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ORIGINAL ARTICLE  
Year : 2017  |  Volume : 60  |  Issue : 1  |  Page : 8-14
Calretinin expression as a reliable prognostic marker in different molecular subtypes of breast carcinoma


1 Department of Pathology, Port Said Faculty of Medicine, Port Said University, Port Said, Egypt
2 Department of Pathology, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
3 Department of Oncology Surgery, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt
4 Department of Community Medicine and Public Health, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt

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Date of Web Publication14-Feb-2017
 

   Abstract 

Background: Calretinin (CR), a known mesothelial marker, is expressed in both epithelial and mesenchymal malignancies including breast cancer. Aims: We aimed to measure the frequency of CR expression in correlation with other clinicopathological parameters of different molecular subtypes of invasive breast carcinoma and to study its prognostic implications in this common cancer.Study Design: Tissue microarrays were constructed from 225 tissue samples of breast carcinoma cases. Subjects and Methods: Immunostaining for CR in addition to estrogen receptors, progesterone receptors, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor, CK5/6, and Ki-67 for molecular subtyping. Statistical Analysis Used: Chi-square and Fisher's exact tests were done using SPSS 18.0 software (IBM Inc.). Survival data were analyzed using Kaplan–Meier test, Log-rank test, and Cox proportional hazard models. Results: Cases of invasive breast carcinomas with different grades were classified into 84 luminal A, 45 luminal B, 27 HER2 positive, 40 basal-like, and 29 unclassified. High CR expression was associated with tumors of high grade (P < 0.0001), high locoregional recurrence (P = 0.005), hormonal receptors negative, and high Ki-67 indices. They frequently display a basal-like phenotype (70%, P < 0.0001), HER2 (59.3%), and luminal B (33.3%) tumors compared to luminal A (9.5%) and unclassified subtypes (17.2%). Moreover, it is associated with poor overall patient survival (P = 0.034), but it does not affect disease-free survival. Conclusions: Calretinin could be a reliable predictor marker of adverse prognosis in breast cancer.

Keywords: Basal-like, breast carcinoma, calretinin

How to cite this article:
Farrag MS, El-karef AA, Amin MM, Helal NM, Ali OF, Farrag NS. Calretinin expression as a reliable prognostic marker in different molecular subtypes of breast carcinoma. Indian J Pathol Microbiol 2017;60:8-14

How to cite this URL:
Farrag MS, El-karef AA, Amin MM, Helal NM, Ali OF, Farrag NS. Calretinin expression as a reliable prognostic marker in different molecular subtypes of breast carcinoma. Indian J Pathol Microbiol [serial online] 2017 [cited 2017 Apr 28];60:8-14. Available from: http://www.ijpmonline.org/text.asp?2017/60/1/8/200046



   Introduction Top


Breast cancer is the leading cause of females' cancer death worldwide.[1] Gene expression analyses classified it into subgroups (luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)/neu overexpressing, and triple negative profile).[2]

Triple-negative tumors are high-grade tumors of poor overall survival (OS).[3] The basal-like subgroup highly expresses genes of basal-type cells.[4] Additional markers are needed to confirm breast origin when they metastasize and plan novel therapies.[5]

Calretinin (CR) is a calcium buffer of calmodulin superfamily.[6] It has multiple functions depending on various parameters such as cell type.[7] In addition to mesothelioma, CR is expressed in other tumor types [6] such as breast carcinoma, particularly basal-like tumors.[5]

In this study, we aimed at examining CR expression in different molecular subtypes of breast carcinoma and demonstrated its prognostic importance.


   Subjects and Methods Top


This retrospective study was carried out on 225 formalin-fixed paraffin-embedded mastectomy specimens of invasive breast carcinoma, chosen randomly in surgical pathology laboratory at Oncology Center, Mansoura, Egypt. Only cases who did not receive preoperative neoadjuvant chemotherapy or radiotherapy were included and following the guidelines of Mansoura University Ethical Committee (Code No. PhD/22/2014).

All clinicopathological data of these 225 cases were revised as regards age, location, size, multiplicity, histological type, histological grade according to the Nottingham modification of the Bloom–Richardson scoring system,[8] lymphovascular invasion, necrosis, metaplastic component, number of LN metastases (N), distant metastasis (M), and TNM staging.

