anti-EGFR Therapy In Colorectal Cancer Research Articles

Unveiling acquired resistance to anti-EGFR therapies in colorectal cancer: a long and winding road.

Emergence of acquired resistance limits the efficacy of the anti-EGFR therapies cetuximab and panitumumab in metastatic colorectal cancer. In the last decade, preclinical and clinical cohort studies have uncovered genomic alterations that confer a selective advantage to tumor cells under EGFR blockade, mainly downstream re-activation of RAS-MEK signaling and mutations in the extracellular domain of EGFR (EGFR-ECD). Liquid biopsies (genotyping of ctDNA) have been established as an excellent tool to easily monitor the dynamics of genomic alterations resistance in the blood of patients and to select patients for rechallenge with anti-EGFR therapies. Accordingly, several clinical trials have shown clinical benefit of rechallenge with anti-EGFR therapy in genomically-selected patients using ctDNA. However, alternative mechanisms underpinning resistance beyond genomics -mainly related to the tumor microenvironment-have been unveiled, specifically relevant in patients receiving chemotherapy-based multi-drug treatment in first line. This review explores the complexity of the multifaceted mechanisms that mediate secondary resistance to anti-EGFR therapies and potential therapeutic strategies to circumvent acquired resistance.

Abstract CT078: Phase 1 study of SGN-EGFRd2 in solid tumors (SGNEGFRd2-001)

Abstract Background: Epidermal growth factor receptor (EGFR) is a cell surface receptor expressed in a variety of solid tumors. Gamma delta (γδ)-T cells represent a conserved T cell subset that can induce cell death in a wide range of malignancies. The presence of γ9δ2-T cells in solid tumors strongly correlates with better patient survival (Gentles 2015; Tosolini 2017). In addition to direct, potent killing by release of cytotoxic molecules, activated γ9δ2-T cells process and present antigen and contribute to a cascade response resulting in downstream activation of innate and adaptive immune cells to mediate further tumor cell killing (Brandes 2005; Devilder 2006; Vantourout 2013). Novel approaches that improve targeting and activation of γ9δ2-T cells may lead to the development of effective and safe cancer treatments. SGN-EGFRd2 is an investigational, bispecific humanized heavy chain-only antibody (HcAb). Advantages of HcAbs include their small size, high solubility, high stability, and excellent tissue penetration in vivo (Bannas 2017). SGN-EGFRd2 simultaneously binds EGFR and the γ9δ2-T cell receptor, resulting in the conditional activation of γ9δ2-T cells. Importantly, full activation of γ9δ2-T cells requires a secondary phosphoantigen stress signal present only in malignant and certain infected cells (Deseke 2020; Herrmann 2020; Rigau 2020; Vantourout 2013), but not normal healthy cells, conferring preferential tumor-directed cytotoxicity. The proposed cytotoxic mechanism of action is independent of KRAS and BRAF mutations (King 2023) known to confer resistance to approved anti-EGFR therapies in colorectal cancer (CRC). This first-in-human study is evaluating the safety, tolerability, and antitumor activity of SGN-EGFRd2 in patients with advanced solid tumors. Methods: SGNEGFRd2-001 (NCT05983133) is an open-label, multicenter, phase 1, dose escalation and expansion study evaluating SGN-EGFRd2 monotherapy in patients with relapsed/refractory (R/R) CRC, head and neck squamous cell cancer, non-small cell lung cancer, and pancreatic ductal adenocarcinoma in 3 parts: dose escalation (Part A; n ~ 75), dose optimization (Part B; optional; up to n = 40), and dose expansion (Part C; up to n = 160). Patients must have R/R disease, or be intolerant to standard of care therapies, with no appropriate standard therapy available. Patients must have measurable disease per RECIST v1.1, an ECOG performance status of 0 or 1, and adequate organ function. Patients are eligible regardless of tumor EGFR expression or EGFR/KRAS/BRAF mutation status. Patients will receive SGN-EGFRd2 as an intravenous infusion. Primary study objectives are safety and tolerability, maximum tolerated dose, and recommended dose and schedule. Secondary objectives include pharmacokinetics, immunogenicity, and antitumor activity. Tumor samples will be analyzed for exploratory biomarkers. Accrual is ongoing in the US. Additional sites in Europe and Canada are planned. Citation Format: Hirva Mamdani, Joel Randolph Hecht, Rachel E. Sanborn, Maria Corinna Palanca-Wessels, Mingjin Yan, Martin Gutierrez, David L. Bajor. Phase 1 study of SGN-EGFRd2 in solid tumors (SGNEGFRd2-001) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT078.

