Mutant Metastatic Colorectal Cancer Research Articles

IL-8 and eNOS polymorphisms predict bevacizumab-based first line treatment outcomes in RAS mutant metastatic colorectal cancer patients.

BackgroundPredictive biomarkers of efficacy and toxicity of bevacizumab have not yet been validated. This study assessed the influence of IL-8, eNOS and VEGF-A polymorphisms in RAS mutated metastatic colorectal cancer patients receiving bevacizumab-based chemotherapy.Methods120 patients treated with first-line combination FOLFOX6 plus bevacizumab were included. A historical cohort of 112 RAS mutated colorectal cancer patients treated with FOLFOX6 alone served as control group. The following SNPs were analyzed: IL-8 c.-251T>A; eNOS c.-786T>C and c.-894G>T; VEGF-A c.936C>T, c.958T>C, c.1154A>G and c.2578C>A. Correlation of SNPs, baseline IL-8 serum levels and bevacizumab-efficacy was done.ResultsIn the bevacizumab group, carriers of the IL-8 alleles c.-251TA+AA showed a shorter PFS (P=0.002) and OS (P=0.03) compared to TT alleles. Patients with pre-treatment IL-8 < 18.25 pg/ml showed significantly longer median PFS and OS (PFS: 10.9 vs 7.6 months, P=0.005; OS: 30.7 vs 18.2 months, P<0.001) compared to patients with IL-8 higher levels (>18,25 pg/ml). IL-8 c.-251TA+AA carriers had significantly higher IL-8 levels (P<0.0001). Multivariate analysis confirmed association of IL-8 polymorphism with PFS, and of IL-8 baseline levels with both PFS and OS. IL-8 SNP did not affect the outcome in the control group. The eNOS polymorphism c.-894G>T was found associated with higher severe toxicity (P=0.0002) in patients carrying the c.-894TT genotype.ConclusionsAlthough our data need prospective validation, IL-8 and eNOS SNPs may be have a role as predictive biomarkers for bevacizumab efficacy and toxicity.

Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer.

KRAS mutations are an established predictor of lack of response to EGFR-targeted therapies in patients with metastatic colorectal cancer (mCRC). However, little is known about the role of the rarer NRAS mutations as a mechanism of primary resistance to the anti-EGFR monoclonal antibody cetuximab in wild-type KRAS mCRC. Using isogenic mCRC cells with a heterozygous knock-in of the NRAS activating mutation Q61K, we aimed to elucidate the mechanism(s) by which mutant NRAS blocks cetuximab from inhibiting mCRC growth. NRASQ61K/+ cells were refractory to cetuximab-induced growth inhibition. Pathway-oriented proteome profiling revealed that cetuximab-unresponsive ERK1/2 phosphorylation was the sole biomarker distinguishing cetuximab-refractory NRASQ61K/+ from cetuximab-sensitive NRAS+/+ cells. We therefore employed four representative MEK1/2 inhibitors (binimetinib, trametinib, selumetinib, and pimasertib) to evaluate the therapeutic value of MEK/ERK signaling in cetuximab-refractory NRAS mutation-induced mCRC. Co-treatment with an ineffective dose of cetuximab augmented, up to more than 1,300-fold, the cytotoxic effects of pimasertib against NRASQ61K/+ cells. Simultaneous combination of MEK1/2 inhibitors with cetuximab resulted in extremely high and dose-dependent synthetic lethal effects, which were executed, at least in part, by exacerbated apoptotic cell death. Dynamic monitoring of real-time cell growth rates confirmed that cetuximab synergistically sensitized NRASQ61K/+ cellsto MEK1/2 inhibition. Our discovery of a synthetic lethal interaction of cetuximab in combination with MEK1/2 inhibition for the NRAS mutant subgroup of mCRC underscores the importance of therapeutic intervention both in the MEK-ERK and EGFR pathways to achieve maximal therapeutic efficacy against NRAS-mutant mCRC tumors.

