Abstract A021: On-treatment ctDNA monitoring of pancreatic cancer holds promise for improved treatment stratification

Abstract

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease characterized by rapidly occurring chemoresistance due to clonal evolution. In addition, since most cases are unresectable, tissue analyses are limited to diagnostic biopsy specimens which hampers molecular analyses and does not reflect the genetic tumor heterogeneity. Hence, there is an urgency to develop new complementary tools to detect, characterize and monitor PDAC. The aim of the ongoing prospective, observational study “Chemotherapy, Host Response and Molecular Dynamics in Periampullary Cancer (CHAMP)” (NCT03724994) is to gain new insights into the clonal evolution and parallel immune responses, under the pressure of different cytotoxic treatments, in PDAC and other periampullary cancers. Methods: In a pilot study comprising ten CHAMP patients, an in-depth genomic analysis of ctDNA in serial blood samples (3-4 samples/patient) and matched tumor tissue, either from resected specimens or diagnostic biopsies, was performed using a broad targeted pan-cancer panel. Within this small case series, three patients with resectable disease received adjuvant chemotherapy and seven patients received palliative chemotherapy. Detected ctDNA fluctuation patterns were correlated to tumor progression. Results: In the three patients receiving adjuvant treatment, ctDNA could not be detected in the blood at any time point. For the five patients receiving palliative treatment, varying quantities of ctDNA were detected before the start of treatment (baseline), followed by a decrease during the first month of therapy. Quantitative ctDNA fluctuations were also observed to largely follow the clinical disease course as signs of radiological tumor progression were supported by elevated ctDNA levels. The concordance of known driver mutations in ctDNA detected at baseline and matched tumor tissue was overall high. Yet, a few discrepancies were seen, such as an ARID1A mutation detected only in ctDNA at the time of radiological tumor progression in one patient. Of note, a potentially druggable KRAS p.G12C mutation was observed in both tumor tissue and ctDNA in the same patient. In two palliative patients, one of whom did not respond to treatment, no ctDNA could be detected at any time point. Conclusion: The results from this pilot study emphasize the value of ctDNA analyses, both for characterization and on-treatment monitoring of PDAC. This is of particular importance in cases where no tissue biopsies are available, and at disease relapse or progression. Studies on 50 additional CHAMP patients are now ongoing, wherein a novel ultra-sensitive ctDNA profiling assay is utilized to further detect minimal residual disease and clinically actionable targets. Studies comparing the clonal landscape in treatment naïve primary tumors and/or metastases, serial blood samples, and primary and/or metastatic tumor tissue obtained postmortem, are also in progress. Citation Format: Alexandra Petersson, Sofie Olsson Hau, Jakob Eberhard, Markus Heidenblad, David Gisselsson, Karin Jirström. On-treatment ctDNA monitoring of pancreatic cancer holds promise for improved treatment stratification [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A021.