Association between the expression of hormone receptors, Her-2/neu overexpression and tumor characteristics in women with primary breast cancer

Read printer friendly
 Subscribe in a reader

Share with others

 

Marjan Rahnamaye Farzami M.D. A.P.C.P.
Assistant Professor of Reference Health Laboratory, Research Center


Address:

Soghra Anjarani M.D. A.P.C.P.
Pathologist Reference Health Laboratory


Address:

Nooshafarin Safadel M.D. A.P.C.P.
Assistant Professor of Reference Health Laboratory, Research Center


Address:

Rana Amini M.D. A.P.C.P.
Assistant Professor of Reference Health Laboratory, Research Center


Address:

Mehran Ghazi Moghaddam M.D. A.P.C.P.
Pathologist
Armin Pathobiology Laboratory

Address:

Bijan Roosta M.D. A.P.C.P.
Professor of Pathology
Armin Pathobiology Laboratory

Address:

Shahryar Nazari M.D. A.P.C.P.
Pathologist
Armin Pathobiology Laboratory

Address:

Shahram Sane M.D. A.P.C.P.
Pathologist
Armin Pathobiology Laboratory

Address:

Citation: M. R. Farzami, S. Anjarani, N. Safadel, R. Amini, M. G. Moghaddam, B. Roosta, S. Nazari & S. Sane : Association between the expression of hormone receptors, Her-2/neu overexpression and tumor characteristics in women with primary breast cancer. The Internet Journal of Pathology. 2009 Volume 8 Number 2

Keywords: HER-2/neu overexpression | Primary breast cancer | Estrogen receptor (ER) | Progestron receptor (PR)

Abstract

Her-2/neu overexpression has been correlated with poor prognostic tumors.
The association between breast tumor characteristics and expression of ER, PR, Her-2/neu overexpression, patient's age, tumor size, type and grade were retrospectively evaluated in 226 primary breast cancer referred to Armin pathobiology laboratory in 2005.
We found that 21.7% of cases had HER-2/neu overexpression. HER-2/neu overexpression in ER negative cases(28.4%) was higher than ER positive cases(18.4%) and HER-2/neu overexpression in PR negative cases(28.4%) was higher than PR positive cases(18.0%). The frequency of HER-2/neu overexpression decreased from ER-PR- to ER+PR+(30.7% to 18.8%).The frequency of HER-2/neu overexpression decreased significantly(P<0.05) from ER-PR- to ER+PR+(45.5% to 20.5%) in low grade tumors and HER-2/neu overexpression decreased from ER-PR- to ER+PR+(18.8% to 15.4%) in high grade tumors but this difference was not significant(P=0.790).
Our results revealed higher proportion of ER- and PR- tumors associated with HER-2/neu overexpression, also younger patients have higher rate of HER-2/neu overexpression.

Introduction

The HER-2/neu(c-erbB-2) is an oncogene that encodes a transmembrane glycoprotein with tyrosin kinase activity known as p185, which belongs to the family of epidermal growth factor receptor ^1,2. Cells transfected with HER-2/neu acquire a more malignant phenotype¸ with stimulation of cell proliferation¸ invasion and metastasis. This has been confirmed in the clinic: women with Her-2/neu positive breast cancer have a worse prognosis than those with Her-2/neu negative cancer ^1,3,4. although Her-2/neu overexpression has been correlated with poor prognostic tumor characteristics such as higher histological grade¸ S phase fraction¸ increased tumor size¸ increased number of involved lymph nodes¸ absence of lobular histology and negative or lower Estrogen receptor (ER) expression ^1,5 but its role as an independent prognostic factor is not significant in multivariate analysis ^1,6.

Semiquantitative measurement using immunohistochemistery (IHC) for the Her-2/neu membrane receptor protein can accurately predict gene amplification ⁷.

Estrogen receptor (ER) correlates inversely with the presence of epidermal growth factor receptor ¹ also it has been suggested that there is an inverse relation between the expression of the progesterone receptor (PR) and Her-2/neu in women with ER⁺ breast cancer ^5,8.

The aim of this study was to determine the relation between Her-2/neu overexpression and other clinicopathological factors in women with operable breast cancer.

