Abstract P1-12-03: Association between tumor genotype and development of brain metastases in patients with hormone receptor positive (HR+)/HER2- metastatic breast cancer
Authors: Fitzgerald DM , Henderson LE , Isakoff SJ , Moy B , Oh K , Shih HA , Dias-Santagata D , Borger DR , Iafrate AJ , Brastianos PK , Bardia A , Juric D 
Published: March 2017

Abstract
Introduction: Historically, brain metastases are considered to be uncommon in HR+/HER2- breast cancer compared to triple-negative or HER2+ breast cancer. However, improved systemic therapy and prolonged overall survival in patients with metastatic HR+/HER2- breast cancer may result in increased incidence of brain metastases as most currently available therapeutic agents do not penetrate blood-brain barrier giving the brain a sanctuary site status. Although certain tumor cells may also exhibit brain-specific tropism or may have selective growth advantage in the brain microenvironment, biological factors that govern metastases to brain, including role of PIK3CA mutations, are poorly understood. In this study, we review our clinical experience with the brain metastases among patients with metastatic ER+/HER2- breast cancer, including their association with PIK3CA genotype.
Methods: Since 2008, at our institution, a multiplexed tumor genotyping assay (SNaPshot), has been utilized to assess for presence of potentially actionable oncogenic driver mutations, including PIK3CA, using DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue. We identified patients with metastatic HR+/HER2- breast cancer who had tumor genotyping performed at any point during their care and who had at least 6 months of follow-up in our clinic. Relevant clinical information, including development of brain metastases, was gathered from chart reviews.
Results: From a total of 251 patients with HR+/HER2- metastatic breast cancer, 23.5% (N=59) developed brain metastases. Approximately 1/3rd of patients (31.7%, N = 20) had brain metastases seen on imaging as an incidental finding, while others presented with 1-2 symptoms that could be associated with CNS disease, including ataxia/weakness (34.9%), visual/speech difficulties (26.9%), headaches (23.8%), altered mental status (14.3%), seizures (14.3%), and nausea (9.5%). PIK3CA mutations were identified in 45.2% of all patients, including mutations in both helical (exon 9) and kinase (exon 20) domains. Patients with tumors harboring PIK3CA mutations had significantly higher incidence of brain metastases, as compared to those without PIK3CA mutations (30.7%, versus 18.7%; p = 0.034). The median time between diagnosis of metastatic disease and diagnosis of brain metastasis was longer among those patients with PIK3CA mutation (32 months) as compared to those without PIK3CA mutation (18 months).
Conclusion: Brain metastases are common among patients with HR+/HER2- breast cancer, particularly HR+/HER2- breast cancer harboring PIK3CA mutations where it approaches the incidence historically seen in HER2+ breast cancer. Early recognition and appropriate diagnostic work-up of any symptoms potentially associated with presence of CNS disease is necessary in PIK3CA-mutant HR+/HER2- breast cancer. Further studies are needed to explain the mechanistic link between the PIK3CA mutant phenotype, phosphatidylinositol 3-kinase (PI3K) pathway activation and CNS disease.
Citation Format: Fitzgerald DM, Henderson LE, Isakoff SJ, Moy B, Oh K, Shih HA, Dias-Santagata D, Borger DR, Iafrate AJ, Brastianos PK, Bardia A, Juric D. Association between tumor genotype and development of brain metastases in patients with hormone receptor positive (HR+)/HER2- metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-12-03.