), which are characterized by distinct transcriptomic

* Corresponding author. E-mail address: [email protected] (A. Ding).

features and, most importantly, patient outcomes [11,12]. TNBC is defined by the lack of expression of the estrogen and progesterone receptors and human epidermal growth factor receptor 2 (HER2), which accounts for 15e20% of breast cancer patients. It is the most aggressive subtype of IDC, characterized by occurrence at young age, early relapse especially visceral metastasis and poor prognosis [11]. There are lots of studies focusing on IMPC and IDC, but few comparing IMPC and TNBC-IDC, which both exhibit aggressive behavior and have poor prognosis. Therefore, we conducted an extensive comparison study of IMPC and TNBC to provide a more complete and reliable overview of their clinicopathologic features and differences in prognosis. Patients and methods Patients We retrospectively reviewed the data of 95 patients with IMPC and 200 patients with pure TNBC-IDC. They were treated at the

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Department of Breast Surgery of Obstetrics and Gynecology Hospital of Fudan University from January 2007 to December 2013. Any patient who showed a clear IMPC component was enrolled in this study regardless of the extent of the IMPC component. Among the IMPC cases, 14 patients (14.7%) were identified as having pure IMPC, whereas the others had mixed IMPC. The nonmicropapillary invasive carcinoma components of the mixed IMPC cases were as follows: IDC, mucinous carcinoma, and ductal carcinoma in situ. This study was approved and exempted from patient permission by Institutional Review Boards. All patients received standard treatment, including mastectomy or breast-conserving surgery (BCS) plus axillary lymph node dissection (ALND)/sentinel lymph node biopsy (SLNB), adjuvant/neoadjuvant chemotherapy composed of different regimens according to the standards used at the time of surgery followed by radiotherapy (if required) and/or endocrine therapy (if required). All patients with positive lymph node metastasis received ALND. Patients were excluded for the following reasons: male gender, in situ lesion, curative resection was not conducted, distant metastasis was confirmed before surgery. The histologic grade, Ki-67 index and the proportion of the IMPC component of each mixed IMPC specimen were not analyzed due to lack of available information in many cases. Follow-up information regarding tumor relapse and survival status was available through outpatient departmental records and personal contact with the patients via mail and telephone calls until December 2014. Patterns of failure Local-regional recurrence free survival (LRRFS) was defined as the interval from diagnosis to the date of the recurrence of tumors in the ipsilateral breast and/or chest wall or in the ipsilateral axilla, infraclavicular, or supraclavicular areas. Metastasis free survival (MFS) was defined as the interval from the same start date to the date of distant relapse. Overall survival (OS) was defined as the interval between diagnosis and death due to breast cancer progression. Those without any evidence of relapse were censored at the last date on which they were known to be alive. Patients who died of other causes were censored at the date of their death for OS analysis. All recurrences were diagnosed by either clinical or radiological examinations. Immunohistochemistry (IHC) profile The status of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2) was determined by immunohistochemical (IHC) staining. The cut-off value for ER positivity and PR positivity was 1% of tumor cells with positive nuclear staining. Tumors with an IHC score of 3þ based on circumferential membrane-bound staining (DakoCytomation, Carpinteria, CA, US) or with amplification confirmed by florescent in situ hybridization (FISH) were defined as HER-2positive. Tumors with an IHC score of 2þ were recommended FISH test. Statistical analysis Comparisons of clinicopathologic characteristics of the different subgroups were performed using an independent sample t-test and Pearson's chi-square test; Fisher's exact test was used when needed. Survival curves were constructed using the KaplaneMeier method, and univariate survival difference was determined with the log-rank test. All variables with statistical significance in the univariate analysis were investigated by multivariate analysis. Adjusted hazard ratios (HRs) with 95% confidence intervals were calculated using Cox proportional hazards model. All the statistical

