Long Term Outcome of Surrogate Subtypes of Primary Operable Breast Cancer According to Securin Expression

doi:10.21203/rs.3.rs-2986797/v1

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Long Term Outcome of Surrogate Subtypes of Primary Operable Breast Cancer According to Securin Expression

https://doi.org/10.21203/rs.3.rs-2986797/v1

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Background: Despite dramatic advances in cancer research, breast cancer remains a major health problem. In this heterogeneous disease, patients with different molecular subtypes have a different therapeutic approach and prognosis. Securin is known to participate in maintaining chromosomal integrity during the cell cycle through regulation of metaphase-anaphase transition, DNA damage repair and apoptosis. The aim of this study was to evaluate the prognostic role of securin expression as a measure of chromosomal instability in different surrogate subtypes of breast cancer in order to discriminate patients with worse prognosis.

Materials and methods: Breast cancer paraffin-embedded tissue specimens were obtained from a consecutive series of 215 patients with primary operable invasive breast carcinomas referred to the University Hospital Centre Zagreb, Croatia, from 2002 to 2003. Immunohistochemical (IHC) staining for securin was performed, and all relevant clinical and histopathological data were collected. Surrogate subtypes were defined according to St Gallen's consensus criteria. All patients were followed-up prospectively according to standard institutional practise for local and distant reccurence and death to collect data on disease-free (DFS) and overall survival (OS).

Results: In this patient cohort, median securin expression was 7 % of positive cells, ranging from 1 % to 42 %. Statistically significant correlation between tumor size and securin expression (p = 0.0272) and securin and Ki 67% expression (p = 0.0065) was shown. Securin expression differs among surrogate subtypes of breast cancer with highest expression in HER2+ subtype (median= 12). Univariate analysis has shown that in luminal A subtype and triple negative subtype there is statistically significant correlation between securin expression and DFS as well as OS. According to logistic regression analysis, it has also been shown that securin expression was independent prognostic factor for ten-year overall survival (OS).

Conclusion: Our study has shown that patients with BC overexpressing securin have a worse long-term prognosis in comparison with those without overexpression but only in luminal A like and triple negative like surrogate subtypes.

Securin

prognosis

breast cancer

surrogate subtypes

triple negative

luminal A

Nowadays breast cancer (BC) is the most common cancer which affects women. Even though a lot of effort is put into raising BC awareness and in BC research, it still remains a major health concern [1]. Immunohistochemistry and gene expression profiling are most common methods which are used to identify biological subtypes of breast cancer [2]. An adequate therapy for BC is mostly chosen according to tumor stage, histologic grade, expression of progesterone receptor (PR), estrogen receptor (ER), human epidermal growth factor receptor-2 (HER2) amplification and through classifying different morphological subtypes. Tumorigenesis and BC development are usually not connected only to a mutation of single genes. For most cancers, tumorigenesis is caused by combination of chromosomal instability (CIN) and by an aneuploid set of chromosomes [3–5]. By the definition, CIN is an increased rate of acquiring different chromosomal abnormalities, aneuploidy is a state of abnormal chromosomal number [6]. A paramount mark of chromosomal instability is an unequal separation of newly replicated chromosomes during anaphase [7, 8]. Unequal separation of chromosomes leads to genetic heterogeneity between tumor cells at each cell cycle which is associated with poor prognosis and resistance to different therapy protocols [9]. Since chromosome segregation defects occur during mitosis, specifically during metaphase and anaphase, most of the research on CIN is finding errors during those mitotic phases. Missegregation of chromosomes can be caused by defects in formation or inactivation of cohesion, a complex which binds two sister-chromatids [10–12]. Main enzyme responsible for separating sister-chromatids is separase (extra spindle poles-like 1), a cysteine protease and endopeptidase, which initiates two consecutive events that occur during anaphase [13–16]. First event starts during metaphase-anaphase transition, separase activates cleavage of the Scc1/Rad21 subunit of cohesion, which inactivates the complex. Finally, in the second event, separase takes part in the final separation of the sister-chromatids [17, 18]. If the proteolytic activity of separase increases substantially, it can lead to uncontrolled centriole duplication, aneuploidy and chromosomal missegregation [19, 20]. Chromosomal instability will occur if there is either premature or delayed activation of separase, since it is the main enzyme of metaphase–anaphase transition. Function of separase is controlled by two inhibitory complex interactions, which involves either cyclin B1/CDK1 (G2 mitotic-specific cyclin-B1/cyclin-dependent kinase 1) or securin (pituitary tumor-transforming gene 1 protein) [16]. Securin is an anaphase inhibitor, it forms a complex with separase and thus arresting the cell cycle at metaphase. Ubiquitin-dependent destruction of securin-separase link will lead to activation of separase, triggering premature separation of sister-chromatids [21]. Uncontrolled inhibition of separase activity by securin will result in uncontrolled and premature separation of the sister- chromatids, which results in aneuploidy and subsequently will set off tumorigenesis [22].

