Biomarkers are becoming an essential part of precision medicine and personalized treatment of patients, enhancing our ability to better select the right patients for the right treatment.
To date, RAS status is the only validated negative predictive biomarker for the use of the anti-epidermal growth factor receptor monoclonal antibodies (ie, panitumumab and cetuximab [Erbitux, Eli Lilly]) among patients with metastatic colorectal cancer (mCRC). About 50% of these patients harbor RAS mutations (including KRAS exons 2, 3 and 4 and NRAS exons 2, 3 and 4) and do not benefit from anti-EGFR treatments. Therefore, testing for RAS status before selection of targeted therapy in mCRC is recommended in all clinical guidelines. In fact, potential harm was observed to the population with RAS mutations when treated with anti-EGFR therapy, highlighting the importance of appropriate patient selection for this treatment.
However, several genomic and nongenomic mechanisms of primary resistance to anti-EGFR therapy have been identified among patients with RAS wild-type mCRC. BRAF V600E mutations and tumor sidedness represent the most robust negative predictive biomarkers beyond the presence of a RAS mutation. Therefore, patients with left-sided, RAS and BRAF wild-type mCRC are considered optimal candidates for anti-EGFR therapy. Nonetheless, primary and acquired resistance to anti-EGFR therapy remains an important clinical issue.
In this study, Morano and colleagues report a prespecified retrospective analysis of 199 evaluable patients with RAS and BRAF wild-type mCRC previously enrolled in the phase 2 VALENTINO trial. The aim of this study was to investigate the prognostic and predictive role of a more accurate analysis of multiple and less frequent genomic alterations (PRESSING panel) in combination with assessment of tumor sidedness for the selection of patients candidates for anti-EGFR antibody therapy.
The authors demonstrated that implementing the PRESSING panel together with tumor sidedness allowed a better negative selection of RAS and BRAF wild-type patients who were not likely to respond to anti-EGFR therapy. This finding has the potential to not only spare many patients unnecessary adverse effects, but also financial toxicity.
PRESSING status was defined as positive if alterations occurred in any biomarker in the panel, whereas negative status applied when all biomarker alterations were wild-type.
The authors demonstrated that patients with left-sided and PRESSING-negative tumors achieved the most favorable prognosis in both PFS (median, 13.7 months) and OS (2-year OS rate, 69.7%), whereas the subgroup with right-sided and PRESSING-positive tumors had the worst prognosis (median PFS, 7.7 months; 2-year OS rate, 40.9%).
Moreover, researchers reported the strongest association with poor PFS (P = .001) and OS (P = .007) in the multivariable models for PRESSING-positive tumors. Conversely, sidedness was no longer significant, but this could be due to the low number of right-sided tumors in the study group. Nevertheless, a borderline correlation occurred between primary tumor sidedness and the PRESSING panel, with a higher rate of PRESSING positivity in right-sided tumors (37.9%) vs. left-sided tumors (22.3%).
This study further corroborates previous reports showing that several genomic alterations, such as HER2 or MET amplification, ALK/ROS1/NTRKs/RET fusions, PIK3CA/PTEN/AKT1 and RAS mutations with low mutant allele fraction, microsatellite instability, and primary tumor side (right-sided tumors), may be responsible for primary resistance to anti-EGFR treatments. This suggests that the currently recommended evaluation of RAS and BRAF mutational status may not be enough in clinical practice to select patients suitable for panitumumab or cetuximab treatment in combination with chemotherapy in first and later lines of treatment.
It is important to note that the authors could not investigate the predictive role of tumor sidedness and PRESSING panel status with regard to anti-EGFR therapy because both arms in the VALENTINO trial were treated with panitumumab. In addition, the authors were not able to distinguish the prognostic and/or predictive effect of each individual genomic alteration included in the PRESSING panel and, therefore, some could be falsely perceived as potential mechanisms of resistance just by being associated with the panel. However, given the rarity of these alterations, it may be logistically impossible to formally validate them in prospective clinical studies or in post hoc analyses of randomized clinical trials as negative predictive biomarkers for response to EGFR-targeted therapies. In addition, it is well-known that nongenetic alterations may also drive resistance to anti-EGFR therapy, particularly in right-sided tumors, which are not included in the PRESSING panel and deserve further study.
In conclusion, this study sheds more light on anti-EGFR primary resistance mechanisms in patients with mCRC, which enhances our ability to better select patients for initial anti-EGFR-based therapy based on factors beyond tumor sidedness and RAS and BRAF status.
Further studies are warranted to validate Morano and colleagues’ findings and to find novel mechanisms of primary and acquired resistance to anti-EGFR therapy. This will continue to help us to accurately tailor targeted treatment to individual patients with mCRC.
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Mohamed Salem, MD
HemOnc Today Next Gen Innovator
Levine Cancer Institute at Atrium Health
Alberto Puccini, MD
University of Genoa
IRCCS Ospedale Policlinico San Martino, Genoa, Italy
Disclosures: Salem reports speaker and consultant roles with Taiho, and a consultant role with Exelixis. Puccini reports no relevant financial disclosures.