BRAF Mutant Metastatic Colorectal Cancer Research Articles

Efficacy-effectiveness analysis on survival in a population-based real-world study of BRAF-mutated metastatic colorectal cancer patients treated with encorafenib-cetuximab.

Encorafenib-cetuximab has been approved for pretreated BRAFV600E-mutated metastatic colorectal cancer (mCRC) patients based on efficacy demonstrated in the randomized phase III BEACON trial. The aim of this real-world effectiveness study is to improve knowledge on the generalizability of trial results. This population-based real-world study includes all mCRC patients in the Netherlands treated with encorafenib-cetuximab since approval. Individual patient data and pathology reports were collected. Overall survival (OS) was compared to BEACON and subgroup analyses were conducted for patients who would have been eligible and ineligible for BEACON. 166 patients were included with a median follow-up time of 14.5 months. Median OS was 6.7 months (95% CI:6.0-8.3) and differed from BEACON (9.3 months; 95% CI:8.0-11.3, p-value 0.002). Thirty-six percent of real-world patients would have been ineligible for the BEACON trial. Trial ineligible subgroups with symptomatic brain metastases and WHO performance status ≥2 had the poorest median OS of 5.0 months (95% CI:4.0-NR) and 3.9 months (95% CI:2.4-NR). This real-world cohort of mCRC patients treated with encorafenib-cetuximab showed a clinically relevant efficacy-effectiveness gap for OS. The chance of survival benefit from encorafenib-cetuximab in patients with brain metastases and/or WHO performance status ≥2 is negligible as neither efficacy nor effectiveness has been demonstrated.

BRAF V600E-mutated Colorectal Neuroendocrine Carcinoma Effectively Treated with a Chemotherapy Protocol for BRAF-mutated Metastatic Colorectal Cancer: A Case Report

BRAF V600E-mutated Colorectal Neuroendocrine Carcinoma Effectively Treated with a Chemotherapy Protocol for BRAF-mutated Metastatic Colorectal Cancer: A Case Report

Overall survival of patients with BRAF-mutant metastatic colorectal cancer treated with encorafenib-cetuximab in a real-world nationwide study in the Netherlands.

3589 Background: Approximately 10-15% of patients with metastatic colorectal cancer (mCRC) have BRAFV600E mutated tumors. Encorafenib plus cetuximab (EC) combination treatment was approved following the results of the randomized phase III BEACON trial and is currently recommended for all pretreated patients with BRAFV600E-mutant mCRC. Selection of patients in randomized controlled trials is based on restrictive eligibility criteria and often not representative of the patient population in daily clinical practice. Complementary real-world effectiveness studies can improve knowledge on the generalizability of trial results, and support decision making in clinical practice. Methods: This population-based study included all mCRC patients in the Netherlands treated with EC since approval in October 2020 until June 2022. Individual patient data and original pathology reports were collected. Primary endpoint was overall survival (OS), defined as time from EC initiation until death by any cause, analyzed by Kaplan-Meier curves. WebPlotDigitizer was used to reconstruct the Kaplan-Meier survival curve of the BEACON trial. Uni- and multivariable analyses were performed. Subgroup analyses were conducted for patients who would have been eligible for the BEACON trial based on key eligibility criteria: BRAFV600E mutation, 1-2 prior regimens, world health organization performance status (WHO PS) of 0-1, normal neutrophil count, absence of brain metastases, no prior RAS/RAF/MEK treatment, and no concurrent malignancies. Results: 155 patients were included with a median follow-up time of 11.1 months. Patient characteristics differed from BEACON in mean age (64 versus 60 years), primary tumor sidedness (69% versus 50% right-sided) and WHO PS (23% versus 51% WHO 0). Median OS of the total real-world cohort was 6.6 months (95% CI: 6.0-8.3) and differed significantly from BEACON (9.3 months; 95% CI: 8.0-11.3; p = 0.003). 35% of real-world patients treated with EC would not have been eligible for the BEACON trial, showing an inferior median OS of 6.0 months (95% CI: 4.6-9.2) compared to 7.0 months (95% CI: 6.4-9.8) in trial eligible real-world patients. WHO PS was independently associated with poor survival in multivariable analysis. Patients with WHO PS≥2 had a median OS of 3.9 months (95% CI: 2.4-NA) with a hazard rate of 2.5 (95% CI: 1.1-5.5; p = 0.003). Conclusions: This largest to date - unselected - population-based cohort of mCRC patients treated with EC showed an efficacy-effectiveness gap for OS. These outcomes should be considered in clinical practice for treatment decision making. Omitting EC for subgroups demonstrating very short OS, such as patients with WHO PS ≥2, needs to be considered. Further research is warranted to adapt treatment guidelines towards a more personalized approach for patients with BRAFV600E-mutated mCRC.