The aim of this study was to evaluate the prognostic role of securin expression as a measure of CIN in different surrogate subtypes of BC in order to discriminate patients with worse prognosis despite surrogate subtype characteristics.

Clinicopathological characteristics of breast carcinoma patients. Breast cancer paraffin-embedded tissue specimens were obtained from a consecutive series of 215 female patients with primary operable invasive breast carcinomas referred to the University Hospital Centre Zagreb, Croatia, between September 2002 and September 2003. Two of them were excluded from the study due to incomplete data, so definitive study cohort consisted of 213 patients. All of them initially underwent either radical or breast conserving surgery with complete axillary lymph node dissection. Adjuvant radiotherapy and adjuvant systemic chemotherapy +/- endocrine therapy were applied according to the guidelines used at the time study began. All of the patients were followed-up prospectively for at least ten years according to routine institutional practice with local recurrence, distant metastases or death as primary outcome endpoints. Tumor samples and clinical information were obtained under Institutional Review Board approval. All histological slides were examined by one pathologist, and all samples were graded according to Elston and Ellis grading scheme [23]. For all patients, tumor size, histological type, histological and nuclear grade, estrogen receptors (ER) and progesteron receptor (PR) expression, axillary lymph nodes involvement, HER-2 status, Ki-67 and presence of lymphovascular invasion were obtained as well as all treatment information. Immunohistochemistry for ER (H7096, Dako), PR (M3569, Dako), Ki-67 (MIB1, Dako) and HER-2 (Herceptest, Dako, dilution 1:50) was performed on formalin-fixed, paraffin-embedded tissue slides with standard avidin–biotin-immunoperoxidase staining method using TechMate automatic stainer (Dako, Glostrup, Denmark). The evaluation of the staining results was similar to that used in routine diagnostics, and samples were considered positive when 10% of the cells was stained with ER and PR. For HER-2 status, tumors were considered positive if scored as 3 + according to Herceptest criteria, and dual SISH with amplification ratio of ≥ 2.0 was used to segregate immunohistochemically equivocal (2+) results. In addition, intrinsic breast cancer classification for the genetically identified breast cancer subtypes was performed as approximations recommended by the 12th St Gallen International Breast Cancer Conference Expert Panel [2, 24–27].

Tissue microarray (TMA) preparation and immunohistochemical determination of securin. The most representative area of the tumor was punched with a special needle (SAKURA, Japan) to produce a BC tissue microarray (TMA) including three cores (triplets) 0.2 cm in diameter from original paraffin blocks. The cores were re-embedded into arrayed blank recipient blocks using manual ‘‘arrayer’’ (Beecher Instruments, Sun Prairie, Wisconsin, USA). Using this method, 60 tumor samples were analyzed on one single slide. Immunohistochemical (IHC) determination of securin expression was obtained on TMA's [28, 29]. IHC staining of securin was performed on 4-micrometar thick formalin-fixed and paraffin-embedded sections according to a standard procedure using immunostaining machine TechMate 500. For securin IHC staining, antigen retrieval was performed by repeated microwave heating in 10 ml sodium citrate buffer (pH6). Slides were stained with monoclonal antibody applied at the concentration of 1:20 (clone DCS-280, ab3305, Abcam, Cambridge, UK), and detection was performed by biotin-avidin reaction (Vectastain ABC reagent, Vector Laboratories, Burlingame, CA, USA). Diaminobenzidine was used as a chromogen (Sigma, St Louis, MO, USA). Evaluation of securin staining was performed on tumor tissue as a fraction (%) of positive tumor cells at the areas of mostly cellular tumor (Fig. 1, Table 1).

