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Lung Cancer. 2020 Mar 18;143:60-66. doi: 10.1016/j.lungcan.2020.03.012. [Epub ahead of print]

Prognostic value and therapeutic implications of expanded molecular testing for resected early stage lung adenocarcinoma.

Author information

1
The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA; Division of Thoracic Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA. Electronic address: Peter.Kneuertz@osumc.edu.
2
The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA; Division of Thoracic Medical Oncology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
3
The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA; Division of Thoracic Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
4
The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA; Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
5
Center for Biostatistics, The Ohio State University, Columbus, OH, USA.
6
The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA; Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

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

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