Pharmacogenetic Profiling for Cetuximab Plus Irinotecan Therapy in Patients With Refractory Advanced Colorectal Cancer

2008 ◽  
Vol 26 (9) ◽  
pp. 1427-1434 ◽  
Author(s):  
Francesco Graziano ◽  
Annamaria Ruzzo ◽  
Fotios Loupakis ◽  
Emanuele Canestrari ◽  
Daniele Santini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Salvage Therapy ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Skin Toxicity ◽  
Egfr Expression ◽  
Intron 1 ◽  
Epidermal Growth

PurposeRegulation of epidermal growth factor receptor (EGFR) signaling pathways may play a relevant role in determining the activity of cetuximab therapy in patients with metastatic colorectal cancer (MCRC). We investigated possible associations between genetic variants and clinical outcomes of MCRC patients treated with cetuximab-irinotecan salvage therapy.Patients and MethodsPatients who underwent cetuximab-irinotecan salvage therapy after disease progression during or after first-line bolus/infusional fluorouracil, leucovorin, and oxaliplatin chemotherapy and a second-line irinotecan-based regimen were considered eligible for analysis of polymorphisms with putative influence on cetuximab-related pathways. Epidermal growth factor (EGF) 61A>G, EGF receptor (EGFR) 216G>T, EGFR 497G>A, EGFR intron-1 (CA)ndinucleotide short (S)/long (L) variant, cyclin-D1 870A>G, immunoglobulin-G fragment-C receptors RIIIa 158G>T, and RIIa 131G>A were studied for a possible association with overall survival (OS) as the primary end point. Additional analyses were addressed at possible associations among polymorphisms and EGFR expression, toxicity, and response.ResultsIn 110 assessable patients, significant association with favorable OS was observed for EGFR intron-1 S/S and EGF 61 G/G genotypes. In the multivariate model, EGFR intron-1 S/S and EGF 61 G/G genotypes showed a hazard ratio of 0.41 (95% CI, 0.21 to 0.78; P = .006) and 0.44 (95% CI, 0.23 to 0.84; P = .01), respectively. EGFR intron-1 S/S carriers showed more frequent G2-G3 skin toxicity (χ2test = 12.7; P = .001) and treatment response (χ2test = 9.45; P = .008) than EGFR intron-1 L/L carriers.ConclusionAlthough additional studies are required for confirmation, our findings could optimize the use of cetuximab in MCRC patients.

Epidermal growth factor receptor (EGFR) expression in colorectal cancer in Slovakia

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 20103-20103
Author(s):  
T. Salek ◽  
J. Mardiak ◽  
F. Ondrias ◽  
J. Bodnar ◽  
L. Klimcakova
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Cellular Processes ◽  
Egfr Expression ◽  
Promising Therapeutic Target ◽  
Epidermal Growth ◽  
Improve Clinical Outcome

20103 Background: EGFR is involved in the epidermal growth factor pathway that regulates cellular processes and is associated with the development of malignancy.EGFR targeted therapy could be an alternative option to improve clinical outcome in tumors with EGFR expression. Methods: From 09/2004 till 12/2005 we evaluated histologic specimens of 130 patients (89 male, 41 female) with colorectal cancer. EGFR expression was examined by immunohistochemistry using theEGFR Detection Kit (Dako Corporation) in paraffin-embedded colon/rectum tumors and graded as percentage of cells stained. Results: EGFR positivity (1% and more) was observed in 106 pts (81.5%) and EGFR negativity in 24 pts (18.5%). Median of positivity in percentage is 40 (1–95). Conclusions: The EGF receptor is overexpressed in many human tumors and is a promising therapeutic target. No significant financial relationships to disclose.

Cetuximab Shows Activity in Colorectal Cancer Patients With Tumors That Do Not Express the Epidermal Growth Factor Receptor by Immunohistochemistry

2005 ◽  
Vol 23 (9) ◽  
pp. 1803-1810 ◽  
Author(s):  
Ki Young Chung ◽  
Jinru Shia ◽  
Nancy E. Kemeny ◽  
Manish Shah ◽  
Gary K. Schwartz ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cancer Patients ◽  
Growth Factor Receptor ◽  
Pathology Report ◽  
Egfr Expression ◽  
Epidermal Growth ◽  
Colorectal Cancer Patients

Purpose To establish evidence of activity, or lack thereof, of cetuximab-based therapy in patients with refractory colorectal cancer with tumors that do not demonstrate epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC). Patients and Methods Pharmacy computer records were reviewed to identify all patients who received cetuximab at Memorial Sloan-Kettering Cancer Center in a nonstudy setting during the first 3 months of cetuximab's commercial availability. Medical records of these patients were then reviewed to identify colorectal cancer patients who had experienced failure with a prior irinotecan-based regimen and who had a pathology report indicating an EGFR-negative tumor by IHC. Pathology slides from these patients were reviewed by a reference pathologist to confirm EGFR negativity, and computed tomography scans during cetuximab-based therapy were reviewed by a reference radiologist. Response rates were reported using WHO criteria. Results Sixteen chemotherapy-refractory, EGFR-negative colorectal cancer patients who received cetuximab in a nonstudy setting were identified. Fourteen of these patients received cetuximab plus irinotecan, and two received cetuximab monotherapy. In the 16 patients, four major objective responses were seen (response rate, 25%; 95% CI, 4% to 46%). Conclusion Colorectal cancer patients with EGFR-negative tumors have the potential to respond to cetuximab-based therapies. EGFR analysis by current IHC techniques does not seem to have predictive value, and selection or exclusion of patients for cetuximab therapy on the basis of currently available EGFR IHC does not seem warranted.

scholarly journals Physiological functions of keratinocyte epidermal growth factor receptors and their role in the development of skin toxicity during targeted cancer therapy