analysis was performed using SPSS 19.0 software package (SPSS, Chicago, IL, USA). Two-sided P < 0.05 was considered statistically significant. Results Clinicopathologic characteristics and survival analysis of IMPC The mean age of 95 IMPC patients was 58.85 ± 11.49 years old (range 37e69). The mean size of tumor was 3.66 ± 1.62 cm (range 1.5e7.0). The median number of positive lymph nodes was 3 (range 0e22). The mean number of lymph nodes removed was 16.53 ± 4.79 (range 8e23). There were altogether 69 cases (72.6%) with positive lymph nodes, of which 54 cases in ALND and 15 cases in SLNB. In the 15 cases with positive SLNs, 10 cases had further positive non-SLNs. The ER positivity was as high as 83.2%, with 74.7% PR positivity and 21.1% HER2 overexpression. The clinicopathologic characteristics were summarized in Table 1. Univariate analysis revealed that higher pN stage and presence of LVI were associated with decreased LRRFS, MFS and OS (Table 1). The survival curves of lymph node stage were shown in Fig. 1 according to the classifications of pN stage (pN0-pN3) or lymph node status (positive or negative) or positive pN stage (pN1epN3). There was a statistically significant separation between the KaplaneMeier survival curves by each classification for LRRFS and MFS (P < 0.05) (Fig. 1AeF). But for OS, there was statistically significant separation between the KaplaneMeier survival curves by lymph node involvement (P ¼ 0.047, 0.042, respectively) (Fig. 1GeH), while only a tendency of separation between survival

Table 1 Clinicopathologic characteristics and univariate analysis of survival in IMPC. Cases n Menopause status Pre-menopause Post-menopause pT stage pT1 pT2 pT3 Lymph node status Positive Negative pN stage pN0 pN1 pN2 pN3 LVI Positive Negative ER status Positive Negative PR status Positive Negative HER2 status IHC (3þ) or FISH (þ) IHC () (þ) (þþ) Surgery Mastectomy BCS Chemotherapy Adjuvant Neoadjuvant

Univariate analysis (P value) %

36 59

37.9 62.1

28 46 21

29.5 48.4 22.1

69 26

72.6 27.4

26 24 21 24

27.4 25.3 22.1 25.3

49 46

51.6 48.4

79 16

83.2 16.8

71 24

74.7 25.3

20 75

21.1 78.9

74 21

77.9 22.1

67 28

70.5 29.5

5y-LRRFS

5y-MFS

5y-OS

0.936

0.968

0.367

0.411

0.216

0.147

0.014

0.050

0.052

0.005

0.005

0.047

0.024

0.038

0.047

0.792

0.156

0.170

0.512

0.249

0.309

0.385

0.179

0.167

0.070

0.151

0.463

0.084

0.063

0.214

LVI: lymphovascular invasion. BCS: breast-conserving surgery.

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Fig. 1. Survival curves for IMPC according to various lymph node status. AeC: LRRFS according to pN stage, lymph node status and positive pN stage; DeF: MFS according to pN stage, lymph node status and positive pN stage; GeI: OS according to pN stage, lymph node status and positive pN stage.

curves of pN1epN3 without statistical significance (P ¼ 0.085) (Fig. 1I). When pN and LVI were entered into the Cox proportional hazards model as covariates, pN was the independent prognostic factor of LRRFS (P ¼ 0.045) and MFS (P ¼ 0.048), but not of OS (P ¼ 0.165). LVI lost significance for LRRFS, MFS or OS (LRRFS: P ¼ 0.141, MFS: P ¼ 0.353, OS: P ¼ 0.492) (Table 2).

