Hormone receptors do not predict the HER2/neu status in all age groups of women with an operable breast cancer

H. J. Huang1,2, P. Neven1,3,*, M. Drijkoningen3,4, R. Paridaens3,5, H. Wildiers3,5, E. Van Limbergen3,6, P. Berteloot1, F. Amant1,3, I. Vergote1 and M. R. Christiaens3,7

1 Division of Gynecologic Oncology in Department of Obstetrics and Gynecology, Levven University Hospital, Levven, Belgium; 2 Division of Gynecologic Oncology in Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taoyuan, Taiwan; 3 Multidisciplinary Breast Centre, 4 Department of Pathology, 5 Department of Medical Oncology, 6 Department of Radiooncology and 7 Department of Surgery, Leuven University Hospital, Leuven, Belgium

* Correspondence to: Dr P. Neven, Leuven University Hospital, Herestraat 49, Leuven, Belgium. Tel: +32-16-344634; Fax: +32-16-344629; E-mail: Patrick.Neven{at}uz.kuleuven.ac.be


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background: In breast cancer, there is an inverse relationship between HER2/neu overexpression and receptors for estrogen (ER) or progesterone (PR). Some clinical observations such as the age-related association between hormone receptors and tumour grade, which predicts HER2/neu overexpression, suggest an age-related relationship.

Patients and methods: Our study population consisted of 1362 consecutive women receiving primary surgery for non-metastatic invasive breast cancer. We compared the relationship between both hormone receptors and HER2/neu overexpression in different age groups taking other tumour characteristics into account.

Results: In a multivariate model, considering the overall group, a negative ER, a negative PR and a high tumour grade were predictive for HER2/neu overexpression (P <0.001). Considering 246 women aged ≤45 years, the only predictor for HER2/neu overexpression in this age category was a high tumour grade (P = 0.003). Considering the 1116 women aged >45 years, ER (P = 0.001), PR (P = 0.001) and tumour grade (P <0.001) were associated with HER2/neu (P <0.001).

Conclusion: Our findings indicate that the association between ER, PR and HER2/neu overexpression varies with age. The hormone receptors are not an independent predictor for the HER2/neu status in young women while they are in elder patients.

Key words: estrogen receptor, progesterone receptor, HER2/neu, breast tumours


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The HER2/neu gene encodes a 185-kDa transmembrane phosphoglycoprotein with tyrosine kinase activity and is a member of the human epidermal growth factor receptor gene family [1Go]. HER2/neu gene amplification occurs in about one-quarter to one-fifth of breast cancers [2Go, 3Go]. Cells transfected with HER2/neu acquire a more malignant phenotype, with stimulation of cell proliferation, invasion and metastasis [4Go]. Clinically, HER2/neu overexpression has been correlated with several poor prognostic breast cancer characteristics. They are more likely to be hormone receptor-negative or express lower levels of estrogen receptor (ER) than if they are HER2/neu negative [5Go–10Go]. They are more likely to be high tumour grade with a high S-phase fraction [7Go, 8Go] and larger [11Go] with more involved lymph nodes if they are node positive [5Go]. HER2/neu positive tumours seem to have more lymphoid infiltration with mutated p53 status [12Go]. The absence of lobular histology, unless tumours belong to the poorly differentiated pleiomorphic type of lobular carcinoma, is another characteristic of HER2/neu positive cases [13Go]. In breast cancer, the association of HER2 gene amplification with a poor prognosis [14Go], lower response to hormone therapy [15Go, 16Go] and CMF (cyclophosphamide, methotrexate, fluorouracil)-based chemotherapy [17Go] has been confirmed by several studies.

The HER2/neu membrane receptor can be analysed by semi-quantitative measurement using immunohistochemistry (IHC) that accurately predicts gene amplification [18Go]. Testing of HER2/neu is currently standard practice because it estimates the response to the anti-HER2/neu antibody, trastuzumab, which in monotherapy or combination with chemotherapy improves the disease outcome of HER2/neu over-expressors with metastatic breast cancer [19Go].

