A new genomic marker facilitates targeted therapy for a type of metastatic colorectal cancer

by time news

Identifying the molecular characteristics of tumors is the basis that allows the advancement of personalized medicine to be established. Knowing what these are, it is possible not only to design new targeted treatments, but also to be able to know which patients will be the ones that respond best to these therapies. Now, a study carried out by researchers from the Vall d’Hebron Institute of Oncology (VHIO), which is part of the Campus Vall d’Hebron, have discovered mutations in a gene that could help select those patients who respond best to anti-BRAF/EGFR therapies in microsatellite-stable (MSS) metastatic colorectal cancer. The results of his research have just been published in the prestigious journal “Nature Medicine”.

Specifically, the work carried out has served to discover that mutations in the RNF43 gene, which are commonly found in colorectal cancer, predict which MSS metastatic colorectal cancer patients with the BRAFV600E mutation will achieve both a better response rate to anti-BRAF/EGFR therapy as a longer time free of disease progression and overall survival.

“This study has made it possible to identify a genomic biomarker that, added to the BRAFV600E mutation, allows us to identify with greater precision those patients who can benefit most from the targeted therapy. This opens the door to incorporating this biomarker into ongoing clinical trials to better identify the most appropriate therapeutic sequence and to prioritize these treatments in those patients most likely to respond”, explains Elena Élez, a researcher at the VHIO Gastrointestinal and Endocrine Tumors Group and medical oncologist at the Vall d’Hebron University Hospital (HUVH), who has been in charge of directing the clinical part of the study

BRAFV600E mutations are found in approximately 10% of metastatic colorectal cancers. Although it is a rare mutation, it is associated with a negative prognosis. Patients who present with it are generally resistant to therapies and develop resistance to treatments very quickly, and no substantial progress has been made in its treatment until recently. In 2019, the BEACON CRC trial, led by Dr. Josep Tabernero, head of the Vall d’Hebron Medical Oncology Service and director of the VHIO, showed that targeted therapy including BRAF (encorafenib) and EGFR (cetuximab) inhibitors was effective in achieving significantly longer overall survival and a higher response rate than standard therapy in these patients, making the double combination a standard of second- and third-line treatment.

This rare colorectal tumor subtype, but with a very poor prognosis, has recently received a new targeted treatment

“However, although this represented a significant improvement in the treatment of these patients for the first time, in practice we continued to see that a proportion of them did not respond. This raised the need to discover why this was happening and raised the challenge of finding biomarkers that would help us identify precisely which patients responded to this therapeutic combination”, commented Rodrigo A. Toledo, translational researcher of the Gastrointestinal and Endocrine Tumors Group del VHIO, coordinator of the liquid biopsy work module of the Center for Biomedical Research in the Cancer Network (CIBERONC), and who has co-directed this research and who was in charge of coordinating all the genomic sequencing work and the experimental part of the project. Dr. Toledo had the support of the Olga Torres Foundation for this research through a scholarship for young researchers in the area of ​​colorectal cancer research.

An extensive genomic analysis

An extensive genomic analysis

In order to glimpse what were the genomic characteristics that made a group of patients respond positively to therapy, the VHIO researchers considered an extensive genomic analysis that evaluated more than 20,000 genes.

To do this, they had a first cohort of 46 patients from the Vall d’Hebron University Hospital who had received this combination of therapies, whose results were validated with a second cohort of 52 patients of three Italian academic hospitals (Fondazione IRCCS Istituto. Nazionale dei Tumori of Milan, University Hospital of Pisa and Veneto Oncological Institute IOV-IRCCS de Padua). For the fundamental result, the collaboration of Filippo Pietrantonio, of the IRCCS Foundation of the National Cancer Institute of Milan, of the Chiara Cremolini, of the Hospital Universitario de Pisa, and of the Sara Lonardi, of the Oncological Institute Veneto IOV-IRCCS of Padua.

Likewise, to confirm the value of the data obtained in both cohorts, 68 patients treated in different hospitals who received chemotherapy and antiangiogenic agents that did not involve anti-BRAF therapy were added.

“In total we have had the data of 166 patientsa very important number if one takes into account that we are talking about a rare type of cancer, which can account for around 7% of all colorectal cancers», explains Elena Elez.

Predictive value of mutations

By performing a genomic analysis of responders versus non-responders, VHIO investigators found that mutations in the RNF43 gene, present in 29% of BRAFV600E metastatic colorectal tumors, were strongly associated with the clinical outcome of therapies based in anti-BRAF/EGFR. “Specifically, we were able to verify that those patients with MSS-type colorectal tumors who had mutations in RNF43 responded better than those who did not. Specifically, we found that the appearance of the mutation was associated with a better response rate and progression-free survival of the disease and, more importantly, with an overall survival twice as long”, explains Rodrigo A. Toledo.

In this way, it was specifically observed that the response rate among patients with the RNF43 mutation reached 72.7%, while in those who did not, it was only 30.8%.

With regard to disease-free progression, among patients with the RNF43 mutation, the median was 10.1 months compared to 4.1 months in the group without mutation, while overall survival among the former was 13 .6 months compared to 7 months in the group without mutation.

“This finding has an important implication, the incorporation of the RNF43 mutation as a biomarker. This could help define the optimal treatment sequence in patients with BRAFV600E metastatic colorectal cancer with MSS who, unlike patients with microsatellite instability, lacked biomarkers that help in decision-making, ends by explaining Josep Tabernero, highlighting the importance what this means for the advancement of precision medicine and how, thanks to the work of centers such as VHIO, it is possible to carry out translational medicine that transfers research carried out in laboratories to clinical practice.

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