Combination of NK Cells and Cetuximab to Enhance Anti-Tumor Responses in RAS Mutant Metastatic Colorectal Cancer.

The ability of Natural Killer (NK) cells to kill tumor targets has been extensively studied in various hematological malignancies. However, NK cell therapy directed against solid tumors is still in early development. Epidermal Growth Factor Receptor (EGFR) targeted therapies using monoclonal antibodies (mAbs) such as cetuximab and panitumumab are widely used for the treatment of metastatic colorectal cancer (mCRC). Still, the clinical efficacy of this treatment is hampered by mutations in RAS gene, allowing tumors to escape from anti-EGFR mAb therapy. It is well established that NK cells kill tumor cells by natural cytotoxicity and can in addition be activated upon binding of IgG1 mAbs through Fc receptors (CD16/FcγRIIIa) on their surface, thereby mediating antibody dependent cellular cytotoxicity (ADCC). In the current study, activated Peripheral Blood NK cells (PBNK) were combined with anti-EGFR mAbs to study their effect on the killing of EGFR+/- cancer cell lines, including those with RAS mutations. In vitro cytotoxicity experiments using colon cancer primary tumors and cell lines COLO320, Caco-2, SW620, SW480 and HT-29, demonstrated that PBNK cells are cytotoxic for a range of tumor cells, regardless of EGFR, RAS or BRAF status and at low E:T ratios. Cetuximab enhanced the cytotoxic activity of NK cells on EGFR+ tumor cells (either RASwt, RASmut or BRAFmut) in a CD16 dependent manner, whereas it could not increase the killing of EGFR- COLO320. Our study provides a rationale to strengthen NK cell immunotherapy through a combination with cetuximab for RAS and BRAF mutant mCRC patients.

Identifying SNPs associated with progression-free survival (PFS) and overall survival (OS) in patients with KRAS wildtype and mutant metastatic colorectal cancer (mCRC) using Random Survival Forests (RSF).

3604Background: Patients (pts) with newly diagnosed mCRC treated with 1st-line bevacizumab (Bev) based therapy have median OS over 2 years. All pts eventually progress: response rates are ≈60% and ...

Analysis of medical practices for French patients with BRAF mutant metastatic colorectal cancer.

e15070Background: BRAF V600E mutations are rare in metastatic colorectal cancers (mCRC). Recent results showed that BRAF mutant tumors usually have a poor prognosis, resist to anti-EGFR treatment a...

Molecular Biomarkers in the Personalized Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is a disease in which pathogenesis is influenced by genetic and epigenetic events that occur with tumor initiation and progression. Large variation exists in individual patient prognosis and response to chemotherapy, caused by molecular heterogeneity. Certain biomarkers have been identified that can predict clinical outcome beyond tumor staging, and inform treatment selection. Molecular testing is routinely performed in clinical practice for the selection of patients for targeted biological agents or immunotherapy, and is advocated for prognostic stratification. Estimating prognosis can avoid undertreatment or overtreatment and also guide the intensity of patient follow-up. Classifiers of CRC have been developed that integrate genetic and/or epigenetic features. The mutational status of KRAS and BRAF(V600E) oncogenes combined with analysis of the DNA mismatch repair system with/without the CpG island methylator phenotype (CIMP) has been shown to identify colon cancer subtypes with distinct clinical features and prognoses. Gene expression profiling has also been used to subtype CRCs and can overcome the limitations of single/limited gene testing. A recent effort identified 4 consensus molecular subtypes of biological relevance that were associated with different patient outcomes. Efforts to validate and refine these subtypes to include additional genomic features are ongoing. The focus of this article is to highlight molecular markers that can inform clinical decision-making in patients with CRC.

Survival determinants with matched targeted therapies in BRAF mutant metastatic colorectal cancer (mCRC).