Pervasive conditional selection of driver mutations and modular epistasis networks in cancer.

Cancer driver mutations often display mutual exclusion or co-occurrence, underscoring the key role of epistasis in carcinogenesis. However, estimating the magnitude of epistasis and quantifying its effect on tumor evolution remains a challenge. We develop a method (Coselens) to quantify conditional selection on the excess of nonsynonymous substitutions in cancer genes. Coselens infers the number of drivers per gene in different partitions of a cancer genomics dataset using covariance-based mutation models and determines whether coding mutations in a gene affect selection for drivers in any other gene. Using Coselens, we identify 296 conditionally selected gene pairs across 16 cancer types in the TCGA dataset. Conditional selection affects 25%-50% of driver substitutions in tumors with >2 drivers. Conditionally co-selected genes form modular networks, whose structures challenge the traditional interpretation of within-pathway mutual exclusivity and across-pathway synergy, suggesting a more complex scenario where gene-specific across-pathway epistasis shapes differentiated cancer subtypes.

Identification of an optimal circulating tumor DNA (ctDNA) shedding threshold to detect actionable driver mutations in colorectal and pancreatic adenocarcinoma.

3571 Background: In colorectal cancer (CRC), mutations in KRAS, NRAS, and BRAF predict resistance to anti-EGFR therapies. In pancreatic ductal adenocarcinoma (PDAC), ~90% of patients harbor KRAS mutations, while KRAS wild-type tumors often have clinically actionable fusion alterations. Thus, in both cancers, the accurate ascertainment of RAS and BRAF driver status is essential. Sequencing of cell-free DNA (cfDNA) from plasma allows convenient assessment of a tumor’s molecular profile, but sensitivity can be limited by low ctDNA shedding. We sought to establish a ctDNA shedding threshold at which actionable driver mutations can be reliably detected. Methods: Molecular reports and matched clinical data were obtained from the Duke Molecular Registry of Tumors and the SCRUM-Japan GOZILA and GI-SCREEN. CRC or PDAC patients with a pathogenic KRAS, NRAS, or BRAF activating point mutation (“driver”) present on tissue next-generation sequencing (NGS) assays and who also had cfDNA assay available were included. Tissue NGS included Foundation One CDx and Oncomine Comprehensive Assay. Guardant 360 (G360) was the sole plasma cfDNA assay. 131 CRC and 24 PDAC cases with 189 total G360 assays met criteria and were included. Samples were analyzed according to detection of the driver mutation and the maximum mutant allele frequency (MAF) of non-driver mutations on G360. An optimal cut-point for max MAF was explored among the CRC and PDAC patients using a maximally selected Wilcoxon rank statistic method. Results: 76.8% of driver mutations were in KRAS, 22.6% in BRAF, and 1.9% in NRAS with an overlap of 1 BRAF and 1 NRAS mutation with a KRAS mutation. Overall sensitivity of G360 for drivers was 83.0% for CRC and 54.2% for PDAC. No variants were detected on G360 in 9.1% of CRC and 37.5% of PDAC. Sensitivity for driver mutations increased with higher maximum non-driver MAF, with MAF > 1% predicting sensitivity > 98% (Table). Optimal cut-point analysis identified MAF of > 0.34% (p < 0.0001), above which the driver was identified in 97% of patients and below which only 27%. Conclusions: In our study, non-driver MAF > 1% on cfDNA NGS predicts high sensitivity for RAS and BRAF mutations and thus is adequate to guide clinical decisions such as anti-EGFR therapy in CRC, evaluation for fusions in PDAC, and validity in clinical trials. MAF ≤0.34% is a clear threshold to consider an assay inadequate and thus seek alternative testing. Sensitivity rises for MAF between 0.35 and 1% but will require greater patient numbers to establish clinically relevant sensitivity thresholds. These results will be updated with additional data for final presentation. [Table: see text]

