HER-2 positive breast cancer: decreasing proportion but stable incidence in Finnish population from 1982 to 2005
© Köninki et al.; licensee BioMed Central Ltd. 2009
Received: 11 February 2009
Accepted: 18 June 2009
Published: 18 June 2009
Classification of breast cancers according to the HER-2 oncogene status is of central importance in the selection of post-surgical therapies. A decrease in the proportion of HER-2-positive breast cancer has been suspected, but no data on the incidence trends at population level have been reported.
We studied the proportion of HER-2-positive breast cancers by chromogenic in situ hybridization (CISH) in three cohorts (years 1982 to 1986 (n = 310), 1989 to 1992 (n = 108), and 2004 to 2005 (n = 713)) in the population of the Pirkanmaa hospital district (approximately 220,000 women). Cancer incidence rates were age-adjusted to the world standard population.
The proportion of HER-2-positive breast cancer declined from 21.6% (average in 1982 to 1986) to 13.6% (average in 2004 to 2005). However, during the same time period the age-adjusted incidence of all invasive breast cancers had increased by 40%. These opposite trends balanced each other and indicated that the incidence of HER-2-positive breast cancer has remained unchanged (Poisson regression coefficient for time trend 1.000; 95% CI = 0.989 to 1.012). In contrast, the incidence of HER-2-negative cancer showed 2% annual increase (Poisson regression coefficient 1.021, 95% CI = 1.016 to 1.026). Although HER-2-negative cancers were more likely to be diagnosed by mammography screening, the changes were more likely to be explained by etiological risk factors favoring HER-2-negative (and hormone receptor-positive) disease such as menopausal hormone therapy.
These results document a significant decrease in the proportion of HER-2-positive breast cancer. However, the incidence of HER-2-positive cancer at the population level was found to be unchanged.
The human epidermal growth factor receptor-2 (HER-2) proto-oncogene has been in the focus of cancer research during the past two decades. It is well established that amplification of the HER-2 oncogene correlates with poor prognosis of patients . More importantly, HER-2 oncogene is the molecular target of trastuzumab and lapatinib based therapies that are widely used in the treatment of HER-2-positive breast cancer. Currently all newly diagnosed breast cancers are assayed for HER-2 oncogene status [2–5]. HER-2-targeted therapies cause significant amounts of workload and costs, so accurate information on the incidence of HER-2-positive breast cancer is required to estimate the resources needed in clinics.
The incidence of HER-2 amplification in population-based cohorts of breast cancer is not known precisely. As reviewed by Cardoso and colleagues , the proportion of HER-2-positive tumors and/or overexpression has ranged between 10 and 40% in different studies. The figures are generally higher in older literature and in studies using immunohistochemical assays, which are considered to be less specific than assays based on in situ hybridization. Most studies describe relatively small cohorts of patients often including defined subtypes (node-negative, node-positive or in situ cancers). Due to the prognostic correlations studied, most studies describe patient populations whose breast cancers have been diagnosed 5 to 20 years earlier. It is well known that the overall incidence of breast cancer has increased significantly during the past decades [7, 8]. Yet the time trends in the incidence of HER-2-positive breast cancer have remained unclear.
As a reference laboratory responsible for HER-2 tumor diagnostics, our laboratory has followed up the proportion of HER-2-positive tumors analyzed as part of our internal quality assurance. In this study we wanted to explore the apparent discrepancy between our current figures for HER-2 positivity (< 15%) and those previously reported in the literature (20 to 30%) [9, 10]. Direct comparison between the current situation and the published studies was not possible, because the specificity and sensitivity of the HER-2 assay methods (immunohistochemistry vs. in situ hybridization) are likely to differ. Therefore, we studied the incidence trends of HER-2-positive breast cancer using chromogenic in situ hybridization (CISH) from 1131 samples of breast cancers diagnosed between 1982 and 2005 in a geographically defined hospital district, namely Pirkanmaa in Finland.