649 Background: BRAF mutation (mt) occurs in 5-8% of mCRC and is associated with poor prognosis. Matched targeted therapies for this population are increasingly available in clinical trials. Methods: From Nov 2010 to June 2015, a total of 32 chemorefractory BRAF mt mCRC patients (pts) were enrolled in phase I trials with anti-BRAF matched therapy at Vall d´Hebron Institute of Oncology. BRAF mt was determined by real-time PCR (50%), mass spectrometry (Sequenom, 28%) or next-generation sequencing (Amplicon MiSeq, 22%). All demographic, treatment and survival data were retrospectively analyzed. Results: Median age was 60.4 years (range 42.8-73.5), 62% had right-sided CRC primaries and 59% were stage IV at diagnosis. Median treatment lines before matched therapy was 2 (range 1-4). Co-existing RNFA43, PI3KCA and GNAS mt were found in 4, 2 and 1 pts, respectively. Median time from diagnosis to start of anti-BRAF therapy was 18.6 months (m) (CI95% 14-36) and median time from diagnosis of mCRC to death was 28.4m (CI95% 25-50). A total of 41 anti-BRAF matched therapies were delivered, 9 pts received more than 1 regimen. BRAF inhibitor (inh) monotherapy was delivered in 34% of cases; BRAF plus MEK/EGFR/WNT/PI3K/CDK inh doublets or triplets to 37% and 29% pts, respectively. Survival from start of anti-BRAF to death was 8.9m (CI95% 7-15), without significant differences if 1 or more than 1 anti-BRAF regimen was given (HR: 0.82, p=0.6). Partial responses were observed in 7 cases (17%, 4 doublets and 3 triplets) and complete response in 2 cases (5%, 1 doublet and 1 triplet). Median time on treatment (ToT) with anti-BRAF therapy was 2.83m (CI95% 2-5.5). Of note, ToT was significantly longer for triplets compared to mono/doublets: 5.5m (CI95% 2.7-not reached) vs. 1.9m (CI95% 1.6-3.7; HR: 0.46 [CI95% 0.2-1.0], p=0.05). Median BRAFmt allele fraction (adjusted for tumor purity) was 0.25 (0.13-0.68); no correlation with ToT on anti-BRAF therapy was observed (p=0.36). Conclusions: In a selected BRAF mt population enrolled in early trials with anti-BRAF matched therapy at our institution, survival in the metastatic setting was remarkably high. Triplet matched therapies seem to control disease for longer time than mono/doublets.

A prospective translational study investigating molecular predictors of resistance and response to regorafenib (REG) monotherapy in RAS mutant (mt) metastatic colorectal cancer (mCRC): Initial magnetic resonance imaging (MRI) sub-study result.

580 Background: REG that has single agent efficacy in patients (pts) with refractory mCRC, is known to have anti-angiogenic activities. The benefit of REG in unselected pts is modest. Thus, the identification of predictive biomarkers is critical for treatment stratification. PROSPECT-R study aims to identify genetic and radiological mechanisms of primary and acquired REG resistance in RAS mt mCRC patients. Methods: Multiparametric MRI studies including dynamic contrast enhancement (DCE)-MRI and diffusion weighted imaging (DWI) were acquired pre- and at day 15 post-treatment on a 1.5T Siemens Avanto MR scanner. Regions of interest of the entire chosen target metastatic lesion were drawn by a senior radiologist and the following imaging parameters were generated: volume transfer constant (Ktrans) derived from a pharmacokinetic analysis based on the extended Kety model and apparent diffusion coefficient (ADC) calculated using a mono-exponential fitting algorithm; median values of ADC and Ktrans were reported. Results: The first seven enrolled pts were analysed; a single target lesion per patient was chosen (5 liver and 2 pelvic metastases). At day 15 post treatment, a marked decrease (68-81%) of median tumour Ktrans was observed in 4 out of 7 pts; the remaining 3 patients showed no significant median Ktrans change (-36 to + 17%). Overall, the cohort average Ktrans decreased from 0.17 to 0.07 min-1(58%). No significant ADC changes were observed at day 15. Of the 4 pts with Ktrans reduction on day 15, 1 achieved RECIST 1.1 partial response (38% reduction in target lesions), 2 had stable disease and 1 progressed, based on CT assessments performed at 8 weeks of REG therapy; 3/7 pts with no Ktrans change progressed within 2 months of initiating REG. When modified Choi criteria were applied, 3/4 pts with Ktrans reduction were classified as responders. Conclusions: REG may have early anti-angiogenic affects; DCE-MRI could be a potential predicting biomarker in pts treated with REG. Further analysis within PROSPECT-R may elucidate genetic biomarkers to validate these findings. Clinical trial information: EUDRACT No: 2014- 003579-51.

