Brain Mets Can Acquire HER2-Positivity in HER2-Negative Breast Cancer Patients

Brain metastases from primary breast cancer tumors often acquire clinically actionable genetic alterations, according to a small study. About one fifth of ERBB2/HER2-negative cases switched to HER2-positivity in the brain metastases.

“Limited therapeutic options exist for patients with brain metastases,” wrote study authors led by Nolan Priedigkeit, BS, of the University of Pittsburgh. “ERBB2/HER2-positive brain metastases have demonstrated encouraging responses to ERBB2/HER2-targeted therapies in recent clinical trials.” ERBB2/HER2-negative brain metastases, however, have shown no such response.

Researchers conducted targeted gene expression profiling on a cohort of 20 primary breast tumors and their patient-matched brain metastases in order to define any clinically actionable metastasis-acquired alterations. The results were published online ahead of print in JAMA Oncology, and presented simultaneously at the San Antonio Breast Cancer Symposium.

In total, 17 of 20 brain metastases maintained their PAM50 subtype; 15 of 20 retained the Oncotype DX clinical risk score as well. In spite of the similarity in those scores, 100 genes were found to be recurrently altered; 55 genes harbored twofold expression gains and/or losses in a quarter of the cases or more. KRT17, KRT5, and KRT14 were the most frequently downregulated, and RAB6B and GRB7 were the most frequently upregulated genes.

Ten of the genes tested for are considered clinically actionable; 17 of the 20 cases had at least one such gene that was altered in brain metastases. ERBB2/HER2 was the most recurrent alteration that showed a twofold or greater expression increase; this occurred in 35% of brain metastases. Three of those cases with substantially increased expression were classified as ERBB2/HER2-negative in the primary breast tumor, and immunohistochemical analysis showed that they became ERBB2/HER2-positive in the brain metastasis.

Six cases also showed increased expression of FGFR4, and three showed a greater than fourfold increase.

The investigators also analyzed a separate cohort of 7,884 breast cancers, including 3,135 cases of local disease and 4,130 cases of metastases, looking for alterations between the local and metastatic sites. Across all metastatic sites there was no significant difference with regard to ERBB2/HER2, but there was a significant enrichment of alterations specifically in brain metastases (24%) when compared with local disease (13%; P < .001).

“Breast cancer brain metastases are remarkably similar transcriptionally to patient-matched primary tumors; yet, recurrent expression changes in clinically actionable genes are common,” the authors concluded. “Given this evolution, metastasis-acquired features should inform targeted therapy selection and trial eligibilities in advanced cancer settings.” They added that the changes apparent to ERBB2/HER2 “warrant immediate clinical attention,” as many of those patients would not otherwise be offered relevant targeted therapies.