The BEETS (JACCRO CC-18) trial: an observational and translational study of BRAF-mutated metastatic colorectal cancer.

For BRAF V600E-mutated metastatic colorectal cancer (mCRC), the BEACON phase 3 trial showed survival benefit of triplet therapy with cetuximab (anti-EGFR antibody), encorafenib (BRAF inhibitor) and binimetinib (MEK inhibitor) as well as doublet therapy with cetuximab and encorafenib over irinotecan-based chemotherapy plus anti-EGFR antibody. Both regimens are standards of care in Japan, but definite biomarkers for predicting efficacy and selecting treatment remain lacking. The mechanisms underlying resistance to these regimens also warrant urgent exploration to further evolve treatment. This prospective observational/translational study evaluated real-word clinical outcomes with cetuximab and encorafenib with or without binimetinib for BRAF-mutated mCRC patients and investigated biomarkers for response and resistance by collecting blood samples before and after treatment. Clinical Trial Registration: UMIN000045530 (https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000051983).

The possibilities of therapy of patients with metastatic colorectal cancer with <i>BRAF</i> V600E mutation. Clinical cases

Mutation in the BRAF V600E gene in metastatic colorectal cancer (CRC) occurs in 510% of cases and is a significant problem due to the aggressive course and extremely unfavorable prognosis. In recent years, new treatment options for BRAF mutated CRC have been emerging, for example, combinations of BRAF inhibitors, anti-EGFR antibodies with optional addition of MEK inhibitors. The possibility of local treatment methods is also being discussed. Objective: to evaluate the effectiveness of triple targeted therapy in BRAF-mutated metastatic colorectal cancer. On the example of 2 clinical cases of long-term treatment of patients with this molecular subtype, possible treatment options are discussed.

Effect of Food and a Proton-Pump Inhibitor on the Absorption of Encorafenib: An In Vivo-In Vitro-In Silico Approach.

Encorafenib is a kinase inhibitor indicated for the treatment of patients with BRAF mutant melanoma and BRAF mutant metastatic colorectal cancer. To understand the effect of food and coadministration with a proton-pump inhibitor (PPI), in vitro, in vivo, and in silico data were generated to optimize the clinical dose, evaluate safety, and better understand the oral absorption process under these conditions. Study 1 evaluated the effect of food on the plasma pharmacokinetics, safety, and tolerability after a single oral dose of encorafenib 100 mg. Study 2 evaluated the same end points with coadministration of encorafenib and rabeprazole (PPI perpetrator). The in vitro gastrointestinal TIM-1 model was used to investigate the release of encorafenib and the amount available for absorption under different testing conditions (fasted, fed, and with the use of a PPI). The fasted, fed, and PPI states were predicted for the encorafenib commercial capsule in GastroPlus 9.8. In study 1, both AUCinf and AUClast decreased by 4% with the administration of a high-fat meal. The Cmax was 36% lower than with fasted conditions. All 3 exposure parameters in study 2 (AUCinf, AUClast, and Cmax) had mean changes of <10% when encorafenib was coadministered with a PPI. Using the in vitro gastrointestinal simulator TIM-1, the model demonstrated a similar release of drug, as the bioaccessible fraction, in the 3 conditions was equal (≥80%), predicting no PPI or food effect for this drug formulation. The modeling in GastroPlus 9.8 demonstrated complete absorption of encorafenib when formulated as an amorphous solid dispersion. To obtain these results, it was crucial to integrate the amorphous solubility of the drug that shows a 20-fold higher solubility at pH 6.8 compared with crystalline solubility. The increased amorphous solubility is likely the reason no PPI effect was observed compared with fasted state conditions. The prolongation in gastric emptying in the fed state resulted in delayed plasma Tmax for encorafenib. No dose adjustment is necessary when encorafenib is administered in the fed state or when coadministered with a PPI. Both the TIM-1 and physiologically based pharmacokinetic model results were consistent with the observed clinical data, suggesting that these will be valuable tools for future work.