Differential radiographic appearance of BRAF V600E mutant metastatic colorectal cancer (mCRC) in patients matched by primary tumor location.

554 Background: BRAF mutation status and location of CRC primary each correlate with pattern of metastatic spread. We sought to determine whether presence of a BRAF V600E (BRAF) mutation is differentially associated with sites and appearance of metastatic disease in patients matched by primary tumor location. Methods: 40 patients with BRAF mutant mCRC were matched to 80 patients with BRAF wild-type CRC by location of primary tumor (right colon, left colon or rectum), sex, and age ( &lt; 50; 50+). CT scans were reviewed for disease characterization. BRAF mutation status, clinicopathological characteristics, and sites of metastatic disease were associated using proportion tests. Results: Of the 120 matched patients,60% were female. The distribution of primary tumor locations was: 60% right colon, 30% left colon, and 10% rectum. Median age at diagnosis was 57, range 20-88 yrs. Significantly higher frequencies of peritoneal metastases (p = 0.045) and ascites (p = 0.0038) occurred in patients with BRAF mutant tumors. Among patients with right colon primaries, no significant difference in sites of disease by BRAF mutation status was observed. In patients with left colon primaries, BRAF mutations associated with less frequent liver metastases (42% vs. 79%, p = 0.024) and more frequent ascites (58% vs. 12%, p = 0.0038). Disease was not measurable by RECIST version 1.1 criteria in 20% of patients with BRAF mutations, most often with peritoneal metastases and ascites. Conclusions: Presence of a BRAF V600E mutation associated with a greater proportion of peritoneal metastases and ascites, even among patients matched for primary tumor location. Of 20 patients with BRAF mutant mCRC and peritoneal metastases plus ascites, 6 patients (30%) had disease that was not measurable by RECIST version 1.1. Radiographic characterization provides a window on BRAF mutant mCRC biology and also reveals a challenge for response evaluation on clinical trials. [Table: see text]

Meta-analysis comparing the efficacy of anti-EGFR monoclonal antibody therapy between KRAS G13D and other KRAS mutant metastatic colorectal cancer tumours

BackgroundMetastatic colorectal cancer (mCRC) tumours harbouring a RAS mutation are associated with a lack of treatment benefit from anti-EGFR monoclonal antibodies (mAbs). However, observational evidence has led to speculation that mCRC patients with KRAS G13D mutant (MT) tumours may derive a benefit from treatment with anti-EGFR mAbs. MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate whether the efficacy of anti-EGFR mAbs for mCRC differs between tumours harbouring a KRAS G13D mutation (KRAS G13D) and KRAS mutations other than G13D (other KRAS MT). ResultsEight RCTs (n = 5967) met the inclusion criteria for assessment of both overall survival (OS) and progression-free survival (PFS). For other KRAS MT the hazard ratio for OS benefit with addition of anti-EGFR mAb therapy was 1.06 (95% confidence interval [CI]; 0.96, 1.17), compared to 1.08 (95% CI; 0.73, 1.60) for KRAS G13D [test for interaction p=0.99]. In contrast, the hazard ratio for KRAS wild-type (WT) tumours was 0.85 (95% CI; 0.76, 0.95). Regarding PFS benefit with anti-EGFR mAbs, the hazard ratio was 1.07 (95% CI; 0.92, 1.26) for other KRAS MT, 0.96 (95% CI; 0.73, 1.27) for KRAS G13D, and 0.68 (95% CI; 0.54, 0.85) for KRAS WT. Again, the test for interaction (p=0.46) demonstrated no significant difference in PFS benefit for anti-EGFR mAb therapy between KRAS G13D and other KRAS MT. ConclusionThis meta-analysis demonstrates no significant difference between KRAS G13D and other KRAS MT tumours in terms of treatment benefit from anti-EGFR mAbs for mCRC.

