scholarly journals An Early-Onset Advanced Rectal Cancer Patient With Increased KRAS Gene Copy Number Showed A Primary Resistance to Cetuximab in Combination With Chemotherapy: A Case Report

2021 ◽  
Vol 11 ◽  
Author(s):  
Tian Fang ◽  
Tingting Liang ◽  
Yizhuo Wang ◽  
Haitao Wu ◽  
Shuhan Liu ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Copy Number ◽  
Tumor Tissue ◽  
Rectal Cancer Patient ◽  
Gene Copy ◽  
Amplification Refractory Mutation System ◽  
Sequencing Analysis ◽  
Wild Type ◽  
Primary Resistance ◽  
First Case

Mutations in KRAS (codon 12/13), NRAS, BRAFV600E, and amplification of ERBB2 and MET account for 70–80% of anti-epidermal growth factor receptor (EGFR) monoclonal antibody primary resistance. However, the list of anti-EGFR monoclonal antibody primary resistance biomarkers is still incomplete. Herein, we report a case of wild-type RAS/BRAF metastatic colorectal cancer (CRC) with resistance to anti-EGFR monoclonal antibody and chemotherapy. Initially, mutation detection in postoperative tumor tissue by using amplification-refractory mutation system polymerase chain reaction indicated wild-type RAS/BRAF without point mutations, insertion deletions, or fusion mutations. Therefore, we recommended combined therapy of cetuximab and FOLFIRI after failure of platinum-based adjuvant chemotherapy, but the disease continued to progress. Next generation sequencing analysis of the postoperative tumor tissue revealed that KRAS copy number was increased and detected SMAD4, RNF43, and PREX2 mutations. This is the first case of advanced CRC with increased copy numbers of KRAS resistant to cetuximab and chemotherapy, which results in poor patient survival, and other mutated genes may be associated with the outcomes. Our findings indicate KRAS copy number alterations should also be examined, especially with anti-EGFR monoclonal antibody therapy in CRC, since it may be related with the primary resistance to these drugs.

Gain of ALK gene copy number to predict lack of response to anti-EGFR treatment in advanced chemorefractory colorectal cancer (CRC) with KRAS/NRAS/BRAF/PI3KCA wild-type status.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3641-3641
Author(s):  
Filippo Pietrantonio ◽  
Anna Tessari ◽  
Rosalba Miceli ◽  
Pamela Biondani ◽  
Federica Perrone ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Copy Number ◽  
Response Rate ◽  
Gene Copy Number ◽  
Predictive Biomarkers ◽  
Gene Copy ◽  
Wild Type ◽  
Data Set ◽  
Exact Test ◽  
Need For Treatment

3641 Background: KRAS, BRAF, NRAS and exon 20 PIK3CA quadruple wild-type CRC is associated with 41.2% response rate to anti-EGFR treatments. Even in molecular characterized patients, there is still a subset of non responders. The identification of additional predictive biomarkers is an unmet clinical need for treatment personalization. Alterations of ALK oncoprotein may interfere with the biological activity of EGFR through cross-talk of downstream signalling pathways. Methods: This retrospective analysis aimed to investigate the correlation between ALK gene copy number (GCN), assessed by fluorescence in situ hybridization (FISH), and clinical outcome in KRAS/NRAS/BRAF/PI3KCA wild-type chemorefractory advanced CRC patients receiving cetuximab or panitumumab. FISH was perfomed with break-apart ALK (2p23) probes and gain of ALK GCN was defined as a mean of 3 to 5 signals in ≥10% of cells and amplification as ≥6 signals. Association of ALK status with RECIST response was performed by Fisher’s exact test. Results: Forty-one patients were identified, of whom 17 (41%) were ALK GCN positive, whereas the remaining 24 cases (59%) were ALK GCN negative. No ALK translocations were detected. Overall response rate was 19/41 (46%). We observed a partial response in 3/17 patients with ALK GCN positive versus 16/24 patients with ALK GCN negative (18% versus 67%, respectively; P=0.0036). Kaplan-meier curves for comparison of median progression-free and overall survival, as well as correlation with ALK expression by immunohistochemistry, will be presented at the Meeting exploring the whole National Cancer Institute data-set. Conclusions: In this study population with KRAS/NRAS/BRAF/PI3KCA wild-type tumors, the response rate greater than 40% is in line with literature data. ALK GCN may be a biomarker for clinical outcome prediction in advanced chemorefractory CRC patients treated with cetuximab or panitumumab.