Table 1

Descriptive statistics of fractions (%) of securin positive tumor cells among surrogate subtypes
Breakdown Table of Descriptive Statistics Smallest N for any variable: 213
SURROGATE	SECURIN Means	SECURIN N	SECURIN Std. Dev.	SECURIN Min	SECURIN Max	SECURIN Q25	SECURIN Median	SECURIN Q75
Luminal A	8.45	107	6.96	1.00	41.00	4.00	6.00	11.00
Luminal B HER2 negative	8.35	20	5.98	2.00	21.00	3.50	6.00	12.50
Luminal B HER2 positive	13.68	19	9.49	3.00	34.00	6.00	8.00	19.00
HER2 positive	13.38	16	8.92	2.00	32.00	7.00	12.00	18.00
Triple negative	11.73	51	9.86	2.00	42.00	5.00	7.00	17.00
All groups	10.06	213	8.24	1.00	42.00	5.00	7.00	15.00

Statistical analysis. Values for Ki-67, tumor diameter and securin were given as continuous variables. Non-parametric tests (Mann-Whitney U test, Kruskal-Wallis ANOVA) were used to analyse differences in securin expression according to other clinicopathological variables (nodal status, histological and nuclear grade, estrogen and progesterone receptor status). Spearman's test was used to analyse correlations of securin expression with other continuous variables. Univariate survival curves were generated by the Kaplan-Meier method, and differences in survival were assessed by Gehan-Wilcoxon test. Disease-free survival (DFS) and overall survival (OS) were used as end points. A multivariate logistic regression analysis was used to identify the predictive value of prognostic factors including tumor size, grade, nodal status and securin expression on ten-year survival [30, 31]. All the tests of statistical significance were two-sided. P < 0.05 was considered to indicate a statistically significant difference. Statistical calculations were performed using Statistica 6.0 software. P values < 0.05 were regarded as statistically significant.

Clinicopathological data of 213 breast carcinoma patients are shown in Table 2. More than 60% of patients was older than 50 and had invasive ductal carcinoma. Most of those ductal carcinomas were less than 2 cm in diameter, and histological and nuclear grade was II. Vascular invasion was found in 6.57% of patients, and positive axillary lymph nodes were found in 35% of them. More than half of the patients had positive steroid receptors, and HER-2 was positive in 16.43% of patients. Around 96% of patients received some form of adjuvant therapy according to guidelines used at the time study began.

Table 2

Clinicopathologic characteristics of the 213 breast cancer tumors
Variable	Category	Number	%
Age	< 50	72	33.80
Age	> 50	141	66.20
Menopause	No	80	37.56
Menopause	Yes	133	62.44
Tumor size	< 2 cm	119	55.35
	2–5 cm	85	39.53
	> 5 cm	11	5.12
Histological grade	1	33	15.49
	2	110	51.64
	3	70	32.86
Nuclear grade	1	19	8.92
Nuclear grade	2	123	57.75
Vascular invasion	Negative	199	93.42
Vascular invasion	Positive	14	6.57
Lymph nodes status	Negative	102	47.87
Lymph nodes status	Positive	74	34.74
Surrogate subtypes	Luminal A	107	50.23
	Luminal B HER2 negative	20	9.39
	Luminal B HER2 positive	19	8.92
	HER2 positive	16	7.51
	Triple negative	51	23.94
Adjuvant Therapy	Total	206	96.71
	Chemotherapy	163	76.53
	Hormonal therapy	147	69.01
	Radiotherapy	150	70.42

