Abstract 2406: Circulating tumor DNA as a potential indicator of treatment response in patients with surgically unresectable PDAC
Authors: Silva Fabio Pittella , Kimura Yasutoshi , Motoya Masayo , Nakamura Toru , Murakami Takeshi , Watanabe Kazunori , Low Siew-Kee , Nakamura Yusuke 
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly heterogeneous and extremely aggressive neoplasm. Most patients with PDAC present with symptomatic, surgically unresectable disease at initial diagnosis. Systemic chemotherapy is the standard care for patients diagnosed with unresectable PDAC, despite the dismal survival rate due to disease recurrence. In this context, liquid biopsy based ctDNA monitoring may aid to improve detection accuracy and allow real time disease prognosis. Here we aimed to investigate the utility of ctDNA in longitudinal tumor monitoring to assess treatment response and to predict disease recurrence. We performed targeted NGS sequencing to investigate over 900 mutations (SNVs) and 12 copy number variations (CNVs) in 53 genes, using the Ion S5 Oncomine PanCancer gene panel in 40 PDAC patients with unresectable disease. Serial plasma samples were obtained from patients in the course of 24 months, including samples collected before the first intervention (baseline) as well as within 2 months after initiation of chemotherapy. Patients were followed for a period of up to 2-years from diagnosis through treatment, to death or final follow-up. Genomic DNA from paired plasma-buffy coat samples were sequenced to exclude clonal hematopoiesis. Overall detection of ctDNA alterations in baseline samples was 55% (22/40) with increasingly higher detection rates and mutation loads in advanced disease (88% in stage IV patients). Alterations including SNVs and CNVs were preferentially distributed among 9 genes; mutations in TP53 (45%), KRAS (38%) and SMAD4 (5%) were most commonly identified. To asses response to chemotherapy, the presence of residual ctDNA after clinical intervention was evaluated by comparing total ctDNA MAF (mutant allele frequency) detected in plasma at diagnosis and within 2 months of chemotherapy. 71% (17/24) of patients who reached progressive disease (PD) had detectable baseline mutations and 79% (19/24) had persistent residual mutations at 2 months of treatment. Conversely, 94% (15/16) of non-PD patients had no detectable ctDNA or had a significant reduction in total MAF after 2 months of chemotherapy. Absence of residual ctDNA after 2 months of chemotherapy was associated with a better OS (p=0.031; HR = 3.48). On the other hand, residual ctDNA after 2 months of chemotherapy was associated with a shorter PFS (p=0.042; HR = 3.28). Our study demonstrates that monitoring ctDNA levels derived from plasma provides valuable insights into the therapeutic response in patients with unresectable PDAC, even in the absence of matched tumor genotyping. We found a significant correlation between increased ctDNA levels following the initiation of treatment and poorer survival outcomes.
Citation Format: Fabio Pittella Silva, Yasutoshi Kimura, Masayo Motoya, Toru Nakamura, Takeshi Murakami, Kazunori Watanabe, Siew-Kee Low, Yusuke Nakamura. Circulating tumor DNA as a potential indicator of treatment response in patients with surgically unresectable PDAC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2406.