Predicting early brain metastases based on clinicopathological factors and gene expression analysis in advanced HER2-positive breast cancer patients

Abstract

The overexpression or amplification of the human epidermal growth factor receptor 2 gene (HER2/neu) is associated with high risk of brain metastasis (BM). The identification of patients at highest immediate risk of BM could optimize screening and facilitate interventional trials. We performed gene expression analysis using complementary deoxyribonucleic acid-mediated annealing, selection, extension and ligation and real-time quantitative reverse transcription PCR (qRT-PCR) in primary tumor samples from two independent cohorts of advanced HER2 positive breast cancer patients. Additionally, we analyzed predictive relevance of clinicopathological factors in this series. Study group included discovery Cohort A (84 patients) and validation Cohort B (75 patients). The only independent variables associated with the development of early BM in both cohorts were the visceral location of first distant relapse [Cohort A: hazard ratio (HR) 7.4, 95 % CI 2.4–22.3; p < 0.001; Cohort B: HR 6.1, 95 % CI 1.5–25.6; p = 0.01] and the lack of trastuzumab administration in the metastatic setting (Cohort A: HR 5.0, 95 % CI 1.4–10.0; p = 0.009; Cohort B: HR 10.0, 95 % CI 2.0–100.0; p = 0.008). A profile including 13 genes was associated with early (≤36 months) symptomatic BM in the discovery cohort. This was refined by qRT-PCR to a 3-gene classifier (RAD51, HDGF, TPR) highly predictive of early BM (HR 5.3, 95 % CI 1.6–16.7; p = 0.005; multivariate analysis). However, predictive value of the classifier was not confirmed in the independent validation Cohort B. The presence of visceral metastases and the lack of trastuzumab administration in the metastatic setting apparently increase the likelihood of early BM in advanced HER2-positive breast cancer.

Radiological Patterns of Brain Metastases in Breast Cancer Patients: A Subproject of the German Brain Metastases in Breast Cancer (BMBC) Registry

“…The analysis of the correlation between BM patterns and previous systemic therapy showed that HER2-positive patients treated with trastuzumab before the diagnosis of BMs had a lower number of BMs in comparison with patients without HER2-targeted therapy. A protective role of the HER2-targeted therapy concerning the BMs was also suggested by the findings of Duchnowska et al, where no trastuzumab administration in the metastatic setting was an independent variable in the development of early BMs [8]. …”

Risk factors for breast cancer brain metastases: a systematic review

“…The majority of the eligible studies were limited to reporting univariate association between BC subtypes or a single candidate factor with TTBM. Only fourteen studies provided multivariable TTBM estimates for variables [11,28,39,58,63,70,76,83,84,90,94,96,102,104].…”

“…With the exception of one study where only a small proportion of the patients received hormonotherapy or HER2 targeted therapies [106], studies that stratified patients into four BC subtypes (HR+/ HER2-, HR+/HER2+, HR-/HER2+ and HR-/HER2-) and measured TTBM interval from primary BC [28,38,54,86,90,92,97,100,104,105] or MBC diagnosis [28,38,55], the non-luminal subtypes (HR-/HER2-and HR-/ HER2+) were found to associate with significantly shorter TTBM, compared to the luminal ones (HR+/HER2-, HR+/HER2+). Comparison of the two HR-positive groups revealed HR/HER2 co-positivity to constantly associate with shorter TTBM [84,102]. Similar results were observed across seven studies [24,30,70,84,91,97,98] stratifying patients into three BC subtypes (HR+/HER2-, HR±/HER2+, and HR-/HER2-), with the TNBC tumors demonstrating the shortest TTBM (20-25.5 months from primary diagnosis and 9-14 months from MBC) and HR+/HER2-the longest (42-63.5 months from primary diagnosis and 20.6-34 months from MBC).…”

Association between AT1 and AT2 angiotensin II receptor expression with cell proliferation and angiogenesis in operable breast cancer

“…The prognosis depends on multiple factors, such as stage and age at diagnosis, degree of differentiation, cellular proliferation, estrogen, and progesterone receptor positivity and overexpression of HER2/neu [2]. These factors also represent the basis of current therapies to HER2-targeted treatments or adjuvant/palliative hormonal treatment [3][4][5].…”