Association of securin and other tumor characteristics: In this cohort of 213 breast carcinoma samples, median of securin expression was 7% of positive cells, ranging from 1–42% (Table 1). Spearman rank correlations analysis shows that there is a statistically significant correlation (p = 0.0272) between tumor size and securin expression (Table 3). Also, a positive correlation was found between securin expression and proliferation marker Ki 67% (p = 0.0065). Using Mann-Whitney U test (Table 3), we did not find statistically significant difference between lymph node positivity and securin expression (p = 0.27) and between vascular invasion and securin expression (p = 0.37) respectively. Using Kruskal-Wallis ANOVA test (Table 4), differences in securin expression according to grade and specific cancer subtypes were analyzed. Higher nuclear grade had higher nuclear expression of securin (1 vs. 2 vs. 3 : p = 0.0007). In nuclear grades 1 vs. 2 (p = 0.58) difference was not statistically significant. In nuclear grades 1 vs. 3 (p = 0.09) the difference was borderline but has not reached statistical significance. In nuclear grade 2 vs. 3 (p = 0.0002) difference between securin expression was statistically significant. Expression of securin was linked to higher histological grade comparing all 3 histological grades (1 vs. 2 vs. 3 : p = 0.0007). In histological grades 1 vs. 2 (p = 0.46) difference was not statistically significant. Comparing grades (1 vs. 3 : p = 0.0040) and ( 2 vs. 3 : p = 0.0006), it was found that the differences in securin expression were statistically significant. In general, there is a statistically significant difference in securin expression between different surrogate immunohistochemical subtypes of BC. On average, securin expression is highest in HER2 + subtype (median = 12). Comparing HER2 + subtype to other subtypes, it was found that HER2 + has statistically significant higher securin expression then luminal A (p = 0.0141), and comparing to luminal B HER2- subtype, the correlation was near statistical significance (p = 0.0596). There was no difference between HER2 + and luminal B HER2+ (p = 0.99) and HER2 + and triple negative subtype (p = 0.29). Luminal A has statistically significant lower securin expression than luminal B HER2+ (p = 0.0064) and than HER2+ (p = 0.0141). The difference between luminal A and triple negative was near the statistical signifincance (p = 0.0597). Securin expression in luminal B HER2- subtype was statistically significantly lower than in luminal B HER2+ (p = 0.0357).

Table 3

Association of securin and other tumor characteristic (Mann-Whitney and Spearmans Correlations)
Mann-Whitney U test				Spearman rank correlations
Variable		SECURIN		Variable	SECURIN
Variable		U	p	Variable	R	p
Nodal status	negative	3409.50	0.27	SECURIN and T/cm	0.15	0.0272
Nodal status	positive	3409.50	0.27	SECURIN and T/cm	0.15	0.0272
Vascular invasion	negative	1194.00	0.37	SECURIN and Ki67%	0.19	0.0065
Vascular invasion	positive	1194.00	0.37	SECURIN and Ki67%	0.19	0.0065

Table 4

Association of securin and other tumor characteristic (Kruskal-Wallis ANOVA)
Variable	Category	SECURIN
Variable	Category	H	p
Nuclear grade	1 vs 2 vs 3	14.44	0.0007
	1 vs 2	0.31	0.58
	1 vs 3	2.93	0.09
	2 vs 3	14.24	0.0002
Histological grade	1 vs 2 vs 3	14.39	0.0007
	1 vs 2	0.55	0.46
	1 vs 3	8.29	0.0040
	2 vs 3	11.84	0.0006
Surrogate subtypes	HER2 + vs Luminal A	6.03	0.0141
	HER2 + vs Luminal B HER2 negative	3.55	0.0596
	HER2 + vs Luminal B HER2 positive	0.28	0.99
	HER2 + vs Triple negative	1.11	0.29
	Luminal A vs Luminal B HER2 positive	7.43	0.0064
	Luminal A vs Triple negative	3.54	0.0597
	Luminal B HER2 negative vs Luminal B HER2 positive	4.41	0.0357

Prognostic impact of securin expression on patient’s outcome (univariate analysis)

The study confirmed the prognostic significance of securin expression on DFS and OS (Table 5).