EMT-mediated regulation of CXCL1/5 for resistance to anti-EGFR therapy in colorectal cancer.

The emergence of RAS/RAF mutant clone is the main feature of EGFR inhibitor resistance in KRAS wild-type colon cancer. However, its molecular mechanism is thought to be multifactorial, mainly due to cellular heterogeneity. In order to better understand the resistance mechanism in a single clone level, we successfully isolated nine cells with cetuximab-resistant (CR) clonality from in vitro system. All CR cells harbored either KRAS or BRAF mutations. Characteristically, these cells showed a higher EMT (Epithelial to mesenchymal transition) signature, showing increased EMT markers such as SNAI2. Moreover, the expression level of CXCL1/5, a secreted protein, was significantly higher in CR cells compared to the parental cells. In these CR cells, CXCL1/5 expression was coordinately regulated by SNAI2/NFKB and transactivated EGFR through CXCR/MMPI/EGF axis via autocrine singling. We also observed that combined cetuximab/MEK inhibitor not only showed growth inhibition but also reduced the secreted amounts of CXCL1/5. We further found that serum CXCL1/5 level was positively correlated with the presence of RAS/RAF mutation in colon cancer patients during cetuximab therapy, suggesting its role as a biomarker. These data indicated that the application of serum CXCL1/5 could be a potential serologic biomarker for predicting resistance to EGFR therapy in colorectal cancer.

Non-Coding RNAs Regulate the Resistance to Anti-EGFR Therapy in Colorectal Cancer.

Colorectal cancer (CRC) is the third prevalent cancer worldwide, the morbidity and mortality of which have been increasing in recent years. As molecular targeting agents, anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (McAbs) have significantly increased the progression-free survival (PFS) and overall survival (OS) of metastatic CRC (mCRC) patients. Nevertheless, most patients are eventually resistant to anti-EGFR McAbs. With the intensive study of the mechanism of anti-EGFR drug resistance, a variety of biomarkers and pathways have been found to participate in CRC resistance to anti-EGFR therapy. More and more studies have implicated non-coding RNAs (ncRNAs) primarily including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are widely involved in tumorigenesis and tumor progression. They function as essential regulators controlling the expression and function of oncogenes. Increasing data have shown ncRNAs affect the resistance of molecular targeted drugs in CRC including anti-EGFR McAbs. In this paper, we have reviewed the advance in mechanisms of ncRNAs in regulating anti-EGFR McAbs therapy resistance in CRC. It provides insight into exploring ncRNAs as new molecular targets and prognostic markers for CRC.

The Role of EREG/EGFR Pathway in Tumor Progression.

Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung cancer and colorectal cancer (CRC). Epiregulin (EREG) is one of the EGFR ligands and is low expressed in most normal tissues. Elevated EREG in various cancers mainly activates EGFR signaling pathways and promotes cancer progression. Notably, a higher EREG expression level in CRC with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) is related to better efficacy of therapeutic treatment. By contrast, the resistance of anti-EGFR therapy in CRC was driven by low EREG expression, aberrant genetic mutation and signal pathway alterations. Additionally, EREG overexpression in non-small cell lung cancer (NSCLC) is anticipated to be a therapeutic target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that EREG derived from macrophages promotes NSCLC cell resistance to EGFR-TKI treatment. The emerging events of EREG-mediated tumor promotion signals are generated by autocrine and paracrine loops that arise from tumor epithelial cells, fibroblasts, and macrophages in the tumor microenvironment (TME). The TME is a crucial element for the development of various cancer types and drug resistance. The regulation of EREG/EGFR pathways depends on distinct oncogenic driver mutations and cell contexts that allows specific pharmacological targeting alone or combinational treatment for tailored therapy. Novel strategies targeting EREG/EGFR, tumor-associated macrophages, and alternative activation oncoproteins are under development or undergoing clinical trials. In this review, we summarize the clinical outcomes of EREG expression and the interaction of this ligand in the TME. The EREG/EGFR pathway may be a potential target and may be combined with other driver mutation targets to combat specific cancers.

Molecular subtype-specific efficacy of anti-EGFR therapy in colorectal cancer is dependent on the chemotherapy backbone

BackgroundPatient selection for addition of anti-EGFR therapy to chemotherapy for patients with RAS and BRAF wildtype metastatic colorectal cancer can still be optimised. Here we investigate the effect of anti-EGFR therapy on survival in different consensus molecular subtypes (CMSs) and stratified by primary tumour location.MethodsRetrospective analyses, using the immunohistochemistry-based CMS classifier, were performed in the COIN (first-line oxaliplatin backbone with or without cetuximab) and PICCOLO trial (second-line irinotecan with or without panitumumab). Tumour tissue was available for 323 patients (20%) and 349 (41%), respectively.ResultsWhen using an irinotecan backbone, anti-EGFR therapy is effective in both CMS2/3 and CMS4 in left-sided primary tumours (progression-free survival (PFS): HR 0.44, 95% CI 0.26–0.75, P = 0.003 and HR 0.12, 95% CI 0.04–0.36, P < 0.001, respectively) and in CMS4 right-sided tumours (PFS HR 0.17, 95% CI 0.04–0.71, P = 0.02). Efficacy using an oxaliplatin backbone was restricted to left-sided CMS2/3 tumours (HR 0.57, 95% CI 0.36–0.96, P = 0.034).ConclusionsThe subtype-specific efficacy of anti-EGFR therapy is dependent on the chemotherapy backbone. This may provide the possibility of subtype-specific treatment strategies for a more optimal use of anti-EGFR therapy.

HER2 positivity as a biomarker for poor prognosis and unresponsiveness to anti-EGFR therapy in colorectal cancer.

To investigate the role of HER2 positivity in prognosis and unresponsiveness to anti-EGFR therapy for colorectal cancer. Patients who underwent primary CRC tumor resection were included. HER2 status of CRC was confirmed by immunohistochemistry and fluorescence in situ hybridization tests. Comparison of survival analysis between HER2 positivity and negativity was evaluated by a stratified log-rank test and summarized with the use of Kaplan-Meier and Cox proportional hazards methods. The treatment effects of cetuximab were further compared in full subgroup analyses. 1240 patients were enrolled, including 763 with stage I-III CRC and 477 with stage IV CRC. 57 (4.6%) CRC patients presented HER2 positivity in the entire cohort. The survival analysis showed that patients with HER2 positivity had significantly worse disease-free survival and overall survival in stage III and IV CRC. The multivariable analysis also confirmed that HER2 positivity was a significantly independent risk factor in stage III and IV CRC. Univariate and multivariable survival analysis showed no prognostic significance of HER2 positivity in stage I-II CRC patients. Prespecified subgroup analysis showed no favorable trends in progression-free survival and overall survival for cetuximab in the patients with HER2 positivity, KRAS/NRAS/BRAF wild-type metastatic CRC (interaction P values = 0.005 and 0.014). For stage III and IV CRC patients, HER2 positivity was confirmed as an independent prognostic risk factor. It could help predict the unresponsiveness to anti-EGFR therapy for metastatic CRC.