Clinical and survival characteristics of patients with BRAF-mutated metastatic colorectal cancer (mCRC) who receive metastases surgery in a Spanish cohort.

66 Background: Patients with mCRC harboring BRAF mutation have worse prognosis and poor outcomes. However, those who have resectable metastatic disease and undergo surgery may have better outcomes compared to those who do not. Differences in clinical characteristics are not well known and may be critical to identify patients with better prognosis. Methods: We performed a retrospective analysis of 299 patients with mCRC in a tumor registry from 2015 to 2021. We compared the clinical characteristics and survival trends of both cohorts (BRAF mutated and BRAF wild type). Furthermore, we analyzed clinical and survival features of 23 patients with BRAF mutated mCRC who received metastases resection. Results: We identified 34 patients with BRAF mutation (11.37%). Several characteristics were significantly more frequent in this group: age &lt;65 years (n = 24, OR 1.38, p = 0.03), female sex (n = 24, OR 1.74, p = 0.008), primary tumor in the right colon (n = 15, OR 1.93, p = 0.003), peritoneal carcinomatosis (n = 18, OR 2.29, p = 0.007) and increased CA19.9 levels at diagnosis (n = 18, OR 1.79, p = 0.003). They received more peritoneal surgery (n = 12, OR 4.27, p = 0.000) and less liver metastases resection (n = 7, OR 0.51, p = 0.011). Median PFS in the first line of treatment was shorter in patients with BRAF mutation (9.5 vs 12.6 months; HR 1.69; IC 95%: 1.16 – 2.45; p = 0.006); however, we did not found differences in OS. Within the 23 patients with BRAF mutated mCRC who underwent surgery (67,64%), we found significant differences compared with those without metastases surgery: primary tumor resection (n = 21, OR 2.51, p = 0.0017) and having a single metastatic location (n = 18, OR 2.04, p = 0.01). Other features were more frequent in patients who underwent surgery but did not reach statistical significance: right colon location (63.6% vs 37.5%), metachronic disease (47.8% vs 18.2%), normal CEA (50% vs 25%) and CA19.9 (45% vs 12%) at diagnosis, and receiving 3 or more lines of systemic treatment (57% vs 22%). Median PFS after metastasectomy was 14.9 months, but we found no differences between both groups. Conclusions: In our cohort, BRAF mutated mCRC patients were more frequently younger, women, had right-sided primary tumors, higher rates of peritoneal metastases and abnormal CA19.9 levels at diagnosis, including worse outcomes in terms of PFS. On the other hand, resection of the primary tumor and single metastatic location were associated with higher probability of having metastases surgery, although in this study no subsequent survival benefit was found, probably due to the small number of BRAF mutated patients analyzed.

Economic evaluation of encorafenib with cetuximab in patients with BRAF V600E-mutant metastatic colorectal cancer in France: a cost-effectiveness analysis using data from the BEACON CRC randomised controlled trial

ObjectiveThe BEACON CRC randomised controlled trial (NCT02928224) in BRAF-mutant metastatic colorectal cancer (mCRC) patients showed improved overall survival for the combination treatment of encorafenib (BRAF inhibitor) with cetuximab (EGFR inhibitor)...