Three TMA blocks were done manually using pencil tip method with its modification.[9],[10] Paraffin blocks including tumor areas were determined on their hematoxylin- and eosin-stained sections. We selected and marked areas of morphological value on the actual tumor block. We cored the actual tumor block and put a 1 mm core to the recipient block which is named “master block.” Three representative cores of tumor were arrayed for each specimen.

As regards immunohistochemical analysis, sections from paraffin-embedded tissue microarrays were cut at 4 µm, deparaffinized with xylene, and rehydrated with graded alcohols. Antigen retrieval with heat was performed in target retrieval solution pH 6.0 for estrogen receptors (ERs), progesterone receptors (PRs), HER2, Ki-67, and CR, high pH target retrieval solution for CK5/6 and enzyme digestion with 0.05% protease K for 30 min at 37 for epidermal growth factor receptor (EGFR), Primary antibodies for ER (rabbit monoclonal, Clone SP1, Cell Marque, USA), PR (mouse monoclonal, clone PgR636, Dako, Glostrup, Denmark), and HER2/neu (mouse monoclonal, clone CB-11, cell marque, USA) were used as a usual routine clinical diagnostic procedure.

Other primary antibodies include antibodies for CK5/6 (mouse monoclonal, clone AE1/AE3, Dako, Denmark), Ki-67 (rabbit PAb, clone MIB-1, Neo Markers, USA), EGFR (mouse monoclonal, Clone 111.6, Neo Markers, USA), and CR (mouse monoclonal, clone DAK-Calret1, Dako, Denmark). All antibodies were used according to manufacturer instructions. Appropriate positive and negative controls were prepared simultaneously with test slides. Mesothelioma, pancreatic duct, and skin were used as positive control for CR, EGFR, and CK5/6, respectively.

ER and PR stains were considered positive if expression was observed in more than 1% of tumor nuclei.[11] For HER2 status, we followed the criteria established by the manufacturer and national guidelines. Tumors were considered negative with a score of 0 and +1. Tumors were considered positive with a score of +3 when strong complete membranous staining was observed in at least 10% of tumor cells.[5] Cases of score 2+ were excluded from our study as they require fluorescence in situ hybridization assay to confirm HER2 amplification.

As regards EGFR staining, EGFR stain was considered positive in cases with any cytoplasmic and/or membranous staining in tumor cells whether this stain was weak or strong.[12] Similarly, CK5/6 stain was considered positive in cases with any cytoplasmic and/or membranous staining in tumor cells including weak and strong staining. Ki-67 staining was interpreted as low or high using a 14% threshold.[11]

For CR, nuclear and/or cytoplasmic staining was considered positive.[13],[14] The degree of immunoreactivity was assessed using a combined score. This combined score comprises the distribution and intensity of staining. As regards distribution, scores 0–3 were determined according to the percentage of positive tumor cells (0, 0%; 1, <25%; 2, 25%–50%; and 3, >50%). Similarly, the intensity of staining was assessed in positive tumor cells (0, 0; 1, 1+; 2, 2+; and 3, 3+). The overall score can be obtained by multiplying both intensity and extent scores. Thus, the overall score can from 0 to 9. We classified them as follows: score 0 was considered negative, score 1–2 was considered weak staining, score 3–6 was considered moderate staining, and score 9 was strong staining. Both negative and weak staining were characterized as a low-level expression of CR. Both moderate and strong staining were considered as a high-level expression of CR.[5]

Based on the immunohistochemical expression of ER, PR, HER2, EGFR, CK5/6, and Ki-67 proliferation index, tumors were stratified into luminal A (ER + and/or PR+, HER2, any EGFR and/or CK5/6, and Ki-67 <14%); luminal B including luminal B/HER2 negative (ER + and/or PR+, HER2, any EGFR and/or CK5/6, and Ki-67 ≥14%) and luminal B/HER2 positive (ER + and/or PR+, HER2+, any EGFR and/or CK5/6, and any Ki-67); HER2 enriched (HER2+ and ER/PR); basal-like (ER, PR, HER2, CK5/6+, and/or EGFR+); and unclassified (ER, PR, HER2, EGFR, CK5/6).[11]

Statistical analysis was performed by Chi-square and Fisher's exact tests of significance between CR expression with other clinicopathological and histological parameters using SPSS 18.0 software (IBM Inc, Chicago). Survival data were analyzed using Kaplan–Meier test. Overall survival time was estimated from the time of diagnosis to death. The disease-free survival (DFS) is the interval from the date of primary surgery to first locoregional recurrence or distant metastases. We compared survival curves using the log-rank test. For multivariate analysis, Cox proportional hazard models were done. A two-tailed P ≤ 0.05 was considered statistically significant in all tests.


