Acquired Clinically Actionable Alterations Common In Breast Cancer Brain Metastases

Gene expression differences between the primary breast cancer and brain metastases have clinical implications for treatment

medwireNews: Brain metastases in patients with breast cancer can acquire alterations in clinically actionable genes, with ERBB2/HER2 expression gains the most common in patients otherwise negative for the marker, shows a molecular analysis.

“These observations have immediate clinical implications for patients with ERBB2/HER2–negative breast cancer” as many of them are unlikely to be given ERBB2/HER2-targeted therapies, say the researchers, adding that the findings “support comprehensive profiling of metastases to inform clinical care.”

The study included paired specimens from the primary cancer and resected brain metastases from 20 breast cancer patients, of whom 10 were oestrogen receptor-negative and 10 were positive.

Although the intrinsic subtype of the brain metastases, as assessed by the PAM50 gene signature, and the clinical risk score, as assessed by OncotypeDX, did not differ from that of the primary tumour in the majority of cases (17 and 15, respectively), the expression of individual genes was altered.

Specifically, the expression of at least one of 10 clinically actionable genes was different in the brain metastases versus breast cancer in all but three patients.

Gain of ERBB2/HER2 expression was the most common alteration, with at least twofold increases in 35% of brain metastases samples. Of note, three patients who acquired an ERBB2/HER2 alteration had been classified as ERBB2/HER2-negative on the basis of the breast cancer specimen.

In an independent whole-exome sequencing cohort comprising 17 paired brain metastases and breast cancer samples, two of nine cases designated ERBB2/HER2-negative showed gains in ERBB2/HER2 expression in the brain metastases samples – in one case as a result of a copy number gain and the other due to the acquisition of the activating V777L mutation.

Furthermore, analysis of a metastases-enriched cohort of 7884 breast cancers showed that brain metastases were significantly more likely to harbour ERBB2/HER2 alterations than local tumours, with rates of 24% and 13%, respectively. By contrast, ERBB2/HER2 alterations were not more common when local tumours and metastases from all sites were compared.

Researcher Adrian Lee, from the University of Pittsburgh Medical Center in Pennsylvania, USA, and colleagues also detected changes in other clinically relevant genes in brain metastases relative to the primary sample in their study cohort, including gains in FGFR4, FLT2, AURKA and EGFR, and loss of ESR1.

They write in JAMA Oncology: “Breast cancer [brain metastases] are remarkably similar transcriptionally to patient-matched primary tumors; yet, recurrent expression changes in clinically actionable genes are common.

“Given this evolution, metastasis-acquired features should inform targeted therapy selection and trial eligibilities in advanced cancer settings.”


Priedigkeit N, Hartmaier RJ, Chen Y, et al. Intrinsic subtype switching and acquired ERBB2/HER2 amplifications and mutations in breast cancerbrain metastases. JAMA Oncol; Advance online publication 7 December 2016. doi:10.1001/jamaoncol.2016.5630

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