Molecular Portraits Predict Chemotherapy Outcomes in Rare Liver Cancer

by Christos Evangelou, MSc, PhD – Medical Writer and Editor

In a recent study, researchers at the University of Copenhagen, University of Glasgow, and the University of Modena and Reggio Emilia uncovered molecular signatures in tumor biopsies that can predict whether patients with a rare type of liver cancer will rapidly deteriorate or live for years after starting chemotherapy.1

Although their findings require further validation, this molecular signature could provide a clinical-grade tool to predict chemotherapy response and select patients for alternative first-line therapies. This study also offers biological insights into divergent chemotherapy outcomes to guide new therapeutic strategies.

“Molecular profiling of biopsies used to diagnose intrahepatic cholangiocarcinoma can predict an individual patient’s future benefit from chemotherapy, establishing a tool that could select patients with high-risk but sensitive tumors for chemotherapy,” said Professor Chiara Braconi, MD, PhD, who was the co-lead investigator of this study.

The report was published in the journal Gut.

Rationale: Defining Molecular Determinants of Chemotherapy Outcomes in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) arises from the bile ducts within the liver. Its incidence is increasing globally, and over half of patients are diagnosed after the cancer has spread, requiring chemotherapy as the standard treatment.1 Some patients rapidly progress within months despite receiving chemotherapy, whereas others live for years. However, there are currently no biomarkers to predict chemotherapy response before starting treatment.

“Despite recent advances in cancer treatment, chemotherapy remains the main cornerstone in the systemic therapy of biliary cancer,” said Dr. Braconi. “There is a small niche of patients who benefit from chemotherapy in the long term, and understanding who these patients are will enable a more effective approach in guiding treatment for biliary cancers.”

As novel targeted therapies become available, identifying patients who are unlikely to respond to standard chemotherapy is crucial so they can be offered alternative options.

Approach: Transcriptomic Profiling of Biopsies From Responders vs. Non-responders

Researchers identified 13 patients with advanced iCCA who appeared similar in their clinical characteristics at diagnosis but subsequently had extremely different benefit from chemotherapy.

“All of the rapid progressors survived less than 6 months, which is less than half the median survival time, whereas all of the long survivors survived more than 23 months, which is double the median survival time,” explained Dr. Braconi.

Pretreatment biopsies were subjected to advanced transcriptomic profiling, digital pathology analyses, and digital spatial profiling. “By employing a novel molecular profiling technology that enables us to work with small amounts of biopsy tissue, we could perform whole-transcriptome profiling of biomaterial from patients with advanced-stage disease, providing a more representative population profile of this disease at diagnosis,” said Professor Jesper B. Andersen PhD, who was the second co-lead in this collaborative study.

These analyses led to the identification of 504 genes that were differentially expressed between the two groups. Assistant Professor Colm J. O’Rourke derived a gene expression signature, termed rapid progressor-long survivor (RPLS) signature, which scored each biopsy and accurately separated rapid progressors from long survivors.

RPLS Signature Predicts Innate Chemoresistance

A closer investigation of the RPLS signature revealed that the signature may represent a metric of innate chemoresistance potential in iCCA.

“Our work demonstrates the importance of RNA profiling in addition to DNA profiling for guiding patient care in the clinic,” noted Dr. Andersen. He explained that the molecular characterization of these patients has largely focused on identifying genes whose DNA sequences are altered in tumor cells. However, many patients have few or no DNA alterations with therapeutic significance.

Further analyses indicated that the RPLS signature originated predominantly from cancer cells and tumor-associated immune cells, called myeloid cells. In addition, the signature was associated with defective tumor-immune dynamics, implicating tumor-induced immune tolerogenicity and immunosuppressive signaling as defining characteristics of rapidly progressing tumors.

“We know that immune cells and other cells in tumor tissues significantly impact chemotherapy response, but these cell types do not harbor DNA alterations. By performing RNA profiling, we obtained a much more holistic overview of how responsive an individual’s tumor may be to this type of treatment,” said Dr. Braconi.

RPLS Scores Predict Patient Survival After Chemotherapy

The researchers found that the RPLS signature predicted 5-year survival in several cohorts of patients with resected iCCA tumors, totaling over 600 patients. However, the signature was not prognostic in extrahepatic CCA, indicating that the liver microenvironment strongly influences the biology captured by the signature.

According to Dr. Andersen, these findings suggest that different biological mechanisms dominate chemotherapy response in bile duct tumors based on where they arise within the bile duct and further support that bile duct cancer is, in fact, a collection of distinct cancers.

“These findings also highlight dysfunctional innate immune cells as a hallmark of rapidly progressing tumors and suggest possible therapeutic strategies to improve outcomes in patients who currently do not do well on chemotherapy,” she added.

In addition, among nearly 1000 patients with diverse metastatic cancers, the RPLS signature only predicted chemotherapy outcomes in liver metastases from colorectal cancer. It was not prognostic in matched primary colorectal tumors from patients undergoing chemotherapy. This liver-specific association “raises the possibility that the RPLS signature might be informative for cancers that originate in or spread to the liver, the most common site of metastatic invasion.”

Future Work

Despite these promising findings, future studies are required to validate the prognostic value of the RPLS signature in larger cohorts. The researchers also aim to model rapid progressor biology to identify therapeutic targets and test candidate drugs that boost chemosensitivity.

According to the authors, further development and clinical investigation of precision chemotherapy approaches, such as the RPLS scoring method, are needed to improve patient care as new scientific breakthroughs occur, ensuring that optimal treatment is provided as early as possible.

“In the next stage, we will refine the 504 RPLS genes into an optimized formula on a technological platform that can be implemented in any clinical laboratory. This will require training and validating the signature on large national and international cohorts of patients with advanced disease,” said Dr. O’Rourke, PhD, who is leading the two research groups’ efforts to optimize the RPLS score.

“Ultimately, our aim is to test the performance of the optimized RPLS signature in a prospective clinical trial where it can be used to prioritize chemotherapy or alternative treatment up-front on a patient-by-patient basis,” said Dr. Braconi.

This work was performed under the frame of the European Network for the Study of Cholangiocarcinoma (ENSCCA) and the COST Action Collaboration (COST Action CA18122 European Cholangiocarcinoma Network Euro-Cholangio-Net), and that it was supported by the Chief Scientist Office, Scotland, and the CRUK Scotland Cancer Centre.


  1. O’Rourke CJ, Salati M, Rae C, et al. Molecular portraits of patients with intrahepatic cholangiocarcinoma who diverge as rapid progressors or long survivors on chemotherapy. Gut. 2023;gutjnl-2023-330748. doi:10.1136/gutjnl-2023-330748

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