Researchers have unmasked mutations in the RNF43 gene as predictive biomarkers of a response to treatment with anti-BRAF/EGFR combination therapy in patients with microsatellite-stable BRAF V600E–mutated metastatic colorectal cancer. Data showed that patients with tumors harboring loss-of-function mutations in RNF43 responded favorably to a dual BRAF/EGFR blockade and achieved improved progression-free as well as overall survival rates, according to a new study published by Élez et al in Nature Medicine.
BRAF/EGFR Inhibition
Mutations in BRAF V600E occur in around 10% of metastatic colorectal cancers, and while they are relatively rare, they are associated with a poor prognosis. Tumors harboring this alteration are generally refractory to treatment and rapidly develop cancer drug resistance. In 2019, findings from the phase III BEACON trial, published by Kopetz et al in The New England Journal of Medicine, rang in a new standard of care with the combination of BRAF (encorafenib) and EGFR (cetuximab) inhibition in previously treated patients with BRAF V600E–mutated metastatic colorectal cancer.
“While this [combination] therapy can significantly improve outcomes in some of these patients, others do not show benefit. Up until now, the underlying genetic determinants of efficacy have not been described. We therefore sought to determine which genes were enriched for somatic mutations in responder and nonresponder groups,” said co-corresponding study author Elena Élez, MD, PhD, a senior clinical investigator in the Gastrointestinal and Endocrine Tumors Group at the Vall d’Hebron Institute of Oncology.
Study Details
Forty-six patients from the Vall d’Hebron Barcelona Hospital Campus were prospectively included in the discovery cohort, and 52 patients from three other participating university hospitals in Italy were included in the validation group. To confirm the study findings from both cohorts treated with anti-BRAF/EGFR therapy, the investigators assessed data from 68 additional patients who had received other treatments such as chemotherapy plus antiangiogenic agents—without anti-BRAF therapy—at all four participating hospitals.
“We performed extensive genomic analysis of over 20,000 genes. In total, we analyzed data from 166 patients, which represents a significant number considering the rarity of this tumor subtype that accounts for around 10% of all colorectal cancers,” observed co-corresponding author Rodrigo A. Toledo, MSc, PhD, a translational investigator in the Gastrointestinal and Endocrine Tumors Group at the Vall d’Hebron Institute of Oncology.
The genomic analysis of responders vs nonresponders showed that RNF43 mutations, identified in 29% of BRAF V600E–mutated microsatellite-stable metastatic colorectal cancer “cold” tumors, were strongly associated with a clinical response to anti-BRAF/EGFR-based combinations in these patients. Results showed that patients presenting with these mutations responded better than those who did not, and also experienced longer progression-free and overall survival.
The response rate among patients with BRAF V600E–mutated microsatellite-stable metastatic colorectal cancer carrying an RNF43 mutation was 72.7%, and was 30.8% in those without the mutation. In patients with tumors harboring the RNF43 mutation, median disease-free progression was 10.1 months vs 4.1 months in those without the mutation. Importantly, overall survival in the former group was 13.6 months compared to 7 months in the latter.
Clinical Implications
“Our data point to RNF43 as a potential stratification biomarker that could help steer treatment decision-making as well as define the optimal sequence of treatment in patients with microsatellite-stable, BRAF V600E–mutant metastatic colorectal cancer. [Just as] importantly, it could also help to identify those patients for whom alternative treatment options are very much needed,” added Dr. Toledo.
While these results could usher in a much-needed biomarker of response in this setting, the study authors suggested that further research should seek to incorporate this candidate biomarker in routine testing, along with BRAF and microsatellite stability/microsatellite instability status, to evaluate their possible integration with other transcriptomic, microbiome, and microenvironmental indicators.
“The discovery and validation of robust biomarkers of drug response in this patient population will help to prioritize anti-BRAF/EGFR combinations in those patients who are more likely to derive benefit, as well as optimize the clinical management of such a heterogeneous and highly complex disease,” concluded Dr. Élez.
Disclosure: For full disclosures of the study authors, visit nature.com.
