Abstract B11: EGFR polymorphism as a predictor of clinical outcome in advanced lung cancer patients treated with EGFR-TKI

Abstract

Background: Mutations in the epidermal growth factor receptor (EGFR) have been confirmed as predictors of efficacy for EGFR-tyrosine kinase inhibitors (TKIs). We investigated whether polymorphisms of the EGFR gene were associated with clinical outcome in NSCLC patients treated with EGFR-TKI. Methods: A polymorphic dinucleotide repeat (CA simple sequence repeat 1 [CA-SSR1]) in intron one and single nucleotide polymorphisms in the promoter region (SNP -216 GG or GT) were evaluated in 71 NSCLC patients by PCR-RFLP and DNA sequencing. Genetic polymorphisms were correlated with clinical outcomes of EGFR-TKIs. Results: SNP-216G/T polymorphisms were associated with the efficacy of EGFR-TKI. The response rate for the SNP-216G/T was significantly higher than that for the GG (62.5% vs. 27.4%, P=0.044). SNP-216G/T genotype was also associated with longer progression-free survival compared with GG genotype (16.7 months vs. 5.1 months, P=0.005). However, Genotypes for the CA-SSR1 was not associated with the efficacy of EGFR-TKI. Conclusions: SNP-216G/T polymorphism is potential predictor for clinical outcome in NSCLC patients treated with EGFR-TKI.

Side effects of tyrosine kinase inhibitors therapy in patients with non‑small cell lung cancer and associations with EGFR polymorphisms: A systematic review and meta‑analysis

“…Typical side effects of the drugs used in NSCLC treatment (for both monoclonal antibodies and small molecule TKIs) are skin rash and diarrhea (49,50). Since the EGFR is commonly affected by somatic mutations in altered neoplastic cells and the EGFR gene is highly polymorphic, the potential cause of those toxic manifestations of drugs may be EGFR genetic variability (11,(13)(14)(15)(16). SNPs or microsatellite tandem repeats are typically found in the EGFR promoter region and intron 1.…”

“…To the best of our knowledge, the mechanism of skin rash development has not yet been elucidated. One hypothesis is that there is a genetic susceptibility for rash development, where altered EGFR expression alters the TKI response (11,(13)(14)(15)(16)28). Another is that poor vascularization of the tumor tissue and drug concentrations at a level that does not inhibit tumor growth may cause a skin rash by over-saturation of EGFR (18,55).…”

“…However, acquired resistance in connection with EGFR T790 mutations limited the efficacy of the EGFR-TKI (11,12). The role of polymorphisms [including single nucleotide polymorphisms (SNPs) and short tandem CA repeats] of the EGFR gene as another potential molecular target that improved clinical outcomes is well-established (13)(14)(15)(16). Recently, a meta-analysis elucidated that among rs712829 (-216G>T), rs11568315 (CA repeat), rs2293347 (D994D) and rs4947492, -216G>T and variable CA repeat polymorphisms significantly affected OS and PFS time in gefitinib-or erlotinib-treated patients with NSCLC (17).…”

Frequencies of EGFR single nucleotide polymorphisms in non-small cell lung cancer patients and healthy individuals in the Republic of Serbia: a preliminary study

“…Unfortunately, it has been noticed that not all of the treated patients are good responders to therapy [9][10][11][12]. In addition to other predictive biomarkers, EGFR polymorphisms have been associated with the outcome of the TKI therapy [13], suggesting that polymorphisms should be in the course of the future scientific concern.…”

Optimization of PCR Conditions for Amplification of GC-RichEGFRPromoter Sequence

“…Nevertheless, carriers of ‐216T allele had an improved progression‐free survival on gefitinib . Similar results were reported by Jung et al , as a higher response rate to gefitinib or erlotinib treatment and longer progression‐free survival corresponded to ‐216G/T compared to G/G genotype. Based on these data, it would not be surprising if the observed potential to predict efficacy and safety of the cancer treatment nominates these two polymorphisms for possible pharmacogenetic biomarkers for EGFR‐TKI activity.…”