RAS Amplification as a Negative Predictor of Benefit from Anti-EGFR-Containing Therapy Regimens in Metastatic Colorectal Cancer.

RAS short variant (SV) mutations in colorectal cancer (CRC) are associated with lack of benefit from epidermal growth factor receptor (EGFR) monoclonal antibody (EGFRmAb). However, the clinical implications for RAS amplification (RASa) as a biomarker for anti-EGFR therapy in CRC remain ill defined. Genomic analysis was performed using the Foundation Medicine (FM) comprehensive genomic profiling database of 37,233 CRC cases. Clinical outcomes were assessed using two independent cohorts: the City of Hope (COH) cohort of 338 patients with metastatic CRC (mCRC) and the Flatiron Health-FM real-world clinicogenomic database (CGDB) of 3,904 patients with mCRC. RASa was detected in 1.6% (614/37,233) of primarily mCRC. RASa 6-9 (n = 241, 39%), 10-19 (n = 165, 27%), and ≥ 20 (n = 209, 34%) copy number subsets had co-RAS SV/BRAF V600E in 63%/3%, 31%/0.6%, and 4.8%/0% of cases, respectively. In the COH cohort, six patients with RASa (13-54 copies) received EGFRmAb, four of six had progressive disease, two had stable disease, and median time to treatment discontinuation (TTD) was 2.5 months. Of the CGDB EGFRmAb-treated patients, those with RASa (n = 9) had median TTD of 4.7 months and overall survival (OS) of 11.4 months, those with RAS SV (n = 101) had median TTD and OS of 5.3 and 9.4 months, and those with RAS/BRAF wild-type (n = 608) had median TTD and OS of 7.6 and 13.7 months. Patients with RASa without RAS mutations (1.1% of mCRC) may have poor outcomes on EGFRmAb, although numbers herein were small, and interpretation is confounded by combination chemotherapy. Larger independent studies are warranted to determine if RASa, including degree of amplification, may act similarly to RAS mutation as a resistance mechanism to EGFRmAb therapies. Genomic data suggest that RAS amplification occurs as the sole RAS/RAF alteration in >1% of colorectal cancer cases and that degree of amplification inversely correlates with co-occurring MAPK pathway alterations. Preliminary clinical evidence suggests that RAS amplification may function similarly to RAS mutation as a negative predictor of benefit from anti-epidermal growth factor receptor therapies in colorectal cancer. More clinical data are needed, and comprehensive genomic profiling, including detection of RAS amplification, should be used in trial design to inform therapy selection.

Analysis of KRAS mutations in circulating tumor DNA and colorectal cancer tissue

ABSTRACT The mutation status of KRAS is important for anti-EGFR therapy in colorectal cancer (CRC) patients; however, detection of KRAS mutations in circulating tumor DNA (ctDNA) is problematic. We investigated tissue and plasma assays for KRAS mutations in CRC patients. The KRAS status of 407 CRC patients was evaluated using integration of amplification refractory mutation system polymerase chain reaction (PCR), melting curves and wild type DNA blocking (IAMB) in tissue and plasma samples. Disparate cases were re-evaluated by Sanger sequencing of tissue samples. General characteristics and tumor biomarkers including CEA, CA19-9 and CA125 were characterized. The prevalence of KRAS mutations was 40.8% in plasma and 49.1% in tissue. The overall percent agreement, positive percent agreement and negative percent agreement were 82.3, 76.3 and 90.8%, respectively. Older patients and higher TNM stage exhibited increased sensitivity for detecting KRAS mutations in plasma. We found 54.1% of patients with KRAS mutations using parallel analysis of tissue and plasma; only 36.4% of patients were detected by series analysis. We found that plasma based KRAS detection with IAMB technology is an alternative to tissue based KRAS testing. KRAS mutations can be identified more easily when both assays are used together

Inactivation of NF1 Promotes Resistance to EGFR Inhibition in KRAS/NRAS/BRAFV600 -Wild-Type Colorectal Cancer.

