Abstract 204TiP
Background
Hypomethylating agents such as 5-azacitidine (Aza) have been studied in breast cancer primarily to understand the role in resistance to endocrine therapy.Though prior studies evaluating hypomethylating agents failed to establish consistent clinical benefit, the drugs have been shown consistently to be safe and well tolerated.Emerging data in multiple cancers demonstrate hypomethylating agents activate retroviral gene expression resulting in increased neoantigen presentation subsequently increasing the immunogenicity. Moreover, hypomethylating agents may also reverse epigenetic reprogramming of the exhaustion phenotype observed in tumor infiltrating lymphocytes (TILs). In clinical studies, combinations of Aza plus immune checkpoint inhibitors increase response rates compared to checkpoint inhibitor therapy alone. We therefore now test the hypothesize that low-dose Aza may increase TILs and improve their function in breast cancer. Our study will focus on patients with high-risk early-stage breast cancer subtypes that are often notable for immunologically ‘cold’ tumors.
Trial design
UICC BRE-04 (NCT04891068) is a pre-op window trial testing low-dose Aza in early-stage high-risk breast cancer. Patients (Age 18-99; ECOG 0-2) who are diagnosed with T1b-T3 primary invasive breast cancers that were negative for the ER, PR or HER2 receptors (triple negative breast cancer, TNBC) or ER+ with at least one adverse feature (HER2+, Node +, high-risk gene expression profile, or PR-) are eligible. The intervention involves 5 continuous days of Aza 50mg/m2 SQ. Following the window, patients undergo standard surgical excision at which time tissue is collected or for patients planning to undergo a full course of pre-operative systemic therapy, a breast mass biopsy is performed. Pre-treatment and post-window tissues are evaluated for the primary outcome of delta-TIL count (change in infiltration). In addition, safety data will be collected and correlative studies of TIL profile (multiplex IHC and single-cell proteomics), expression analysis/RNA seq, and TCR repertoire are planned. Target enrollment is for 20 patients with TNBC and 20 with high-risk ER+ disease. Enrollment has commenced.
Clinical trial identification
NCT04891068