Clinicopathologic characteristics and survival analysis of TNBC The mean age of 200 TNBC patients was 49.75 ± 9.98 years old (range 22e70). The mean size of tumor was 2.96 ± 1.02 cm (range 1.0e15.0). The median number of positive lymph nodes was 0 (range 0e24). The mean number of lymph nodes removed was 15.94 ± 5.04 (range 8e35). There were altogether 79 cases (39.5%)

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Table 2 Multivariate analysis of survival in IMPC. LRRFS

pN pN1:pN0 pN2:pN0 pN3:pN0 LVI Positive:negative

MFS 95% CI

P

HR

95% CI

P

HR

95% CI

P

1.992 5.236 6.025

0. 363e10.937 1.110e24.699 1.307e27.776

0.045 0.428 0.036 0.021

1.828 4.214 9.142

0.165e20.241 0.471e37.739 1.136e73.559

0.048 0.623 0.198 0.038

1.691 2.855 6.380

0.153e18.712 0.296e27.486 0.774e52.597

0.165 0.669 0.364 0.085

1.927

0.805e4.611

0.141

1.676

0.563e4.990

0.353

1.538

0.451e5.239

0.492

with positive lymph nodes, of which 55 cases in ALND and 24 cases in SLNB. In the 24 cases with positive SLNs, 6 cases had further positive non-SLNs. The clinicopathologic characteristics were summarized in Table 3. Univariate analysis revealed that larger tumor size, higher pN stage, lymph node involvement and presence of LVI were associated with decreased LRRFS, MFS and OS (Table 3). The survival curves of lymph node stage were shown in Fig. 2 according to the classifications of pN stage (pN0epN3) or lymph node status (positive or negative) or positive pN stage (pN1epN3). Although there was statistically significant difference among pN stages for LRRFS, MFS and OS (P < 0.05) (Fig. 2A,D,G), further analysis showed that there was a statistically significant separation between the KaplaneMeier survival curves of lymph node involvement (P < 0.05) (Fig. 2B,E,H) rather than of pN1epN3(P ¼ 0.977 for LRRFS, 0.128 for MFS, 0.129 for OS) (Fig. 2C,F,I). When pT, lymph node status and LVI were entered into the Cox proportional hazards model as covariates, pT and LVI were both independent prognostic factors of MFS (pT: P ¼ 0.006, LVI: P ¼ 0.010) and OS (pT: P ¼ 0.006, LVI: P ¼ 0.001), but both lost significance for LRRFS (pT: P ¼ 0.060, LVI: P ¼ 0.503) (Table 4).

Table 3 Clinicopathologic characteristics and univariate analysis of survival in TNBC. Cases n Menopause status Pre-menopause Post-menopause Histologic grade II III pT stage pT1 pT2 pT3 Lymph node status Positive Negative pN stage pN0 pN1 pN2 pN3 LVI Positive Negative Surgery Mastectomy BCS Chemotherapy Adjuvant Neoadjuvant