Materials and methods
Characteristics of the study cohorts
Patient cohort (year of primary diagnosis)
Number of breast
cancers diagnosed per year**
Number of breast cancers in the cohort
Age at diagnosis (median, range)
Proportion of axillary lymph node negative cancers
Proportion of estrogen receptor-positive cancers
Proportion of progesterone receptor-positive cancers
1982 to 1986
63 (27 to 92)
59 (30 to 88)
1989 to 1992
60 (28 to 92)
64 (34 to 88)
2004 to 2005
60 (25 to 94)
Formalin-fixed and paraffin-embedded tumor samples were used for this study. Amplification of HER-2 was determined in all tumors by using CISH as previously described [13, 14]. The cut-off for amplification was set at six gene copies per cell or the presence of a typical gene copy cluster . The study was approved by the Ethical Committee at Tampere University Hospital.
The age-standardized breast cancer incidence was calculated using the World Health Organization (WHO) standard population . Time trends in the proportion and incidence of HER-2-positive tumors were analyzed by regression methods, using a generalized linear model with binomial distribution and logarithmic link function and incidence trendswith Poisson regression, both in Stata 8.0 (StataCorp, College Station, Tx, USA). The outcome was a HER-2-positive tumor and the explanatory variable was the year of diagnosis as continuous variable. The exponentiated regression coefficient indicates average change in the proportion of HER-2-positive tumors per year relative to the first year analyzed. Statistical significance was assessed using a likelihood ratio test.
Trends in the incidence and proportion of HER-2-positive breast cancer from 1982 to 2005 in the Pirkanmaa Hospital District
Breast cancer cohort
Mean annual age-adjusted incidence*
Proportion of HER-2-positive breast cancers
Estimated age-adjusted incidence of HER-2-positive breast cancer
Estimated age-adjusted incidence of HER-2-negative breast cancer
1982 to 1986
1989 to 1992
2004 to 2005
Characteristics of breast cancers diagnosed from 2004 to 2005 by the method of detection (screening vs. clinical)
Proportion detected by screening mammography (%)
All patients *
Our results indicate that the commonly used phrase '20% to 30% of breast cancers show HER-2 oncogene amplification' does not appear to be valid in a well-defined population-based cohort of Finnish breast cancer patients diagnosed in recent years. In our patient population, less than 15% of breast cancers showed amplification of the HER-2 oncogene. Thus, there is an apparent discrepancy with earlier literature , for which we sought to find an explanation by analyzing tumors from our archives retrospectively using the current CISH method. Comparison of the historical and more recent cohorts indicated that the proportion of HER-2-positive invasive breast cancer has clearly declined. The proportion found in the oldest cohort (1982 to 1986) was in good agreement with that reported in the literature, including a study from the same population , although our previous study was based on detection of HER-2 protein overexpression by immunohistochemistry instead of gene amplification .
As in most western countries, the age-adjusted incidence of all breast cancers had increased during the study period. In the Pirkanmaa Hospital District the increase in age-adjusted incidence was estimated to be 40%. Thus, we were able to disentangle the two opposing trends, that is, the decrease of the proportion of HER-2-positive breast cancer and increase in overall breast cancer incidence at the population level. These two trends were found to balance out each other. Our data indicated that the incidence of HER-2-positive breast cancer in the female population had remained stable. The increased incidence of breast cancer seemed to be due to HER-2-negative disease. To the best of our knowledge incidence trends in HER-2-negative and HER-2-positive breast cancers have not been reported in the literature.
