Evaluation of toll-like receptor (TLR)-7 agonist imiquimod applied topically to breast cancer chest wall recurrences or skin metastases.

Abstract

TPS138 Background: Purpose: To assess the clinical and biological activity of imiquimod applied topically to breast cancer metastatic to skin. Breast cancer is the most frequent malignancy and the most common tumor, excluding melanoma to metastasize to the skin in women. Chestwall recurrence is debilitating for patients, substantially affecting quality of life (QOL). Current treatment modalities for nonresectable lesions are rarely curative, indicating the need for more effective and less toxic therapies. Imiquimod (IMQ), a synthetic TLR7 agonist has immunomodulatory activity with profound effects on the tumor environment, leading to clearance of primary skin malignancies. We have shown that IMQ recruits and activates dendritic cells (DC) and primes immune responses to coadministered tumor antigens in cancer patients. We have also demonstrated IMQ's antitumor efficacy in BALB/c mouse–derived TSA mammary adenocarcinoma, a poorly immunogenic tumor that ulcerates through the skin, closely mimicking the clinical scenario of patients with chestwall recurrence. Methods: Eligibility includes patients with biopsy-confirmed breast cancer, measurable skin metastases, ECOG PS 0-2 and adequate organ/marrow function. IMQ 5% cream is applied topically to skin metastases overnight for 5 days/week for 8 weeks followed by a 4-week rest period. Additional cycles are permitted. This phase II study uses a Simon optimal two-stage design: 10 patients in stage I (currently 3 enrolled), if response is observed, an additional 19 patients will enroll in stage II. Primary endpoint is 12 week antitumor response, assessed by clinical exam and computer-aided surface area calculation of skin metastases. Furthermore, effects of IMQ treatment on symptoms and health-related QOL will be determined. Tumor biopsies will be studied for immune signatures. Breast cancer skin metastases are infiltrated by inflammatory cells, including DC with markers of activation as well as tolerogenic function (e.g., IDO), and T cells with markers of effector (e.g., granzyme) as well as regulatory functions (e.g., FoxP3). The effect of IMQ treatment on the balance between these subsets will be determined. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Graceway Pharmaceuticals