Next-generation sequencing-guided molecular-targeted therapy and immunotherapy for biliary tract cancers

Abstract

Background: Chemotherapy is a standard regimen for advanced or relapsed biliary tract cancer (BTC) with a 5-year overall survival (OS) rate of approximately 5% and a median OS of less than a year. Targeted therapies and immunotherapy aimed at providing more personalized treatments for BTCs have been tested. The objective of this study was to evaluate the effects of targeted therapy and immunotherapy on advanced BTC patients.

Methods: Twenty-four advanced/relapsed BTC patients were enrolled and examined with next-generation sequencing (NGS). Eight of them received NGS-guided targeted or immunotherapy, and the other 16 patients underwent routine chemotherapy. Comparison analysis of OS and objective response rate (ORR) was performed.

Results: IDH1, BRCA2, MAP2K1, and BRAF (V600E) were the major actionable genes mutated in this cohort. Patients who received NGS-guided therapy exhibited higher OS (not achieved vs. 6.5 months, p < 0.001) and ORR (87.5% vs. 25%, p < 0.001) than those without targetable mutations and who received first-line chemotherapy. BTCs harboring mutations in IDH1, ATM/BRCA2, or MAP2K1/BRAF (V600E) received treatment with dasatinib, olaparib, or trametinib, respectively. Three of the patients had high tumor mutation burden (TMB-H) and were treated with immune-checkpoint inhibitors and chemotherapy. All these patients achieved complete response or partial response.

Conclusions: NGS-guided targeted therapy and immunotherapy are promising personalized therapies for advanced or relapsed BTCs. TMB is a useful biomarker for predicting immunotherapy efficacy.

Keywords: Biliary tract cancer; Immunotherapy; Next-generation sequencing; Personalized medicine; Targeted therapy.

Fig. 1

Genomic mutation profiles from 24 biliary tract cancers. a Number of samples in the four tumor types. b Mutational landscape. The X-axis represents each case sample, and the Y-axis represents each mutated gene. The bar graph on the left shows the mutation frequency of each mutated gene in the 24 samples. The top column represents the tumor mutation burden (TMB) value (mutations/Mb). Green represents substitution/Indel mutations, red represents gene amplification mutations, blue represents homozygous deletion mutations, yellow represents fusion/rearrangement mutations, and purple represents truncation mutations. c Mutational of mutation types in all mutational sites

Fig. 2

Treatment using a next-generation sequencing (NGS)-guided approach leads to a survival benefit. a Overall survival (OS) according to a NGS-guided or non-NGS-guided approach. b OS according to a high (TMB-H) or low (TMB-L) tumor mutation burden. c Best percentage change from baseline in the size of the target lesion in the NGS (green) and non-NGS-guided (pink) cohorts

Fig. 3

Complete response to gemcitabine plus nivolumab in relapsed distal cholangiocarcinoma (dCCA). Imaging of Case 6 over the course of therapy. a Timeline of clinical course. b Dynamic change of CA19-9 levels, which decreased to normal levels on October 11, 2019 and have remained within the normal range (last follow-up on March 29, 2020). c Representative micrographs of PD-L1 expression. d Magnetic resonance imaging (MRI) showing the lesion of an enlarged lymph node disappearing after treatment with nivolumab combined with gemcitabine on July 19, 2019. The complete response has been sustained (last follow-up on March 29, 2020)

Fig. 4

Partial response to gemcitabine plus nivolumab in relapsed distal cholangiocarcinoma (dCCA). Imaging of Case 7 over the course of therapy. The patient underwent Whipple surgery and had relapsed liver metastasis 2 months after surgery. a Timeline of the clinical course. b Dynamic change of CA19-9 levels, which decreased to normal on August 27, 2019 and have remained within the normal range (last follow-up on March 29, 2020). c Representative micrographs of PD-L1 expression. d Magnetic resonance imaging (MRI) showing intrahepatic lesion shrinkage after treatment with nivolumab since June 2, 2019. The tumor showed a volume reduction of 80% after combination treatment with nivolumab plus gemcitabine on September 12, 2019

Fig. 5

Partial response to gemcitabine and nivolumab in relapsed intrahepatic cholangiocarcinoma cancer (ICC). Imaging of Case 8 over the course of therapy. a Timeline of the clinical course. b Dynamic change of CA19-9 levels. c Representative micrographs of PD-L1 expression with magnetic resonance imaging (MRI). d The lesion near the caudate lobe disappeared after treatment with nivolumab combined with gemcitabine since May 5, 2019. The complete response was sustained up to February 29, 2020. Notably, a liver abscess occurred in the left lateral lobe on June 3, 2019, and the patient developed fever. After ultrasound-guided drainage, the liver abscess disappeared, and the body temperature returned to normal (picture not shown)