491P Comparison of Ctdna Profiles from HR+/HER2-low and HR+/HER2-0 Advanced Breast Cancer Patients

Despite the substantial progress in systemic treatment of hormone receptor-positive (HR+) breast cancer, a significant proportion of patients has dismal prognosis. A meaningful proportion of these patients has HER2-low disease. Circulating tumor DNA (ctDNA) profiles between HER2-low and HER2-0 have not yet been comprehensively investigated. 67 plasma samples from 59 metastatic breast cancer patients (HR+/HER2-low, n=53; HR+/HER2-0, n=14) were collected either before starting 1st line or 2nd line treatment. Tumor fractions were assessed using an untargeted aneuploidy screening and expressed as z-scores (mFAST-SeqS). The mutational landscape of ctDNA was established using a 77-gene panel (AVENIO ctDNA Expanded). Tumor fractions, the number of somatic variants and variant allele frequencies (VAF) were compared between HER2-low and HER2-0 patients. HER2-low patients had significantly higher z-scores compared to HER2-0 patients (median 3.22 vs. 1.65, rank-sum p-value 0.025). In contrast, neither the highest nor the average VAF differed significantly between the two groups. HER2-low patients had a median of 3 detected variants (range 1-20), with a median of 2 clonal (range 0-9) and 1 subclonal (range 0-19) variants. HER2-0 patients presented with a median of 5 variants (range 1-12), including a median of 3 clonal (range 1-4) and 1 subclonal (range 0-8) variants. In contrast to previous reports, PIK3CA mutations were more prevalent in HER2-0 patients (57.1%) compared to HER2-low patients (35.8%), whereas TP53 mutations were identified at the same extent with 28.6% in HER2-0 and 22.6% in HER2-low patients. Our results suggest a significant difference in the tumor fractions in plasma between HER2-0 and HER2-low patients. Moreover, the mutational landscape of our cohort revealed differences from previous reports, indicating that further investigations are needed to elucidate and establish the distinct features of HER2-low breast tumors.