The development of brain metastases (BM) is associated with significant morbidity and virtually 100% mortality. BM develop in 10-16% breast cancer patients, with highest incidence for HER2-positive and triple-negative disease. Median survival is 5-22 months depending on treatment and prognostic indicators. There are no standard targeted drug therapies available for BM.
We have demonstrated that HER3 (ERBB3) tyrosine kinase is over-expressed in in BM compared to matching primary breast and lung cancers, suggesting it may be activated to exploit the abundance of neuregulin (NRG) ligand in the brain. In support of this, we detected very low expression of NRG in clinical samples by RNAseq, and could suppress the growth of intracranial MDA-MB-231 breast cancer xenografts by co-grafting a neutralizing Nrg-1 antibody, or treating the mice with Herceptin (i.p.). ERBB3 RNA levels correlate strongly with ERBB2 in clinical samples, but at the protein level HER3 is ubiquitously activated (phosphorylated) in cases comprising a range of HER2 activation levels. IHC analysis of a large archival BM cohort (n=170; 7 primary cancer types) showed strong, complete pHER3 membrane staining in 57.7% cases. Collectively these data suggest that targeting HER3 may be a good therapeutic strategy.
We are currently embarking on a pilot clinical bioimaging study of BM from HER2+ breast cancer, using a PET/Pertuzumab conjugate. We plan to assess the feasibility of this theranostic approach for the management of patients with brain metastases.