   Results Top


As regards tumor characteristics, cases of this study were distributed as 198 (88%) of invasive carcinoma of no special type (NST), 17 cases (7.6%) of invasive lobular carcinoma, 10 cases (4.4%) of other subtypes which include 5 cases of mixed ductal and lobular carcinoma, 1 case of carcinoma with neuroendocrine features, 1 case of mucinous carcinoma, 2 cases of papillary carcinoma, and 1 case of carcinoma with medullary features. Grade 2 tumors were 174 cases (77.3%), whereas Grade 3 included 42 cases (18.7%) and only 9 cases were Grade 1 (4%). Stage 3 tumors were 120 cases (53.3%), whereas Stage 2 included 97 cases (43.1%) and 8 cases were Stage 1 (3.6%). Clinical follow-up was available for all cases. Mean follow-up was 35.5 months (range, 1–61.9 months). CR expression was high in 72 cases (32%) and low in 153 cases (68%).

Regarding CR expression and clinicopathological parameters, tumors with locoregional recurrence showed a significant high CR expression (P = 0.005) (77.8% vs. 22.2% with low expression). Other clinicopathological parameters showed no significant association with CR expression [Table 1].
Table 1: Correlation of calretinin expression and other clinicopathological, histological parameters, and immunohistochemical markers

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As regards CR expression and histological parameters, tumors with Grade 3 showed significant high CR expression (P < .001) (61.9% vs. 25.1% of Grade 1, 2 tumors). Moreover, invasive carcinoma of NST showed a significant high CR expression (P = 0.013) (69 cases/34.8%) of carcinoma NST cases showed high CR expression versus only 3 cases/11.1% of other subtypes which showed high CR expression. No significant association was found between CR expression and other histological parameters [Table 1] and [Figure 1].
Figure 1: High-grade infiltrating duct carcinoma of no special type (H and E) (a), of basal-like subtype with positive CK5/6 (b), and epidermal growth factor receptor immunostaining (c). It showed high calretinin expression with positive cytoplasmic and nuclear staining (d) and high Ki-67 index (e) (×400)

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CR expression was also correlated with other immunohistochemical markers in breast cancer as follows: immunohistochemical stains revealed a significant association between high CR expression and hormonal receptors (ER and PR), HER2/neu, Ki-67, and basal markers (CK5/6 and EGFR). Negative ER was significantly associated with high CR expression (P = 0.005). Negative PR, positive HER2/neu, positive Ck5/6, positive EGFR, and high Ki-67 showed also high significant association with high CR expression (P < 0.001) [Table 1] and [Figure 1].

We compared CR expression in different molecular subtypes of invasive breast carcinoma. Different molecular subtypes of breast cancer showed varied CR expression. Nearly 70% of cases of basal-like subtype showed a significant high CR expression compared to 30% of cases that showed low CR expression [Figure 1]. Taking the basal-like tumors as a reference, there was a significant low CR expression (P < 0.001) in 90.5% of luminal A subtype, 66.7% of luminal B subtype (P = 0.001), and 82.8% of unclassified subtype (P < 0.001). However, HER2/neu-enriched tumors showed a tendency to high CR expression in 59.3% of cases (P = 0.364) [Table 2].
Table 2: Calretinin expression in different molecular subtypes of invasive breast carcinoma

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Finally, we correlated CR expression and survival. A univariate analysis of survival was performed to evaluate the impact of conventional prognostic predictors and CR expression on patient survival. Kaplan-Meier survival curves were constructed, followed by the log-rank test. Cox regression test was performed for multivariate analysis.

