Prognostic implications of immunohistochemistry markers for EGFR-TKI therapy in Chinese patients with advanced lung adenocarcinoma harboring EGFR mutations

Abstract

BackgroundEpidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer predict dramatic clinical responses to tyrosine kinase inhibitor (TKI) treatment. The conclusion on EGFR mutation-specific antibodies by immunohistochemistry (IHC) is not consistent. We evaluated the clinical availability of EGFR mutation-specific antibodies, investigating the prediction role of mutant EGFRs and other IHC markers in TKI therapy in patients with advanced lung adenocarcinoma.Materials and methodsWe analyzed 637 primary lung adenocarcinomas from an unselected Chinese population. For IHC, antibodies against EGFR exon 19 E746_A750 deletions, exon 21 L858R mutations, thyroid transcription factor-1 (TTF-1), and Napsin-A were applied. Positivity was defined as staining score >0.ResultsSpecificities of E746_A750 and L858R antibodies were 99.6% and 99.3%, while sensitivities were 86.0% and 82.7%, respectively. Tumors with Napsin-A positivity, TTF-1 positivity, EGFR mutations, and lepidic pattern showed a lower marker of proliferation index (Ki67). Higher expression scores of mutant EGFR protein, TTF-1 positivity, lower Ki67 proliferation index, and lepidic pattern were associated with longer progression-free survival.ConclusionHigh scores of mutant EGFR, Napsin-A positivity, TTF-1 positivity, lower Ki67 index, and lepidic pattern were favorable predictors for TKI therapy in patients with advanced lung adenocarcinoma.

Epidermal Growth Factor Receptor Mutation Frequency in Squamous Cell Carcinoma and Its Diagnostic Performance in Cytological Samples: A Molecular and Immunohistochemical Study

“…However, it is still practiced in low resource centers due to unavailability of infrastructure and expertise. The sensitivity and specificity of EGFR mutation vary widely between different studies (sensitivity 47-84%, specificity 89-99%), which may be due to the inherent technical problems of IHC [8-10, 40, 46-47]. In the present study EGFR mutation-specific IHC was available in 112 cases, of which 19 cases showed L858R mutation with a sensitivity and specificity of 55% and 91.2% respectively.…”

“…Ragazzi et al showed the sensitivity and specificity for DEL19 (E746-750) IHC as 56% and 100%, respectively and sensitivity and specificity for exon 21 (L858R point mutation) as 70.4% and 89%, respectively [45]. Zhang et al from China included all grades of staining as positive (1+ to 3+ staining) and showed a sensitivity and specificity of 99.6% and 99.3%, respectively for L858R whereas low sensitivity (86.0% and 82.7% respectively) for DEL19 (Table 6) [8-10, 46, 47]. The overall sensitivity and specificity of mutation-specific EGFR IHC were 48.3% and 92.2% in the present study.…”

Thyroid transcription factor 1 (TTF‐1) negativity as a predictor of unfavorable response to EGFR‐TKI therapy in advanced lung adenocarcinoma patients with EGFR mutations

“…In our study, the TTF-1-negative patients had significantly worse ORR, DCR and mPFS compared with TTF-1-positive patients with EGFR-mutant LUAD, which is consistent with previous studies. 23,28 However, the mechanism underlying the impact of TTF-1 expression status on the efficacy of EGFR-TKIs is not completely understood. Ingram et al showed that silencing TTF-1 in LUAD cells led to their dedifferentiation via activation of the RAS-RAF-MEK-ERK signaling pathway and the downregulation of DUSP6, a key downstream regulator of the EGFR pathway involved in cell proliferation, survival, and differentiation.…”