Materials and methods

The association between breast tumor characteristics and expression of ER, PR¸ Her-2/neu overexpression, patient’s age, largest tumor size, tumor type and tumor grade were retrospectively evaluated in 226 women with primary breast cancer referred to Armin pathobiology laboratory in 1384. The evaluation of histopathologic characteristics was carried out on paraffin –embedded tissue blocks which were stained with Hematoxylin & Eosin. The Immunohistochemistry staining for ER, PR and Her-2/neu were done on paraffin-embedded tissue blocks according to the envision method using primary monoclonal antibodies ( Dako Kits).

The DAKO scoring system for Her-2/neu was defined as negative for scores 0 &1+ and positive for score 2+ & 3+ and overexpression for score 3+ (Table1)¹.

Using the H score for ER and PR¸ a negative result was defined as a score of ≤50¸ weakly positive as 51-100¸ moderately positive as 101-200 and strongly positive as >200. Tumor grading was performed according to Richardson & Bloom grading system ¹.

In a univariate analysis the association between ER, PR and Her-2/neu was evaluated and the chi square test was used to examine the categorical variables and the association between ER, PR expression and other clinicopathologic variables.

The results were considered statistically significant if the P value was < 0.05. All analysis were performed with SPSS version 11.0 for windows.

Results

Table 2 summarizes the clinicopathological features of all 226 women with primary operable breast cancer. HER-2/neu was expressed as defined by a DAKO score 3+ and a DAKO score 2+ or 3+ in 21.7% and 36.3% of all patients, respectively.

Table 3 shows data of HER-2/neu overexpression scoring in primary operable breast cancers based on DAKO scoring system.(univariate analysis). There was no correlation between HER-2/neu overexpression and ER state, PR state, tumor grade, tumor size and patient age.

Table 4 shows the frequency of HER-2/neu overexpression in the different ER/PR phenotypes (ER^-PR^-, ER^-PR⁺, ER⁺PR^- and ER⁺PR⁺) of breast cancer. The frequency of HER-2/neu overexpression decreased from ER^-PR^- to ER⁺PR⁺ (30.7% to 18.8%) but this difference was not significant (p=0.057).

Table 5 shows the frequency of HER-2/neu overexpression in the different joint ER/PR phenotypes (ER^-PR^-, ER^-PR⁺, ER⁺PR^- and ER⁺PR⁺) in low and high grade tumors.

The frequency of HER-2/neu overexpression decreased significantly (P<0.05) from ER^-PR^- to ER⁺PR⁺(45.5% to 20.5%) in patients with low grade tumor, also the frequency of HER-2/neu overexpression decreased from ER^-PR^- to ER⁺PR⁺(18.8% to 15.4%) in patients with high grade tumor but this difference was not significant.

Table 1: scoring system for Her-2/neu

Table 2: summarises the clinicopathological features of all 226 women with primary operable breast cancer

Table 3: Association between Her-2/neu overexpression and tumor characteristics in 226 women with primary breast cancer

Table 4: Frequency of HER-2/neu overexpression by joint ER/PR status

Table 5: Frequency of HER-2/neu overexpression for low grade and high grade tumor by joint ER/PR status

Discussion

In our study, we found that 36.3% of cases were HER-2/neu positive (score 2-3) and 21.7% of cases showed HER-2/neu overexpression (score 3). HER-2/neu overexpression is found in 20% to 30% of cases with invasive carcinoma ^1,9,10,11,12.

Presence of estrogen receptor was significantly associated with high nuclear and low histologic grades and older patients' age groups ¹.

We found that 62.4% and 61.5% of cases were ER positive and PR positive, respectively. The percentage of ER positive cases reported in literatures is 60% to 70% ^12,13 or 70% to 90% ¹⁴ and PR positive cases are reported 60% to 70% ¹⁴.

Our results show 86.6% of breast cancers were low grade (grade 1-2) and 19.4% were high grade (grade 3). (Missing cases, not included).

In our study 80.8% of cases were Ductal carcioma, 9.5% Lobular carcinoma and 3.6% were other histologic types including Medullary, Colloid, tubular, mucinous carcinoma and adenocarcinoma. (Missing cases, not included).

