Dynamic monitoring of ctDNA to predict response to immunotherapy plus chemotherapy in BTC.

Abstract

e14550 Background: The survival of advanced BTC patients, especially those who received palliative surgery was unfavorable and the treatment options for these patients were limited. Immune checkpoint inhibitors （ICIs） were approved for the treatment for patients with BTC. However, only a subset of patients benefits from this treatment and the clinical performance was not well evaluated. Therefore, there is a need for a method that can promptly and dynamically evaluate the efficacy of patients receiving immunotherapy. Previous studies have shown that ctDNA can detect relapse and monitor therapeutic efficacy in diverse cancer. We performed a retrospective observational study examining whether ctDNA could serve as a biomarker to track treatment responses in BTC. Methods: Patients diagnosed with advanced BTC and who received ICI were screened and enrolled between January 2020 and October 2022 at Shanghai Eastern Hepatobiliary Surgery Hospital. The key inclusion criteria for patients were as follows: a recent diagnosis of gallbladder/intrahepatic cholangiocarcinoma; received immunotherapy (or plus target therapy); received ctDNA NGS monitoring. Patients were excluded based on the following criteria: patients with multiple primary cancers, or had history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation, or HIV infected person, or severe infections with poor clinical control. Blood samples were collected for ctDNA analysis at the beginning, after 3 and 6 months of ICI treatment. Results: The median age was 66 (42-79), and 12 (44.4%) were male. The ECOG score was mostly 1 (23 cases, 85.2%). Most of the patients were stage IV (21, 77.8%), and there were 5 (18.5%) stage III patients, 1 (3.7%) stage II and 0 (0%) stage I patients. The BTC patients were mostly histologically diagnosed with gallbladder cancer (GBC, 11, 40.7%) and intrahepatic cholangiocarcinoma (8 cases, 29.63%). There were 55% patients received palliative surgery. Among all mutations detected in ctDNA, the mutation status of KRSA at baseline was detected to be related to patient survival, and the KRAS-mut group had a significantly lower probability of overall survival compared to the KRAS-WT group (p=0.014). Patients with more than 3 new mutations during treatment presented a significantly unfavorable OS (p=0.025) and a trend of unfavorable PFS (p=0.062). Besides, patients with increasing amounts of total ctDNA during dynamic monitoring showed significantly worse overall survival probability (p=0.023). Conclusions: Mutation of KRAS in tissues at baseline might be a predictive marker of response to immunotherapy and survival prognosis. ctDNA as a compose biomarker can monitor treatment responses and predict overall survival. Considering the small size and the relatively short follow-up time of our cohort, further prospective and randomized controlled studies are indispensable.