We investigated the role of KRAS codons 61 and 146 and BRAF V600E mutations in predicting resistance to cetuximab plus irinotecan...None of 13 BRAF-mutated patients responded vs 24 of 74 BRAF wild type (P=0.016). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P=0.073). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P=0.073)...Patients bearing KRAS or BRAF mutations had poorer response rate (0 vs 37%, P=0.0005) and PFS (HR: 0.51, P=0.006) compared with KRAS and BRAF wild-type patients.

CO.17 trial compared cetuximab versus best supportive care (BSC) in RAS/BRAF-unselected mCRC. 17 trial using BEAMing for KRAS/NRAS (codons 12/13/59/61/117/146) and BRAF V600E. Cetuximab did not improve OS/PFS for KRAS-, NRAS-, or BRAF-mutated tumors…

...Expecting a minimum 20% difference (60 vs. 40%) on PFS at 12 months between groups and with the following assumptions: Alpha error (bilateral): 5% Beta error: 20% Results are reported by subgroups to compare outcome measure according to BRAF mutation. ...

...- Available specimens at the PCO for BRAF mutation detection...

...KRAS/BRAF mutant disease or KRAS wild type w/previous anti-EGFR treatment 5....

...Advanced colorectal cancer with genetic mutation that failed or intolerated standard treatment; Cohort 1, NGS test indicated Her2 amplification, regardless of the Her2-IHC result, regardless of the status of the Ras gene; Cohort 2, NGS test indicated Her2 mutation, non-amplified status, regardless of the Ras gene status; Cohort 3, confirmed by NGS test BRAF mutation; cohort 4, BRCA1/2 mutation confirmed by NGS test; 4. ...

...Patients with initial RAS mutant, BRAF wild-type left-sided mCRC....

...Also, in cases where the BRAF tumour status is known there must be no mutation. ...

...Prior confirmation of tumour KRAS status as either KRAS WT (with no mutations or changes in BRAF, NRAS, PIK3CA exon20) OR KRAS G13D mutation,6. ...

...Patients who have histologically or cytologically confirmed adenocarcinoma of the colon or rectum, excluding appendix carcinoma or anal canal carcinoma, with RAS and BRAF wild-type mutation status....

...We conducted a phase II trial (WJOG8916G) to evaluate the efficacy and safety of the combination of trifluridine/tipiracil and cetuximab rechallenge in patients (pts) with metastatic colorectal cancer (mCRC)…RAS, BRAF, and PIK3CA muts in ctDNA were associated with worse clinical efficacy outcomes in mCRC patients receiving anti-EGFR antibody rechallenge plus trifluridine/tipiracil.

Patients received FOLFOX6 with cetuximab (500 mg/m2) every second week. BRAF mutations were detected in 11.3%. These patients had a significantly lower ORR, and median PFS and OS.

1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab...In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types, with a response rate of 8.3% (2/24) in carriers of BRAF mutations versus 38.0% in BRAF wild types (124/326; OR 0.15, 95% CI 0.02-0.51; p=0.0012); and 7.7% (1/13) in carriers of NRAS mutations versus 38.1% in NRAS wild types (110/289; OR 0.14, 0.007-0.70; p=0.013).

We retrospectively collected tumors from 173 patients with mCRC. All but one patient received a cetuximab-based regimen as second-line or greater therapy...In patients with KRAS wild-type tumors (n = 116), BRAF mutations (n = 5) were weakly associated with lack of response (P = .063) but were strongly associated with shorter progression-free survival (P < .001) and shorter overall survival (OS; P < .001).

Our results prospectively validated observations in patients: none of the 7 NRAS- and 3 BRAF-mutant cases (10.6% and 4.5%, respectively) or the 4 cases with KRAS rare mutations (6.1%) responded to cetuximab with tumor shrinkage or stabilization.

Overall, the addition of C or P treatment in the BRAF-mut subgroup did not significantly improve PFS (HR, 0.88; 95% confidence interval (CI), 0.67-1.14; p=0.33), OS (HR, 0.91; 95% CI, 0.62-1.34; p=0.63) and ORR (relative risk, 1.31; 95% CI 0.83-2.08, p=0.25) compared with control regimens.

Compared with patients with RAS wt/BRAF wt tumors (n = 124; median overall survival, 28.5 months), those with RAS mutations (n = 10; median, 16.3 months; hazard ratio, 0.43; 95% confidence interval, 0.20-0.89; P = .020) or BRAF mutations (n = 14; median, 11.7 months; hazard ratio, 0.23; 95% confidence interval, 0.12-0.41; P < .0001) had worse overall survival, which remained significant (P < .04) when adjusting for differences in baseline characteristics among the mutation subgroups.

In contrast, BRAF mutations (0% for responders vs. 26.1% for non-responders, p = 0.0044) and KRAS (0% for responders vs. 21.7% for non-responders, p = 0.0117) were observed exclusively in non-responders. Three of the 4 subjects with NRAS mutations were non-responders (p = 0.3053) while both PTEN mutations were detected in responders (p = 0.4993). Collective mutation frequencies of KRAS, NRAS, and BRAF combined were higher in non-responders (p = 0.0001).

RAS/RAF mutations are negatively associated with response to cetuximab or panitumumab...BRAF mutations alone were also not significantly associated with objective response to therapy (P = 0.312). Importantly, however, the presence of K-RAS and/or BRAF mutations was negatively associated with partial response (P = 0.005) and the logistic regression confirmed this association (odds ratio, 0.071; 95% confidence interval, 0.08–0.619; P = 0.017).

The biomarker distribution was as follows: BRAF mutant, 20 patients (11%); PIK3CA mutated/PTEN loss, 98 patients (58%); DP, 23 patients (12.7%). The clinical variables in the clinical score were progression status >0, left-sided tumor, and resectable liver metastasis as the only metastatic site....The addition of BRAF, PIK3CA/PTEN, and DP to a clinical score does not improve the discrimination of 12-month PFS.