We compared HER-2/neu overexpression in hormone receptor positives and hormone receptor negatives in relation to other clinicopathologic characteristics in primary operable breast cancer. HER-2/neu overexpression in ER negative cases (28.4%) was higher than ER positive cases (18.4%) and HER-2/neu overexpression in PR negative cases (28.4%) was higher than PR positive cases (18.0%), although these differences were not significant. According to most of the studies, presence of estrogen receptor (ER) and progestron receptor (PR) correlates inversely with HER-2/neu overexpression ^{1,9,11,14,15,16,17,18,19}.

Patients 50 years of age or younger were more likely to have HER-2/neu overexpression than patients older than 50 years (25.4% versus 15.5%). It should be pointed out that higher rates of HER-2/neu overexpression in young patients have been documented in previous studies ^{8,9,10,17,20,21}, but in other studies, no correlation were found between age of patient and HER-2/neu overexpression ^11,16,22,23.

We did not find any correlation between size of the tumor with HER-2/neu overexpression, which is similar to some previous studies ^16,22,24 and disagree with other studies ^9,15,18.

We also found no correlation between grade of the tumor and HER-2/neu overexpression, which is similar to some studies ^20,22,23,25 and disagree with other studies ^{11,12,15,16,18,19}.

The frequency of HER-2/neu overexpression decreased from ER^-PR^- to ER⁺PR⁺ (30.7% to 18.8%) but this difference was not significant (p=0.057). In another study, this decrease was significant ¹⁵.

The frequency of HER-2/neu overexpression decreased significantly (P<0.05) from ER^-PR^- to ER⁺PR⁺(45.5% to 20.5%) in patients with low grade tumor, also the frequency of HER-2/neu overexpression decreased from ER^-PR^- to ER⁺PR⁺ (18.8% to 15.4%) in patients with high grade tumor but this difference was not significant (P=0.790). In two other studies, these decreases in low and high grade tumors were significant ^14,15.

Our results show higher proportion of ER^- and PR^- tumors associated with HER-/neu overexpression, also younger patients have higher rate of HER-2/neu overexpression.

References

1. Rosai J, Ackerman LV. Surgical pathology. 9th ed. New York: Mosby; 2004.p. 1819-1826. (s)

2. Suo Z, Risberg B, Karlsson MG, Villman K, Skovlund E, Nesland JM. The expression of EGFR family ligands in breast carcinoma. Snt J Surg Pathol. 2002;10:91-99. (s)

3. Krongvist P, Kuopio T, Nykanen M. Predicting aggressive outcome in T1N0M0 breast cancer. Br J Cancer. 2004;9:277-81. (s)

4. Bull SB, Ozeolik H, Pinnaduwage D. The combination of p53 mutation and neu/erbB-2 amplification is associated with poor survival in node-negative breast cancer. J Clin Oncol. 2004;22:86-96. (s)

5. Konecny G, Pauletti G, Pegram M. Quantitative association between HER-2/neu and steroid hormone receptors in hormone receptors in hormone receptor-positive primary breast cancer. J Nail Cancer Inst. 2003;95:142-53. (s)

6. Rosen PP, Lesser ML, Arroyo CD, Cranor M, Borgen P, Norton L. Immunohistochemical detection of HER-2/neu in patients with axillary lymphnode-negative breast carcinoma. Cancer. 1995;75:1320-1326. (s)

7. Yaziji H, Goldstein LC, Barry TS. HER-2 testing in breast cancer using parallel tissue-based methods. JAMA. 2004;291:1972-7. (s)

8. Taucher S, Rudas M, mader RM, Gnant M, Dubsky P, Bachleitner T. Do we need HER-2/neu testing for all patients with primary breast carcinoma? Cancer. 2003;98:2547-53. (s)

9. Almasri N, Hamad M. Immunohistochemical evaluation of human epidermal growth factor receptor 2 and estrogene and progesterone receptors in breast carcinoma in Jordan. Breast Cancer Res. 2005 May;7(5):598-604. (s)

10. Fusun T, Semsi A, Cem U, Mevlut T, Zafer K, Kazim U. Association of HER-2/neu overexpression with the number of involved axillary lymph nodes in hormone reseptor positive breast cancer patients. Exp Oncol. 2005 Jun;27(2):145-9. (s)

