EGFR and KRAS Mutations in the Non-Tumoral Lung. Prognosis in Patients with Adenocarcinoma

Roberto Chalela,Lara Pijuan,Raquel Longarón,Albert Sánchez-Font,Sergi Pascual-Guardia,Diana Badenes-Bonet,Edurne Arriola,Víctor Curull,Joaquim Gea,Beatriz Bellosillo

doi:10.3390/jcm8040529

Abstract

Tumor recurrence is frequent and survival rates remain extremely low in lung adenocarcinoma (ADC). We hypothesize that carcinogenic factors will promote loco-regional modifications not only in the future tumor, but throughout the exposed lung. Objective: To analyze whether the most prevalent mutations observed in ADC can also be observed in the non-neoplastic lung tissue, as well as the short-term prognosis implications of this finding. Methods: Non-tumoral lung parenchyma specimens obtained during surgery from 47 patients with EGFR and/or KRAS abnormalities in their ADC tumors underwent similar genomic testing. Short-term outcomes were also recorded. Results: The same mutations were present in the tumor and the histologically normal tissue in 21.3% of patients (SM group). Although local recurrences were similar in both groups, distant metastases were more frequent in the former (60 vs. 5.4%, p < 0.001). Moreover, SM patients showed lower time-to-progression (8.5 vs. 11.7 months, p < 0.001) and disease-free survival (8.5 vs. 11.2 months, p < 0.001). COX regression showed a higher risk of progression or death (DFS) in the SM group (HR 5.94, p < 0.01]. Similar results were observed when adjusting for potential confounding variables. Conclusions: These results confirm that genetic changes are present in the apparently normal lung in many ADC patients, and this finding has prognostic implications.

Highlights

Lung cancer is the second most frequently diagnosed tumor and the leading cause of cancer-related deaths worldwide [1,2]
All the malignant cells present DNA modifications at some point during this process and/or the proliferation step. These DNA acquired changes are known as somatic genomic alterations, being divided into “passenger mutations”, those which are supposed not to be related with the development of cancer; and “driver mutations”, if they are directly involved in carcinogenesis [11,12,13]
This situation overlaps with oncogenic driver alterations that have potential therapeutic implications such as mutations occurring in KRAS, EGFR, BRAF, MET, ERBB2 and gene fusions taking place in ALK, ROS1 or RET [14,15]

Summary

Introduction

Lung cancer is the second most frequently diagnosed tumor and the leading cause of cancer-related deaths worldwide [1,2]. All the malignant cells present DNA modifications at some point during this process and/or the proliferation step These DNA acquired changes are known as somatic genomic alterations, being divided into “passenger mutations”, those which are supposed not to be related with the development of cancer; and “driver mutations”, if they are directly involved in carcinogenesis [11,12,13]. Both ADC and squamous cell lung carcinoma have a high mutational burden when compared with other cancers. The aims of the present study were to identify whether the most prevalent mutations observed in lung ADC were present in the histologically non-tumoral lung tissue (NTL) of the same patient and, if this was the case, to assess their potential usefulness as prognostic markers

Objectives

Results

Discussion

Conclusion