OS

HR

Univariate analysis (P value) %

109 91

54.5 45.5

64 136

32.0 68.0

73 110 17

36.5 55.0 8.5

79 121

39.5 60.5

121 50 18 11

60.5 25.0 9.0 5.5

54 146

27.0 73.0

139 61

69.5 30.5

176 24

88.0 12.0

5y-LRRFS

5y-MFS

5y-OS

0.143

0.146

0.549

0.855

0.580

0.922

0.002

<0.001

<0.001

0.002

0.018

0.032

0.026

0.013

0.002

0.010

<0.001

<0.001

0.944

0.501

0.482

0.074

0.083

0.137

Comparison between IMPC and TNBC The comparison of clinicopathologic characteristics between IMPC and TNBC was presented in Table 5. IMPC exhibited more aggressive features than TNBC, including larger tumor size (3.66 ± 1.62 cm versus 2.96 ± 1.02, P ¼ 0.003), especially higher proportion of tumors greater than 5 cm (22.1% versus 8.5%, P ¼ 0.017), a greater proportion of nodal involvement (72.6% versus 39.5%, P < 0.001), especially higher proportion of pN2 and pN3 cases (47.4% versus 14.5%, P < 0.001), and an increased incidence of LVI (51.6% versus 27.0%, P < 0.001). A higher frequency of neoadjuvant chemotherapy administration was observed in IMPC than in TNBC (29.5% versus 12.0%, P < 0.001), probably because these patients were more likely to have higher pT and pN stage. The patients of TNBC were relatively younger than those of IMPC (49.75 ± 9.98 versus 58.85 ± 11.49, P ¼ 0.002), with higher proportion of pre-menopausal cases (54.5% versus 37.9%, P ¼ 0.008). No significant difference was observed between the two subtypes regarding mean lymph nodes removed (P ¼ 0.339) and proportion of surgery type (P ¼ 0.133). Notably, an obvious separation of the KaplaneMeier survival curves between two surgery types was observed for LRRFS and MFS favoring mastectomy in IMPC although it did not reach statistical significance (P ¼ 0.070, 0.151, respectively, Fig. 3), while the curves were close to each other in TNBC without significant difference between each other. The overall median follow-up duration was 61 months (range 24e96 months). The median follow-up was 60 months (range 24e96 months) in IMPC group and 61 months (range 24e96 months) in TNBC group. The comparison of survivals between IMPC and TNBC was shown in Fig. 4. As an entire cohort, 5y-LRRFS rate was lower in IMPC than in TNBC (71.4 ± 4.8% vs. 89.8 ± 2.2%, P < 0.001, Fig. 4A), but 5y-MFS rate and 5y-OS rate were similar (for MFS, IMPC vs. TNBC: 79.8 ± 4.4% vs. 73.7 ± 3.1%, P ¼ 0.091, Fig. 4D; for OS, IMPC vs. TNBC: 81.9 ± 4.7% vs. 79.8 ± 3.1%, P ¼ 0.475, Fig. 4G). For patients with positive lymph nodes, 5y-LRRFS rate was lower in IMPC than in TNBC (64.2 ± 5.9% vs. 81.7 ± 4.4%, P ¼ 0.048, Fig. 4B). Although there was a tendency of lower 5y-MFS rate in TNBC than in IMPC (74.8 ± 5.5% vs. 63.8 ± 5.5%, P ¼ 0.053, Fig. 4E), this did not reach statistical significance. The two subtypes had similar 5y-OS rate (IMPC vs. TNBC: 78.3 ± 5.7% vs. 73.9 ± 5.5%, P ¼ 0.247, Fig. 4H). For patients with negative lymph nodes, 5y-LRRFS rate and 5yOS rate were similar in IMPC and TNBC (for LRRFS, IMPC vs. TNBC: 90.5 ± 6.5% vs. 95.0 ± 2.0%, P ¼ 0.563, Fig. 4C; for OS, IMPC vs. TNBC: 95.5 ± 4.4% vs. 83.4 ± 3.6%, P ¼ 0.270, Fig. 4I). Although there was an obvious tendency of lower 5y-MFS rate in TNBC than in IMPC (96.2 ± 3.8% vs. 80.1 ± 3.6%, P ¼ 0.052, Fig. 4F), this did not reach statistical significance. Discussion Breast cancer is a histologically heterogeneous disease that displays various biological behaviors and pathologic subtypes [13].

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Fig. 2. Survival curves for TNBC according to various lymph node status. AeC: LRRFS according to pN stage, lymph node status and positive pN stage; DeF: MFS according to pN stage, lymph node status and positive pN stage; GeI: OS according to pN stage, lymph node status and positive pN stage.

IMPC is a rare histologic type that appears to be more aggressive compared with other breast cancers due to its increased probability of lymphovascular invasion and lymph node metastasis [14,15]. TNBC is one of the molecular subtypes, which has poorer survival compared with other molecular subtypes regardless of stage at diagnosis [16].

As breast cancer molecular subtype is based on the gene expression profiles of largely IDC NOS (non-specific type) and a few ILCs (invasive lobular carcinoma) only [11], it is unknown whether the molecular classification system also applies to the other histological special types. According to immunohistochemical expression, IMPC mainly presented Luminal B subtype rarely TNBC, which