P-309 PROSPECT-R: A PROSPECTive translational study investigating molecular predictors of resistance and response to Regorafenib (REG) monotherapy in RAS mutant (mt) metastatic colorectal cancer (CRC)

Introduction: Background: CRC is the third commonest cancer worldwide and is associated with a high morbidity and mortality. REG, a multi-kinase inhibitor with anti-angiogenic (VEGFR 2/3, TIE-2), anti-stromal (PDGFR-β, FGFR) and anti-oncogenic (KIT, RET and B-RAF) activities has single agent efficacy in patients (pts) with refractory metastatic CRCs (R-CRC). The benefit of REG in unselected pts is modest. Thus, the identification of predictive molecular biomarkers is critical for treatment stratification. The PROSPECT-R study aims to identify genetic and non-genetic mechanisms of primary and acquired REG resistance in RAS mt R-CRC patients, for whom other treatment options are highly limited Methods: PROSPECT-R is a single-centre phase II translational study in R-CRC pts previously treated with standard chemotherapy drugs (fluoropyrimidine, oxaliplatin, irinotecan) and at least one anti-angiogenic antibody. Whole exome sequencing (WES) is performed on archival diagnostic specimens and on fresh biopsies collected immediately before REG treatment, at the time of response or stable disease (8 weeks) and at progression (PD). Live cells are isolated from biopsies and cultured in vitro or in mice to allow functional validation of putative REG resistance drivers and the development of rational combination therapies to overcome resistance. Blood samples are collected every 4 weeks for analysis of candidate circulating makers (tumour DNA and micro-RNA). Additionally, dynamic contrast enhanced and diffusion weighted magnetic resonance imaging are performed pre-treatment and on day 15 for imaging biomarker development. Treatment efficacy is measured by regular computed tomography scans and serum tumour markers. The identification of genetic biomarkers of REG resistance by WES is the primary endpoint, while secondary outcomes include identification of response and resistance biomarkers by proteomic, epigenetic, radiological and ex-vivo studies. The study aims to recruit 20-30 pts with paired biopsies (pre-treatment and PD). Recruitment started in January 2015 and to date 4 pts have started treatment on the study.

Pilot trial of combined BRAF and EGFR inhibition in BRAF-mutant metastatic colorectal cancer patients.

BRAF-mutant metastatic colorectal cancer (mCRC) forms an aggressive subset of colorectal cancer with minimal response to selective RAF inhibitors. Preclinical data show that reactivation of EGFR signaling occurs in colorectal tumor cells treated with RAF inhibitors and that the addition of an EGFR inhibitor enhances antitumor activity. These data suggest that combined therapy with RAF and EGFR inhibitors could be an effective strategy for treating BRAF V600E mCRC. We undertook a pilot trial to assess the response rate and safety of the BRAF inhibitor vemurafenib combined with anti-EGFR antibody panitumumab in patients with BRAF-mutant mCRC. Patients received standard approved doses of panitumumab and vemurafenib. Fifteen patients were treated. Performance status was Eastern Cooperative Oncology Group (ECOG) 0 in 4 patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and 8 (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Treatment was well tolerated, with less cutaneous toxicity than would be expected with either agent, and no cases of keratoacanthomas/squamous cell carcinomas. Tumor regressions were seen in 10 of 12 evaluable patients with partial responses in 2 patients (100% and 64% regression lasting 40 and 24 weeks, respectively), and stable disease lasting over 6 months in 2 patients. Combined RAF and EGFR inhibition is well tolerated, with less cutaneous toxicity than would be expected with either agent, and results in modest clinical activity in this highly aggressive and chemoresistant subset of CRC.