The inverse association between HER2/neu and hormone receptors has been linked with the fact that estrogens suppress HER2/neu through the ER [20Go]. It is unclear whether this inverse association differs in different age groups. Tumour grade as an important predictor for HER2/neu overexpression, shows an association with hormone receptor expression that differs between young and older women and this maybe reflected with an age-related association between hormone receptors and HER2/neu [21Go–23Go]. Another observation is that premenopausal hormone responsive breast cancers remain sensitive to anti-estrogens, whereas a lower response to tamoxifen has been suggested in postmenopausal women if HER2/neu is also expressed [16Go, 24Go]. We therefore believe that the inverse association between the HER2/neu and hormone receptors status may differ by age. We have previously shown that the negative association between progesterone receptors (PR) and HER2/neu in women with an ER-positive breast cancer is age-related [25Go]. As of today, no such data have been reported for ER or PR considering ER-positive and ER-negative breast cancers together.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Charts from 1688 consecutive women with breast cancers, treated between January 2000 and July 2003 at Leuven University Hospital were retrospectively evaluated. Women who had recurrent tumour or received neo-adjuvant therapy, as well as those where any variable of the tumour, such as tumour size, tumour grade, steroid hormone receptors, axillary lymph node status and HER2/neu status, was not available were excluded. A total of 1362 patients receiving primary surgery were considered in the analyses.

Assessments
The following factors were included for evaluation: patient's age at diagnosis, maximal microscopic tumour size, worse tumour grade, axillary lymph node status, ER, PR and HER2/neu status. ER, PR and HER2/neu IHC stains according to the Envision method were performed. Immunocytochemical stains were performed on 4 µm paraffin sections, using a water bath for heat-induced epitope retrieval and Envision-HRP with DAB (Dakocytomation, Glostrup, Denmark) for visualization of the antibody complexes. Primary antibodies (Novocastra, Newcastle upon Tyne, UK) directed against estrogen receptor alfa (NCL-ER-6F11), progesterone receptor A (NCL-PgR-312, clone 16) and c-erbB-2 oncoprotein internal domain (CB11) were applied in a dilution of 1/30, 1/40 and 1/40, respectively.

ER, PR and HER2/neu IHC stains were semi-quantitatively evaluated. Using the H score for ER or PR, a negative result was defined when staining showed 50 or less, and positive between 51 and 300. The DAKO scoring system for HER2/neu was defined as negative for a DAKO score of 0, 1+ or 2+ and positive when a DAKO score of 3+ was given. Tumour grading was performed according to the Ellis and Elston grading system [26Go].

Analysis of the results
To justify which age is the best cut-off for an inverse association between HER2/neu and both of the hormone receptors, we compared the proportion of tumours being HER2/neu positive by receptor status for ER or PR in each of the seven age plots, with a range of 5 years starting at age ≤45 years and ending at age >70 years. We identified in the age group ≤45 years that in the univariate model a positive ER was only of borderline significance and a positive PR was not significant in predicting HER2/neu overexpression. In the group age >45 years, there was in all of the six remaining age plots a negative relationship between the hormone receptors and HER2/neu, both for ER and PR. The statistical analysis was therefore done for the two age groups ≤45 years and >45 years.

The chi-square test was used to examine the categorical variables and the association between HER2/neu overexpression and other clinicopathological factors in univariate analysis. Multivariate analysis with logistic regression was used to find out the independent factors predicting HER2/neu overexpression. All statistical tests were two-sided and P <0.05 was considered significant. All statistical analyses were performed with Statistical Package for the Social Sciences (SPSS) software version 11.0.1 for Windows (SPSS Inc, Chicago, IL, USA).


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
HER2/neu by receptor status and age plots of 5 years
HER2/neu expression by ER and PR status per age plot of 5 years are shown in Table 1A and 1B for ER and PR, respectively. The clinico-pathological characteristics by age ≤45 or >45 years in 1362 women are presented in Table 2. The frequency of ER-positive (H score 51–300), PR-positive (H score 51–300) and HER2/neu-postive (score 3+) tumours is 81.1%, 64.2% and 10.9%, respectively, in patients with primary operable breast cancers. Compared with women aged >45, those ≤45 years were less likely to be ER-positive, more likely to have a high tumour grade, a large tumour size and an axillary lymph node positive status. There were no differences in HER2/neu or PR status comparing these age categories (Table 2).


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Table 1. (a) Association between HER2/neu and ER in women with a primary operable breast cancer by age range of 5 years (n = 1362)

 

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Table 1. (b) Association between HER2/neu and PR in women with a primary operable breast cancer by age range of 5 years (n = 1362)

 

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Table 2. Clinico-pathological features by age (n = 1362)

 
Hormone receptors and HER2/neu in all patients
The results from the uni- and multivariate analysis for the association between HER2/neu overexpression (score 3+) and different clinicopathological factors are presented in Table 3. The multivariate analysis revealed that ER status [odd ratio (OR) 2.163, 95% CI 1.335–3.505; P = 0.002], PR status (OR 1.744, 95% CI 1.094–2.779; P = 0.019) and tumour grade (OR 3.268, 95% CI 2.115–5.050; P <0.001) were independently associated with HER2/neu overexpression (Table 3b).