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Table 4 Multivariate analysis of survival in TNBC. LRRFS

pT pT2:pT1 pT3:pT1 Lymph node status Positive:negative LVI Positive:negative

MFS

OS

HR

95% CI

P

HR

95% CI

P

HR

95% CI

P

3.508 7.847

0.775e15.882 1.411e43.642

0.060 0.103 0.019

2.566 4.536

1.210e5.444 1.760e11.692

0.006 0.014 0.002

2.444 5.559

1.013e5.895 1.932e15.995

0.006 0.047 0.001

2.497

0.819e7.615

0.108

1.047

0.549e1.998

0.888

1.866

0.400e1.875

0.715

1.442

0.495e4.203

0.503

2.332

1.226e4.437

0.010

3.699

1.748e7.831

0.001

was demonstrated in various previous studies [14,17], while TNBC showed histological type mainly of IDC NOS, rarely IMPC [18]. The two entities rarely overlap. A recent expression profile study of various special types of breast cancer has also suggested a unique molecular genetic disease profile for IMPC [19]. Remarkably, the IDCs NOS and ILCs consist of different molecular subtypes, whereas the histological special types are very homogeneous and each be et al. demonstrated longs to only one molecular subtype. Marchio that IMPCs had distinct histological features and molecular genetic profiles supporting the contention that they constituted a distinct pathological entity [20]. Generally, ER and PR positive status is generally associated with an improved differentiation of tumors and an improved outcome, but IMPC appears to be an exception. Our study demonstrated a high percentage of ER and PR positivity in IMPCs (83.2% and 74.7%, respectively), which was in accordance with other reports [6,14,21]. Albert Chen et al. conducted the largest retrospective IMPC data set of 624 IMPC patients from the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database and reported an ER positivity rate of 85% [21]. These results are higher compared

Table 5 Comparison of clinicopathologic characteristics between IMPC and TNBC. IMPC n Mean age Mean tumor size Mean removed lymph nodes Menopause status Pre-menopause Post-menopause pT stage pT1 pT2 pT3 pT according to cutoff value of T  5 cm T > 5 cm Lymph node status Positive Negative pN stage pN0 pN1 pN2 pN3 LVI Positive Negative Surgery Mastectomy BCS Chemotherapy Adjuvant Neoadjuvant