P41-7 Two cases of BRAF mutant mCRC with intestinal stenosis responded to encorafenib + binimetinib + cetuximab: A case report

BRAF mutant metastatic Colorectal Cancer (mCRC) has a poor prognosis and response to chemotherapy. The oral agents, encorafenib and binimetinib in combination with cetuximab (BEACON-3) was approved as 2nd-line therapy for BRAF mutant mCRC in Japan. However, we often experience mCRC patients with intestinal stenosis. These patients may not be eligible for oral medication due to decline of drug absorption. We report two cases of BRAF mutant mCRC that developed intestinal stenosis during 1st-line therapy and responded to BEACON-3.

BRAF-mutant metastatic colorectal cancer: Prognostic and predictive value of primary tumor location—A pooled analysis of the AIO studies FIRE-1, CIOX, XELAVIRI, FIRE-3, and VOLFI.

3576 Background: Primary tumor location (PTL: left vs. right) is an established prognostic marker in metastatic colorectal cancer (mCRC) and has predictive impact for anti-EGFR antibody (mAb) efficacy in patients with RAS ( KRAS and NRAS) wild-type (WT) mCRC. This analysis of five pooled studies evaluates PTL as a prognostic and - concerning anti-EGFR mAb efficacy - predictive marker in BRAF V600E-mutant/ RAS WT and mCRC. Methods: The analysis is based on individual patient data of five pooled 1st-line studies with varying treatment strategies: the pooled population comprises of BRAF V600E-mutant/ RAS WT ( BRAFmt) mCRC with known PTL. For analysis, treatment was stratified into two groups: treated with or without anti-EGFR mAb. Dichotomous variables (overall response rate, ORR; characteristics) were compared by Chi-Square or Fisher’s exact test and time-to event endpoints (progressive-free survival, PFS; overall survival, OS) by Kaplan-Meier method, log rank test and Cox regression. Results: Of 102 patients (pts) with BRAFmt mCRC, 55 pts (54%) presented with right-sided primary tumors (RPT), 47 (46%) presented with left-sided primary tumors (LPT). Pts with RPT were more likely to be female ( p= 0.04). ORR was inferior in RPT compared to LPT (35% vs. 55%; p= 0.04). No difference was seen in PFS (HR 0.8 (95% CI 0.6-1.3; p= 0.32) or OS (HR 0.8; 95% CI 0.8-1.3; p= 0.46). In male pts PTL trended to be associated with longer OS (HR 0.6; 95% CI 0.3-1.0; p= 0.06). 25 pts with RPT (45%) and 21 with LPT (45%) received anti-EGFR mAb. In pts with LPT anti-EGFR mAb based treatment was associated with higher ORR (81% vs. 35%; p&lt; 0.01). No effect was seen in RPT (ORR 35% vs. 36%; p= 0.82). Anti-EGFR mAb treatment resulted in inferior PFS in RPT (HR 2.0; 95% CI 1.1-3.5; p= 0.02) and showed a trend towards improved PFS in LPT (HR 0.6; 95% CI 0.3-1.1; p= 0.11). Pts with RPT had a worse OS when treated with anti-EGFR mAb (HR 1.8; 95% CI 1.0-3.1; p= 0.05), whereas pts with LPT appeared to have a favorable outcome when treated with an anti-EGFR mAb containing regimen (HR 0.4; 95% CI 0.2-0.7; p&lt; 0.01). Conclusions: This exploratory analysis of five studies suggests that PTL has limited prognostic impact in BRAFmt mCRC but might carry predictive information regarding anti-EGFR mAb efficacy in a 1st-line treatment setting. Further prospective studies are needed to validate these results and to grasp the differences in the heterogeneous group of BRAFmt pts. Clinical trial information: FIRE-1 was before mandatory registration, NCT00254137, NCT00433927, NCT01249638, NCT01328171.

P-57 An observational/translational study of BRAF inhibitor combination therapy for BRAF-mutant metastatic colorectal cancer including biomarker research: BEETS trial (JACCRO CC-18)

BRAF inhibitor combination therapy became the standard of care for BRAF -mutated metastatic colorectal cancer (mCRC) based on the BEACON CRC trial, which showed a survival benefit of the three-drug combination regimen with BRAF and MEK inhibitors plus anti-EGFR antibody as well as the two-drug combination regimen with BRAF inhibitor and anti-EGFR antibody over standard chemotherapy. The two-drug combination regimen is approved in Europe and the US, while both three- and two-drug combination regimens are approved in Japan.