2021 ◽  
Vol 24 (2) ◽  
pp. 111-118
Author(s):  
Ekaterina V. Orlova
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Egf Receptor ◽  
Growth Factor Receptor ◽  
Pancreatic Head ◽  
Skin Toxicity ◽  
Receptor Activation ◽  
Tyrosine Kinase Receptor ◽  
Long Term Treatment ◽  
Epidermal Growth

The binding of epidermal growth factor (EGFR) receptors is a good target for the treatment of lung, colon, pancreatic, head and neck cancers. The adverse events that develop as a result of therapy, in the form of lesions of the skin and mucous membranes, is a serious problem for the doctor to choose a long-term treatment strategy. The developing symptoms of skin toxicity, as skin problems in patients are often called, are worrisome and often affect the quality of life and compliance with the treatment regimen. Thus, it is important for doctors to know the prerequisites and ways to manage skin toxicity associated with the use of tyrosine kinase receptor inhibitors of epidermal growth factor. The mechanism and consequences of EGF receptor activation are described to explain the development of undesirable skin toxicity associated with inhibition of the epidermal growth factor receptor.

Epidermal Growth Factor Receptor (EGFR) Status in Primary Colorectal Tumors Does Not Correlate With EGFR Expression in Related Metastatic Sites: Implications for Treatment With EGFR-Targeted Monoclonal Antibodies

2004 ◽  
Vol 22 (23) ◽  
pp. 4772-4778 ◽  
Author(s):  
Mario Scartozzi ◽  
Italo Bearzi ◽  
Rossana Berardi ◽  
Alessandra Mandolesi ◽  
Guidalberto Fabris ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Monoclonal Antibodies ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Primary Tumors ◽  
Egfr Expression ◽  
Epidermal Growth ◽  
Metastatic Sites

Purpose We hypothesized that the detection of epidermal growth factor receptor (EGFR) expression performed in primary tumors for treatment with EGFR-targeted monoclonal antibodies could not always correlate with EGFR status in metastatic sites, thus making cancer cells in these sites resistant to therapy. The aim of our study was to correlate EGFR expression on primary tumors and related metastases in order to find out whether assessing EGFR status on primary cancer is to be considered an effective tool for planning treatment with EGFR-targeted antibodies. Patients and Methods We retrospectively evaluated EGFR immunohistochemistry from primary tumors and related metastatic sites in 99 colorectal cancer patients. The site of primary tumor was colon in 77 patients (78%) and rectum in 22 patients (22%). Metastatic sites analyzed were liver in 84 patients (81%), lung in 13 patients (13%), bone in one patient (1%), and brain in five patients (5%). EGFR status was defined as positive if the percentage of malignant cells stained was ≥ 1%. Results EGFR status was positive in 53 primary tumors (53%). In 19 primary tumors expressing EGFR (36%), the corresponding metastatic site was found negative, whereas it was found positive in seven metastases (15%) from EGFR-negative primary cancers. The difference between these two groups of patients (ie, EGFR-positive to EGFR-negative v EGFR-negative to EGFR-positive) was statistically significant (P = .036). Conclusion Our results suggest that the detection of the EGFR in primary colorectal cancer could be inadequate for planning therapy with EGFR-targeted monoclonal antibodies in a considerable proportion of both EGFR-positive and -negative primary tumors (36% and 15%, respectively).

scholarly journals Heterogeneity of Epidermal Growth Factor Receptor Status and Mutations of KRAS/PIK3CA in Circulating Tumor Cells of Patients with Colorectal Cancer

2013 ◽  
Vol 59 (1) ◽  
pp. 252-260 ◽  
Author(s):  
Christin Gasch ◽  
Thomas Bauernhofer ◽  
Martin Pichler ◽  
Sabine Langer-Freitag ◽  
Matthias Reeh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Egfr Gene ◽  
Egfr Expression ◽  
Epidermal Growth ◽  
Viral Oncogene Homolog

BACKGROUND Molecular characterization of circulating tumor cells (CTCs) is pivotal to increasing the diagnostic specificity of CTC assays and investigating therapeutic targets and their downstream pathways on CTCs. We focused on epidermal growth factor receptor (EGFR) and genes relevant for its inhibition in patients with colorectal cancer (CRC). METHODS We used the CellSearch® system for CTC detection in peripheral blood samples from 49 patients with metastatic CRC (mCRC) and 32 patients with nonmetastatic CRC (nmCRC). We assessed EGFR expression in 741 CTCs from 27 patients with mCRC and 6 patients with nmCRC using a fluorescein-conjugated antibody with the CellSearch Epithelial Cell Kit. DNA of a single CTC isolated by micromanipulation was propagated by whole-genome amplification and analyzed by quantitative PCR for EGFR gene amplification and sequencing for KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), BRAF (v-raf murine sarcoma viral oncogene homolog B1), and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α) mutations. RESULTS At least 2 CTCs were detected in 24 of 49 patients with mCRC and 7 of 32 patients with nmCRC. In 7 of 33 patients, CTCs with increased EGFR expression were identified. Heterogeneity in EGFR expression was observed between CTCs from the same patient. EGFR gene amplification was found in 7 of 26 CTCs from 3 patients. The investigated BRAF gene locus was not mutated in 44 analyzed CTCs, whereas KRAS mutations were detected in 5 of 15 CTCs from 1 patient and PIK3CA mutations in 14 of 36 CTCs from 4 patients. CONCLUSIONS Molecular characterization of single CTCs demonstrated considerable intra- and interpatient heterogeneity of EGFR expression and genetic alterations in EGFR, KRAS, and PIK3CA, possibly explaining the variable response rates to EGFR inhibition in patients with CRC.

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