Abstract
BackgroundAfter analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment. BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies. However, it remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer. We assessed whether selection according to RAS/PIK3CA/BRAF mutational status could be beneficial for patients treated with bevacizumab as first-line treatment for metastatic colorectal cancer.MethodsOf the 1001 consecutive colorectal cancer patients examined for RAS, PIK3CA, and BRAF tumor mutations using a multiplex kit (Luminex®), we studied 90 patients who received combination chemotherapy with bevacizumab as first-line treatment for metastatic colorectal cancer. The objective response rate (ORR) and progression-free survival (PFS) were evaluated according to mutational status.ResultsThe ORR was higher among patients with wild-type tumors (64.3%) compared to those with tumors that were only wild type with respect to KRAS exon 2 (54.8%), and the differences in ORR between patients with wild-type and mutant-type tumors were greater when considering only KRAS exon 2 mutations (6.8%) rather than RAS/PIK3CA/BRAF mutations (18.4%). There were no statistically significant differences in ORR or PFS between all wild-type tumors and tumors carrying any of the mutations. Multivariate analysis revealed that liver metastasis and RAS and BRAF mutations were independent negative factors for disease progression after first-line treatment with bevacizumab.ConclusionsPatient selection according to RAS/PIK3CA/BRAF mutations could help select patients who will achieve a better response to bevacizumab treatment. We found no clinical benefit of restricting combination therapy with bevacizumab for metastatic colorectal cancer patients with EGFR-wild type tumors.
Highlights
After analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-Epidermal growth factor receptor (EGFR) antibody treatment
We evaluated the significance of RAS/PIK3CA/BRAF tumor mutations in patients receiving combination chemotherapy with Bmab as the first-line treatment for metastatic colorectal cancer (mCRC), and we assessed whether these mutations could be used to select patients who would derive the greatest clinical benefit from Bmab
right-sided colon cancer (RCC) was defined as a tumor arising from the cecum to the transverse colon, excluding the appendix, while left-sided colorectal cancer (LCRC) was defined as a tumor arising from the descending colon to the rectum
Summary
After analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment. BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies It remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer. After a retrospective analysis of minor RAS mutations (e.g. KRAS exon 3 and 4/NRAS) in the FIRE-3 and PRIME studies [2, 3], the so called “all RAS mutation” came to be regarded as a negative biomarker for anti-EGFR antibody treatment [4]. In addition to RAS, BRAF and PIK3CA mutations are potential biomarkers of response to anti-EGFR targeted therapies [5] It remains unknown whether EGFR pathway mutations affect the efficacy of bevacizumab (Bmab) in metastatic colorectal cancer (mCRC). We evaluated the significance of RAS/PIK3CA/BRAF tumor mutations in patients receiving combination chemotherapy with Bmab as the first-line treatment for mCRC, and we assessed whether these mutations could be used to select patients who would derive the greatest clinical benefit from Bmab
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