Lung cancer in never-smoker Asian females is driven by oncogenic mutations, most often involving EGFR

Abstract

The aim of this study was to determine the distribution of known oncogenic driver mutations in female never-smoker Asian patients with lung adenocarcinoma. We analyzed 214 mutations across 26 lung cancer-associated genes and three fusion genes using the MassARRAY LungCarta Panel and the ALK, ROS1, and RET fusion assays in 198 consecutively resected lung adenocarcinomas from never-smoker females at a single institution. EGFR mutation, which was the most frequent driver gene mutation, was detected in 124 (63%) cases. Mutation of ALK, KRAS, PIK3CA, ERBB2, BRAF, ROS1, and RET genesoccurred in 7%, 4%, 2.5%, 1.5%, 1%, 1%, and 1% of cases, respectively. Thus, 79% of lung adenocarcinomas from never-smoker females harbored well-known oncogenic mutations. Mucinous adenocarcinomas tended to have a lower frequency of known driver gene mutations than other histologic subtypes. EGFR mutation was associated with older age and a predominantly acinar pattern, while ALK rearrangement was associated with younger age and a predominantly solid pattern. Lung cancer in never-smoker Asian females is a distinct entity, with the majority of these cancers developing from oncogenic mutations.

Keywords: EGFR; adenocarcinoma; driver mutation; never-smoker female; non-small cell lung cancer.

Figure 1. Process of patient (female never smoker with lung adenocarcinoma) selection in this study

(A) Distribution of lung cancer according to histology subtype. (B) Distribution of lung adenocarcinoma according to gender. (C) Distribution of lung adenocarcinoma from female according to smoking status. Patients with no medical record of smoking status were excluded. The record of year 2012 was not shown due to lack of smoking information.

Figure 2. Frequency of driver gene mutations in lung adenocarcinomas from East Asian never-smoker females

Figure 3. Diagram demonstrating driver gene mutation status and clinicopathologic features in 198 adenocarcinomas from East Asian never-smoker females

Most mutations were mutually exclusive with the rare exception of concurrent mutation of EGFR/PIK3CA (n = 3), EGFR/TP53 (n = 1), ALK/TP53 (n = 2), KRAS/PIK3CA (n = 1), and KRAS/ERBB2 (n = 1). Patients who received concurrent chemoradiation therapy and those who did not undergo lymph node dissection were excluded in the analysis of TNM stage.

Figure 4. Frequency of driver gene mutations according to predominant histologic subtype

(A) Lepidic, (B) Acinar, (C) Papillary, (D) Solid, (E) Mucinous subtype. In acinar subtype, four cases with concurrent mutations of EGFR/PIK3CA (n = 3) and EGFR/TP53 (n = 1) are represented as an EGFR mutation, and 2 cases of ALK/TP53 mutation as an ALK mutation. In mucinous subtype, two cases with concurrent mutations of KRAS/PIK3CA and KRAS/ERBB2 are represented as a KRAS mutation.