EGFR variant allele frequency predicts EGFR-TKI efficacy in lung adenocarcinoma: a multicenter study

Balazs Gieszer; Zsolt Megyesfalvi; Viktoria Dulai; Judit Papay; Ilona Kovalszky; Jozsef Timar; Janos Fillinger; Tunde Harko; Orsolya Pipek; Vanda Teglasi; Eszter Regos; Gergo Papp; Zoltan Szallasi; Viktoria Laszlo; Ferenc Renyi-Vamos; Gabriella Galffy; Csaba Bodor; Balazs Dome; Judit Moldvay

doi:10.21037/tlcr-20-814

EGFR variant allele frequency predicts EGFR-TKI efficacy in lung adenocarcinoma: a multicenter study

Transl Lung Cancer Res. 2021 Feb;10(2):662-674. doi: 10.21037/tlcr-20-814.

Authors

Balazs Gieszer¹, Zsolt Megyesfalvi^{1

2

3}, Viktoria Dulai², Judit Papay⁴, Ilona Kovalszky⁴, Jozsef Timar⁵, Janos Fillinger^{1

2}, Tunde Harko², Orsolya Pipek⁶, Vanda Teglasi⁴, Eszter Regos⁴, Gergo Papp⁴, Zoltan Szallasi^{7

8}, Viktoria Laszlo^{2

3}, Ferenc Renyi-Vamos^{1

2}, Gabriella Galffy⁹, Csaba Bodor⁴, Balazs Dome^{1

2

3}, Judit Moldvay^{2

7}

Affiliations

¹ Department of Thoracic Surgery, Semmelweis University and National Institute of Oncology, Budapest, Hungary.
² National Koranyi Institute of Pulmonology, Budapest, Hungary.
³ Department of Thoracic Surgery, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
⁴ 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
⁵ 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
⁶ Department of Physics of Complex Systems, Eotvos Lorand University, Budapest, Hungary.
⁷ MTA-SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
⁸ Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
⁹ Torokbalint County Institute of Pulmonology, Torokbalint, Hungary.

Abstract

Background: Although lung adenocarcinoma (LADC) with sensitizing mutations of the epidermal growth factor receptor (EGFR) is highly sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKIs), in most cases disease progression inevitably occurs. Our aim was to investigate the predictive and prognostic significance of adjusted tumoral EGFR variant allele frequency (EGFR-aVAF) in the above setting.

Methods: Eighty-nine Caucasian advanced-stage LADC patients with known exon-specific EGFR mutations undergoing EGFR-TKI treatment were included. The correlations of EGFR-aVAF with clinicopathological variables including progression-free and overall survival (PFS and OS, respectively) were retrospectively analyzed.

Results: Of 89 EGFR-mutant LADC patients, 46 (51.7%) had exon 19 deletion, while 41 (46.1%) and 2 (2.2%) patients had exon 21- and exon 18-point mutations, respectively. Tumoral EGFR-aVAF was significantly higher in patients harboring EGFR exon 19 mutations than in those with exon 21-mutant tumors (P<0.001). Notably, patients with EGFR exon 19 mutant tumors demonstrated significantly improved PFS (P=0.003) and OS (P=0.02) compared to patients with exon 21 mutations. Irrespective of specific exon mutations, a statistically significant positive linear correlation was found between EGFR-aVAF of tumoral tissue and PFS (r=0.319; P=0.002). High (≥70%) EGFR-aVAF was an independent predictor of longer PFS [vs. low (<70%) EGFR-aVAF; median PFSs were 52 vs. 26 weeks, respectively; P<0.001]. Additionally, patients with high EGFR-aVAF also had significantly improved OS than those with low EGFR-aVAF (P=0.011).

Conclusions: Our study suggests that high (≥70%) EGFR-aVAF of tumoral tissue predicts benefit from EGFR-TKI treatment in advanced LADC and, moreover, that exon 19 EGFR mutation is associated with high EGFR-aVAF and improved survival outcomes.

Keywords: Epidermal growth factor receptor mutation (EGFR mutation); lung adenocarcinoma (LADC); variant allele frequency (VAF).