Stereotactic Radiosurgery with Concurrent HER2-directed Therapy is Associated with Improved Objective Response for Breast Cancer Brain Metastasis

Abstract

HER2-positive breast cancer patients remain at high risk of intracranial relapse following treatment of their primary disease and experience increased rates of intracranial failure after stereotactic radiosurgery (SRS). The objective of this study was to evaluate the rates of intracranial of CNS-penetrating HER2 directed therapy with SRS. Patients with newly-diagnosed HER2-amplified breast cancer brain metastases from 2005-2014 who underwent SRS were included and divided into two cohorts based on receipt of concurrent lapatinib. The primary outcome was the magnitude of best objective response after SRS relative to pre-SRS maximum diameter. Secondary outcomes included the proportion of lesions achieving a complete response, partial response, stable disease, or progressive disease according to the RECIST criteria, along with distant intracranial failure, radiation necrosis, and overall survival. Multivariable analysis for best objective response was conducted on a per-lesion basis using multivariable linear regression and for overall survival on a per-patient basis using Cox proportional hazards modeling. Eighty-four patients with 487 brain metastases met inclusion criteria during the study period: 132 lesions (27%) were treated with SRS and concurrent lapatinib while 355 (73%) were treated with SRS without lapatinib. During the initial treatment and follow-up period, 1004 MRIs were reviewed over which 3435 measurements were made (average of 7 measurements per lesion, Range: 2-31). The best objective response was superior in the concurrent lapatinib group (median 100% vs. 70% reduction, p<0.001). Secondary outcomes were also superior in the concurrent lapatinib group, with a greater number of complete responses (58% vs. 39%, p<0.001) and lower rates of progressive disease (9% vs. 13%, p<0.001). Best objective response and overall response generally improved as lapatinib was delivered closer to SRS. After multivariable linear regression, concurrent lapatinib remained statistically significantly associated with improved objective response (mean 11.01% decrease, 95% CI 4.1 – 18.0%, p=0.002). After proportional hazards modeling, concurrent lapatinib was associated with a trend toward longer overall survival (HR 0.59, 95% CI 0.31 – 1.06, p=0.077). Distant intracranial failure rates were similar with or without lapatinib (48% vs. 49%, p=0.91). The risk of radiation necrosis was low and although the rates increased with lesion size, concurrent lapatinib did not increase this risk, even amongst the largest lesions >1.5 cm (2.0 vs. 5.5%, p=0.27). This study provides objective response data supporting the role of concurrent lapatinib with SRS for women with HER2-positive breast cancer brain metastases. Patients treated with combined therapy experienced the highest rates of lesion control, lowest rates of progressive disease, and improvements in overall survival without an increased risk of radiation necrosis.