Table 5

Influence of securin on patient's outcome (results of univariate analysis)
Surrogate subtype	SECURIN ( % of positive cells)	DFS p value	SECURIN (% of positive cells)	OS p value
Luminal A	> 9	0.00002	> 8	0.0022
Luminal B	> 6	0.68	> 6	0.26
Luminal B HER 2 positive	> 8	0.52	> 8	0.12
HER2 positive	> 12	0.42	> 12	0.31
Triple negative	> 12	0.0231	> 9	0.0357

Univariate analysis shows that in luminal A subtype and triple negative subtype there is statistically significant poor prognostic impact of securin expression on both outcomes: DFS as well as OS (Fig. 2 and Fig. 3). For luminal A tumors, those with expression of securin > 9 and triple negative BC with securin > 12 have a statistically significant shorter DFS (p = 0.00002 and p = 0.0231, respectively). Similar prognostic impact of securin expression was also shown for OS. The study confirmed a statistically significant shorter OS for luminal A and triple negative subtypes of BC. For luminal A those with securin > 8, and for triple negative those with securin > 9 (p = 0.0022 and p = 0.0357, respectively).

Multivariate analysis of securin expression influence on patient’s outcome

It has also been shown that securin expression was an independent prognostic factor for ten-year overall survival (OS) according to logistic regression analysis (Table 6). Other factors included into the model were tumor size, nodal status and tumor grade. We investigated the difference in ten-year survival of patients with securin > 8 and those with securin < 8. Patients with securin < 8 have 3.2 higher chance of surviving more than 10 years in comparison with patients who have securin > 8 (p = 0.0012, 95% CI 1.59–6.36).

Table 6

Multivariate analysis of prognostic factors influence on overall survival (OS)
Prognostic factor	p	+ 95%CL	-95%CL
Tumor size TM 4	0.34	7.50	0.50
Tumor size TM 2	0.29	3.02	0.71
Grade 3	0.65	2.56	0.56
Nodal status	0.21	3.09	0.78
Securin	0.0012	6.37	1.59

The long-term treatment outcomes of early BC differ as a reflection of the heterogeneous biological features of the different intrinsic molecular subtypes, each of which merits its own specific therapeutic approach [32]. Molecular classification recognizes five intrinsic or molecular subtypes of BC: luminal A, luminal B, HER 2+, basal, and normal, based on tumor gene expression profiles [2, 24]. Determination of intrinsic subtypes is too high in most countries around the world, and in daily practice subtypes are defined by immunohistochemical expression of steroid receptors, HER2 receptors and Ki-67 proliferation index. Criteria are based according to 2013 St. Gallen Consensus, they are widely accepted as surrogates for intrinsic molecular subtypes [33].

The choice of adjuvant systemic therapy is based on tumor subtype, disease volume at the time of diagnosis, and classic prognostic and predictive factors, taking into account patient preferences and the presence of comorbidities [34–36].

It is difficult to predict the prognosis of breast cancer at the level of each individual patient. Unfavorable outcomes still occur in patients in whom, based on known prognostic factors, we expected a good prognosis, as well as the opposite situation in subtypes with a poor prognosis. Therefore, new prognostic markers that would distinguish patients with unexpected outcomes within well-defined surrogate subtypes are intensively investigated.

When looking at long-term prognosis, the luminal A-like and TNBC like subtypes are at the opposite ends of the prognostic spectrum. Despite a generally good prognosis, some patients with luminal A breast cancer still experience local and/or distant recurrences. Risk stratification is important in the decision to use adjuvant chemotherapy before adjuvant endocrine therapy. Possible benefit from chemotherapy can be determined by gene expression profiling assays such as Oncotype Dx (21-gene recurrence score), MammaPrint, and Prosigna [37–39]. Despite the lower rates of chemotherapy use, the 21-gene recurrence score results in an overall increased cost to the health care system [40]. On the other side of the spectrum, TNBC-like tumors are aggressive tumors, tend to affect younger women, metastasize early despite optimal adjuvant treatment. There is considerable heterogeneity among them, which allows them to be classified into different molecular subtypes [41–43].

In this study, securin as a measure of chromosomal instability was evaluated in BC surrogate subtypes defined according to the immunohistochemical St. Gallen consensus from 2013 [33]. Karra et al first published the finding that increased securin expression predicted abnormal DNA content in human BC with a 9.8-fold increased risk for aneuploid DNA. Another study showed that securin has a strong independent prognostic value for disease-specific survival, with a significant difference in survival between patients with low and high securin expression [44, 45]. Our results are consistent with those of Talaat et al where a correlation of securin with Ki-67 was found, suggesting that securin may contribute to the prognostic value of Ki-67 in the assessment of intratumoral heterogeneity in patients with invasive breast cancer with a poor clinical outcome [46].