11. Yau TK, Sze H, Soong IS, Hioe F, Khoo US, Lee AW. HER2 overexpression of breast cancers in Hong Kong: prevalence and concordance between immunohistochemistry and in-situ hybridisation assays. Hong Kong Med J. 2008 Apr;14(2):130-5. (s)

12. Adebamowo CA, Famooto A, Ogundiran TO, Aniagwu T, Nkwodimmah C, Akang EE. Immunohistochemical and molecular subtypes of breast cancer in Nigeria. Breast Cancer Res Treat. 2008 Jul;110(1):183-8. (s)

13. Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol. 1998;11:155-168. (s)

14. Priti L, Lee K, Beiyun C. Correlation of HER-2 status with estrogen and progesterone reseptors and histologic features in 3655 invasive breast carcinomas. Am J Clin Pathol. 2005 Apr;123(4):541-6 (s)

15. Huang HJ, Neven P, Drijkoningen M, Paridaens R, Wildiers H,Van Limbergen E. Association between tumor characteristics and HER-2/neu by immunohistochemistry in 1362 women with primary operable breast cancer. J Clin Pathol. 2005 Jun; 58(6):611-6. (s)

16. Ariga R, Zarif A, Korasick J, Reddy V, Siziopikou K, Gattuso P. correlation of HER-2/neu gene amplification with other prognostic and predictive factors in female breast carcinoma. Breast J. 2005 Jul-Aug;11(4):278-80. (s)

17. Huang HJ, Neven P, Drijkoningen M, Paridaens R, Wildiers H,Van Limbergen E. Association between HER-2/neu and the progesterone receptor in oestrogen-dependent breast cancer is age-related. Breast Cancer Res Treat. 2005 May;91(1):81-7. (s)

18. Ivkovic-Kapicl T, Knezevic-Usaj S, Djilas-Ivanovic D, Panjkovic M. Correlation of HER-2/neu protein overexpression with other prognostic and predictive factors in invasive ductal breast cancer. In Vivo. 2007 Jul-Aug;21(4):673-8. (s)

19. Selvarajan S, Wong KY, Khoo KS, Bay BH, Tan PH. Over-expression of c-erbB-2 correlates with nuclear morphometry and prognosis in breast carcinoma in Asian women. Pathology. 2006 Dec;38(6):528-33. (s)

20- Homaei-Shandiz F, Ghavam-Nassiri MR, Sharifi N, Homaei-Shandiz AH, Taghizadeh-Kermani A, Torshizi SA. Evaluation of the relationship between human epidermal growth factor receptor-2/neu (c-erbB-2) amplification and pathologic grading in patients with breast cancer. Saudi Med J. 2006 Dec;27(12):1810-4. (s)

21. Hartley MC, McKinley BP, Rogers EA, Kalbaugh CA, Messich HS, Blackhurst DW. Differential expression of prognostic factors and effect on survival in young (< or =40) breast cancer patients: a case-control study. Am Surg. 2006 Dec;72(12):1189-94. (s)

22. Anim JT, John B, Abdulsathar S SA, Prasad A, Saji T, Akhtar N. Relationship between the expression of various markers and prognostic factors in breast cancer. Acta Histochem. 2005;107(2):87-93. (s)

23. Ratnatunga N, Liyanapathirana LV. Hormone receptor expression and Her/2neu amplification in breast carcinoma in a cohort of Sri Lankans. Ceylon Med J. 2007 Dec;52(4):133-6. (s)

24. Radovic S, Babic M, Doric M, Secic S, Beslic S, Balta E. Immunohistochemical evaluation of the HER-2 protein in the infiltrative lobular breast cancer. Med Arh. 2006;60(4):213-6. (s)

25. McKenzie F, Jeffreys M, 't Mannetje A, Pearce N. Prognostic factors in women with breast cancer: inequalities by ethnicity and socioeconomic position in New Zealand. Cancer Causes Control. 2008 May;19(4):403-11. (s)

This article was last modified on Mon, 11 May 09 17:27:35 -0500

This page was generated on Mon, 22 Mar 10 09:16:47 -0500, and may be cached.