Abstract
BackgroundSeveral genetic driver alterations have been identified in micropapillary lung adenocarcinoma (MPA). However, the frequency of co-alteration of ROS1, EGFR, and EML4-ALK is yet unclear. Herein, we investigated the relationship between clinicopathologic characteristics and well-identified driver mutations of MPA compared with non-micropapillary lung adenocarcinoma (LA).MethodsFormalin-fixed paraffin-embedded (FFPE) sections derived from lung adenocarcinoma patients who never received adjuvant chemotherapy or radiation therapy prior to surgical resection were collected from October 2016 to June 2019. EGFR mutations, ROS1 rearrangements, and EML4-ALK fusion were identified in a set of 131 MPA and LA cases by using the amplification refractory mutation system (ARMS). The response rate and duration of response were assessed using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).ResultsEGFR mutations had occurred in 42 (76.4%) MPA patients and 42 (55.3%) LA patients. Interestingly, ROS1 rearrangements were highly enriched only in the MPA cases (6/55, 10.9%) but rarely in the LA cases (1/76, 1.3%). Furthermore, 7.3% (4/55) MPA samples had double gene mutations, while only 1.3% (1/76) LA cases had double gene alterations. Of 5 patients with harboring two driver oncogene mutations, four patients (80%) obtained partial response, and one patient (20%) suffered recurrence.ConclusionsA higher prevalence of ROS1 rearrangement or combined mutations of ROS1, EGFR, and EML4-ALK may play a critical role in the tumorigenesis of MPA. These findings provide a novel therapeutic strategy for patients with malignant MPA through combining TKIs than one TKI.
Highlights
Lung cancer remains to be the leading cause of cancerrelated death worldwide, and the most frequent histological subtype is lung adenocarcinoma [1]
We discovered that different genetic driver alterations often co-existed in the micropapillary lung adenocarcinoma (MPA) group, for instance, epidermal growth factor receptor (EGFR) combined with ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) (n = 2) and EML4-anaplastic lymphoma kinase (ALK) combined with ROS1 (n = 2), while only one lung adenocarcinoma (LA) case harbored EGFR combined with ROS1, suggesting that co-existent alterations of EGFR, ROS1, and EML4-ALK were more frequent in MPA than in LA (p = 0.043, Table 2)
These results indicate the potential combined treatments of MPA with two different Tyrosine kinase inhibitor (TKI) targeted to EGFR and ROS1
Summary
Lung cancer remains to be the leading cause of cancerrelated death worldwide, and the most frequent histological subtype is lung adenocarcinoma [1]. Several oncogenic drivers have been identified in lung adenocarcinoma, including mutations in the epidermal growth factor receptor (EGFR) [8], fusions of anaplastic lymphoma kinase (ALK) [9], and rearrangements of ROS. An additional novel oncogenic fusion gene, ROS1, was identified, which accounted for 1–2% of all lung adenocarcinoma patients. Of special interest, this ratio increased to 5–7% for lung adenocarcinoma patients without EGFR/KRAS/BRAF/ALK mutations [16]. With the development of tyrosine kinase inhibitors (TKIs), TKIs served as the first-line option for patients harboring EGFR-sensitive mutations, ALK fusions, or ROS1 rearrangements. We investigated the relationship between clinicopathologic characteristics and well-identified driver mutations of MPA compared with non-micropapillary lung adenocarcinoma (LA)
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