Faculty Bibliography

HER2-positive breast cancer is a known risk factor for CNS metastases, and the use of trastuzumab in the adjuvant setting does not prevent brain metastases. The purpose of this study is to compare outcomes in HER2-positive and HER2-negative intracranial disease treated with stereotactic radiosurgery (SRS). Among 57 breast cancer patients with brain metastases, 28 patients were HER2-positive. All patients were treated with SRS as their first treatment modality for CNS metastases. The median dose was 20 Gy (range 12-20 Gy). Statistical analysis was performed using the Kaplan-Meier method and chi (2) test. With a median follow-up of 11.0 months, the median time to progression in the HER2-positive group compared with the HER2-negative group was 7 versus 11 months (p = 0.080), respectively. Salvage therapy was performed in 50 % of HER2-positive patients compared with 21 % of HER2-negative patients (p = 0.02). The median OS for the HER2-positive group compared with the HER2-negative group was 22 versus 12 months (p = 0.053). Stereotactic radiosurgery results in excellent local control in the treatment for breast cancer brain metastases. Compared with HER2-negative disease, HER2-positive disease appears to show higher rates of intracranial relapse despite better overall survival rates. This data suggests that we need effective adjuvant therapy to prevent and treat brain metastases in HER2-positive patients.

PURPOSE: Skin metastases of breast cancer remain a therapeutic challenge. Toll-like receptor 7 agonist imiquimod is an immune response modifier and can induce immune-mediated rejection of primary skin malignancies when topically applied. Here we tested the hypothesis that topical imiquimod stimulates local antitumor immunity and induces the regression of breast cancer skin metastases. EXPERIMENTAL DESIGN: A prospective clinical trial was designed to evaluate the local tumor response rate of breast cancer skin metastases treated with topical imiquimod, applied 5 d/wk for 8 weeks. Safety and immunologic correlates were secondary objectives. RESULTS: Ten patients were enrolled and completed the study. Imiquimod treatment was well tolerated, with only grade 1 to 2 transient local and systemic side effects consistent with imiquimod's immunomodulatory effects. Two patients achieved a partial response [20%; 95% confidence interval (CI), 3%-56%]. Responders showed histologic tumor regression with evidence of an immune-mediated response, showed by changes in the tumor lymphocytic infiltrate and locally produced cytokines. CONCLUSION: Topical imiquimod is a beneficial treatment modality for breast cancer metastatic to skin/chest wall and is well tolerated. Importantly, imiquimod can promote a proimmunogenic tumor microenvironment in breast cancer. Preclinical data generated by our group suggest superior results with a combination of imiquimod and ionizing radiation and we are currently testing in patients whether the combination can further improve antitumor immune and clinical responses.