Association of polymorphisms in AKT1 and EGFR with clinical outcome and toxicity in non-small cell lung cancer patients treated with gefitinib
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Association of polymorphisms in AKT1 and EGFR with clinical outcome and toxicity in non-small cell lung cancer patients treated with gefitinib. / Giovannetti, Elisa; Zucali, Paolo A; Peters, Godefridus J; Cortesi, Filippo; D'Incecco, Armida; Smit, Egbert F; Falcone, Alfredo; Burgers, Jacobus A; Santoro, Armando; Danesi, Romano; Giaccone, Giuseppe; Tibaldi, Carmelo.
In: MOL CANCER THER, Vol. 9, No. 3, 03.2010, p. 581-93.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Association of polymorphisms in AKT1 and EGFR with clinical outcome and toxicity in non-small cell lung cancer patients treated with gefitinib
AU - Giovannetti, Elisa
AU - Zucali, Paolo A
AU - Peters, Godefridus J
AU - Cortesi, Filippo
AU - D'Incecco, Armida
AU - Smit, Egbert F
AU - Falcone, Alfredo
AU - Burgers, Jacobus A
AU - Santoro, Armando
AU - Danesi, Romano
AU - Giaccone, Giuseppe
AU - Tibaldi, Carmelo
PY - 2010/3
Y1 - 2010/3
N2 - EGFR mutations are strongly predictive of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor activity in non-small cell lung cancer (NSCLC), but resistance mechanisms are not completely understood. The interindividual variability in toxicity also points out to the need of novel pharmacogenetic markers to select patients before therapy. Therefore, we evaluated the associations between EGFR and AKT1 polymorphisms and outcome/toxicity in gefitinib-treated NSCLC patients. Polymorphic loci in EGFR, and AKT1, and EGFR and K-Ras mutations were assessed in DNA isolated from blood samples and/or paraffin-embedded tumor from 96 gefitinib-treated NSCLC patients. Univariate and multivariate analyses compared genetic variants with clinical efficacy and toxicity using Fisher's, log-rank test, and Cox's proportional hazards model. AKT1-SNP4 association with survival was also evaluated in 127 chemotherapy-treated/gefitinib-naive patients, whereas its relationship with AKT1 expression and gefitinib cytotoxicity was studied in 15 NSCLC cell lines. AKT1-SNP4 A/A genotype was associated with shorter time-to-progression (P = 0.04) and overall survival (P = 0.007). Multivariate analyses and comparison with the gefitinib-nontreated population underlined its predictive significance, whereas the in vitro studies showed the association of lower AKT1 mRNA levels with gefitinib resistance. In contrast, EGFR-activating mutations were significantly correlated with response, longer time-to-progression, and overall survival, whereas EGFR -191C/A (P < 0.001), -216 G/T (P < 0.01), and R497K (P = 0.02) polymorphisms were strongly associated with grade >1 diarrhea. AKT1-SNP4 A/A genotype seems to be a candidate biomarker of primary resistance, whereas EGFR -191C/A, -216G/T, and R497K polymorphisms are associated with diarrhea when using gefitinib in NSCLC patients, thus offering potential new tools for treatment optimization.
AB - EGFR mutations are strongly predictive of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor activity in non-small cell lung cancer (NSCLC), but resistance mechanisms are not completely understood. The interindividual variability in toxicity also points out to the need of novel pharmacogenetic markers to select patients before therapy. Therefore, we evaluated the associations between EGFR and AKT1 polymorphisms and outcome/toxicity in gefitinib-treated NSCLC patients. Polymorphic loci in EGFR, and AKT1, and EGFR and K-Ras mutations were assessed in DNA isolated from blood samples and/or paraffin-embedded tumor from 96 gefitinib-treated NSCLC patients. Univariate and multivariate analyses compared genetic variants with clinical efficacy and toxicity using Fisher's, log-rank test, and Cox's proportional hazards model. AKT1-SNP4 association with survival was also evaluated in 127 chemotherapy-treated/gefitinib-naive patients, whereas its relationship with AKT1 expression and gefitinib cytotoxicity was studied in 15 NSCLC cell lines. AKT1-SNP4 A/A genotype was associated with shorter time-to-progression (P = 0.04) and overall survival (P = 0.007). Multivariate analyses and comparison with the gefitinib-nontreated population underlined its predictive significance, whereas the in vitro studies showed the association of lower AKT1 mRNA levels with gefitinib resistance. In contrast, EGFR-activating mutations were significantly correlated with response, longer time-to-progression, and overall survival, whereas EGFR -191C/A (P < 0.001), -216 G/T (P < 0.01), and R497K (P = 0.02) polymorphisms were strongly associated with grade >1 diarrhea. AKT1-SNP4 A/A genotype seems to be a candidate biomarker of primary resistance, whereas EGFR -191C/A, -216G/T, and R497K polymorphisms are associated with diarrhea when using gefitinib in NSCLC patients, thus offering potential new tools for treatment optimization.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Antineoplastic Agents/adverse effects
KW - Biomarkers, Pharmacological/analysis
KW - Carcinoma, Non-Small-Cell Lung/diagnosis
KW - Drug Resistance, Neoplasm/genetics
KW - Drug-Related Side Effects and Adverse Reactions/genetics
KW - ErbB Receptors/genetics
KW - Female
KW - Gefitinib
KW - Humans
KW - Lung Neoplasms/diagnosis
KW - Male
KW - Middle Aged
KW - Polymorphism, Single Nucleotide/physiology
KW - Prognosis
KW - Proto-Oncogene Proteins c-akt/genetics
KW - Quinazolines/adverse effects
KW - Retrospective Studies
KW - Survival Analysis
KW - Treatment Outcome
U2 - 10.1158/1535-7163.MCT-09-0665
DO - 10.1158/1535-7163.MCT-09-0665
M3 - SCORING: Journal article
C2 - 20159991
VL - 9
SP - 581
EP - 593
JO - MOL CANCER THER
JF - MOL CANCER THER
SN - 1535-7163
IS - 3
ER -