Pilot study of vemurafenib and panitumumab combination therapy in patients with BRAF V600E mutated metastatic colorectal cancer.

611 Background: BRAF mutant metastatic colorectal cancer (mCRC) is an aggressive subset of colorectal cancer that exhibits minimal response to selective RAF inhibitors. Preclinical data suggest that epidermal growth factor receptor (EGFR) reactivation with RAF inhibition attenuates the efficacy of RAF inhibitors in mCRC and that combined EGFR and RAF inhibition may be a promising therapeutic strategy. Methods: We undertook a pilot trial to assess the response rate and safety of the combination of the selective RAF inhibitior vemurafenib and anti-EGFR antibody panitumumab in patients with BRAF mutant mCRC. Patients received panitumumab 6 mg/kg IV every 14 days starting on day 1 and vemurafenib 960 mg orally twice daily continuously starting on day 8, with treatment staggered for planned correlative studies. Results: Fifteen patients received treatment. Median age was 62 years (range 22-83 years), seven patients (47%) were male, and 11 patients (73%) had a right-sided primary tumor. Performance status was ECOG 0 in four patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and eight patients (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Acneiform rash (all grade 1 or 2) (53%), fatigue (53%), and arthralgias (40%) were the most frequently observed treatment-related adverse events. Treatment response was assessed in 12 patients because two patients died from disease progression before the first scan and one patient withdrew consent soon after starting treatment. Two patients (13%) had confirmed partial responses (100% and 64% regression) lasting 40 and 24 weeks, respectively. Eight patients (53%) had stable disease (SD) with tumor regression of &gt;15% by RECIST measurement in six of these patients, including two of whom achieved stable disease lasting over six months. Conclusions: Combined RAF and EGFR inhibition is well tolerated and leads to tumor regression in a subset of patients with BRAF mutant mCRC. Planned correlative studies will evaluate degree of pathway inhibition and reactivation of other upsteam pathways with vemurafenib and panitumumab treatment. Clinical trial information: NCT01791309.

539P - Tumor Heterogeneity and Efficacy of First-Line Cetuximab + Folfiri in Kras Mutant Metastatic Colorectal Cancer (Mcrc) Patients (Pts) of the Capri Goim Trial

