Abstract 1563: The impact of heterogeneity of AKT1/2 copy number alterations between primary tumors and lymph node metastases in non-small cell lung cancer
Authors: Tsuchiya Kazuo , Yoshimura Katsuhiro , Inoue Yusuke , Iwashita Yuji , Yamashita Takashi , Kawase Akikazu , Tanahashi Masayuki , Ogawa Hiroshi , Funai Kazuhito , Shinmura Kazuya , Niwa Hiroshi , Suda Takafumi , Sugimura Haruhiko 
Published: August 2019

Abstract
Background: Copy number alterations (CNAs) arise during the evolution of tumors as a consequence of its genomic instability. It is reported that the increase of gene copy number of AKT1/2 correlated with clinicopathological profiles in lung cancer. On the other hand, tumor heterogeneity was also reported to associate with clinical outcomes of the patients in several cancers. However, the clinical significance of AKT1/2 CNAs in patients with non-small cell lung cancer (NSCLC) has been still unclear, especially its contribution to patients’ prognoses. We here explored the relationships between intertumoral heterogeneity of CNAs of AKT1/2 and clinicopathological features using the resected tissue pairs of primary sites and corresponding lymph node metastases (LNM).
Method: AKT1/2 CNAs in 130 tissue pairs of NSCLC were assessed by fluorescent in situ hybridization (FISH), which were classified into three categories: amplification, polysomy, and disomy. The associations between CNAs and clinical features were retrospectively analyzed. In addition, we investigated the effect of the increased AKT1/2 copy number and intertumoral heterogeneity of AKT1/2 CNAs between the resected tissue pairs on the patient prognoses.
Result: The median age of patients was 66.0 years old (33-84 years old) and 98 (75.4%) patients were male. 100 (76.9%) patients had smoking history and 69 (53.1%) patients had adenocarcinoma. AKT1 CNAs including amplification and polysomy were observed in 27.3% of primary sites (2.3% for amplification and 25% for polysomy), and in 43.8% of LNM (9.4% for amplification and 34.4% for polysomy). AKT2 CNAs were observed in 33.1% of primary sites (5.5% for amplification and 27.6% for polysomy), and in 36.3% of LNM (9.7% for amplification and 26.6% for polysomy). AKT1 CNAs were significantly associated with sex (p=0.004 for primary sites, p=0.034 for LNM) and smoking history (p=0.004 for primary sites, p=0.038 for LNM). EGFR mutations were more frequently observed in the patients with AKT1/2 CNAs in primary sites (p=0.009 for AKT1, and p=0.037 for AKT2). The mean copy number significantly increased in the LNM compared to the primary sites in AKT1 (2.1 for primary sites vs 3.4 for LNM, p&lt;0.001), whereas there were no significant differences but an increasing tendency in AKT2 (2.9 for primary sites vs 3.5 for LNM, p=0.147). There were no significant differences for recurrence-free survival (RFS) according to AKT1/2 CNA categories. However, cases with the increased AKT1/2 copy number in the corresponding LNM showed significantly worse survivals for RFS (Log-rank, p=0.02 for AKT1, and p=0.04 for AKT2).
Conclusion: AKT1/2 copy number increased in LNM compared to primary sited, and which also associated with worse prognosis. The intertumoral heterogeneity of AKT1/2 CNAs may possess distinct clinical significance in NSCLC.
Citation Format: Kazuo Tsuchiya, Katsuhiro Yoshimura, Yusuke Inoue, Yuji Iwashita, Takashi Yamashita, Akikazu Kawase, Masayuki Tanahashi, Hiroshi Ogawa, Kazuhito Funai, Kazuya Shinmura, Hiroshi Niwa, Takafumi Suda, Haruhiko Sugimura. The impact of heterogeneity of AKT1/2 copy number alterations between primary tumors and lymph node metastases in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1563.