Elsevier

European Journal of Cancer

Volume 45, Issue 16, November 2009, Pages 2792-2798
European Journal of Cancer

Triple-negative and HER2-overexpressing breast cancers exhibit an elevated risk and an earlier occurrence of cerebral metastases

https://doi.org/10.1016/j.ejca.2009.06.027Get rights and content

Abstract

Purpose

Evaluation of the influence of immunohistochemically defined breast cancer (BC) subtypes and other risk factors on the development of cerebral metastases (CM).

Methods

Exploratory analysis of a hospital-based prospective tumour registry including all patients with primary BC treated in our EUSOMA breast unit between 1998 and 2006.

Results

The study cohort contained 2441 patients, including 284 patients (11.6%) with triple-negative (oestrogen receptor (ER), progesterone receptor (PR) and HER2-negative) and 245 patients (10.1%) with HER2-overexpressing BC subtypes. Overall, 80 patients (3.3%) developed CM within a median follow-up period of 47 months, 19 (23.8%) of them with triple-negative and 19 (23.8%) with HER2-positive tumours. Therefore, 6.7% of all patients with triple-negative and 7.8% of patients with HER2-positive breast cancer developed CM. Multivariate analysis indicated that the highest risk for CM was triple-negative breast cancer. Further independent risk factors were: HER2-overexpression, early onset BC (age < 50 years), and large tumour size (pT3/4). Among those patients developing CM, triple-negative BC showed the shortest interval between primary diagnosis and occurrence of CM with a median of 22 months, compared to 30 and 63.5 months in HER2-positive and ER+/HER2- BC, respectively. Survival after occurrence of CM did not differ among the subtypes.

Conclusion

Patients with triple-negative or HER2-positive BC have a higher risk for CM compared with patients bearing the ER+/HER2- phenotype and develop CM earlier in the course of disease. A risk profile for CM might help adjust surveillance in high risk populations and identify patients with a need for new treatment strategies.

Introduction

Breast cancer (BC) is the second most common solid malignancy that spreads to the brain.1 Historical data suggest an incidence of symptomatic cerebral metastases (CM) in BC patients between 5% and 16%2, 3; autopsy studies revealed an even higher incidence of up to 34%.1, 2, 4 Patients suffering from symptomatic CM have a poor prognosis with a median survival time after diagnosis ranging between 3 and 9 months.5, 6 Early onset BC, HER2-overexpression, high tumour grade and oestrogen receptor (ER) negativity have been described as independent risk factors for development of CM.5, 7, 8, 9, 10

In past years, carcinomas of the breast have been classified into six subgroups based on gene expression patterns, each subgroup showing a different clinical outcome. Patients with tumours bearing the basal-like subtype showed the shortest overall survival.11 Triple-negative BC (oestrogen receptor negative (ER-), progesterone receptor negative (PR-) and HER2-negative (HER2-)) specimens exhibit the basal-like phenotype in 91% of all cases and, therefore, triple negativity can be used as a clinical surrogate for the genotypically defined basal-like phenotype.12 As mentioned above, HER2-overexpression is associated with a more aggressive course of disease.13 According to ER status, HER2-overexpressing BC can be classified into two subgroups: the HER2 subtype (ER-negative) and the Luminal B subtype (ER-positive).14

The goals of our study were (1) to determine the incidence of CM in a large cohort of patients with BC, (2) to evaluate the influence of BC subtypes (specifically triple negativity and HER2-overexpression) and other risk factors on the development of CM, and (3) to analyse the clinical course of patients with CM in BC.

Section snippets

Patients and methods

The data for this exploratory analysis were derived from the prospectively running clinical tumour registry of our EUSOMA (European Society of Breast Cancer Specialists) breast cancer unit at a city hospital (Dr. Horst Schmidt Kliniken) in Wiesbaden, Germany. The tumour registry data from BC patients included tumour characteristics, modalities and outcomes of treatments, which are updated annually by the registry physician. The follow-up information is also updated at least annually, either

Patients’ characteristics

The final study cohort consisted of 2441 patients with primary invasive BC. Of those, 284 (11.6%) patients had triple-negative BC, 245 (10.1%) showed HER2-positive phenotypes and 1912 (78.3%) patients expressed SR+/HER2- phenotypes.

Patient characteristics are displayed in Table 1. Statistically significant differences among the three groups were seen regarding age at BC diagnosis, size of the primary tumour, lymph-node involvement and grading. Patients with triple-negative and HER2-positive BC

Discussion

This retrospective, single-institution study analysing the risk factors for development of brain metastases was based on a relatively large population with 2441 patients with invasive BC. Although some related studies were conducted on a larger cohort,15, 16 other comparable analyses were done on a smaller scale.17, 18, 19

The frequency of symptomatic CM has been reported to be between 5 and 16%,2, 3 and in asymptomatic patients even up to 34%.1, 10, 20 A higher incidence of symptomatic brain

Conflict of interest statement

None declared.

Acknowledgement

We thank Dr. S. Yu-Poth, Dr. M. Kandel and Dr. V. Stinshoff who provided valuable support regarding manuscript reading and language improvement.

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    This manuscript was partially presented orally at the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago 2008.

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