Through the use of an unbiased, genome-scale CRISPR modifier screen, we identified NF1 suppression as a mechanism of resistance to EGFR inhibition in NRAS/KRAS/BRAFV600 -wild-type colorectal cancer cells. Reduced NF1 expression permitted sustained signaling through the MAPK pathway to promote cell proliferation in the presence of EGFR inhibition. Targeting of MEK in combination with EGFR inhibition leads to synergistic antiproliferative activity. Human KRAS/NRAS/BRAFV600 -wild-type colorectal cancer cell lines with NF1 mutations displayed reduced NF1 mRNA or protein expression and were resistant to EGFR blockade by gefitinib or cetuximab. Cooccurring loss-of-function mutations in PTEN were associated with resistance to dual EGFR/MEK inhibition but cotreatment with a PI3K inhibitor further suppressed proliferation. Loss of NF1 may be a useful biomarker to identify patients that are less likely to benefit from single-agent anti-EGFR therapy in colorectal cancer and may direct potential combination strategies. IMPLICATIONS: This study suggests that further clinical validation of NF1 status as predictor of response to anti-EGFR targeting antibodies in patients with colorectal cancer with KRAS/NRAS/BRAFV600 -wild-type tumors is warranted.

Oral mucositis associated with anti-EGFR therapy in colorectal cancer: single institutional retrospective cohort study

BackgroundChemotherapy-induced oral mucositis impairs the quality of life. The difference in severity of oral mucositis between different anti-epidermal growth factor receptor (EGFR) antibodies combined with cytotoxic drugs in colorectal cancer is unclear. The aim of this study was to investigate the differences in oral mucositis between panitumumab (Pmab) and cetuximab (Cmab) combined with 5-fluorouracil (5-FU).MethodsWe conducted a retrospective cohort study. A total of 75 colorectal cancer outpatients treated with an anti-EGFR antibody combined with FOLFOX, FOLFIRI, or 5-FU/leucovorin as the first- to third-line treatment were included. The primary endpoint was the incidence of grade 2–3 oral mucositis. The secondary endpoint was the time to onset of oral mucositis. We also compared the incidence of toxicities of interest, skin toxicity, hypomagnesaemia and neutropenia, and time to treatment failure (TTF) between the two groups.ResultsThirty-two patients treated with Pmab and 43 patients treated with Cmab were evaluated. Patient characteristics were similar between the two groups. The incidence of grade 2–3 oral mucositis was significantly higher with Pmab than with Cmab (31.3% vs 9.3%, P < 0.05). Moreover, the incidence of grade 3 oral mucositis was significantly higher in patients treated with Pmab (18.8% vs 0%, P < 0.01). The mean (SD) cycles to onset of the worst oral mucositis was 3.0 (2.9) in the Pmab group and 2.3 (1.7) in the Cmab group (P = 0.29). Oral mucositis was characterized by glossitis and cheilitis. The incidences of other toxicities were the following (Pmab vs Cmab): grade 2–3 skin toxicity: 68.8% vs 74.4% (P = 0.61), grade 2–3 hypomagnesaemia: 9.3% vs 7.0% (P = 1.00), grade 3–4 neutropenia: 28.1% vs 37.2% (P = 0.46). The median TTF was not significantly different, i.e., 223 days vs 200 days (P = 0.39) for Pmab vs Cmab.ConclusionsPmab-based chemotherapy resulted in significantly higher grades of oral mucositis compared with Cmab-based chemotherapy. The oral condition should be monitored carefully and early supportive care should be provided for patients treated with Pmab-based chemotherapy.

Not all RAS mutations created equal: Functional and clinical characterization of 80 different KRAS and NRAS mutations.

