The mechanism of resistance to anti-EGFR therapy varies by treatment regimen in patients with advanced RAS/RAF wild-type colorectal cancer (CRC), according to a recent study published in the Journal of Clinical Oncology . Although acquired genomic alterations are common in patients receiving single-agent EGFR inhibitors in third-line, other drug resistance mechanisms dominate in patients receiving anti-EGFR combined with chemotherapy. "We are the first study to truly demonstrate that patients treated with third-line anti-EGFR alone and responded were more likely to develop acquired mutations than patients who used anti-EGFR alone in first-line treatment," said Christine Parseghian, Ph.D., a study author at the University of Texas MD Anderson Cancer Center. "These results are consistent with other latest data from similar analyses and are critical to inform future clinical trials." The researchers concluded that these results are consistent with other latest data from similar analyses and are critical to inform future clinical trials. "This has direct practical implications for prospective studies that are challenging EGFR, which have been guided by acquired MAPK mutations to date, and the findings highlight the need to address non-genomic drug resistance mechanisms," said Dr. Parseghian.
Research Design
Given that the occurrence of drug resistance is related to the increased risk of death, determining the resistance mechanism of anti-EGFR treatment has always been an important goal of CRCh research. It is well known that acquired resistance mutations can only be found in about 40% of patients, suggesting that other resistance mechanisms may have breakthroughs. To further investigate this, Dr. Parseghian and colleagues analyzed paired samples of circulating tumor DNA (ctDNA) to noninvasively evaluate molecular changes associated with drug resistance after anti-EGFR treatment.
The study focused on paired plasma samples from patients with RAS/BRAF/EGFR wild-type metastatic CRC from three large randomized trials of first-line anti-EGFR combined with chemotherapy (147 patients) or third-line anti-EGFR monotherapy (422 patients). By comparing paired samples of baseline and disease progression, researchers can evaluate the evolution of drug resistance. They also evaluated gene transcriptional changes in CRC cell lines that occur against EGFR therapy and chemotherapy resistance.
mainly found
researchers found that the acquired mutation rate in patients treated with single-agent EGFR inhibitors was higher than that in patients receiving anti-EGFR combined with chemotherapy (46% vs 9%; P0.001). It has been previously suggested that therapeutic resistance may occur when subclonal mutations present at baseline expand and become dominant. However, in these analyses, baseline subclonal mutations rarely expand into cloning in progress. Among all baseline samples tested, 27% of patients had subclonal mutations of KRAS/NRAS/BRAF/MAP2K1/EGFR, of which 171 mutations were detected. Only 8% of these mutations were clonal at progression; more commonly, they were still subclonal (44%) or undetectable (49%).
researchers also conducted preclinical studies to investigate the common drug resistance mechanisms against EGFR and chemotherapy in front-line settings. They found that CRC models with acquired resistance to cetuximab or chemotherapy were cross-resisted to alternative drugs through transcriptional mechanisms. "In summary, our results lead to the hypothesis that in front-line environments, tumor cells are more likely to produce a single transcriptome resistance mechanism that is sufficient to combat anti-EGFR and cytotoxic chemotherapy." In contrast, in later treatment, the genomic mechanism of drug resistance predominates when cytotoxic drugs are not usually used in combination or the cytotoxic regimen provides less selective pressure.
Future Directions
Although these studies provide important insights into the potential mechanisms of anti-EGFR treatment for drug resistance, many questions remain unanswered and further work is needed to uncover the role of transcriptome resistance mechanisms and determine the potential impact on treatment. However, these findings provide the basis for finding resistance to targeted therapies and the use of ctDNA to predict re-challenge responses against EGFR.
References
1. Parseghian CM, Sun R, Woods M, et al. Resistance Mechanisms to Anti-EGFR Therapy in RAS/RAF Wildtype Colorectal Cancer Vary by Regimen and Line-of-Therapy. J Clin Oncol. 2022;JCO220142.
2. Raghav K, Ou FS, Venook AP, et al. Acquired genomic alterations on first-line chemotherapy with cetuximab in advanced colorectal cancer: circulating tumor DNA analysis of the CALGB/SWOG-80405 Trial (Alliance). J Clin Oncol. 2022 [Online ahead of print].
3. Sartore-Bianchi, A., Pietrantonio, F., Lonardi, S. et al. Circulating tumor DNA to guide rechallenge with panitumumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial. Nat Med. 2022;28(8):1612-1618.
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