Only relatively few studies have examined epidemiologic time trends of biologic subtypes of breast cancer. An increase in the incidence of hormone receptor-positive breast cancer has been documented [15–17]. As HER-2 and hormone receptors are inversely associated (e.g. P < 0.0001 in reference ; the p-value was calculated for our results in this study and the same phenomenon has been shown also in the reference 6), these observations are in line with our results of decreased incidence HER-2. Similar to the published reports, we also found a significant increase in the proportion of estrogen receptor-positive tumors in this study (from 59.4% in 1982 to 1986 to 89.8% in 2004 to 2005; Table 1). However, the data may be biased, because the estrogen receptor assay method had changed (ligand-binding assay was used in 1982 to 1986; immunohistochemistry on frozen sections in 1989 to 1992; immunohistochemistry on paraffin sections in 2004 to 2005). The sensitivity of these assay methods may differ and the possible bias is impossible to determine retrospectively.
In addition to hormone receptor data, changes in breast cancer histopathology has also been documented in the literature [18, 19]. Increasing incidence of invasive lobular carcinoma [18, 19] is in line with the decrease of HER-2-positive breast cancers, because these two features are inversely correlated [20, 21]. Thus, based on the literature, the decreased proportion of HER-2-positive breast cancer may at least partly be explained by the increase of hormone receptor-positive and lobular carcinoma, which are mostly HER-2 negative.
Given the fact that the incidence of different subtypes of breast cancer really is changing, this suggests that the known risk factors of breast cancer do not affect all subtypes equally. As the incidence of HER-2-positive breast cancer was found to be constant, we can assume that the magnitude of its causative risk factors, which remain unknown, have probably remained unchanged. On the other hand, our results suggest that the impact of the risk factors for HER-2-negative cancer may have increased. One such risk factor could be menopausal hormone replacement therapy (HRT), which is a well-defined risk factor for breast cancer in general [22, 23]. The use of HRT increased in Finland five-fold in the period from 1980 to 2000 , although a slight decrease occurred after 2003 . However, the decrease in HRT use in Finland has been much smaller than in many other countries .
Several studies have demonstrated that the breast cancers in women who have used HRT are more frequently estrogen receptor and progesterone receptor positive than in those who have not used HRT [26, 27]. Because it is well known that HER-2 amplification is inversely associated with hormone receptor positivity , it is possible that use of HRT may be associated with a risk of HER-2-negative disease. This theory is also supported by the association between HRT and increased incidence of invasive lobular breast carcinoma [28, 29].
One possible explanation for the observed time trends is that intensified screening for breast cancer may detect a larger proportion of slowly growing HER-2-negative tumors with a longer lead-time than other tumor types. In line with previous studies that have characterized biomarker profiles of screen-detected breast cancers , our results demonstrated that HER-2-positive tumors are underrepresented in the screen-detected patient group, similar to that of tumors characterized by negative hormone receptor status or with a lack of all three markers (triple negative). In our study, screening is likely to give a partial explanation to the shift in biomarker profiles. Nationwide screening mammography was not in practice during the first period of the study (1982 to 1986), but was introduced gradually in 1989 to 1992; in 2004 to 2005 almost 90% of all women aged between 50 and 69 years participated in bi-annual mammography screening . In the newest cohort (age group 50+ years) with clinically detected disease, the proportion of HER-2-positive disease (12.8%) was much lower than in early cohorts in 1982 to 1986 (19.1%, patients over 50 years old). This suggests that screening bias is a less important factor to explain the decrease seen in the proportion of HER-2-positive disease.
These results document a significant decrease in the proportion of HER-2-positive breast cancer in an epidemiologically defined patient cohort during 1982 to 2005. At the same time, the overall incidence of breast cancer showed an increase of 40%. The estimated incidence of HER-2-positive cancer at the population level was found to be stable.
chromogenic in situ hybridization
human epidermal growth factor receptor-2
hormone replacement therapy.
The authors wish to thank Professor Risto Sankila (Finnish Cancer Registry, Helsinki, Finland) for providing epidemiologic data of breast cancer in the Pirkanmaa Hospital district, Dr Paula Kujala for providing clinical data and Sari Toivola for technical assistance. Financial support was from the Academy of Finland, the Finnish Cancer Foundation, the Finnish Medical Foundation, Juselius Foundation, and the Scientific Foundation of the Pirkanmaa Hospital District.
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