Dcis Neoadjuvant Therapy: Targeting The Autophagy Pathway In Malignant Precursor Cells

TPS341 Background: We found that fresh human breast ductal carcinoma in situ (DCIS) lesions contain pre-existing carcinoma precursor cells which require autophagy (auto-self, phagy-eating) for survival. Autophagy promotes survival of DCIS cells within the hypoxic duct microenvironment. Based on this finding, we are testing the safety and effectiveness of chloroquine phosphate (CQ), alone or in combination with tamoxifen, administered for a 3 month period to patients with any grade DCIS. This unique DCIS neoadjuvant therapy study design provides immediate molecular and biologic feedback about the in vivo effectiveness of a therapy targeting intraductal neoplastic cells within breast premalignant lesions. Methods: The trial designation is PINC (Preventing Invasive breast Neoplasia with Chloroquine). Current enrollment: trial opened in Jan. 2010. The planned accrual is 30 patients in each treatment arm. Patients with high grade ER positive DCIS receive tamoxifen plus CQ. ER negative patients receive CQ alone. Patients with low grade ER positive DCIS receive tamoxifen only. Eligibility: biopsy proven DCIS, grades I-III, ER positive or ER negative. MRI is performed before and after drug treatment. All patients receive standard of care surgical therapy post drug treatment. Effectiveness is measured at the molecular level and correlated with MRI data. The activated (post translationally modified) state of 59 proteins associated with autophagy, hypoxia, apoptosis, angiogenesis, invasion, and cell cycle pathways are measured by Reverse Phase Protein Microarray, before and after therapy, within the microdissected DCIS biopsy. In parallel, DCIS living organoids are harvested, cultured, and scored for a) invasive potential in autologous human breast stroma ex vivo, b) DCIS progenitor cell yield and growth, and c) growth in NOD SCID mouse xenotransplantation. Full genome molecular cytogenetics is conducted (300,000 SNPs, Illumina HumanCytoSNP profile) and correlated with MRI and protein microarray data. This trial, if successful, provides neoadjuvant therapy for all categories of DCIS and can support a future chemoprevention strategy designed to suppress occult or overt breast premalignant lesions. No significant financial relationships to disclose.