ABSTRACT Aim: Cetuximab treatment in mCRC is restricted to pts with KRAS and NRAS wt tumors. Recent data suggest that low levels of KRAS mutant alleles might confer resistance to anti-EGFR therapies. Methods: In the CAPRI GOIM trial, KRAS exon 2 wt mCRC pts received first line cetuximab plus FOLFIRI. Primary endpoint was progression-free survival (PFS). Tumor samples were assessed by next generation sequencing (NGS) with the Ion AmpliSeq™ Lung and Colon Cancer Panel that covers over 500 mutations in hot spot regions of 22 genes. The allelic frequency of mutant KRAS, NRAS, BRAF and PIK3CA was normalized for the neoplastic cell content and multiplied by 2 to obtain the Heterogeneity Score (HS), which corresponds to the fraction of neoplastic cells carrying a specific mutation. Results: NGS analysis was performed in 182 cases. Forty-five cases (24.7%) had mutations in KRAS, 24 (13.2%) in PIK3CA, 15 (8.2%) in BRAF, and 13 (7.1%) in NRAS. KRAS and NRAS mutations were mutually exclusive, whereas PIK3CA and BRAF mutations were detected in RAS mutant tumors. The KRAS HS ranged between 12 and 260, indicating a wide heterogeneity of KRAS mutant alleles content in CRC. However, the KRAS HS mean value of 90,93 and median value of 84,44 suggested that in most CRC the majority of neoplastic cells carry a mutant KRAS allele. Similar findings were observed for NRAS (HS range 35,5-146,67; mean 102,77; median 117,14). In contrast, in BRAF (HS range 17,14-120; mean 54,82; median 54,29) and PIK3CA (HS range 14,29-120; mean 54,82; median 54,29) mutant cases only a fraction of neoplastic cells seem to carry the mutant allele. The RR was 70% in KRAS mutant pts with an HS 40 pts (high KRAS; n.35); mPFS were 7,97 and 8,37 months for low KRAS and high KRAS subgroups, respectively. Importantly, 7/10 low KRAS tumors had additional mutations in PIK3CA (n.6), TP53 (n.4), BRAF (n.2), ERBB2 (n.1), FGFR3 (n.1), and/or FBXW7 (n.1). Conclusions: Pts carrying low levels of mutant KRAS alleles showed a mPFS similar to pts with high KRAS mutant allele frequency. However, this phenomenon could be due to the complex mutational profile of CRC rather than to the KRAS mutational status. Disclosure: N. Normanno: Advisory Boards: Merck Serono, Amgen; F. Ciardiello: Advisory Boards: Roche, Merck Serono, Astellas, Bayer. All other authors have declared no conflicts of interest.

Targeting BRAF mutant metastatic colorectal cancer: clinical implications and emerging therapeutic strategies.

Increasing knowledge of the underlying signaling pathways and molecular defects involved in colorectal cancer growth or progression enabled the discovery of several prognostic and predictive biomarkers, leading to the development of novel molecularly targeted therapies. The mitogen-activated protein kinase (MAPK) signaling pathway plays a critical role in colorectal cancer progression. Mutations in BRAF, a principal effector of Ras in this signaling cascade, are found in 10% of colorectal cancer and play a clear pathogenic role, particularly in patients with metastatic disease. Intense efforts have therefore focused on targeting BRAF as an oncogenic driver, with mixed early results. This article summarizes the molecular and clinical features of BRAF mutant colorectal cancer, the prognostic and predictive role of BRAFV600E mutation in colorectal cancer, initial clinical trial results in targeting BRAFV600E, and the more recent preclinical insights into potential mechanisms of resistance to BRAF inhibition that have now led to a number of rationale-driven combination therapeutic strategies.

Prognostic relevance of KRAS genotype and the prevalent C.35 G &gt; a mutation in metastatic colorectal cancer (MCRC) patients fitting for intensive FIr-B/FOx triplet chemotherapy plus bevacizumab.

e14575 Background: Bevacizumab (BEV) addiction to chemotherapy can predict increased efficacy in KRAS wild-type and mutant metastatic colorectal cancer (MCRC) patients. Codon 12 KRAS mutations diff...

Phase II study of single-agent cetuximab in KRAS G13D mutant metastatic colorectal cancer (mCRC).

3524 Background: RAS mutant metastatic colorectal cancer (mCRC) patients (pts) are excluded from treatment with anti-EGFR monoclonal antibodies. Nevertheless, retrospective data from large phase II...

Oxaliplatin-Based Chemotherapy Is More Beneficial in KRAS Mutant than in KRAS Wild-Type Metastatic Colorectal Cancer Patients

