Published online ahead of print in Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR), results of a study directed by Teresa Macarulla, Principal Investigator of VHIO’s Gastrointestinal & Endocrine Tumors Group, evidence the value of applying Next-Generation
Sequencing (NGS) in the clinic for the selection of matched targeted therapies in patients with advanced cholangiocarcinoma (CCA).

The investigators, including researchers from other VHIO groups, retrospectively reviewed a total of 327 patients diagnosed with cholangiocarcinoma at the Vall d’Hebron University Hospital (HUVH) between 2011 and 2020.

These patients had undergone tumoural molecular analysis to evaluate the impact on survival of targeted treatments administered according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) categorization.

This evidence-based tool developed by the European Society for Medical Oncology’s Precision Medicine Working Group, provides a systematic framework for ranking mutations as personalised cancer medicine targets, and helps guide treatment decision making according to identified genomic alterations showing higher impact on clinical outcomes.

Specifically, ESCAT defines six categories for the use of therapies targeting molecular alterations, based on the level of evidence taking into account
study and disease context. Genomic alterations are assigned to the tier which best reflects their clinical utility for selecting patients to receive a matched
targeted therapy on the strength of evidence from clinical studies. This offers clinicians a means of prioritising treatment selection.

Based on ESCAT classification, this single institutional study* was designed to compare survival in patients with metastatic CCA harbouring alterations
matched to targeted agents, with patients bearing non-actionable alterations.

Reported data show that patients with alterations classified as ESCAT tier I-II had longer median overall survival than those with alterations classified as ESCAT tier III-IV or without ESCAT alterations, 22.6 months versus 14.3 months, respectively.

“For the first time in the treatment management of advanced cholangiocarcinoma, our results show that targeted treatment administered based on ESCAT’s classification of alteration actionability improves survival of these patients, particularly in the chemotherapy- refractory setting,” said Teresa Macarulla, Medical Oncologist at the Vall d’Hebron University Hospital’s (HUVH) Medical Oncology Department, headed by Josep Tabernero, VHIO’s Director and a co-first author of this study.

Among patients who received targeted therapy, median progression-free survival (PFS) was significantly longer in patients with ESCAT tier I-II alterations compared to those with ESCAT III-IV alterations, 5.0 months versus 1.9 months. These findings support that the implementation of NGS and the application of the ESCAT framework is feasible in routine clinical practice in order to extend matched therapeutic opportunities to CCA patients.

“Cholangiocarcinoma is a highly heterogeneous, therapeutically challenging disease with a notoriously poor prognosis. When patients with advanced disease fail to respond to first-line chemotherapy, second-line treatment options are limited,” observed lead author Helena Verdaguer, a Clinical Investigator of VHIO’s Gastrointestinal & Endocrine Tumors Group and Medical Oncologist at HUVH.

She continued, “Driving personalised, targeted treatments tailored to the molecular specificities of these patients’ tumours must therefore be prioritised.” Considering the prevalence of multiple driver alterations that can be matched to standard-of-care therapies or clinical trial recruitment, ESMO’s
Precision Medicine Working Group, chaired by Joaquin Mateo, Principal Investigator of VHIO’s Prostate Cancer Translational Research, recommends
routine NGS in all cholangiocarcinoma patients.

This study shows that NGS and evidence-based scales, such as ESMO’s ESCAT, can be feasibly integrated in the clinic, and thus used to guide patient selection for targeted therapy. “Moving forward, frameworks that grade genomic alterations as targets for personalised medicine will help clinicians to match optimal treatments to individual patients accordingly. In so doing, we will collectively strive to extend the promise precision oncology to this patient population,” concluded Teresa Macarulla.

Source: Vall d´Hebron Institute of Oncology (VHIO)