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Table 3. (a) Univariate analysis of demographic factors predicting HER2/neu overexpressiona in women with operable breast cancer (n = 1362)

 

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Table 3. (b) Multivariate analysis of demographic factors predicting HER2/neu overexpressiona in women with operable breast cancer (n = 1326)

 
Hormone receptors and HER2/neu in women age ≤45 years
The results from the uni- and multivariate analysis for the association between HER2/neu overexpression (score 3+) and different clinicopathological factors in women aged ≤45 years are given in Table 4. In univariate analysis, the P values for the association between ER status, PR status, tumour grade and HER2/neu are 0.043, 0.384 and 0.001, respectively (Table 3a). In multivariate analysis, only tumour grade (P =0.003) but none of the hormone receptor status was associated with HER2/neu overexpression (Table 4b).


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Table 4. (a) Univariate analysis of demographic factors predicting HER2/neu overexpressiona in women age ≤45 years (n = 246)

 

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Table 4. (b) Multivariate analysis of demographic factors predicting HER2/neu overexpressiona in women age ≤45 years (n = 246)

 
Hormone receptors and HER2/neu in women age >45 years
The results from the uni- and multivariate analysis for the association between HER2/neu overexpression (score 3+) and different clinicopathological factors in women aged >45 years are given in Table 5. The uni- (Table 5a) and multivariate model demonstrated that ER status (OR 2.461, 95% CI 1.445–4.192; P = 0.001), PR status (OR 2.359, 95% CI 1.398–3.983; P = 0.001) and tumour grade (OR 2.989, 95% CI 1.849–4.839; P <0.001) were significantly associated with HER2/neu overexpression (Table 5b).


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Table 5. (a) Univariate analysis of demographic factors predicting HER2/neu overexpressiona in women age >45 years (n = 1116)

 

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Table 5. (b) Multivariate analysis of demographic factors predicting HER2/neu overexpressiona in women age >45 years (n = 1116)

 
Hormone receptors and HER2/neu by age and tumour grade
From these results, it was clear that tumour grade plays an important role in the association between HER2/neu and hormone receptors. We therefore examined the association between HER2/neu status and hormone receptors by stratification with tumour grade (low versus high grade lesions). We compared this association for women in both age groups for ER (Table 6a) and PR (Table 6b). In women aged >45, a negative hormone receptor remained significantly associated with HER2/neu overexpression regardless of tumour grade. In women aged ≤45, a negative hormone receptor remained significantly associated with HER2/neu only in low-grade lesions. In Table 6a, it is difficult to get enough power to show significance for grades 1–2 for the young age group because of the smaller sample size of HER2/neu 3+ only, but the different proportion between 3.2% and 20.0% is a clear trend. In grade 3 lesions, the frequency of HER2/neu positivity was not different between ER-positive (17.5%) and ER-negative (19.1%) cases (P = 0.800). These figures were 22.5% for PR-positive and 14.3% for PR-negative cases (P = 0.194). This observation showed that the hormone receptors are not associated with the HER2/neu status in young women with a high-grade breast cancer.


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Table 6. (a) Frequency of HER2/neu positivitya by tumours grade and age per PR status

 

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Table 6. (b) Frequency of HER2/neu positivitya by tumours grade and age per PR status

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We demonstrated in women with an operable breast cancer that the association between HER2/neu and the hormone receptor status for ER and PR differs by age ≤45 and >45 years. This age-related relationship between ER and HER2/neu is in line with our findings on the age-related association between PR and HER2/neu in women with an ER-positive tumour [25Go]. Our hypothesis of an age effect on the association between hormone receptors and HER2/neu was based on the following preclinical and clinical observations in the literature. The inverse association between hormone receptors and HER2/neu has, in a preclinical model, been linked with the fact that estrogens and its receptor are required to suppress HER2/neu [20Go]. Circulating estrogens are different before than after the menopause and any association between hormone receptors and HER2/neu should therefore be examined by menopausal status or age. Also, in the clinic, it has been shown that ER-positive breast cancers are more likely to be high grade before than after menopause [21Go–23Go, 27Go, 28Go]. The association between hormone receptors and HER2/neu may therefore differ between younger and older women as tumour grade and HER2/neu positivity are strongly correlated. Furthermore, the predictive value of HER2/neu for response to anti-estrogens may be age-related. Love et al. [24Go] indicated that premenopausal women with hormone receptor-positive breast cancer and overexpressing HER2/neu do respond better to anti-estrogens than those with non-overexpressing HER2/neu breast tumours, in contrast to postmenopausal women where a HER2/neu positive status has been related to a lower response to tamoxifen [16Go]. An age-related effect on the association between the hormone receptor and HER2/neu was therefore worth examining.

