Prognostic Value and Therapeutic Implications of Expanded Molecular Testing for Resected Early Stage Lung Adenocarcinoma

Peter J Kneuertz 1, David P Carbone 2, Desmond M D'Souza 3, Konstantin Shilo 4, Mahmoud Abdel-Rasoul 5, Weiqiang Zhao 4, Terrance M Williams 6, Daniel Jones 4, Robert E Merritt 3

Affiliations

PMID: 32208298
DOI: 10.1016/j.lungcan.2020.03.012

Abstract

Objectives: This study aimed to evaluate the prognostic and potential therapeutic value of expanded molecular testing of resected early-stage lung ACA.

Methods: We analyzed 324 patients who underwent lobectomy and lymphadenectomy for clinical Stage I&II lung ACA between 2011-2017. Molecular testing was routinely performed, first by PCR-based Sanger sequencing and FISH and then expanded to a 20 and then 50-gene next generation sequencing (NGS) panel. The frequency of mutations by testing method and their association with disease-free (DFS) and overall survival (OS) were tested.

Results: A total of 241 patients (74.4%) had at least one somatic mutation detected, with KRAS exon 2 (38.1%) and EGFR (17.9%) being the most common. TP53 was the most frequent co-existing mutation. Detection of at least one mutation increased from 49% with selective PCR/FISH testing to 82% with limited NGS/FISH, and 91% with extended NGS/FISH (p < 0.001). The rate of actionable mutations increased from 18% to 32% and 45% with expansion of molecular testing, respectively (p = 0.001). Using NGS, an additional 10 cases with EGFR mutations, and other rare mutations were found, including BRAF (5.9%), MET (5.6%), ERBB2 (4.1%), PIK3CA (2.3%), and DDR2 (2.1%). The expansion of FISH testing resulted in one additional detection of ROS1 and RET (1%) rearrangement. KRAS mutation was associated with worse DFS (HR 1.87; 95%CI 1.14-3.06) and OS (HR 2.09; 95%CI 1.11-3.92). BRAF mutation detected in NGS tested patients was also associated with decreased DFS (HR3.80; 95%CI 1.46-9.89) and OS (HR 7.37; 95%CI 2.36-22.99) on multivariate analysis.

Conclusion: The expansion of molecular testing has resulted in a substantial increase in the detection of potentially therapeutically significant mutations in resected early-stage ACA. KRAS and BRAF mutation status by NGS was prognostic for relapse and survival. These data emphasize opportunities for clinical trials in a growing number surgical ACA patients with available targeted therapies.

Keywords: BRAF; Early stage; KRAS; Lung adenocarcinoma; Molecular target; Mutation; Prognosis.