Elsevier

The Lancet

Volume 387, Issue 10026, 2–8 April 2016, Pages 1415-1426
The Lancet

Articles
Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT)

https://doi.org/10.1016/S0140-6736(16)00004-0Get rights and content

Summary

Background

The molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for known oncogenic drivers is recommended during routine care. Nationally, however, the feasibility and effects on outcomes of this policy are unknown. We aimed to assess the characteristics, molecular profiles, and clinical outcomes of patients who were screened during a 1-year period by a nationwide programme funded by the French National Cancer Institute.

Methods

This study included patients with advanced NSCLC, who were routinely screened for EGFR mutations, ALK rearrangements, as well as HER2 (ERBB2), KRAS, BRAF, and PIK3CA mutations by 28 certified regional genetics centres in France. Patients were assessed consecutively during a 1-year period from April, 2012, to April, 2013. We measured the frequency of molecular alterations in the six routinely screened genes, the turnaround time in obtaining molecular results, and patients' clinical outcomes. This study is registered with ClinicalTrials.gov, number NCT01700582.

Findings

18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18–98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7–16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17 706 analyses for which data were available, HER2 mutations in 98 (1%) of 11 723, KRAS mutations in 4894 (29%) of 17 001, BRAF mutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALK rearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8–25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% [95% CI 34·7–38·2] for presence of a genetic alteration vs 33% [29·5–35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0–18·8] vs 9% [6·7–11·9]; p<0·0001). Presence of a genetic alteration was also associated with improved first-line progression-free survival (10·0 months [95% CI 9·2–10·7] vs 7·1 months [6·1–7·9]; p<0·0001) and overall survival (16·5 months [15·0–18·3] vs 11·8 months [10·1–13·5]; p<0·0001) compared with absence of a genetic alteration.

Interpretation

Routine nationwide molecular profiling of patients with advanced NSCLC is feasible. The frequency of genetic alterations, acceptable turnaround times in obtaining analysis results, and the clinical advantage provided by detection of a genetic alteration suggest that this policy provides a clinical benefit.

Funding

French National Cancer Institute (INCa).

Introduction

Lung cancer is one of the most frequent types of cancer in developed countries and is the leading cause of cancer deaths, with more than 1 million deaths expected per year.1 However, understanding of the molecular hallmarks of this cancer has developed only recently.2 The treatment of lung cancer has entered a new era because of the discovery of epidermal growth factor receptor (EGFR)-activating mutations and anaplastic lymphoma kinase (ALK) gene rearrangements, which lead to changes in outcomes in some patients with lung cancer.3, 4 Moreover, compared with other cancers, lung cancer has one of the highest rates of genetic alterations,5 some of which are actionable via the administration of drugs that have already been approved, are available off-label for other indications (eg, dabrafenib or vemurafenib for BRAF mutations,6 trastuzumab or afatinib for HER2 [also known as ERBB2] mutations,7 and crizotinib for ROS1 rearrangements8), or are under investigation in clinical trials. Therefore, high expectations are placed on personalised (also referred to as stratified or precision) medicine in this setting.

Research in context

Evidence before this study

We did a systematic review of the scientific literature to identify studies assessing nationwide routine molecular profiling of patients with advanced non-small-cell lung cancer (NSCLC) for one or more genetic alterations known (or supposed) to be oncogenic drivers. We searched PubMed for English language reports published up to Dec 3, 2010, with the terms “non small cell lung cancer”, “advanced” or “metastatic”, and “EGFR” or “ALK” or “BRAF” or “HER2” or “PIK3CA” or “KRAS” or “multiplex” or “sequencing” and “nationwide”, or names of various countries around the world. We also searched abstracts from ASCO and ESMO meetings (2007–10). We did not identify any published data.

Added value of this study

Our study shows that routine nationwide molecular profiling of patients with advanced NSCLC is feasible with an acceptable turnaround time in obtaining the results. Even with assessment of a limited number of genetic alterations (ie, currently six genes), the frequency of these genetic alterations might allow the consideration of targeted therapy for treating these patients (either commercially available for EGFR and ALK, or within a clinical trial for the other alterations). Finally, when a genetic alteration was detected, the outcome was a longer median overall survival, suggesting a possible prognostic advantage or a major change in the management of these patients with advanced NSCLC, or both.

Implications of all the available evidence

The Lung Cancer Mutation Consortium (LCMC) initiative (the largest multi-institutional study in developed countries) suggested that molecular profiling helps to orient patients towards targeted therapies and dedicated trials, and individuals with drivers receiving a matched targeted agent lived longer than patients who did not receive genotype-directed therapy. Our study extends the LCMC study to a nationwide scale, and suggests that routine nationwide molecular profiling provides a clinical benefit to patients with advanced NSCLC.

In this context, many medical centres have been organised to provide patients with lung cancer with routine assessments of EGFR mutations and ALK rearrangements. In some of these centres, additional molecular alterations are tested, typically by research programmes.9, 10, 11, 12 The preliminary data obtained from such programmes suggest that molecular profiling helps to orient patients towards targeted therapies and dedicated trials. However, the actual effects of broad molecular screening and subsequent personalised medicine have yet to be addressed in a prospective randomised trial.10 Additionally, the characteristics and efficacy results reported by these programmes are based on a limited series of selected patients. Therefore, a wide overview is needed in an unselected, all-comer population to increase understanding of the epidemiology of lung cancer biomarkers and their potential effect on therapeutic strategies.

The French National Cancer Institute (INCa) funded a nationwide programme for the systematic routine analysis of EGFR mutations and ALK rearrangements as well as HER2, KRAS, BRAF, and PIK3CA mutations in patients with advanced stage, non-squamous, non-small-cell lung cancer (NSCLC) in 28 certified molecular genetics centres covering the whole of France, including overseas entities.13, 14, 15 The Biomarkers France study assessed the characteristics, molecular profiles, and clinical outcomes of patients who were screened by this programme during a 1-year period.

Section snippets

Participants

All consecutive patients with NSCLC who were routinely screened for molecular alterations during a 1-year period at one of the 28 certified molecular genetics centres in France were eligible for inclusion in this study. The prescription of this routine molecular screening, mandatory for advanced non-squamous NSCLC, was solely the responsibility of the treating physician. Notably, national recommendations for screening for EGFR mutations (both activating and Thr790Met), ALK rearrangements, and

Results

The study recruitment period was from April, 2012, to April, 2013, and the database was locked for the current analysis on July 23, 2014. Overall, 19 386 results of routine molecular analyses were recorded in the database. After review, 707 (4%) analyses were excluded (figure 1). The final analysis consisted of 18 679 results, representing 17 664 patients with NSCLC.

Table 1 shows the primary characteristics of the 17 664 patients. The number of samples analysed per patient was typically one

Discussion

One challenge of personalised medicine for patients with cancer is the provision of an assessment of molecular alterations that are related to the management of their disease. The results of our study show the success of a nationwide programme in this setting. The molecular screening done in the programme, which involved nearly 20 000 patients with advanced NSCLC per year, enabled the detection (with an acceptable turnaround time) of at least one potentially actionable molecular alteration in

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