The results of his research can be read at Nature, the most prestigious exhibitor of scientific advances in the world, and may soon be transferred to clinical practice, offering answers in the approach to metastatic colorectal cancer thanks to new genomic data. At the beginning of the era of personalized medicine and with some targeted treatments already rolled out, Drs. Elena Elez and Rodrigo A. Toledoresearchers from Vall d’Hebron Institute of Oncology (VHIO)have gone a step further by giving a new “surname” to metastatic colorectal cancer with stable microsatellites (MSS) and with the BRAFV600E mutation.
They have found that those patients who have mutations in the RNF43 gene are the ones better response rate to anti-BRAF/EGFR therapy have. With this, it improves the time free of disease progression and survival. His next objective is to validate these results in order to bring his discovery to oncology clinics as soon as possible. But their research goes further, since the knowledge generated with the genomic data they have analyzed provides a “extreme value” for global research. And it is that until now, as explained to iHealththere were few colorectal tumors with mutations in the BRAF gene sequenced.
«The BRAFV600 mutation is found in 8-12% of advanced colorectal tumors»
We are talking about a type of cancer that is not very common. What is the incidence of metastatic colorectal cancer with MSS with the BRAFV600E mutation? What percentage or what proportion of these patients do not respond to dual anti-BRAF/EGFR therapy?
E. Elez: 95% of patients diagnosed with metastatic colorectal cancer have a tumor with MSS (microsatellite stable) characteristics. This means that they are tumors that are unlikely to respond to certain therapies, specifically immunotherapy. On the other hand, the BRAFV600 mutation is found in 8-12% of advanced colorectal tumors.
Could there be other mutations in this type of metastatic colorectal cancer that could also become biomarkers?
E. Elez: We know that colorectal cancer is a very heterogeneous tumor. This means, for example, that although we can find a predominant mutation in the tumor, there may be other mutations that occur at the same time. Mutations that could influence the evolution of the disease and/or the response to certain types of treatment. For this reason, we intended to carry out a broader genomic study so that it would allow us to find these other molecular alterations that would allow us to better understand the response to targeted therapies in V600E mutated colorectal cancer.
“We intended to carry out a broader genomic study that would allow us to find other molecular alterations in order to better understand the response to targeted therapies”
For the group of patients who do not have mutations in the RNF-43 gene and who respond less well to therapy, what are the current prospects? Are there research possibilities to find answers?
E. Elez: We are currently working on other biomarkers and potential resistance mechanisms beyond this gene.
They have analyzed more than 20,000 genes. How long ago would this analysis have been materially impossible? How were they able to do the analysis?
R.A. Toledo: The tumor is a disease where healthy cells acquire a series of mutations in their DNA that produce uncontrolled cell proliferation. Thus, sequencing the DNA of tumors is a tool that scientists frequently use to find out how each patient’s tumor was formed, what molecular pathways it adopts for its growth, and finally to search for potential therapeutic targets.
Genomic data from the analysis of 20,000 human genes “enabled us to discover mutations in the RNF43 gene as a biomarker of response to anti-BRAF and EGFR treatment”
To find out why some tumors responded to treatment while others did not, we compared the mutations in tumors from responders and non-responders. To do this, we use a technique called exome, which analyzes all 20,000 genes in the human genome at once. This technique has existed for more than 10 years, but it requires a multidisciplinary group that includes expert biologists and bioinformaticians to be able to carry out the correct analysis and interpretation of the data. These analyzes enabled us to discover mutations in the RNF43 gene as a biomarker of response to treatment with BRAF and EGFR inhibitors.
Can the results obtained from those thousands of genes provide answers to other research questions that you or another team may have?
R.A. Toledo: A study like this has a fairly high level of complexity and multidisciplinarity and, in order to be carried out successfully, involved clinical groups and researchers specialized in cancer genomics, cell biology, bioinformatics and clinical statistics, among others. The advancement of science depends on this multidisciplinarity, and therefore it is extremely collaborative. In addition to the find itself, the data set The genomic gene generated in studies such as ours is extremely valuable for research worldwide, especially because CRC-BRAF tumors are rare and there are few sequenced tumors in current genomic banks.
“A study like this has a fairly high level of complexity and multidisciplinarity. The advancement of science depends on this multidisciplinarity, and therefore it is extremely collaborative»
What procedure must be followed to incorporate this finding as a biomarker for this type of cancer?
R.A. Toledo: The incorporation of a biomarker in the clinic requires clear, reproducible results that add clinical value, such as, for example, in choosing the best treatment to be offered to patients. In our study we obtained strong evidence of the correlation between mutations in the RNF43 gene in MSS colon cancer patients and response to targeted therapy, which we were able to confirm in an external cohort used for validation. The next natural step will be to analyze other cohorts to continue the validation process and understand the potential of this possible new biomarker in the clinic.
What are the next steps that the research team considers regarding this type of cancer and what questions do they want to answer?
R. A. Toledo and E. Elez: From a clinical point of view, it is necessary to continue identifying causes of acquired primary resistance as well as strategies to reverse it. We are interested in expanding the validation process of the predictive potential of RNF43 mutations in the context of BRAF subtype colorectal cancer. In the laboratory we will carry out experiments to understand the molecular consequences of RNF43 mutations related to a better response and to assess whether we can design new targeted therapies that increase patient survival.
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“The genomic data generated in studies like ours are extremely valuable for research worldwide”
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