TNBC %

n

P %

58.85 ± 11.49 3.66 ± 1.62 16.53 ± 4.79

49.75 ± 9.98 2.96 ± 1.02 15.94 ± 5.04

36 59

37.9 62.1

109 91

54.5 45.5

28 46 21 5 cm 74 21

29.5 48.4 22.1

73 110 17

36.5 55.0 8.5

77.9 22.1

183 17

91.5 8.5

69 26

72.6 27.4

79 121

39.5 60.5

26 24 21 24

27.4 25.3 22.1 25.3

121 50 18 11

60.5 25.0 9.0 5.5

49 46

51.6 48.4

54 146

27.0 73.0

74 21

77.9 22.1

139 61

69.5 30.5

67 28

70.5 29.5

176 24

88.0 12.0

0.002 0.003 0.339 0.008

0.051

0.017

<0.001

<0.001

<0.001

0.133

<0.001

with those of common breast cancers. Herein, we speculated that the unique histological characteristics of IMPC determined its more aggressive behavior and poorer outcome, in spite of its higher percentage of hormone receptor expression. Additional larger studies are warranted to confirm this finding. Compared with TNBC, the most important characteristic of IMPC was the higher frequency of lymphovascular spaces invasion, lymph node metastasis and a greater number of positive lymph nodes, which was related with prognosis [15,22,23]. It is reported that IMPC typically demonstrated a lymph node metastasis rate of 46e95% [1,3,21,24] compared with 34% for IDC. In our study, the incidence of lymphovascular invasion and axillary lymph node metastases in IMPC was 51.6% and 72.6%, respectively. The results of univariate analysis also showed that both lymphovascular invasion and nodal stage were correlated with survival; and pN stage was the only prognostic factor of LRRFS and MFS according to multivariate analysis. Probably relatively small sample size and few events of breast cancer related death resulted in inadequate statistical efficacy for pN to be the independent prognostic factor for OS. Chen AC et al. found that patients who had 4 or more positive regional lymph nodes had much worse DFS (P ¼ 8.23e06) and OS (P ¼ 2.63e05) when compared with node negative disease. Interestingly, this association did not correspond in those patients with 1e3 positive lymph nodes, who had DFS (P ¼ 0.93) and OS (P ¼ 0.66) similar to those of patients with node negative disease [21], which was in accord with our study. As was shown in Fig. 1, the separations between survival curves of pN2 and pN0, pN3 and pN0 were apparent while the curves of pN1 and pN0 were relatively close to each other, which were further verified by multivariate analysis in Table 2. In our study, pT was not related with survival, because some small micropapillary carcinomas seemed to show the same proclivity for lymphatic spread and nodal dissemination as larger tumors despite their minute size, which was also reported in the literature [23]. But TNBC was not associated with increased likelihood of nodal metastases. Gangi A et al. pointed out that four or more involved nodes were observed most commonly in the HER2 (19.4%) and luminal B (13.7%) subtypes, but only 9.4% in TNBC (P < 0.0001). Patients with TNBC are not more likely to have involved nodes than those with non-TNBC [25]. And Lin NU et al. demonstrated that TNBC subtype was associated with a lower risk of node positivity (adjusted OR: 0.88, 95% CI: 0.80e0.97, P < 0.001; HER2 tumors as the referent group) [26]. Our study showed that the survival of TNBC was associated with node involvement but was similar among pN1epN3. Hernandez-Aya et al. made a pairwise comparison by nodal status and showed that when comparing N0 with node positive disease, there was a significant difference in OS and RFS in TNBC (P < 0.001 for all comparisons). However, when comparing N1 with N2 and N3 disease regardless of tumor size, there were no significant differences in OS or RFS [27]. So in patients with TNBC, once there was evidence of lymph node metastasis, the prognosis may not be affected by the number of positive

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Fig. 3. Survival comparison between surgery types in IMPC. A: LRRFS comparison between surgery type in IMPC; B: MFS comparison between surgery type in IMPC.

lymph nodes. Our study also showed that larger tumor size and LVI were associated with poorer survival of TNBC. We hypothesized that tumor cells of TNBC may be more likely to detach from larger mass to migrate to distant site through circulation to form a new metastasis. According to the results of our study, although IMPC and TNBC had similar OS, they were presented with different relapse types. IMPC was characterized with higher rate of local-regional recurrence followed by distant metastasis. Yu et al. reported the 5y-DFS of IMPC and IDC were 79.1% and 93.3% (P ¼ 0.0024) whereas the 5yOS were 87.3% and 87.7% (P ¼ 0.1834) [10]. In our study, regardless of as an entire cohort or in node positive cases, lower LRRFS was observed in IMPC than in TNBC while LRRFS was relatively similar in node negative cases (Fig. 4). TNBC was characterized with higher rate of distant metastasis within early time rather than local-regional recurrence. Steward et al. reported that 26.6% TNBC had recurrent disease, including 17.3% with isolated local-regional recurrence, 63.6% with isolated distant recurrence, and 19.1% with both. Of 91 patients with distant recurrences, lung was most common, followed by brain, bone, and liver. Greater than 75% breast cancer-specific mortality resulted from a distant recurrence [28]. In our study, as an entire cohort, although MFS rate was similar between TNBC and IMPC, the distant metastasis took place much earlier in TNBC (mostly within 2 years [29]) than in IMPC (Fig. 4). In cases with positive or negative lymph nodes, obvious tendency of lower MFS rate could be observed in TNBC although it did not reach statistical significance (P ¼ 0.053, 0.052, respectively), probably due to small sample size especially node negative IMPCs. So in node negative cases, TNBC had a tendency of lower MFS and OS rate compared with IMPC. Further investigation is warranted for comparison of node negative IMPC and TNBC. Additionally from our study, there was a tendency of lower LRRFS and MFS rate in BCS for IMPC although it did not reach statistical significance probably due to the relatively small sample size. Further large scale research is needed to make clear the correlation between BCS and survival for IMPC. But we recommend adequate margin and adequate extent of ALND at least in BCS for IMPC. For TNBC, BCS did not add risk to relapse. Freedman GM et al. revealed that TNBC was not at significantly increased risk for isolated LRR at 5-years (3.2%, P ¼ 0.36), so it remained appropriate candidate for breast conservation [30]. And

