Background: RAS mutations have been shown to confer resistance to anti-EGFR treatment. We assessed here the results of the PETACC8 trial (Cetuximab + FOLFOX vs FOLFOX) in full wild type (WT) patients (pts) (RAS & BRAF). The prognostic impact of individual rare RAS and BRAF mutations has been tested. Methods: Exons 2, 3 and 4 of KRAS and NRAS as well as BRAF exon 11 and 15 have been sequenced, using the ampliseq colon lung cancer panel V2, among the pts who have signed informed consent for translational research. The impact of cetuximab on Time To Recurrence (TTR), Disease Free Survival (DFS) and Overall Survival (OS), has been investigated in pts RAS WT, RAS & BRAF double WT tumors and in pts with rare RAS mutations. Results: Among the 2559 pts analyzed, 745 (29%) were known to be mutated for KRAS exon 2 and 163 (6.4%) for BRAF V600E. From the remaining 1654 pts 1054 had given informed consent for additional TR analyses and were NGS assessed, with 227 pts (21%) newly diagnosed as KRAS exon 3,4 or NRAS exon 2,3,4 mutated, and 46 (4.4%) as non-V600E BRAF mutated. Cetuximab was not improving significantly TTR, DFS or OS in pts with RAS WT or RAS & BRAF double WT tumors (HR ranging from 0.77 to 1.05, all p > 0.05). FOLFOX + Cetuximab was either not significantly deleterious in RAS mutant pts (HR ranging from 1.13 to 1.29, all p > 0.05). Outcome was not significantly different with and without cetuximab in pts with RAS or BRAF rare mutations (HR ranging from 1.42 to 1.61, all p > 0.05). When pooling both treatment arms, as compared to double WT pts, KRAS and NRAS codon 61 rare mutants were associated with a worse TTR (KRAS, HR : 2.42 [1.40;4.20] p = 0.001 and NRAS, HR : 2.18 [1.21;3.93] p = 0.008) and DFS (KRAS, HR: 1.98 [1.15;3.42] p = 0.01 and NRAS, HR: 1.99 [1.13;3.50] p = 0.015). This was not the case for other RAS or BRAF rare mutations. Conclusions: In Stage III colon cancer, the addition of cetuximab to standard FOLFOX adjuvant therapy does not improve significantly outcome in RAS and RAS & BRAF double WT pts. No detrimental significant effect was observed in RAS mutant pts. NRAS or KRAS codon 61 seem to be the only rare mutations that has the same pejorative prognostic value than KRAS codon 12 and 13 or BRAF V600E mutations. Clinical trial identification: EudraCT number 2005-003463-23
Adjuvant FOLFOX+ cetuximab vs FOLFOX in full RAS and BRAF wild type stage III colon cancer patients: Results from the PETACC8 trial / Taieb, J.; Le Malicot, K.; Balogoum, R.; Tabernero, J.; Mini, E.; Folprecht, G.; van Laethem, J-L.; Emile, J-F.; Mulot, C.; Fratté, S.; Levaché, C-B.; Saban-Roche, L.; Thaler, J.; Petersen, L. Nørgård; Sanchez, E.; Bridgewater, J.; Perkins, G.; Lepage, C.; Zaanan, A.; Laurent-Puig, P.. - In: ANNALS OF ONCOLOGY. - ISSN 0923-7534. - ELETTRONICO. - 27:(2016), pp. 49-49. [10.1093/annonc/mdw370.10]
Adjuvant FOLFOX+ cetuximab vs FOLFOX in full RAS and BRAF wild type stage III colon cancer patients: Results from the PETACC8 trial
Mini, E.;
2016
Abstract
Background: RAS mutations have been shown to confer resistance to anti-EGFR treatment. We assessed here the results of the PETACC8 trial (Cetuximab + FOLFOX vs FOLFOX) in full wild type (WT) patients (pts) (RAS & BRAF). The prognostic impact of individual rare RAS and BRAF mutations has been tested. Methods: Exons 2, 3 and 4 of KRAS and NRAS as well as BRAF exon 11 and 15 have been sequenced, using the ampliseq colon lung cancer panel V2, among the pts who have signed informed consent for translational research. The impact of cetuximab on Time To Recurrence (TTR), Disease Free Survival (DFS) and Overall Survival (OS), has been investigated in pts RAS WT, RAS & BRAF double WT tumors and in pts with rare RAS mutations. Results: Among the 2559 pts analyzed, 745 (29%) were known to be mutated for KRAS exon 2 and 163 (6.4%) for BRAF V600E. From the remaining 1654 pts 1054 had given informed consent for additional TR analyses and were NGS assessed, with 227 pts (21%) newly diagnosed as KRAS exon 3,4 or NRAS exon 2,3,4 mutated, and 46 (4.4%) as non-V600E BRAF mutated. Cetuximab was not improving significantly TTR, DFS or OS in pts with RAS WT or RAS & BRAF double WT tumors (HR ranging from 0.77 to 1.05, all p > 0.05). FOLFOX + Cetuximab was either not significantly deleterious in RAS mutant pts (HR ranging from 1.13 to 1.29, all p > 0.05). Outcome was not significantly different with and without cetuximab in pts with RAS or BRAF rare mutations (HR ranging from 1.42 to 1.61, all p > 0.05). When pooling both treatment arms, as compared to double WT pts, KRAS and NRAS codon 61 rare mutants were associated with a worse TTR (KRAS, HR : 2.42 [1.40;4.20] p = 0.001 and NRAS, HR : 2.18 [1.21;3.93] p = 0.008) and DFS (KRAS, HR: 1.98 [1.15;3.42] p = 0.01 and NRAS, HR: 1.99 [1.13;3.50] p = 0.015). This was not the case for other RAS or BRAF rare mutations. Conclusions: In Stage III colon cancer, the addition of cetuximab to standard FOLFOX adjuvant therapy does not improve significantly outcome in RAS and RAS & BRAF double WT pts. No detrimental significant effect was observed in RAS mutant pts. NRAS or KRAS codon 61 seem to be the only rare mutations that has the same pejorative prognostic value than KRAS codon 12 and 13 or BRAF V600E mutations. Clinical trial identification: EudraCT number 2005-003463-23
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