Molecular profiling of colorectal pulmonary metastases and primary tumours: implications for targeted treatment.

Sing Yu Moorcraft ,George Ladas,Andrew Wotherspoon,Paula Proszek,Eleftheria Kalaitzaki,Ruwaida Begum,Naureen Starling,Brian A Walker,Ian Chau,David Watkins,Lina Yuan,Sanna Hulkki Wilson,Anne M Bowcock,Amitesh Roy,David Cunningham,Zakaria Eltahir,Thomas R Jones ,Eliza A Hawkes ,Ángeles Montero-Fernandez ,David González De Castro ,Rao S ,Larissa Sena Teixeira Mendes ,Ye Mong To

doi:10.18632/oncotarget.17048

Abstract

This study aimed to molecularly characterise colorectal pulmonary metastases (PM) and investigate whether their molecular profiles were concordant with those of the primary tumour. Clinical data and archival formalin fixed paraffin embedded tissue samples were retrospectively collected from patients who underwent ≥ 1 pulmonary metastasectomies for colorectal cancer between 1997–2012. Primary tumour and metastatic samples were analysed using a targeted capture sequencing panel of 46 cancer-associated genes. The 5-year progression-free and overall survival rates for the 81 patients in this study were 32% (95% CI 22–42%) and 77% (95% CI 66–85%) respectively. Fifty-four patients had samples available from ≥ 1 PM, and sequencing data were successfully obtained from 33 PM from 24 patients. The most frequently mutated genes were APC (71%), KRAS (58%) and TP53 (46%). Seventy-three percent of the 15 patients with matched primary and PM samples and 6 of the 7 patients (86%) with data from ≥ 2 PM had concordant molecular profiles. The concordance for KRAS and NRAS was 100%. At our institutions, patients with resectable colorectal PM had a favourable prognosis. RAS mutations were commonly detected in PM and the molecular profiles of colorectal PM were highly concordant with the primary tumour.

Highlights

Pulmonary metastases (PM) occur in approximately 10–20% of patients with colorectal cancer [1,2,3,4]
The majority of patients with pulmonary metastases (PM) are treated with palliative intent and have a poor prognosis, but pulmonary metastasectomy may be a curative option for carefully selected patients with limited sites of disease
This study provides information on both the clinical and molecular characteristics of patients with colorectal PM

Summary

Introduction

Pulmonary metastases (PM) occur in approximately 10–20% of patients with colorectal cancer [1,2,3,4]. The majority of patients with PM are treated with palliative intent and have a poor prognosis, but pulmonary metastasectomy may be a curative option for carefully selected patients with limited sites of disease. In metastatic/advanced colorectal cancer, a patient’s suitability for treatment with anti-EGFR monoclonal antibodies is determined by the presence of mutations in KRAS and/or NRAS [9]. Discordance between the molecular profiles of the primary tumour and metastases can occur due to heterogeneity of the primary tumour, the progression of specific tumour subclones, the gain or loss of mutations during disease progression or technical issues (such as low DNA quality) leading to inaccurate results [10, 11]. Tumour heterogeneity may limit the efficacy of targeted therapies www.impactjournals.com/oncotarget and it is essential to establish whether there are significant molecular differences between primary tumours and metastatic sites of disease

Objectives

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Conclusion