EGFR gene copy number to predict response to anti-EGFR treatment and survival in RAS wild type and RAS/BRAF/PIK3CA wild type metastatic colorectal cancer.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e15108-e15108
Author(s):  
Olli Carpen ◽  
Annika Ålgars ◽  
Jari Sundström ◽  
Soili Kytölä ◽  
Pia Österlund ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Copy Number ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Wild Type ◽  
Egfr Gene

scholarly journals Genetic Factors Associated with Elevated Carbapenem Resistance in KPC-Producing Klebsiella pneumoniae

2010 ◽  
Vol 54 (10) ◽  
pp. 4201-4207 ◽  
Author(s):  
Brandon Kitchel ◽  
J. Kamile Rasheed ◽  
Andrea Endimiani ◽  
Andrea M. Hujer ◽  
Karen F. Anderson ◽  
...  
Keyword(s):  
United States ◽  
Klebsiella Pneumoniae ◽  
Copy Number ◽  
Gene Copy Number ◽  
Carbapenem Resistance ◽  
The United States ◽  
Gene Copy ◽  
Sequencing Analysis ◽  
Low Level ◽  
High Level

ABSTRACT In the United States, the most prevalent mechanism of carbapenem resistance among Enterobacteriaceae is the production of a Klebsiella pneumoniae carbapenemase (KPC). KPC-producing isolates often exhibit a range of carbapenem MICs. To better understand the factors that contribute to overall carbapenem resistance, we analyzed 27 KPC-producing K. pneumoniae isolates with different levels of carbapenem resistance, 11 with low-level (i.e., meropenem or imipenem MIC ≤ 4 μg/ml), 2 with intermediate-level (i.e., meropenem and imipenem MIC = 8 μg/ml), and 14 with high-level (i.e., imipenem or meropenem MIC ≥ 16 μg/ml) carbapenem resistance, that were received from throughout the United States. Among 14 isolates that exhibited high-level carbapenem resistance, Western blot analysis indicated that 10 produced an elevated amount of KPC. These isolates either contained an increased bla KPC gene copy number (n = 3) or had deletions directly upstream of the bla KPC gene (n = 7). Four additional isolates lacked elevated KPC production but had high-level carbapenem resistance. Porin sequencing analysis identified 22 isolates potentially lacking a functional OmpK35 and three isolates potentially lacking a functional OmpK36. The highest carbapenem MICs were found in two isolates that lacked both functioning porins and produced elevated amounts of KPC. The 11 isolates with low-level carbapenem resistance contained neither an upstream deletion nor increased bla KPC copy number. These results suggest that both bla KPC copy number and deletions in the upstream genetic environment affect the level of KPC production and may contribute to high-level carbapenem resistance in KPC-producing K. pneumoniae, particularly when coupled with OmpK36 porin loss.

scholarly journals HER2 Gene Assessment in Liquid Biopsy of Gastric and Esophagogastric Junction Cancer Patients Qualified for Surgery

2020 ◽  
Author(s):  
Anna Grenda ◽  
Kamila Wojas-Krawczyk ◽  
Tomasz Skoczylas ◽  
Paweł Krawczyk ◽  
Jadwiga Sierocińska-Sawa ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Liquid Biopsy ◽  
Copy Number ◽  
Esophagogastric Junction ◽  
Tumor Tissue ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Gene Copies ◽  
Healthy Donors ◽  
Esophagogastric Junction Cancer

Abstract Background Amplification of HER2 gene (ERBB2) and overexpression of HER2 protein on cancer cells are found in 10-26% of gastric cancer (GC) and esophagogastric junction cancer (EGJC). Gene copy number variation (CNV) could be detected in these patients in liquid biopsy and in cancer cells. Methods We analysed HER2 gene CNV used qPCR method in 87 sera collected from GC and EGJC patients before surgical treatment and in 40 sera obtained from healthy donors. HER2 gene CNV was also assessed in formalin-fixed paraffin-embedded (FFPE) tumor tissue. Furthermore, we assessed the number of HER2 gene copies and HER2 expression in cancer cells using the fluorescent in situ hybridization method (FISH) and immunohistochemistry (IHC). Results We found that the HER2 gene copy number in liquid biopsy was higher in GC and EGJC patients compared to healthy people (p=0.01). Moreover, EGJC patients had higher number of HER2 gene copies than healthy donors (p=0.0016). HER2 CNV examination could distinguish healthy individuals and patients with gastric or esophagogastric junction cancers with sensitivity and specificity of 58% and 98% (AUC=0.707, 95% CI: 0.593-0.821, p=0.004). We found that patients with a high copy number of the HER2 gene in the tumor tissue assessed by qPCR (but not by FISH) have significantly more often a high number of HER2 gene copies in liquid biopsy (p=0.04). Conclusions We suggested that HER2 testing in liquid biopsy could be used as an auxiliary method to analysis of HER2 status in tumor tissue in gastric or esophagogastric junction cancers.

