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EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer.

ABSTRACT: Genetic variability in KRAS and EGFR predicts response to cetuximab in irinotecan refractory colorectal cancer. Whether these markers or others remain predictive in combination biologic therapies including bevacizumab is unknown. We identified predictive biomarkers from patients with irinotecan refractory metastatic colorectal cancer treated with cetuximab plus bevacizumab. Patients who received cetuximab plus bevacizumab for irinotecan refractory colorectal cancer in either of two Phase II trials conducted were identified. Tumor tissue was available for 33 patients. Genomic DNA was extracted and used for mutational analysis of KRAS, BRAF, and p53 genes. Fluorescence in situ hybridization was performed to assess EGFR copy number. The status of single genes and various combinations were tested for association with response. Seven of 33 patients responded to treatment. KRAS mutations were found in 14/33 cases, and 0 responded to treatment (p = 0.01). EGFR gene amplification was seen in 3/33 of tumors and in every case was associated with response to treatment (p < 0.001). TP53 and BRAF mutations were found in 18/33 and 0/33 tumors, respectively, and there were no associations with response to either gene. EGFR gene amplification and KRAS mutations are predictive markers for patients receiving combination biologic therapy of cetuximab plus bevacizumab for metastatic colorectal cancer. One marker or the other is present in the tumor of half of all patients allowing treatment response to be predicted with a high degree of certainty. The role for molecular markers in combination biologic therapy seems promising.

SUBMITTER: Khan SA

PROVIDER: S-EPMC5451302 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer.

Khan Sajid A SA Zeng Zhaoshi Z Shia Jinru J Paty Philip B PB

Pathology oncology research : POR 20161226 3

Genetic variability in KRAS and EGFR predicts response to cetuximab in irinotecan refractory colorectal cancer. Whether these markers or others remain predictive in combination biologic therapies including bevacizumab is unknown. We identified predictive biomarkers from patients with irinotecan refractory metastatic colorectal cancer treated with cetuximab plus bevacizumab. Patients who received cetuximab plus bevacizumab for irinotecan refractory colorectal cancer in either of two Phase II tria ...[more]

PMID: 28025786

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Project description:BackgroundThe anti-EGFR monoclonal antibody cetuximab is used in metastatic colorectal cancer (CRC), and predicting responsive patients garners great interest, due to the high cost of therapy. Mutations in the KRAS gene occur in ~40% of CRC and are a negative predictor of response to cetuximab. However, many KRAS-wildtype patients do not benefit from cetuximab. We previously published a gene expression predictor of sensitivity to erlotinib, an EGFR inhibitor. The purpose of this study was to determine if this predictor could identify KRAS-wildtype CRC patients who will benefit from cetuximab therapy.MethodsMicroarray data from 80 metastatic CRC patients subsequently treated with cetuximab were extracted from the study by Khambata-Ford et al. The study included KRAS status, response, and PFS for each patient. The gene expression data were scaled and analyzed using our predictive model. An improved predictive model of response was identified by removing features in the 180-gene predictor that introduced noise.ResultsForty-three of eighty patients were identified as harboring wildtype-KRAS. When the model was applied to these patients, the predicted-sensitive group had significantly longer PFS than the predicted-resistant group (median 88 days vs. 56 days; mean 117 days vs. 63 days, respectively, p = 0.008). Kaplan-Meier curves were also significantly improved in the predicted-sensitive group (p = 0.0059, HR = 0.4109. The model was simplified to 26 of the original 180 genes and this further improved stratification of PFS (median 147 days vs. 56.5 days in the predicted sensitive and resistant groups, respectively, p < 0.0001). However, the simplified model will require further external validation, as features were selected based on their correlation to PFS in this dataset.ConclusionOur model of sensitivity to EGFR inhibition stratified PFS following cetuximab in KRAS-wildtype CRC patients. This study represents the first true external validation of a molecular predictor of response to cetuximab in KRAS-WT metastatic CRC. Our model may hold clinical utility for identifying patients responsive to cetuximab and may therefore minimize toxicity and cost while maximizing benefit.