Combined targeted therapy for BRAF mutant metastatic colorectal cancer: are we there yet?

Combined targeted therapy for BRAF mutant metastatic colorectal cancer: are we there yet?

A BEACON of hope for BRAF-mutant metastatic colorectal cancer

A BEACON of hope for BRAF-mutant metastatic colorectal cancer

Real-World Outcomes of Patients With BRAF-Mutated Metastatic Colorectal Cancer Treated in the United States

BRAF mutations portend a poor prognosis in metastatic colorectal cancer (mCRC). Whether these patients may benefit from more aggressive frontline chemotherapy with a triplet regimen such as FOLFOXIRI remains unclear. We used real-world data from a cohort of patients in the United States to assess the BRAF testing rate, determine the prevalence of FOLFOXIRI use, and compare survival outcomes in mCRC, stratified by BRAF mutation status and first-line therapy. A nationwide electronic health record-derived deidentified database was reviewed for patients diagnosed with mCRC between 2013 and 2018. Those with documented BRAF mutation testing who received standard first-line therapy were included. Kaplan-Meier estimates with corresponding log-rank tests and Cox proportional hazards modeling compared survival outcomes stratified by BRAF status and first-line therapy. Of 4,457 included patients, 3,991 (89.5%) had BRAF wild-type (BRAFwt) and 466 (10.5%) had BRAF-mutated (BRAFmt) mCRC. Median overall survival (OS) was 15.4 months in the BRAFmt group versus 28.1 months in the BRAFwt group (hazard ratio [HR], 0.48; 95% CI, 0.41-0.56; P<.001). Only 3% of patients with BRAF mutations received first-line FOLFOXIRI ± bevacizumab, with a median OS of 13.8 months compared with 15.5 months in those treated with doublet chemotherapy ± bevacizumab (P=.38). In patients with BRAF mutations, propensity-weighted analysis did not detect a significant improvement in OS with FOLFIRI + bevacizumab (HR, 0.90; 95% CI, 0.58-1.39; P=.63) or FOLFOX/CAPEOX + bevacizumab (HR, 0.81; 95% CI, 0.52-1.26; P=.35) versus doublet chemotherapy alone. In 2018, only 56% of patients diagnosed with mCRC had documented BRAF testing at any time. This real-world data analysis confirms the negative prognostic impact of BRAF mutations in mCRC and suggests that FOLFOXIRI has not been widely adopted in the United States. The proportion of patients with documented BRAF testing in this real-world population was low at 56%. We were unable to show any significant difference in OS of patients with BRAFmt mCRC based on the first-line therapy received.

Treatment Options in BRAF-mutant Metastatic Colorectal Cancer

Treatment of BRAF-mutant colorectal cancer (CRC) traditionally represents an unmet need, mainly due to its unfavourable prognostic outlook, limited options for targeted treatment and scarce benefit from epithelial growth-factor receptor (EGFR) inhibitors. Recently, the development of BRAF V600E inhibitors has expanded the therapeutic armamentarium, although exclusive targeting of BRAF has proved to be an unsuccessful strategy due to reactivation of the mitogen-activated protein kinase pathway through multiple escape mechanisms. Combination strategies that exploit simultaneous inhibition of BRAF, EGFR and/or mitogen-activated protein/extracellular signal-regulated kinase have achieved greater success, with the BEACON CRC trial providing the first evidence for an improvement in survival with a chemotherapy-free approach in pre-treated patients with CRC, leading to regulatory approval for the combination of encorafenib and cetuximab. Subsequent research efforts attempt to build on these foundations, exploring targeted maintenance strategies and conceivably moving the combination towards the first line of therapy soon, as well as laying the foundation for the use of liquid biopsy as a guidance tool in a precision oncology approach.