As regards correlation of CR expression and OS, a significant correlation was found between high CR expression and poor overall patient survival. Mean OS was 53.7 months in cases with low CR expression versus 45.3 months in cases with high CR expression, 26.4% of patients with CR-high tumors died of disease compared with 15% of patients with CR-low tumors (P = 0.034) [Table 3].
Table 3: Correlation of calretinin expression and overall survival

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By applying multivariate Cox regression analysis to test the prognostic yield of all parameters, advanced tumor size (T3 and 4), positive nodal status, basal-like molecular subtype, and distant metastasis proved to be independent significant prognostic factors regarding OS (P = 0.001, 0.012, 0.018, and 0.003, respectively) [Table 4] and [Diagram 1].
Table 4: Multivariate analysis of prognostic factors by the Cox's proportional hazards regression models of patients with breast cancer with respect to overall survival

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Regarding correlation of CR expression and DFS, no significant difference was found between high CR expression and DFS. Mean DFS in cases with high CR expression was 43 months. It was lower than mean DFS in cases with low CR expression which was 51 months, but it showed no statistical significance (P = 0.065) [Table 5] and [Diagram 2].
Table 5: Relation of other clinicopathological parameter and overall survival

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   Discussion Top


To date, only a few studies have addressed the expression of CR in breast carcinoma. In this study, we measured the frequency of CR immunohistochemical expression in invasive breast carcinoma and compared it in different molecular subtypes.

In our study, we demonstrated CR expression in invasive breast carcinoma. It was high in 72 cases (32%) and low in 153 cases (68%). Moreover, tumors with higher histologic Grade 3 showed significant high CR expression compared to tumors with lower Grades 1, 2. This study is in agreement with the study done by Duhig et al.[15] and Taliano et al.[5]

We also found that locoregional recurrence showed statistically significant association with high CR expression. No previous studies to our knowledge demonstrated such relation.

As regards the histologic type, invasive carcinoma of NST showed a significant association with high CR expression where 69 cases (34.8%) of NST carcinoma cases showed high CR expression versus only 3 cases (11.1%) of other subtypes which showed high CR expression (P = 0.013).

As regards other clinicopathological and histological parameters, we did not find a significant association with CR expression.

In this study, there was a high statistically significant association between higher CR expression and adverse hormonal receptors status (negative ER and PR), positive HER2/neu, positive basal markers (CK5/6 and EGFR), and higher Ki-67 indices which has been confirmed as prognostic factor [16] refers to the prognostic importance of CR. This was in line with previous studies by Powell et al.[4], Duhig et al.,[15] and Taliano et al.[5]

In this study, molecular classification of breast carcinoma cases revealed 84 cases (37.7%) of luminal A, 45 cases (20%) of luminal B, 27 cases (12%) of HER2-enriched subtype, 40 cases (17.8%) of basal-like subtype, and 29 cases (12.9%) were unclassified. Thus, triple-negative subtype which includes both basal-like and unclassified subtypes was 30.7%.

These findings are similar to a study performed by El-Hawary et al.,[17] Luminal A subtype was the most prevalent (41.2%) among Egyptian women, followed by triple-negative subtype (28.5%), HER2-expressing subtype (19.4%), and Luminal B subtype (13.9%).

Different molecular subtypes of breast cancer showed different CR expression. Basal-like subtype showed a statistically significant association with high CR expression (70% vs. 30% with low CR expression). Taking the basal-like tumors as a reference, there was significantly lower CR expression in luminal A subtype where 90.5% cases showed low expression (P < 0.001). There was also significantly lower CR expression in luminal B subtype where 66.7% cases showed low expression (P = 0.001). Low CR expression was found in 82.8% of unclassified cases (P < 0.001). However, in HER2/neu enriched tumors, CR expression was also high in 59.3% of cases (P = 0.364).

These findings are in agreement with the study done by Taliano et al.,[5] who found that CR expression is associated with a basal-like subtype of breast cancer where 53% of basal-like tumors showed high-level expression of CR.

Although the expression of CR in the study done by Lugli et al.[6] was not analyzed in relationship to molecular subtype or hormone receptor status, the highest expression of CR was observed in medullary and apocrine breast carcinoma, tumor subtypes that frequently exhibit a basal-like phenotype.[18] In contrast, tumors consistently negative for CR in the study done by Lugli et al.[6] included invasive lobular, tubular, and cribriform carcinomas, tumor subtypes that are usually low grade and characteristically ER + and only very rarely express basal markers.[19]

Our findings of the association of basal-like tumors and high CR expression are also in agreement with two recent, but much smaller studies. One was done by Duhig et al.[15] who observed CR expression in 28 (53%) of 53 cases of Grade 2 and 3 breast carcinoma. Their study also contained 23 basal-like tumors, 17 (74%) of which demonstrated CR expression, including 8 cases with expression in more than 50% of tumor cells. In contrast, only 11 of the nonbasal tumors (36.6%) stained with CR. Their study also contained nine HER2-enriched tumors, four (44.4%) of which demonstrated CR expression. The difference in staining between the basal-like and nonbasal tumors was statistically significant. The second study was done by Powell et al.[4] who evaluated CR expression in 53 breast carcinomas, 16 (30%) of which were Grade 3. Six of the Grade 3 carcinomas in their study were categorized as basal-like, of which four (67%) expressed CR.

