More sensitivity is not always better. In his latest work in Annals of Oncology, a national research team led by researchers from the Bellvitge Biomedical Research Institute (IDIBELL) – Catalan Institute of Oncology (ICO) has shown that the use of new techniques of mutational analysis that allow quantification of mutated alleles does not improve the predictive performance of the currently used techniques. The study presents the results of the phase II ULTRA clinical trial, led by Dr. Ramon Salazar, coordinator of the Oncobell program, and confirms the validity of current mutational studies.
Current therapies in advanced stages of colon and rectal cancer include the use of monoclonal antibodies against the epidermal growth factor receptor EGFR (panitumumab, cetuximab). These drugs are able to block the activation of the EGFR molecular signaling pathway, which is linked to the uncontrolled proliferation of cancer cells. However, when the genes involved in the activation of the pathway, belonging to the RAS family, present mutations, the pathway does not respond to these inhibitors; it is a case of drug resistance.
“This fact, however, provides clinically useful information: the identification of these RAS mutations allows us to identify patients who will not respond to these drugs,” explains Dr. Cristina Santos, first author of the study. “In our study, we wanted to go further and evaluate whether the number of alleles mutated in the tumor correlates with the primary resistance to drugs,” he adds.
The trial, which involved 72 patients with metastatic colorectal cancer, analyzed 38 points susceptible to mutations in the KRAS, NRAS, BRAF and PIK3CA genes. The IDIBELL-ICO research team identified the mutation profiles by quantitative PCR (qPCR), the method usually chosen to make these determinations, and by nanofluidic digital PCR (dPCR), a high sensitivity method capable of detecting and quantifying present mutations at a lower percentage of 1% of the cell population. Both results were correlated with the clinical results of each patient in order to estimate the predictive performance of each technique.
“What we have seen is that, although the high sensitivity dPCR identified a higher number of mutations of the KRAS, NRAS, BRAF and PIK3CA genes present at lower percentages in the tumor, the optimal sensitivity threshold for the prediction of resistance is 5%, so the traditional qPCR is sensitive enough for these determinations in the tumor tissue”, Dr. Santos explains.
The study, which has received the support of the Digestive tumors treatment group (TTD) through an aid from the Ministry of Health, Social Affairs and Equality, has been coordinated by the IDIBELL-ICO doctors and researchers Ramon Salazar and Gabriel Capellá. 12 hospitals participated at national level; the Catalan Institute of Oncology was one of the main recruiting centers.