Tumour mutational burden predicts resistance to EGFR/BRAF blockade in BRAF-mutated microsatellite stable metastatic colorectal cancer

AimTo unveil genomic and immunohistochemical expression profiles associated with primary resistance to EGFR/BRAF targeted therapy in patients with BRAF-mutated and microsatellite stable (MSS) metastatic colorectal cancer. Experimental designIn this multicenter case-control study on patients treated with EGFR/BRAF ± MEK blockade, we compared a primary resistance cohort (N = 20; RECISTv1.1 PD/SD, and progression-free survival [PFS] <16 weeks) versus a sensitive one (N = 19; RECISTv1.1 PR/CR, and PFS ≥16 weeks) in terms of clinical and genomic/expression data by means of comprehensive genomic profiling, tumour mutational burden (TMB), BRAF-mutant transcriptional subtypes (BM) classification and PTEN expression. ResultsLeft-sided tumours (28% of the total) were enriched in the sensitive versus resistant cohort (53% versus 10%, P = 0.010). Genomic alterations in the PIK3CA/MTOR pathway, BM1 status and PTEN loss were similarly distributed among patients with resistant and sensitive tumours. Amplification of CCND1-3 genes were found only in patients with primary resistance (20% versus 0%, P = 0.106). TMB and prevalence of intermediate TMB (TMB-I 6–20 mutations/Mb) were higher in the resistant versus sensitive cohort (median TMB: 6 [IQR, 3–7.29] versus 3 [IQR, 1.26–3.5]; P = 0.013; TMB-I/H: 60% versus 11%; P = 0.001). Patients with TMB-I had shorter PFS (3.3 versus 5.9 months; HR = 2.19, 95%CI, 1.07–4.47, P = 0.031) and overall survival (6.3 versus 10.5 months; HR = 2.22, 95%CI, 1.02–4.81, P = 0.044). ConclusionDespite the small sample size, the association of a relatively higher TMB with limited benefit from EGFR/BRAF blockade in patients with MSS and BRAF-mutated mCRC deserves prospective validation.

BRAF, MEK, and EGFR Triplet Inhibitors as Salvage Therapy in BRAF-Mutated Metastatic Colorectal Cancer-A Case Series Study Target Therapy of BRAF-Mutated mCRC.

Backgroundand objectives: Patients with BRAF-mutated metastatic colorectal cancer have considerably poorer responses to conventional systemic treatment. The real-world effects of triplet therapy with BRAF, mitogen-activated protein kinase kinase, and epidermal growth factor receptor inhibitors in Asia have not been well-reported. Materials and Methods: This single-center case series included patients with BRAF-mutated metastatic colorectal cancer undergoing triplet therapy after failure of prior systemic treatment from 2016 to 2020. The primary outcome was progression-free survival, and secondary outcomes were overall survival, response rate, disease control rate, and adverse events. Results: Nine eligible patients with BRAF-mutated metastatic colorectal cancer receiving triplet therapy were enrolled, with a median follow-up time of 14.5 months (range, 1–26). Most patients (88.8%) had two or more prior systemic treatments, and the triplet regimen was mainly dabrafenib, trametinib, and panitumumab. The overall response rate and disease control rate were 11.1% and 33.3%, respectively. Median progression-free survival and overall survival were 2.9 and 7.4 months, respectively, and a trend toward better overall survival was found with left-sided metastatic colorectal cancer compared with right-sided disease (9.2 vs. 6.9 months, p = 0.093). Adverse events were mostly Grade 1–2, including nausea, hypertension, gastrointestinal symptoms, and skin disorders. Conclusions: In this single-center case series, triplet therapy with BRAF, mitogen-activated protein kinase kinase, and epidermal growth factor receptor inhibitors in BRAF-mutated metastatic colorectal cancer had an acceptable safety profile and reasonable efficacy.

