Distribution and prognosis of molecular breast cancer subtypes defined by immunohistochemical biomarkers in a Spanish population-based study

doi:10.1016/j.ygyno.2013.05.039

Gynecologic Oncology

Volume 130, Issue 3, September 2013, Pages 609-614

https://doi.org/10.1016/j.ygyno.2013.05.039 Get rights and content

Highlights

•
This study showed differences in clinicopathological features and survival rates among breast cancer molecular subtypes classified by immunohistochemical biomarkers.
•
We confirm that molecular subtypes defined by immunohistochemical biomarkers provide useful prognosis information for guiding and evaluating clinical treatment.
•
The prognosis value of molecular subtype persists when adjusting by age, stage and histological grade.

Abstract

Background

The objective of this study is to analyze the distribution, clinicopathological features, relative survival rate and excess risk of death among females diagnosed with invasive breast cancer and classified by molecular subtype from ten Spanish cancer registries.

Method

Three thousand four hundred and eighty incident cases of women – mostly diagnosed in 2005 – were classified into five molecular subtypes according to immunohistochemical status of hormonal receptors and HER2 (human epidermal growth factor receptor 2): estrogen receptor (ER) and/or progesterone receptor (PR)+ and HER2 −, ER + and/or PR + and HER2 +, HER2-overexpressed (ER −, PR − and HER2 +), triple negative (ER, PR and HER2 −) and unclassified (hormonal receptor or/and HER2 unknown). Relative survival rates at 1, 3 and 5 years and relative excess risks (RER) of death adjusting for molecular subtype, age, stage and histological grade were estimated.

Results

Marked differences in clinicopathological characteristics and relative survival rate were observed between molecular subtypes. Compared with women with ER + and/or PR + and HER2 −, ER + and/or PR + and HER2 + cases had an RER of 1.00 (95% CI: 0.66 to 1.52) after adjusting for age, stage and histological grade, whereas HER2-overexpressed, triple negative and women with unclassified subtypes presented an RER of 1.72 (95% CI: 1.15 to 2.57), 3.16 (95% CI: 2.26 to 4.41) and 2.55 (95% CI: 1.96 to 3.32), respectively.

Conclusion

The prognostic value of molecular subtype persists when adjusting for age, stage and histological grade. Hormone receptor-positive tumors were associated with a better prognosis when compared with HER2-overexpressed and triple negative subtypes. Further research is required to improve triple negative prognosis.

Introduction

Breast cancer mortality has decreased in recent years in Spain due to the use of population prevention strategies and improved treatments. Although breast cancer incidence has also been declining since 2003, it is still the most common neoplasm among Spanish women and the most frequent cause of cancer mortality [1], [2]. Breast cancer is a highly heterogeneous disease with regard to its clinical features, biological behavior and treatment response [3], [4]. Analyses based on breast cancer gene expression patterns using microarray technology have identified the following molecular subtypes: luminal A, luminal B, basal-like and HER2-overexpressed (human epidermal growth factor receptor 2) [5], [6]. Several differences have been described between these groups in reference to incidence, survival and risk factors [5], [6], [7], [8], [9], [10], [11], [12], [13], [14]. Current knowledge of molecular breast cancer subtypes has provided a better approach to treatment.

Hormone receptor-positive tumors have been associated with a better prognosis and non-aggressive behavior compared to basal-like and HER2-overexpressed subtypes, whereas basal-like tumors have been associated with the worst prognosis. In clinical terms, this subtype is known as triple negative due to the lack of ER and PR protein expression and the absence of HER2 overexpression. However, approximately 25% of basal-like tumors are not triple negative [4]. Remarkably, there is a lack of target treatment for women diagnosed with a basal-like tumor.

Luminal subtypes are characterized by high expression of hormonal receptors. Luminal A is defined by low expression of HER2 and low proliferation and luminal B by high proliferation. Proliferation is assessable using the Ki-67 index and/or histological grade [8], [15]. Among these two subtypes, luminal B tumors have a worse prognosis than luminal A [9], [13], [16].

