Epidermal Growth Factor Receptor Mutation Status and the Impact on Clinical Outcomes in Patients with Non-Small Cell Lung Cancer

Lung cancer is the major cause of cancer-related death in the world. As reported by American Cancer Society, lung cancer caused more deaths than breast, prostate, colorectal, and brain cancers combined in 2017 [1]. Non-small cell lung cancer (NSCLC) consists of about 85% of all lung cancers and is usually diagnosed at advanced or metastatic stage [2]. Platinum-based regimens have been the mainly conventional chemotherapy for advanced NSCLC treatment with a poor benefit in survival. In the past decade, an increased understanding of the signaling pathways contributed to the development of target agents, and the addition of target therapy to the treatment protocols for NSCLC patients was a major breakthrough and had obtained clinically significant survival benefit [3]. The epidermal growth factor receptor (EGFR) mutations are predictive markers for response to target therapy in NSCLC patients [4]. EGFR is a transmembrane glycoprotein existing on the cell surface and plays an important role in tumor cell survival and proliferation. Tyrosine kinase inhibitors (TKIs) that specifically target EGFR have been used as first-line treatment in EGFR mutation-positive patients [5, 6]. Lindeman et al. [6] reported that the response to TKIs was approximately 68% in patients with activating EGFR mutations, while there was only an 11% response rate in patients with wild type EGFR. Given the benefit of EGFR-TKI therapy, EGFR mutation testing was recommended to NSCLC patients before initiation of first-line therapy, according to clinical practice guidelines [7].

The genetic divergence of EGFR mutations according to ethnicity has been reported. Asian populations have the highest EGFR mutation frequency and it has become very common in clinical practice in some Asian countries to treat patients based on their EGFR status [8, 9]. However, most of the studies conducted on EGFR mutations in Asia were carried out in Korea or Japan, data available on EGFR mutations in China are limited. The present study was to evaluate the EGFR mutation status in Chinese NSCLC patients (Stage I-IV), explore its association with clinical characteristics, and further investigate differences in prognosis between advanced NSCLC patients (Stage IIIB-IV) with and without EGFR mutations.

Many studies have been carried out to estimate EGFR mutation status among NSCLC patients in different regions and populations in order to evaluate the benefits from EGFR-TKI. Results showed that EGFR mutation frequency possesses variability based on ethnicity and regional differences, with 36.3% of positivity in Korea [10], 13.6% in Spain [3], 10.6% in Poland [11], 15.7% in Greece [12], 36.7% in Iran [13], 11.9% in Lebanon [14], and greater in Japan with 53.9% [15]. The prevalence of the EGFR mutations in our study is 43.3%, lower than that reported in a large Asian study including Chinese patients with NSCLC (50.2%) [16], however, it is higher than that which was reported in a multi-center diagnostic survey carried out in the Asia Pacific Region (38.1%) [17]. In general, the frequencies of EGFR mutations in patients from Asian countries are quite high, even up to 68.5% in female non-smokers with adenocarcinoma [18]. The most common mutations detected in the present study are exons19 and 21 (21.0% and 19.3%, respectively). 19-Del mutation and L858R mutation were the most common mutation types for exons 19 and 21, which was in line with previous literature [19].

The median PFS and OS for patients with EGFR mutations were 11 months and 24 months, respectively, while patients with wild type EGFR demonstrated a median 4-month PFS and 12-month OS. The results show prominent benefits in patients with EGFR mutations compared to those with wild type EGFR. Correlations between EGFR mutations and improved PFS and survival in EGFR mutation-positive patients with administration of EGFR-TKI have been reported, while PFS and survival differ due to exon mutation sites. Exons 19 and 21 mutations were associated with sensitivity to EGFR-TKI and it has been reported that the 19-Del mutation was associated with a better response than the L858R mutation when patients were treated with TKI [20, 21]. Mutations in exon 18, including G719A, G719C, and G719S, were also drug sensitizing mutations, however, T790M and 20-Ins mutations had been demonstrated to confer resistance to EGFR-TKI. In the present study, one patient with 20-Ins mutation was observed by the authors. When compared with sensitizing EGFR mutations, the 20-Ins mutation case failed to respond to a combination of pemetrexed and cisplatin and demonstrated a poor prognosis, with only a 3-month survival. The inclusion of patient with 20-Ins mutation resulted in a lower PFS and OS compared to patients with sensitizing EGFR mutations, however this inclusion did not seem to adversely affect overall PFS or OS due to the limited numbers of patients included. Studies reported that T790M was the most common mutant type in exon 20 [22], and in the present study, T790M point mutation was detected in one sample together with 19-Del mutation. Namely, the patient had a rare combination of exon 19 sensitizing mutation and T790M resistance mutation. The mutations are heterogeneous and the EGFR-TKI efficacy in patients with heterogeneous mutations requires individual assessment [23, 24]. Limited to the present study, the patient with heterogeneous mutations received icotinib therapy and demonstrated similar treatment outcomes, compared to sensitizing EGFR mutations, with a 14-month PFS and 23-month survival.

Studies have shown that female, no-smoking status, adenocarcinoma histology, and Asian ethnicity are all favorable factors for EGFR mutations [25, 26]. Similar results were observed in the present study. The statistical analysis showed that the EGFR mutation rate was much higher in female than in male. The reasons for the effect of gender on EGFR mutation rate remained incompletely understood. Differential smoking habits and sex hormones might contribute to the effect [27]. There were more EGFR mutations in positive cases than in never smokers compared with current smokers or former smokers. In the present study, the EGFR mutations were found in 56.8% (75/132) patients who had never smoked and in 25.9% (15/58) current smokers (p <0.001). Likewise, the difference in EGFR mutation rate between NSCLC patients with adenocarcinoma and non-adenocarcinoma was significant (p <0.001). Indeed, molecular testing guidelines recommend EGFR testing to all advanced patients with adenocarcinoma to guide selection of EGFR-TKI therapy, regardless of gender, race, smoking status, or other clinical risk factors [28].

In conclusion, the EGFR mutation rate is 43.3% among all NSCLC patients and the mutations are more frequently observed in exons 19 and 21. EGFR mutations are prevalent in patients who are female, have adenocarcinoma, and have never smoked. Advanced EGFR mutation-positive patients have longer PFS and OS than those with wild type EGFR. But this study has some limitations such as a relatively small number of selected cases and having been a single-center study. Therefore, a larger sample size and multi-center investigations are necessary to make the research results more comprehensive and convincing.