O-9 5-FU/LV + cetuximab + vemurafenib as maintenance therapy for BRAF-mutant (BRAFmut) metastatic colorectal cancer: Efficacy, safety, and exploratory biomarker findings from Cohort 1 of the MODUL trial

O-9 5-FU/LV + cetuximab + vemurafenib as maintenance therapy for BRAF-mutant (BRAFmut) metastatic colorectal cancer: Efficacy, safety, and exploratory biomarker findings from Cohort 1 of the MODUL trial

Exploring clinical and gene expression markers of benefit from FOLFOXIRI/bevacizumab in patients with BRAF-mutated metastatic colorectal cancer: Subgroup analyses of the TRIBE2 study

BackgroundRecent data from the TRIBE2 study have failed to suggest a higher magnitude of benefit from upfront FOLFOXIRI/bevacizumab in patients with BRAF-mutant metastatic colorectal cancer (mCRC) as previously reported in the TRIBE study. Patients and methodsClinical characteristics and gene expression signatures of patients with BRAF-mutant mCRC enrolled in the TRIBE2 study were evaluated with the aim of understanding that patients may derive benefit from the intensification of the upfront chemotherapy. ResultsOf 46 BRAF-mutant tumour samples analysed, 24 (52%) and 22 (48%) were classified as BM1 and BM2, respectively, and 27 (59%) and 19 (41%) were assigned to ligand-independent (LI) and ligand-dependent (LD) Wnt pathway subgroups, respectively. No prognostic impact was shown for both BM1/BM2 and LI/LD subtypes. No interaction was evident between BM1/BM2 or LI/LD signatures and the benefit provided by FOLFOXIRI/bevacizumab. Significant interaction effect was evident in terms of progression-free survival between treatment arm and primary tumour sidedness (P = 0.05) and Eastern Cooperative Oncology Group performance status (ECOG-PS; P < 0.001). ConclusionsGene expression analysis failed to identify patients with BRAF-mutant mCRC candidate to upfront FOLFOXIRI/bevacizumab. ECOG-PS >0 and left-sidedness seem associated with no benefit from the intensified treatment.

Clinicopathologic features and impact of metastasectomy in patients with BRAF-mutant metastatic colorectal cancer.

e15547 Background: BRAF V600E mutation is associated with poor prognosis in patients with metastatic colorectal cancer (mCRC), while the non-V600E mutation mCRC patients showed better prognosis than that of V600E mutation. The clinicopathologic features between V600E and non-V600E mutation has not yet been fully evaluated. And the impact of metastasectomy for patients with BRAF-mutant mCRC was not well-known. Methods: A retrospective study was conducted to evaluate the clinical and pathological characteristics of patients with BRAF-mutant mCRC. Next generation sequencing (22-gene panel) was performed in some of the patients. Survival was also analyzed in the cohort of BRAF V600E and non-V600E mutation with or without metastasectomy. Results: Between December 2014 and August 2020, 116 patients with BRAF-mutant mCRC were enrolled, including 94 patients with BRAF V600E mutation and 22 patients with non-V600E mutation. Significant difference was observed in the prevalence of peritoneal metastasis (69.1% vs. 27.3%, P = 0.001) and lung metastasis (11.7% vs. 36.4%, P = 0.009) between BRAF V600E mutation and non-V600E mutations. In genomic profile, SMAD4 mutation (30.7% vs. 13.7%) showed higher prevalence in patients with BRAF V600E mutation than that of non-V600E mutations, while RAS mutation (18.2% vs. 6.4%) and FBXW7 mutation (13.7% vs 3.1%) had higher incidence in BRAF non-V600E mutations than that of V600E mutation. Patients with BRAF V600E mutation showed a poorer overall survival than those with non-V600E mutations (13.9 vs. 26.8 months, P = 0.038). Totally, 46 patients received metastasectomy after systemic treatment. The median survival for BRAF V600E patients with or without metastasectomy was not reach (42.3+ months) vs. 8.3 months, respectively ( P &lt; 0.001), and for non-V600E patients with or without metastasectomy was not reach (64.2+ months) vs. 23.3 months, respectively (P &lt; 0.001). In multivariate analysis, ECOG performance status (0-1 vs. 2) ( P = 0.001), Staging (IVa-b vs. IVc) ( P = 0.01) and metastasectomy ( P = 0.001) were independent prognostic factors of overall survival. Conclusions: BRAF V600E mutation defines a subgroup of mCRC with worse prognosis. Metastasectomy might improve the survival benefit in carefully selected BRAF-mutant mCRC patients after systemic treatment.