Clinical and molecular features of patients with PIK3CA -mutant ( PIK3CA m) ER+/HER2− breast cancer with detectable circulating tumor DNA (ctDNA) in early breast cancer (eBC).

e12609 Background: We previously reported that ~35% of ER+/HER2- eBC patients with a ctDNA-positive (ctDNA+) test result after surgery had a PIK3CA m primary tumor. Of patients with +ctDNA testing, those with PIK3CA m eBC had worse outcomes (versus PIK3CA -wild type) 1 . However, the impact of ctDNA dynamics during treatment of PIK3CA m eBC remains understudied. Methods: We conducted a retrospective analysis of patients at our institution with ER+/HER2- breast cancer (BC) who had >1 ctDNA+ test result via a personalized, tumor-informed 16-plex mPCR-NGS ctDNA assay (Signatera, Natera, Inc.). PIK3CA m status was determined by analysis of the Signatera whole exome sequencing data. Clinical data were obtained by review of electronic medical records. Results: 41 patients with ER+/HER2- BC and tumor PIK3CA m with >1 ctDNA+ test were identified. 35/41 (85.4%) patients had eBC at time of initial diagnosis; 16/35 (45.7%) of these had a positive ctDNA test in the adjuvant treatment (AT) setting. Median follow up for this cohort is 61.5 months. Among eBC patients that were ctDNA+ in the AT setting, 7/16 (43.8%) patients received chemotherapy, 12/16 (75.0%) received adjuvant endocrine therapy, and 3/16 (18.8%) received adjuvant CDK4/6 inhibitor therapy. The median time from surgery to first ctDNA test for these patients in the AT setting was 15.4 months. The initial ctDNA test was positive for 11/16 (68.8%) patients; 5/16 (31.3%) had a negative initial ctDNA test and later had a ctDNA+ test. 5/16 (31.3%) patients had clearance in the AT setting. 3/5 (60.0%) cleared ctDNA on adjuvant endocrine therapy +/- CDK4/6i and 2/5 (40.0%) cleared ctDNA in the absence of therapy. None of the 5 patients with ctDNA clearance have had distant metastatic recurrence with a median follow up after +ctDNA test of 15.8 months. Median time from first ctDNA+ test to ctDNA clearance was 57 days in the AT setting. 11/16 (68.8%) did not clear ctDNA; 7/11 (63.6%) of these patients had a distant recurrence and 1/11 (9.1%) had a local recurrence. 3/11 (27.3%) did not have recurrence, with a median follow up after first ctDNA+ test of 14.4 months. Of patients with distant metastatic recurrence, the median time from first ctDNA+ to distant recurrence was 6.0 months. Conclusions: This analysis explores ctDNA dynamics and clinical features during treatment for eBC in patients with +ctDNA and tumor PIK3CA mutations. These data indicate that ctDNA clearance is associated with better prognosis even in this high-risk population of patients with PIK3CA m tumors and +ctDNA testing. These data may inform further research and practice in treating ER+/HER2- PIK3CA m early breast cancers. Reference: 1 Lipsyc-Sharf et al. SABCS 2024, PS9-01; https://doi.org/10.1158/1557-3265.SABCS24-PS9-01