3589 Background: Mutations (mts) in RAS predict lack of response to anti-EGFR therapy in colorectal cancer. Outside the “typical RAS” mts ( KRAS/NRAS Codons 12, 13, 59, 61, 117, 146) cited in guidelines and anti-EGFR labeling, clinical impact of other “atypical RAS” mts is uncertain. Methods: Available literature and databases were surveyed to identify 80 KRAS/NRAS mts. We used the NovellusDx Functional Annotation for Cancer Treatment (FACT) to transfect these RAS mts (repeated a mean of 5.5 times/mt) in a cell-based assay that quantifies nuclear ERK localization as a measure of MAPK pathway activation, and normalized to wild type (WT) transfection. In 963 metastatic colorectal cancer patients (pts) with BRAF WT/ KRAS mutant tumors, overall survival (OS) was evaluated by level of RAS signaling activity. Results: Of the surveyed mutations,96% (45/47) of typical mts and 39% (13/33) of atypical mts increased MAPK pathway activation above WT (range: 107%-211% of WT activity). Within the typical RAS mts, mts in NRAS or exon 3, 4 of KRAS had higher activity than mts in exon 2 (codons 12/13) of KRAS, reaffirming the biologic relevance of expanded RAS testing (median activity of 130% vs 178%, P &lt; 0.001). The median activity of atypical RAS mts was lower than typical RAS mts (110% vs 159%, P &lt; 0.001). Several notable exceptions in atypical RAS mts with high activity levels were KRAS V14I, Q22K, D33E, N116S, and F156L (all &gt; 165% of WT activity). Conversely, within the typical RAS mts in the guidelines, KRAS G13C and K117R were not shown to increase activity significantly above WT. Pts with any RAS mt with MAPK activity above the median of typical mts had a worse OS compared to pts below the median in univariate (HR 1.45, 95% CI 1.04-2.32, P = 0.033) and multivariate models (HR 1.96, 95% CI 1.13-3.42, P = 0.017) that controlled for age, gender, sidedness, and synchronous vs metachronous presentation. Conclusions: Functional characterization confirmed activity of RAS mts in the current guidelines, but also suggested that a subset of atypical RAS mutations have similar levels of activation of the MAPK pathway. Within the subset of pts with RAS mts, those mts resulting in high MAPK activity are associated with notably shorter OS.

Mechanisms of resistance to anti-EGFR therapy in colorectal cancer.

Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is effective for patients with RAS wild type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC patients are sensitive to anti-EGFR therapy and even the best cases finally become refractory to this therapy. It has become apparent that the RAS mutations correlate with resistance to anti-EGFR therapy. However, these resistance mechanisms only account for nearly 35% to 50% of nonresponsive patients, suggesting that there might be additional mechanisms. In fact, several novel pathways leading to escape from anti-EGFR therapy have been reported in recent years. In this review, we provide an overview of known and novel mechanisms that contribute to both primary and acquired anti-EGFR therapy resistance, and enlist possible treatment strategies to overcome or reverse this resistance.

ISY-18-2 - Latest Advance to Clinical Development and Future Perspective for RAS/BRAF-mutated Metastatic Colorectal Cancer