multivariate analysis showed that TNBC did not have a significantly increased risk of LRR compared with the luminal A (P ¼ 0.43), luminal B (P ¼ 0.43), and HER2 (P ¼ 0.87) subtypes. BCS for TNBC was not associated with increased LRR compared with non-TNBC subtypes [31]. For exploration of the mechanisms of the two aggressive subtypes, several authors have suggested that tumor expression of tumor necrosis factor (TNF)-alpha, TNF-receptor II, loss of CD44 expression, together with high expression of CD24 or vascular endothelial growth factor or E-cadherin overexpression in IMPC may explain the high lymphovascular invasion propensity [32e35], possibly offering means of targeted therapy. Yu's study showed that CTCs from patients with TNBC predominantly expressed mesenchymal markers and patients who had progressive disease under treatment showed an increased number of mesenchymal CTCs in the post-treatment sample [36]. The epithelialemesenchymal transition of TNBC may partly explain the early distant metastasis without obvious local-regional recurrence, which should be paid attention to for further targeted therapy for this aggressive breast cancer subtype. Some limitations of this study should be acknowledged. First, selection bias was not completely avoided because this was a retrospective cohort study. Second, the current study did not specify the proportion of the IMPC component in each lesion. However, no consensus has yet been reached on the proportion of the IMPC component in a tumor that is required for its pathological diagnosis [37]. In Caterina Marchio's article, it was pointed out that mixed IMPCs harbored similar patterns of genomic aberrations and phenotype compared to pure IMPCs. And they proved that mixed IMPCs were more closely related to pure IMPCs than to IDCs-NST [38]. In addition, previous studies did not find a direct correlation between the ratio of the IMPC component and either lymph node involvement or survival [5,15]. The presence of IMPC components was a significant predictive factor for nodal metastasis, even if it is detected in only a small proportion of the tumor [5]. There was no statistically significant difference between pure IMPC and mixed IMPC, in terms of mean age of the patients, mean tumor size, presence of high-grade tumor, presence of sentinel lymph node metastasis, axillary lymph node metastasis, lymphovascular invasion, local recurrence rate or overall survival [6]. Furthermore, Ki67 pathological data were not routinely obtained from patients, but it may have an effect on survival.

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Fig. 4. Survival comparisons between IMPC and TNBC. AeC: LRRFS comparisons between IMPC and TNBC as an entire cohort (A); for positive lymph node (B); for negative lymph node (C); DeF: MFS comparisons between IMPC and TNBC as an entire cohort (D); for positive lymph node (E); for negative lymph node (F); GeI: OS comparisons between IMPC and TNBC as an entire cohort (G); for positive lymph node (H); for negative lymph node (I).

In conclusion, IMPC and TNBC are two aggressive subtypes with significantly different characteristics. IMPC is featured with high rate of lymph node involvement and a great deal of lymph nodes invaded, which are strongly associated with high rate of LRR. Efforts should be paid on strengthening local treatment, mainly adequate and thorough extent of surgery, and exploring

mechanisms of its high lymphovascular invasion propensity. TNBC is featured with high rate of early distant metastasis without increase of nodal metastasis. The survival is still relatively poor even in node negative cases. Efforts should be paid on exploring mechanisms of early distant metastasis and further targeted therapies to improve the prognosis.

Please cite this article in press as: Chen H-l, Ding A, Comparison of invasive micropapillary and triple negative invasive ductal carcinoma of the breast, The Breast (2015), http://dx.doi.org/10.1016/j.breast.2015.09.001

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Please cite this article in press as: Chen H-l, Ding A, Comparison of invasive micropapillary and triple negative invasive ductal carcinoma of the breast, The Breast (2015), http://dx.doi.org/10.1016/j.breast.2015.09.001