Abstract
Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. The aim of this study was to estimate mortality for patients with the major subtypes of breast cancer as classified using five immunohistochemical markers, to investigate patterns of mortality over time, and to test for heterogeneity by subtype. We pooled data from more than 10,000 cases of invasive breast cancer from 12 studies that had collected information on hormone receptor status, human epidermal growth factor receptor-2 (HER2) status, and at least one basal marker (cytokeratin [CK]5/6 or epidermal growth factor receptor [EGFR]) together with survival time data. Tumours were classified as luminal and nonluminal tumours according to hormone receptor expression. These two groups were further subdivided according to expression of HER2, and finally, the luminal and nonluminal HER2-negative tumours were categorised according to expression of basal markers. Changes in mortality rates over time differed by subtype. In women with luminal HER2-negative subtypes, mortality rates were constant over time, whereas mortality rates associated with the luminal HER2-positive and nonluminal subtypes tended to peak within 5 y of diagnosis and then decline over time. In the first 5 y after diagnosis the nonluminal tumours were associated with a poorer prognosis, but over longer follow-up times the prognosis was poorer in the luminal subtypes, with the worst prognosis at 15 y being in the luminal HER2-positive tumours. Basal marker expression distinguished the HER2-negative luminal and nonluminal tumours into different subtypes. These patterns were independent of any systemic adjuvant therapy. The six subtypes of breast cancer defined by expression of five markers show distinct behaviours with important differences in short term and long term prognosis. Application of these markers in the clinical setting could have the potential to improve the targeting of adjuvant chemotherapy to those most likely to benefit. The different patterns of mortality over time also suggest important biological differences between the subtypes that may result in differences in response to specific therapies, and that stratification of breast cancers by clinically relevant subtypes in clinical trials is urgently required.
Highlights
Breast cancer is a heterogeneous disease that can be classified using a variety of clinical and pathological features
The six subtypes of breast cancer defined by expression of five markers show distinct behaviours with important differences in short term and long term prognosis
Application of these markers in the clinical setting could have the potential to improve the targeting of adjuvant chemotherapy to those most likely to benefit
Summary
Breast cancer is a heterogeneous disease that can be classified using a variety of clinical and pathological features. The normal-like subgroup was typified by high gene expression for basal and low expression for luminal breast epithelium. A subsequent gene expression analysis by Sorlie et al of patterns in 78 breast cancers, three fibroadenomas, and four normal breast tissues suggested that the luminal-like subtype could be further separated into two subgroups: luminal A and luminal B [2]. Overall and relapse-free survivals were most favourable for luminal A tumours and least favourable for ERBB2+ and basal-like breast cancers. Immunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. Surgery is usually followed by radiotherapy or chemotherapy These ‘‘adjuvant’’ therapies are designed to kill any remaining cancer cells but can make women very ill. In the United States, for example, nearly 90% of affected women are still alive five years after their diagnosis
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