Expanded RAS (KRAS and NRAS) testing was the validated predictive biomarker for primary resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with metastatic colorectal cancer (mCRC) (Taniguchi H, Yoshino T, et al. Cancer Sci. 2015). Recently, around half of mCRC showing transformation of RAS status (wild to mutant) has been observed after treatment with anti-EGFR therapy by means of blood-based molecular testing using cell -free tumor DNA in a large-scale retrospective analysis from the pivotal phase 3 trial, suggesting RAS mutation confers acquired resistance to anti-EGFR therapy (Tabernero J, Yoshino T, et al. Lancet Oncol. 2015). On the basis of nonclinical research demonstrating the double blockade of EGFR and MEK intercepts heterogeneous mechanism of action of acquired resistance to anti-EGFR therapy in colorectal cancer, early clinical trials are ongoing to investigate feasibility and biologic activity of the combination with a MEK inhibitor plus an EGFR mAb. BRAF-mutated mCRC carries a poor prognosis, and reactivation of EGFR signaling with BRAF inhibition and/or uninhibited PI3K signaling may explain the limited efficacy of BRAF inhibitor monotherapy in patients with BRAF-mutated mCRC. Recent nonclinical data have demonstrated synergistic activity of the combination of a BRAF inhibitor and an EGFR inhibitor in in vitro and in vivo models of BRAF-mutated CRC. Ongoing early clinical studies, i.e., the combination of a BRAF inhibitor and an EGFR mAb W/or W/O a MEK inhibitor, and a BRAF inhibitor and an EGFR mAb W/or W/O a PI3Kα inhibitor, showed promising clinical activity, including improved overall response rate, progression-free survival and overall survival relative to historical data (Van Cutsem E, Yoshino T, et al. at ESMO-GI 2015 and Tabernero J, Yoshino T, et al. at ASCO2016). Current clinical development for RAS/BRAF-mutated mCRC may represent substantial progression toward more precision medicine.

Resistance to Anti-EGFR Therapy and Strategies to Overcome it: Possible Role of BDNF/TrkBma

Acquired resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies such as cetuximab and panitumumab represents an important limitation to the treatment of colorectal cancer (CRC), and research efforts have increasingly been directed towards understanding molecular mechanisms of resistance. We propose that neurotrophin signaling mediated by brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosinrelated kinase B (TrkB), might be a compensatory mechanism contributing to decreased response to anti-EGFR therapy in CRC. The combined targeting of EGFR and TrkB is a novel strategy worth of further investigation.

Optimizing Anti-EGFR Therapy in Colorectal Cancer.

Treatment with anti-EGFR monoclonal antibodies has been successfully integrated in the continuum of care for metastatic colorectal cancer. The major challenge is the identification of patients who would benefit from treatment. Currently, the best predictor of efficacy is the absence of mutations in KRAS and NRAS genes. Clin Cancer Res; 21(24); 5415-6. ©2015 AACR.See related article by Peeters et al., p. 5469.

259 Fibroblast growth factor 9 gene amplification can induce resistance to anti-EGFR therapy in colorectal cancer

259 Fibroblast growth factor 9 gene amplification can induce resistance to anti-EGFR therapy in colorectal cancer

Abstract 5456: FGF9 gene amplification can induce resistance to anti-EGFR therapy in colorectal cancer

Abstract The prognosis of advanced colorectal cancer (CRC) remains dismal. Fibroblast growth factor (FGF) signals are potent mitogens, morphogens, and inducers of angiogenesis. Abnormal expression of FGF9 has been observed in several malignancies and might result in uncontrolled cell proliferation and carcinogenesis. However, limited information is available regarding the role of FGF9 in CRC. In this study, amplification of FGF9 gene was observed in 14/146 (9.6%) CRC specimens, using a TaqMan copy number assay. FGF9-overexpressed CRC cell lines were created, and FGF9-overexpression induced the resistance to anti-epidermal growth factor receptor (EGFR) therapy (cetuximab or lapatinib) via the FGF receptor (FGFR) signal, which was cancelled by BGJ398, a pan-FGFR inhibitor. In vivo, FGF9-overexpressed xenograft tumors were resistant to cetuximab monotherapy and the combination with BGJ398 overcame the resistance. Considering these results, FGF9 gene amplification may play an important role in the resistance to anti-EGFR therapy in CRC and the combination with an anti-FGFR inhibitor could overcome this resistance. Citation Format: Takuro Mizukami, Yosuke Togashi, Eri Banno, Masato Terashima, Marco A de velasco, Kazuko Sakai, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Narikazu Boku, Kazuto Nishio. FGF9 gene amplification can induce resistance to anti-EGFR therapy in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5456. doi:10.1158/1538-7445.AM2015-5456