To identify better regimens in currently available chemotherapy would be beneficial to KRAS mutant metastatic colorectal cancer (mCRC) patients because they have fewer treatment options than KRAS wild-type mCRC patients. Clinicopathologic features and overall survival (OS) of KRAS mutant and wild-type mCRC patients who had used oxaliplatin-based, irinotecan-based, bevacizumab-based, as well as cetuximab-based regimens were compared to those who had never-used oxaliplatin-based, irinotecan-based, bevacizumab-based, as well as cetuximab-based regimens respectively. Between 2007 and 2012, a total of 394 mCRC patients, in whom 169 KRAS mutant and 225 KRAS wild-type, were enrolled. In KRAS mutant patients who had used oxaliplatin-based regimens (N = 131), the OS was significantly longer than that in KRAS mutant patients who had never-used oxaliplatin-based regimens (N = 38). The OS was 28.8 months [95% confidence interval (CI): 23.2–34.4] in KRAS mutant patients who had used oxaliplatin-based regimens versus 17.8 months [95% CI: 6.5–29.1] in KRAS mutant patients who had never-used oxaliplatin-based regimens (P = 0.026). Notably, OS in KRAS wild-type mCRC patients who had used oxaliplatin-based regimens (N = 185) was not significantly longer than that in KRAS wild-type mCRC patients who had never-used oxaliplatin-based regimens (N = 40) (P = 0.25). Furthermore, the OS in KRAS mutant patients who had used either irinotecan-based, bevacizumab-based or cetuximab-based regimens was not significantly different than that in KRAS mutant patients who had never-used either irinotecan-based, bevacizumab-based or cetuximab-based regimens respectively. In multivariate analyses, patients who had used oxaliplatin-based regimens remains an independent prognostic factor for longer OS in KRAS mutant mCRC patients. In conclusion, oxaliplatin-based regimens are more beneficial in KRAS mutant than in KRAS wild-type mCRC patients.

FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer

BackgroundBRAF V600E mutation plays a negative prognostic role in metastatic colorectal cancer (mCRC), leading to a median Progression Free Survival (PFS) of 4–6months with first-line conventional treatments. Our group recently reported in a retrospective exploratory analysis of a phase II trial that FOLFOXIRI (5-FU/LV+Oxaliplatin+Irinotecan) plus bevacizumab might allow to achieve remarkable results in terms of PFS and Overall Survival (OS) also in this poor-prognosis subgroup. The aim of this work was to prospectively validate our retrospective finding. Patients and methodsThis phase II trial was designed to detect an increase in 6month-Progression Free Rate (6m-PFR) from 45% to 80% in a population of BRAF mutant mCRC patients treated with first-line FOLFOXIRI plus bevacizumab. Secondary end-points were PFS, OS, response rate (RR) and the analysis of outcome parameters in the pooled population consisting of both retrospectively and prospectively included patients. This trial is registered with ClinicalTrials.gov, number NCT01437618. ResultsTwo-hundred-fourteen potentially eligible mCRC patients were screened for BRAF mutational status. Fifteen BRAF mutant patients (7%) were included in the validation cohort. At a median follow up of 25.7months, 6m-PFR was 73%. Median PFS and OS were 9.2 and 24.1months, respectively. In the pooled population, at a median follow up of 40.4months, 6m-PFR was 84%. Median PFS and OS were 11.8 and 24.1months, respectively. Overall RR and disease control rate were 72% and 88%, respectively. ConclusionLacking randomised trials in this specific molecular subgroup, FOLFOXIRI plus bevacizumab might be a reasonable option for the first-line treatment of BRAF mutant mCRC patients.

How Do We Make Choices in Salvage Therapy: Panitumumab, Cetuximab, or Regorafenib?

Colorectal cancer is the fourth commonest cancer worldwide. The survival rate is suboptimal for patients with metastatic disease. The introduction of anti-epidermal growth factor receptor (EGFR) antibodies has remarkably improved clinical outcomes. Two monoclonal antibodies targeting EGFR and one multikinase inhibitor have been approved by the FDA and Health Canada for the treatment of metastatic colorectal cancer; however, only about 10 % of patients respond to this treatment. Having wild-type KRAS is necessary but not sufficient to derive benefit from EGFR inhibition. Interestingly, patients with certain mutations such as p.G13D represent a cetuximab-sensitive subtype of KRAS mutant metastatic colorectal cancer. A few biomarkers have been identified, but we still do not know the best way to administer drugs. In this article we review the clinical data and expert opinions and summarize the recommendations.