An analysis of the prognostic and predictive importance of K-ras mutation status in the National Cancer Institute of Canada Clinical Trials Group BR.21 study of erlotinib versus placebo in the treatment of non-small cell lung cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7005-7005 ◽  
Author(s):  
M. Tsao ◽  
C. Zhu ◽  
A. Sakurada ◽  
T. Zhang ◽  
M. Whitehead ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Copy Number ◽  
Survival Benefit ◽  
Gene Copy Number ◽  
Small Cell ◽  
Gene Copy ◽  
Wild Type ◽  
Small Cell Lung ◽  
Ras Mutation ◽  
Erlotinib Therapy

7005 Background: BR.21 demonstrated a significant survival benefit for patients with advanced non-small cell lung cancer (NSCLC) who received erlotinib vs. placebo (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.58–0.85, p<0.001). Tyrosine kinase (TK) domain mutations and high EGFR gene copy number by fluorescent in situ hybridization (FISH) have been associated with significantly higher response rates to erlotinib, while high gene copy number is a better predictor of survival benefit than mutations. K-ras mutation has been associated with non-responsiveness to EGFR TK inhibitors and poorer outcome for patients treated with erlotinib and chemotherapy. The survival impact of K-ras mutation on single agent erlotinib therapy in NSCLC patients remains unknown. Methods: 731 patients were randomized to BR.21 (488 erlotinib, 243 placebo). K-ras mutation analysis was conducted by sequencing in 246 patient samples. Results: K-ras analysis was successful in 206 patients; 30 (14.6%) demonstrated oncogenic mis-sense mutations on codon 12 or 13 (22 on the erlotinib arm and 8 on the placebo arm). For all 206 patients with known K-ras genotype, the HR for erlotinib was 0.77 (95% CI 0.57–1.06, p=0.06). For the 176 K-ras wild type patients, the univariate HR for erlotinib was 0.69 (95% CI 0.49–0.97, p=0.03). In contrast, the HR for the thirty K-ras mutant patients was 1.67 (95% CI 0.62–4.5, p=0.31), with an interaction p value of 0.09. Overall response rates were 5% (1/20) in K-ras mutant patients, and 10.2% (10/98) in K-ras wild type patients. In patients with K-ras genotype known, the multivariate Cox regression model showed that K-ras mutation was significantly associated with shorter survival (HR 1.63, 95% CI 1.06–2.51, p=0.03). Conclusion: In BR.21, patients with K-ras mutation do not appear to derive any survival benefit from erlotinib therapy. However, the numbers of patients are small and results need to be confirmed in other studies. (Supported by the Canadian Cancer Society, Ontario Cancer Research Network, the Jacqueline Seroussi Memorial Foundation for Cancer Research and OSI Pharmaceuticals). [Table: see text]

scholarly journals Impact of KRAS Mutations on Management of Colorectal Carcinoma

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Kevin M. Sullivan ◽  
Peter S. Kozuch
Keyword(s):  
Colorectal Cancer ◽  
Monoclonal Antibody ◽  
Antibody Therapy ◽  
Growth Factor Receptor ◽  
Monoclonal Antibody Therapy ◽  
Novel Therapies ◽  
Wild Type ◽  
Primary Resistance ◽  
Kras Mutations ◽  
Epidermal Growth

The epidermal growth factor receptor (EGFR) pathway is a therapeutic target in the management of colorectal cancer (CRC). EGFR antagonists are active in this disease; however, only a subset of patients respond to such therapy. A Kirsten ras sarcoma viral oncogene (KRAS) wild-type (WT) status of the tumor is necessary, but possibly not sufficient, for a response to anti-EGFR monoclonal antibody therapy. Mechanisms of primary resistance to such therapy in patients harboring KRAS WT tumors are discussed. Strategies to overcome resistance to anti-EGFR monoclonal antibody therapy, including novel agents and combinations of novel therapies, are explored. Also, the use of anti-EGFR monoclonal antibodies in the adjuvant and neoadjuvant setting is reviewed.

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