To evaluate the accuracy of immunohistochemistry (IHC) method compared to standard PCR-based method for detecting common activating epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) and to evaluate predictive value of IHC EGFR mutation-positive status for EGFR TKIs treatment outcome. Additionally, based on the results of our study we wanted to evaluate estimated cost-effectiveness for the upfront IHC testing.
Activating EGFR mutations are predictive for excellent, approximately 70%, response rate for treatment with EGFR TKIs in patients with advanced NSCLC. Standard method for EGFR mutation detection is PCR method. The sensitivity of PCR method is limited by the amount of tumor cells in the tumor specimen. PCR-based EGFR mutation testing is relatively costly, technically comlex, labour demanding, and has relatively long turn-around-times. IHC method using mutant selective antibodies for detection of specific mutant EGFR proteins enables EGFR mutation analysis in small tumor tissue samples or even tumor cells. IHC is easy to conduct, cheaper, widely available and yields fast results. Previously, IHC EGFR mutation detection with mutation specific EGFR antibodies was studies, revealing very high specificity, around 90%, while sensitivity was limited and variable between studies, ranging 30 % - 100 %. Data on predictive value of IHC determined EGFR mutations on response to EGFR TKI are scarce in the available literature.
Patients and Methods
The trial included 79 consecutive EGFR mutation-positive and 29 EGFR mutation-negative NSCLC cases diagnosed with reflex PCR-based testing. Two mutation-specific antibodies against the most common exon 19 deletion, namely E746-A750del (clone SP111) and L858R mutation (clone SP125) were tested using automated immunostainer. 60/79 EGFR mutation-positive cases were treated with EGFR TKIs for advanced disease and included in treatment outcome analysis. Decision tree was used for the cost-effectiveness analysis.
The overall sensitivity and specificity of IHC-based method compared to the PCR-based one were 84.8 % (95 % CI 75.6–91.6) and 100 % (95 % CI 85.4–100), respectively. The median PFS and OS of patients with IHC positive EGFR mutation status were highly comparable to the total cohort (PFS: 14.3 vs 14.0 months; OS: 34.4 vs 34.4 months). The PCR and IHC cost ratio needs to be about eight-to-one and four-to-one in Caucasian and Asian population, respectively, to economically justify upfront use of IHC.
The trial confirmed an excellent specificity with fairly good sensitivity of IHC with mutation-specific antibodies for common EGFR mutations and the accuracy of IHC testing for predicting response to EGFR TKIs. The use of upfront IHC depends mainly on the population EGFR mutation positivity probability.