Our study showed that breast cancer patients with securin overexpression have a worse prognosis compared to those without overexpression, but only in two surrogate subtypes of early BC, luminal A-like and triple negative-like. Surprisingly, these two subtypes are at different ends of the spectrum according to prognosis, allowing us to further stratify two subgroups of BC, one with a generally good prognosis and one with a dominantly worse prognosis. The prognostic effect of securin expression in TNBC is consistent with the previous findings of Karra et al. as they concluded that high immunoexpression of Cdc20 and securin was associated with extremely poor outcome of BC patients, and TNBCs were strongly overrepresented among cases with high expression of Cdc20 and securin [47].

Karra et al pointed out that Cdc20 and securin expression are important prognostic factors in TNBC, but our study has additional value as has shown prognostic role in luminal A-like breast carcinomas also. In comparison with other BC surrogate subtypes, TNBC is a more aggressive form with a high early recurrence rate. There are recent advances in understanding TNBC as a heterogenous subtype with intrinsic molecular subtypes. Nowadays, the variety of clinical phenotypes of TNBC are recognized but treatment options are still limited with chemotherapy as a mainstay therapy and immune checkpoint inhibitors and targeted treatments being incorporated in certain settings. Further risk stratification in early breast carcinomas with TNBC phenotype is of outmost importance for tailored adjuvant and neoadjuvant systemic treatment decisions.

The results of our study require further validation on larger patient cohorts. Despite limitations of relatively small sample size, there are some advantages in comparison with results published previously. The strengths of our study are long term follow-up of at least ten years and homogenous cohort primary treated at the same institution during only one year allowing thus adherence with the same diagnostic and adjuvant treatment guidelines, making our study cohort more homogenous and minimizing impact of different adjuvant treatments on long-term outcome. In contrast, Karra's et al had a larger cohort but collected over a decade from 1987 till 1997 allowing thus appliance of different adjuvant therapies according to the guidelines valid at the time of diagnosis.

In our study, all primary treatments were done in the single institution (surgery, chemotherapy, radiotherapy, and indication for systemic endocrine therapy) and follow-up procedures also. The additional value of our study is a long prospective follow-up of all patients according to routine institutional guidelines for more than a decade, providing us with accurate 5-year and 10-year survival rates.

What also makes our study different from previously published is finding that securin has possible prognostic impact in luminal A-like subtype of BC also and further studies on this subtype are needed.

Conclusion

This study showed that patients with securin-overexpressing BC have a worse long-term prognosis compared to those without overexpression, but only in the luminal A-like and triple-negative-like surrogate subtypes. Further studies are needed to prospectively test these findings in larger cohorts and also to test the possible involvement of securin in gene expression profiling assays specific for these two BC subtypes defined in our study.

DNA- Deoxyribonucleic acid

IHC- Immunohistochemical

DFS- Disease free survival

OS- Overall survival

HER2- Human epidermal growth factor receptor 2

BC- Breast cancer

PR- Progesterone receptor

ER- Estrogen receptor

CIN- Chromosomal instability

TMA- Tissue microarray

TNBC- Triple negative breast cancer

Cdc20- Cell division cycle protein 20

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics Statement

The usage of archived tissues for manufacturing of TMAs and their analysis for research purposes as well as patient data analysis have been approved by Ethics Committee of the University Hospital Centre Zagreb. All work has been carried out in compliance with the Helsinki Declaration. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Author Contributions

NDP, DV and JJR designed the study, and drafted the manuscript. SW, MK, and JJR performed IHC analysis and scoring. ML, MM, AK and NDP performed collection of all clinical data and statistical analysis. NDP, MM, ML, AK, MSS, DV and JJR participated in data interpretation, and helped to draft the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Funding

This study was granted by the Ministry of Science, Education, and Sports, Republic of Croatia (project 108-1080058-0046). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Consent for publication

Not applicable

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgment

The authors would like to thank all the technical staff for enthusiastic and reliable work in the laboratory. We really appreciate the help of nurses in the sample collection.

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No competing interests reported.

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Long Term Outcome of Surrogate Subtypes of Primary Operable Breast Cancer According to Securin Expression

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2. Materials and methods

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