The lower frequency of HER2/neu overexpression in hormone receptor positive tumours compared with hormone receptor negative breast cancers has been explained by a cross linkage between the two pathways for tumour growth. Apart from steroids and the hormone receptors, breast cancer growth is also regulated by peptide growth factors and both pathways are associated, or cross-talk [20Go, 29Go]. ER and HER2/neu signalling are inversely related through a transcriptional repression of HER2/neu by estradiol binding to ER [20Go]. Our results suggested that the inverse association between the hormone receptor and HER2/neu status does not appear in women aged ≤45 with a high-grade tumour. We have no plausible explanation for this new observation. High-grade ER-positive breast cancers may appear earlier in life if they are HER2/neu positive than if they are HER2/neu negative. This would suggest a growth advantage of high-grade ER-positive tumours through higher levels of circulating estrogens if they are HER2/neu positive. This age-related association between HER2/neu and hormone receptors has to be considered when using HER2/neu as a prognostic factor and probably also when using HER2/neu for treatment-related decisions. Under the age of 45 years, most HER2/neu positive tumours are PR positive whereas this is not the case in any of the older age groups.

The prognostic value of the hormone receptor status in grade 3 tumours may, therefore, be less important in younger than in older women, because high-grade ER-positive cases are as likely to be HER2/neu positive as ER-negative cases. Some have already pointed towards the fact that the prognostic role of a positive ER or PR is restricted to postmenopausal women because a high tumour grade overrules any other prognostic tumour characteristic in premenopausal women [30Go]. In this perspective we believe we can add yet another reason for this observation.

The absence of a negative association between hormone receptors and HER2/neu overexpression in a subgroup of women under the age of 45 also has therapeutic implications. Because PR is a predictive marker for response to anti-estrogens [31Go], our data imply that women aged ≤45 with a HER2/neu positive breast cancer may be more likely to be responsive to anti-estrogens than postmenopausal women with such a tumour. A lower likelihood of response to anti-estrogens such as tamoxifen in postmenopausal HER2/neu overexpressors has been reported [15Go, 16Go], whereas Love et al. [24Go] reported that premenopausal women with an ER-positive HER2/neu positive breast cancer remain sensitive to castration and tamoxifen.

In multivariate analysis HER2/neu overexpression was not associated with a positive lymph node status, with age ≤45 years or with larger tumours (size >20 mm), although others have made this observation [10Go, 11Go]. We, however, did not differentiate between the very young age group, i.e. 35 or 40 years, where HER2/neu seems more likely to be over-expressed [10Go]. We agree with other authors that lymph node status and tumour size do not predict for HER2/neu status in women with breast cancer [7Go, 8Go].

To our knowledge, this study is the first to assess the association between HER2/neu and tumour characteristics such as the hormone receptor status and tumour grade by age ≤45 or >45 years. Other studies have shown that hormone receptor negative breast cancers or high-grade tumours are more likely to be HER2/neu positive than hormone receptor positive breast cancers or low-grade tumours [5Go–11Go]. These studies, however, did not stratify for age and their analysis were only based on a univariate model. Because over 75% of all women with breast cancer appear beyond age 45, an age effect may not become apparent when only considering the overall population.

One shortcoming of our study is that we did not use fluorescence in situ hybridisation (FISH) to measure HER2/neu. Instead, we used IHC staining to analyse ER, PR and HER2/neu, which is easier and less expensive than ligand binding assays for measuring steroid hormone receptors and FISH for measuring HER2/neu. IHC for HER2/neu has an equivalent ability as FISH to predict response to anti-HER2/neu therapy and IHC for measuring steroid hormone receptors is better in predicting response to adjuvant endocrine therapy than ligand binding assays [18Go]. Furthermore, our data are robust in that one single pathologist did the readings for the established prognostic factors. Another important issue is that the large number of patients we included in our analyses is larger than most of the other studies evaluating the association between established tumour characteristics and HER2/neu status.

In conclusion, in women with an operable breast cancer, the hormone receptor status and tumour grade were independently associated with HER2/neu in women aged >45 years. In women aged ≤45 years, ER or PR did not predict for the HER2/neu status in high-grade tumours whereas an absent hormone receptor did predict for HER2/neu overexpression in low-grade tumours. Our findings indicated that the association between hormone receptors (ER or PR) and HER2/neu vary with the age of patients. This association has to be considered when using HER2/neu as a prognostic factor and probably also when using it for treatment-related decisions.


    Acknowledgements
 
H. J. H. received a grant for clinical research from Chang Gung Memorial Hospital in Taiwan.

Received for publication April 8, 2005. Revision received June 26, 2005. Accepted for publication June 27, 2005.


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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