Genotyping assays used to classify breast cancers into molecular subtypes according to gene expression are costly and not affordable for most hospitals. A relatively high concordance (75–90%) is considered to exist between molecular subtypes defined by genomic methods and immunohistochemical (IHC) phenotype [17]. Currently, IHC biomarkers of the estrogen receptor (ER), progesterone receptor (PR) and HER2 are routinely tested and have been used as a surrogate to stratify breast cancer into ER + and/or PR + and HER2 −, ER + and/or PR + and HER2 +, triple negative and HER2-overexpressed tumors.

There is a lack of information regarding population-based distribution and survival by molecular subtype in Spain. The present work analyzes the distribution, clinicopathological features, survival and excess risk of death among females diagnosed with breast cancer classified by molecular subtypes from ten Spanish cancer registries, mostly diagnosed in 2005.

Section snippets

Data

Data were extracted from the ten Spanish population-based cancer registries participating in the “Spanish High Resolution Breast Cancer Study” (Albacete, Castellón, Cuenca, Gipuzkoa, Girona, Granada, La Rioja, Murcia, Navarra and Zaragoza), covering 20% of the Spanish female population, mainly located in the east of Spain. These cancer registries collect incident of invasive breast cancer (IBC) according to guidelines from the International Agency for Research on Cancer (IARC) and European

Distribution

A total of 3,480 incident cases of female IBC were identified in the ten Spanish cancer registries participating in the study. The women's ages ranged from 25 to 97 years old. There were 79.6% (n = 2,771) of cases classified into molecular subtypes. The majority of them were ER + and/or PR + and HER2 − (68.7%), followed by ER + and/or PR + and HER2 + (12.5%), triple negative (11.8%) and HER2-overexpressed (7.0%).

Clinicopathological features

Table 1 summarizes differences in clinicopathological features between molecular subtypes.

Discussion

Molecular subtypes are becoming essential in breast cancer prognosis and selection of a therapeutic approach. This is the first Spanish population-based study to analyze distribution and survival by molecular subtype. The results presented show that the prognostic value of molecular subtypes defined by IHC biomarkers persists when adjusting for age, stage and histological grade, providing useful information to guide and evaluate clinical treatment. These results are in accordance with the

Conclusions

Molecular subtype is becoming increasingly more important in predicting prognosis and treatment response for breast cancer patients. This population-based study of Spanish women confirms that molecular subtypes defined by IHC biomarkers provide useful prognostic information for guiding and evaluating clinical treatment. Marked differences in clinicopathological and survival outcome were observed between molecular subtypes classified according to IHC biomarkers, women with ER + and/or PR + and HER2

Conflicts of Interest statement

The authors have declared no conflicts of interest.

Abbreviations

ANOVA

(analysis of variance)

(confidence intervals)

DCO

(diagnosed by death certificate)

ENC

(European Network of Cancer Registry)

(estrogen receptor)

FISH

(fluorescence in situ hybridization)

HER2

(human epidermal growth factor receptor 2)

IARC

(International Agency for Research on Cancer)

IBC

(invasive breast cancers)

IHC

(immunohistochemical)

(progesterone receptor)

RER

(relative excess risks of death)

(relative survival)

Acknowledgement

This work was supported by the Instituto de Salud Carlos III (PI07/0724; PI07/0606; PI07/0700; PI07/1161; PI07/0439; PI07/0718; PI07/1063) and Puig-Vives M. received an FPU (Formación Profesorado Universitario) fellowship from the Spanish Ministry of Education.

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Distribution and prognosis of molecular breast cancer subtypes defined by immunohistochemical biomarkers in a Spanish population-based study

Highlights

Abstract

Background

Method

Results

Conclusion

Introduction

Section snippets

Data

Distribution

Clinicopathological features

Discussion

Conclusions

Conflicts of Interest statement

Abbreviations

Acknowledgement

Ann Oncol

Ann Oncol

Ann Oncol

Ann Oncol

Mol Oncol

Comput Methods Programs Biomed

Dissecting the heterogeneity of triple-negative breast cancer

J Clin Oncol

Systems biology and genomics of breast cancer

Cold Spring Harb Perspect Biol

Molecular portraits of human breast tumours

Nature

Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications

Proc Natl Acad Sci U S A

Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study

JAMA

Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer

J Natl Cancer Inst

Defining breast cancer prognosis based on molecular phenotypes: results from a large cohort study

Breast Cancer Res Treat

Breast cancer histology and receptor status characterization in Asian Indian and Pakistani women in the U.S.—a SEER analysis

BMC Cancer