Few studies have been reported the prognostic implications of CR expression in human neoplasia. A recent study by Kao et al.[20] identified increased CR expression as a poor prognostic indicator in patients undergoing extrapleural pneumonectomy for malignant mesothelioma.

Our study is the second to discuss the prognostic implications of CR expression in breast carcinoma after Taliano et al.[5] We found a statistically significant correlation between high-level CR expression and poor patient OS. Mean OS was 53.7 months in cases with low CR expression versus 45.3 months in cases with high CR expression, 26.4% of patients with CR-high tumors died of disease compared with 15% of patients with CR-low tumors (P = 0.034).

A univariate analysis was done to test the impact of other different parameters on OS using Kaplan–Meier test followed by log-rank test. It revealed that T3 and T4 disease, positive LN, locoregional recurrence as well as distant metastasis were significant negative prognostic variables (P < 0.001). For the remaining clinicopathological and histological factors, there were no significant prognostic values.

As regards the impact of other immunohistochemical markers on prognosis, negative ER, positive basal marker EGFR, and basal-like molecular subtype were significant negative prognostic variables (P = 0.004, 0.007, and 0.004, respectively). Many studies pointed to the poor prognosis of basal-like breast cancer such as Tawfik et al.[3] and Amin et al.[21]

However, by applying multivariate Cox regression analysis to test the prognostic yield of these parameters, advanced tumor size (T3 and 4), positive nodal status, basal-like molecular subtype, and distant metastasis proved to be independent significant prognostic factors regarding OS (P = 0.001, 0.012, 0.018, and 0.003 respectively).

Taliano et al.[5] were the first to demonstrate a significant association between strong CR expression and poor OS in patients with basal-like subtype of breast cancer. They demonstrated differential CR expression in the four molecular subtypes of grade 3 invasive ductal carcinoma and concluded that high CR expression was a strong predictor of adverse prognosis. They found that the expression of CR in the luminal and HER2 subtypes did not correlate with patient survival. Hence, they suggested a significant correlation of strong CR expression with poor survival in the entire cohort of Grade 3 cancers may be a function of the strong correlation seen in the basal-like group.

On applying multivariate analysis of survival, Taliano et al.[5] found that the tumor stage and high CR expression were the only independent predictors of survival. It differs from our results in this point. We did not find that CR expression is an independent prognostic factor. It may be really dependent prognostic factor, or our result may be due to a large number of censored cases who were 183 cases (81.3%). Censored cases include both living cases and cases who were lost and did not follow-up.

As regards DFS, we did not find a significant difference between high-level CR expression and DFS. Mean DFS in cases with high CR expression was 43 months. It was lower than mean DFS in cases with low CR expression which was 51 months, but it showed no statistical value (P = 0.065).

This finding is in agreement with the study done by Taliano et al.[5] who found that despite the association with decreased OS, no significant difference in DFS between the CR subgroups was apparent in basal-like tumors (P = 0.82).

We also performed a univariate analysis of DFS. It revealed that positive nodal status and negative ER, were significant negative prognostic variable (P = 0.016 and 0.006 respectively). For the remaining clinicopathological, histological, and immunohistochemical factors, there were no significant prognostic values.


   Conclusions Top


CR-expressing breast tumors are more likely to be of high grade with high locoregional recurrence, hormonal receptor negative, and expressing high proliferation marker. They frequently display a basal-like phenotype.

High levels of CR expression appear to be a predictor of adverse prognosis. It is associated with poor overall patient survival, but it does not affect DFS. Further studies are needed to explore whether it is an independent prognostic marker or a dependent one.

Further molecular studies are also needed to introduce CR as a potential new target for breast carcinoma therapy, especially basal-like subgroup to improve their OS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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Correspondence Address:
Mayada Saad Farrag
Department of Pathology, Port Said Faculty of Medicine, Port Said University, Port Said
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.200046

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