Mutation status concordance between primary lesions and metastatic sites of advanced non-small-cell lung cancer and the impact of mutation testing methodologies: a literature review.

James Sherwood,Marianne Ratcliffe,Jill Walker,Simon Dearden

doi:10.1186/s13046-015-0207-9

James Sherwood, Marianne Ratcliffe + Show 2 more

Open Access

https://doi.org/10.1186/s13046-015-0207-9

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Abstract

Increased understanding of the genetic aetiology of advanced non-small-cell lung cancer (aNSCLC) has facilitated personalised therapies that target specific molecular aberrations associated with the disease. Biopsy samples for mutation testing may be taken from primary or metastatic sites, depending on which sample is most accessible, and upon differing diagnostic practices between territories. However, the mutation status concordance between primary tumours and corresponding metastases is the subject of debate. This review aims to ascertain whether molecular diagnostic testing of either the primary or metastatic tumours is equally suitable to determine patient eligibility for targeted therapies. A literature search was performed to identify articles reporting studies of mutations in matched primary and metastatic aNSCLC tumour samples. Clinical results of mutation status concordance between matched primary and metastatic tumour samples from patients with aNSCLC were collated. Articles included in this review (N =26) all reported mutation status data from matched primary and metastatic tumour samples obtained from adult patients with aNSCLC. Generally, substantial concordance was observed between primary and metastatic tumours in terms of EGFR, KRAS, BRAF, p16 and p53 mutations. However, some level of discordance was seen in most studies; mutation testing methodologies appeared to play a key role in this, along with underlying tumour heterogeneity. Substantial concordance in mutation status observed between primary and metastatic tumour sites suggests that diagnostic testing of either tumour type may be suitable to determine a patient’s eligibility for personalised therapies. As with all diagnostic testing, highly sensitive and appropriately validated mutation analysis methodologies are desirable to ensure accuracy. Additional work is also required to define how much discordance is clinically significant given natural tumour heterogeneity. The ability of both primary and metastatic tumour sites to accurately reflect the tumour mutation status will allow more patients to receive therapies personalised to their disease.

Highlights

Lung cancer is the leading cause of cancer mortality [1], with non-small-cell lung cancer (NSCLC) accounting for ~85 % of primary lung cancers [2]
The functional pathways associated with these genes are well-documented [9,10,11], in brief: mutations in epidermal growth factor receptor (EGFR) are known to activate the MAPK/ ERK pathway [10, 11]; mutations in Kirsten rat sarcoma viral oncogenes homolog (KRAS), Murine sarcoma viral oncogene homolog B1 (BRAF) and PIK3CA are known to alter MAPK/ERK activation [10, 11]; and mutations in tumour protein p53 (TP53) are known to lead to loss of function of this tumor suppressor [9]
Research into the concordance of EGFR and KRAS mutation status between matched primary and metastatic tumours exists [33], to the authors’ knowledge, no review to date has systematically assessed the currently available data regarding whether metastatic samples are representative of primary tumour samples in patients with advanced NSCLC (aNSCLC) in terms of multiple mutations, and included consideration of the mutation testing methodologies employed. To address this knowledge gap, we describe in this review the level of mutation status concordance between matched primary and metastatic tumour samples, considering EGFR, KRAS and any other molecular aberrations noted in the included literature, as well as describing the mutation testing methodologies used

Summary

Introduction

Lung cancer is the leading cause of cancer mortality [1], with non-small-cell lung cancer (NSCLC) accounting for ~85 % of primary lung cancers [2]. Metastatic spread of the disease is a complication of advanced NSCLC (aNSCLC) [3], which usually precedes the fatal stages by a few months. Many patients present with metastases at diagnosis [4] due to the relatively asymptomatic earlier stages of the disease. The functional pathways associated with these genes are well-documented [9,10,11], in brief: mutations in EGFR are known to activate the MAPK/ ERK pathway [10, 11]; mutations in KRAS, BRAF and PIK3CA are known to alter MAPK/ERK activation [10, 11]; and mutations in TP53 are known to lead to loss of function of this tumor suppressor [9]

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