Project description:BackgroundThe epidermal growth factor receptor (EGFR)/RAS/RAF/MEK/MAPK pathway is an important pathway in the carcinogenesis, invasion and metastasis of colorectal cancers (CRCs). We conducted a retrospective study to determine the prognostic values of EGFR expression and KRAS mutation in patients with metastatic CRC (mCRC) based on synchronous or metachronous status.MethodsFrom October 2002 to March 2012, 205 patients with mCRC were retrospectively analyzed; 98 were found to have metachronous mCRC while 107 were found to have synchronous mCRC. The EGFR expressions were determinate by IHC (immunohistochemistry) analysis and categorized 1+ (weak intensity), 2+ (moderate intensity), and 3+ (strong intensity). Genomic DNA was isolated from frozen primary CRC tissues and direct sequencing of KRAS was performed. The clinicopathological features of these mCRC patients were retrospectively investigated according to EGFR expression and KRAS mutation status. Moreover, we analyzed the prognostic values of EGFR expression and KRAS mutation among these patients.ResultsOf the 205 patients with mCRC, EGFR expression was analyzed in 167 patients, and positive EGFR expression was noted in 140 of those patients (83.8%). KRAS mutation was investigated in 205 patients and mutations were noted in 88 of those patients (42.9%). In patients with metachronous mCRC, positive EGFR expression was significantly correlated with well-and moderately-differentiated tumors (P=0.028), poorer disease-free survival (DFS) (P<0.001), and overall survival (OS) (P<0.001). Furthermore, positive EGFR expression was a significant independent prognostic factor of DFS (P=0.006, HR: 4.012, 95% CI: 1.130-8.445) and OS (P=0.028, HR: 3.090, 95% CI: 1.477-10.900) in metachronous mCRC patients. KRAS mutation status was not significantly related to DFS and OS of patients with metachronous mCRC; likewise, KRAS mutation status was not significantly different in the progression-free survival (PFS) and OS of patients with synchronous mCRC (all P>0.05).ConclusionsThe present study demonstrated that EGFR expression has prognostic value only for patients with metachronous mCRC. However, KRAS mutation did not have prognostic value in patients with metachronous or synchronous mCRC.

Project description:The selection of colorectal cancer patients for anti-epidermal growth factor receptor (EGFR) antibody therapy is based on the determination of their RAS mutation status-a strongly negative predictive factor-since the protein target, EGFR, is not a reliable predictor of therapeutic response. In this study, we revisited the EGFR protein issue using a cohort of 90 patients with KRAS exon2 wild-type colorectal cancer who have been treated with cetuximab therapy. Twenty-nine of these patients had metastatic tissue available for analysis. The level of EGFR protein expression in the patients was determined by immunohistochemistry and evaluated by H-score (HS) methodology. Progression-free survival (PFS) and overall survival (OS) of the patients were determined according to the EGFR-HS ranges of both the primary and metastatic tissues using Kaplan-Meyer statistics. In the case of primary tumors, EGFR scores lower than HS = 200 were associated with significantly longer OS. In the case of metastatic tissues, all levels lower than the EGFR-HS range chosen were associated with significantly longer OS. These results are explained by the fact that metastatic tissues rarely maintained the expression levels of the primary tumors. On the other hand, high EGFR expression levels in either primary tumors or metastatic tissues were associated with multiple metastatic disease. This suggests a negative prognostic role of EGFR expression. However, in a multivariate analysis, one-sidedness remained a strong independent predictive factor of survival. Previous studies demonstrated that the EGFR expression level depends on sidedness. Therefore, a subgroup analysis of the left- and right-sided cases was performed on both primary and metastatic tissues. In the case of metastic tissues, an analysis confirmed a better OS in low EGFR protein-expressing cases than in high EGFR protein-expressing cases. Collectively, these data suggest that EGFR protein expression is another negative predictive factor of the efficacy of cetuximab therapy of KRAS exon2 wild-type colorectal cancer.

Project description:BackgroundRAS 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.MethodsGenomic 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.ResultsRASa 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.ConclusionPatients 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.Implications for practiceGenomic 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.

Dataset Information

EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer.

Publications

EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer.

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