Abstract PO3-16-01: Personalized circulating tumor DNA assay precisely predicts the response of neoadjuvant chemotherapy in breast cancer patients

Abstract

Abstract Introduction Circulating tumor DNA (ctDNA), which is detected in the blood as cell free DNA fragment from tumor cells, could indicates genomic landscape, tumor burden and treatment response during chemotherapy as a non-invasive method. Especially, personized ctDNA assay by next-generation sequencing(NGS) is able to detect a trace amount of ctDNA and precisely figure out the change of the amount of ctDNA during NAC and follow up period after curative surgery. Here, we performed serial ctDNA evaluations in EBC patients who diagnosed as TNBC or HER2-positive BC and received NAC followed by curative surgery. We aimed to predict NAC response and detect minimal residual disease (MRD) using personalized ctDNA assay. Methods CtDNA was detected by AlphaLiquid®Detect, a tumor-informed personalized MRD detection assay exploring most of the mutations in tumor. Whole exome sequencing (WES) of tumor tissue and peripheral blood mononuclear cells (PBMCs) was performed. Patient-specific somatic mutations were selected using a proprietary algorithm. In brief, clonal variants were prioritized using integrated information including variant allele frequency, population allele frequency databases, somatic variant databases, variant pathogenicity, and genomic context. Up to 100 variants were selected for patient monitoring. A hybridization capture panel consisting of a pool of 4 patients’ selected variants was synthesized. These bespoke panels (BSPs) were used for ctDNA detection. Patients with more than 2 tumor-derived mutations detected in plasma were considered as ctDNA positive. Inclusion criteria included patient who diagnosed as stage IIA-IIIC BC planned to NAC followed by curative surgery. Among BC subtypes, TNBC and HER2-positive BC were allowed. Collection of specimens and associated clinical data used in this study was approved by the Institutional Review Board of Samsung Medical Center (IRB File No.2021-02-033), and we received informed consents for this study. Results From May 2021 to Sep 2022, 158 patients has been enrolled. Archival tissues were not available in 47 patients and tissue WES had failed in six patients. Therefore, 105 patients were enrolled and analyzed their ctDNA at diagnosis based on tissue WES data. Of 105 patients, Median age of BC patients was 49.3 years of age (range: 26.1, 67.8). Thirty-six patients (34.3%) were post-menopausal status and others (65.7%) were pre-menopausal status. In BC pathology at diagnosis, 56 (53.3%) were TNBC and other 49 (46.7%) were HER2-positive BC. Among HER2-positive BC, hormone receptor (HR)-positive were in 21 (20.0%). In clinical stage at diagnosis, stage II were 46 (43.8%) and stage III in 59 (56.2%). In 105 patients, median number of somatic mutations was 60 (interquartile range [IQR]: 38.5, 91). CtDNA detection rate at BC diagnosis was 90.5% and all of BC which not be detected ctDNA was HER2-positive BC with clinical stage II. Median amount of ctDNA at diagnosis was 20 (IQR: 6, 44). In the number of somatic mutations, there was no difference according to BC subtypes (P=0.121) and clinical stage (P=0.700) but the amounts of ctDNA at diagnosis was different. CtDNA was much more detected in TNBC compared to HER2-positive BC (Median: 34.5 vs. 15.9; P< 0.001) and clinical stage III compared to clinical stage II (Median 33.2 vs. 19.5; P=0.002). After NAC, ctDNA at curative surgery was tested in 70 patients. In 70 patients, pathologic complete response(pCR) was observed in 44 patients. CtDNA was detected in ten patients (14.3%) and eight did not achieve pCR and two with pCR (Specificity of assay: 95.5%, positive predictive value: 0.80, P=0.032). Conclusions Personalized ctDNA assay can precisely detected ctDNA at diagnosis and their detection rate was associated with BC subtypes and clinical stage. In addition, ctDNA at curative surgery also can predict NAC response in EBC patients. Long term ctDNA follow up of MRD would be warranted. Citation Format: Ji-Yeon Kim, Hae Hyun Jung, Jeong Eon Lee, Seok Won Kim, Hwang-Phill Kim, Sunghoon Heo, Jongseong Ahn, Tae-You Kim, Young-Hyuck Im. Personalized circulating tumor DNA assay precisely predicts the response of neoadjuvant chemotherapy in breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-16-01.