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Diagnostic test for tyrosine kinase inhibitors treatment for non-small-cells lung cancer (NSCLC)

Source agency:

Agenas (COTE)

Date of Submission:

26/01/2010

Date of Printing:

05/02/2012

Disclaimer:

This report is work in progress and should not be used for external distribution without permission from the originating agency. Users should be aware that reports are based on information available at the time of research and often on a limited literature search.

Technology, Company & Licensing

Technology name:

TheraScreen EGFR29

Technology - description:

In oncology, genetic testing procedures are performed to detect gene mutations in a sample of DNA extracted from the patient’s tumour [www.eurogentest.org]. Diagnostic kits based on real-time PCR (polymerase chain reaction) technology are among the methods used for this purpose. Generally, a specimen of the patient’s tumour is obtained by biopsy and then processed to extract the DNA, according to specific protocols depending on the type of the diagnostic kit used. The genomic material undergoes a real-time PCR procedure and the mutations are analysed by reading the curves (i.e. comparing the mutant DNA with the normal one).
This report is focused on diagnostic kits, based on real-time PCR technology, able to detect EGFR gene mutations in NSCLC patients to select those eligible for treatment with TKIs.

Company or developer:

Qiagen Inc.

Reason for database entry:

High impact on clinical pathway.

Technology - stage in early warning process:

Assessment complete

Technology - stage of development:

Nearly established

Licensing, reimbursement and other approval:

The device identified is the TheraScreen® EGFR29 kit, produced by DxS Ltd and consisting of a series of reagents which enable the analysis of a number of bioptic specimens (20 or 80 depending on the kit format).
The kit obtained CE marking as an in vitro diagnostic in April 2007 for use on the MX3000 Real-Time PCR system (produced by Stratagene Inc.) but is also compatible with all the other real-time PCR systems capable of running the DxS Ltd protocol. The FDA approval application procedure is expected in 2011.
Following the acquisition of DxS Ltd by Qiagen Inc. the kit will be distributed directly in Italy by Qiagen Italia from July 2010; in the past it could be purchased exclusively from the manufacturers DxS Ltd (based in the UK, with no Italian distributor).

Technology - type(s):

Diagnostics

Technology - use(s):

Diagnostic

Patient Indication & Setting

Patient indications:

The technology aims to identify mutations in the EGFR (epidermal growth factor receptor) gene in patients with Non-Small Cell Lung Cancer (NSCLC), to select those suitable for treatment with Tyrosine-Kinase inhibitors (TKIs).

Disease description and associated mortality and morbidity:

Lung cancer is the primary cause of death in industrialised countries. In Italy,the recent epidemiology of lung cancer has changed significantly,mainly due to smoking habits changes which present different gender-based characteristics. After a historical increasing trend, incidence and mortality rates are now decreasing among males. This situation appears different for the female population,where incidence and mortality rates are still rising [AIRT Working group]. Mortality rates are based on data collected in 2008, when 20,599 males and 5,612 females died from lung cancer. From a clinical point of view, a distinction is usually made between small cell lung cancer (microcytoma) and non-small cell lung cancer (which includes squamous cell carcinoma, adenocarcinoma and large cell carcinoma). The importance of this histological distinction is linked to the different treatment as unlike microcytomas, NSCLCs show low sensitivity to chemotherapy [Non-Small Cell Lung Cancer Collaborative Group, 2000]. For the latter, new therapies with biological drugs have been introduced. These substances work in a highly selective way on neoplastic cell regulatory mechanisms. In particular, therapies against EGFR (epidermal growth factor receptor involved in cell proliferation)have already been used [www.cancer.gov]. In NSCLC the expression modes of the EGFR gene are correlated to unfavourable prognosis, a greater capacity for metastatisation and reduced survival [Hirsch FR, 2003]. In NSCLC the principal studies with anti-EGFR drugs mostly used TKIs and demonstrated net improvements in symptoms and quality of life both as first-line treatment and in patients previously treated with other therapies [Sanford M, 2009]. Further, sub-groups of patients who were particularly sensitive to treatment with TKIs were identified:women, Asians,non smokers,and with adenocarcinoma histo-type [Yang CH, 2006; Jiang H, 2009].
Patients with mutated variants of the EGFR gene show greater sensitivity to TKIs. EGFR gene mutations associated with a response to TKIs have been found in some 10-20% of NSCLC patients. The most common mutations of the kinase dominion of the EGFR gene are the Exon 19 deletions and the mutation L858R in Exon 21, which constitute approximately 90% of all EGFR gene mutations [Yu J, 2009]. The remaining 10% are rare missense mutations found mainly in Exon 18 but also in Exons 20 and 21 [Shigematsu H, 2005]. Currently available data indicate the high value of identifying EGFR gene mutations in patients with NSCLC, to select those sensitive to the treatment with TKIs. This technology may support the development of a “personalised medicine”, which represents one of the greatest challenges for the decades to come.These specific diagnostic technologies would enable the definition of the molecular profile of the pathology (in this case NSCLC)and would provide useful information for prognostic and prediction purposes. In this approach,patient sub-groups,sharing biological or genetic characteristics, may be treated with therapies suitable for their specific condition, as currently happens in patients with breast cancer where HER2 mutation was detected. [Jørgensen JT, 2008; Gianni L, 2010].

Number of Patients:

Data on lung cancer epidemiology can be obtained from the Cancer Register which,to date,only covers 32% of the Italian population. Data on all types of cancers are collected by any single accredited register and then recorded into the AIRTUM database,which represents the national archive hosted by the Italian National Health Institute (ISS) [www.tumori.net]. According to the 2010 estimates made by the Cancer Epidemiology department of the CNESPS (National Center for Epidemiology, Surveillance and Health Promotion), in the Italian population in the age group 0-84 years, there will be 23,969 new cases of “lung cancer” (ICD-9-CM 162) in males and 7,082 in females. The prevalence estimate is 78,515 cases (62,463 males and 16,052 females).

Technology - specialities(s):

Oncology & radiotherapy

Technology - setting(s):

Specialist hospital

Setting - further information:

This genetic test can be performed by trained personnel at any Pathology laboratory equipped with real-time PCR.

Impact

Alternative and/or complementary technology:

Substitution technology

Current Technology:

EGFR gene mutations are commonly detected by direct DNA sequencing which is considered the methodology of reference (gold standard). However, direct DNA sequencing requires high quality bioptic specimen, with significant costs also in terms of time and cannot be used for non surgical samples (i.e. serum, plasma or cytological preparations). These limitations make its use difficult in clinical practice [Fassina A, 2009].
Other molecular diagnostics methods, when used to characterise the specimen, do not detect the specific mutations, though they enable observations attributable to them. For example, immunohistochemistry (IHC) does not detect the mutations but detects the expression of EGFR protein; FISH (fluorescent in situ hybridization analysis) does not detect the mutations but identifies the number of copies of the EGFR gene DNA; DHPLC (denaturing high-performance liquid chromatography) enables detection of the mutations, of the micro-deletions and micro-insertions, but does not enable their characterisation [Eberhard DA, 2008].

Health Impact:

The technology would enable definition of the molecular profile of the pathology (NSCLC) and thus would provide information useful to both the prognostic and the therapeutic profiles, enabling appropriate selection of the patients most responsive to the treatment with TKIs.

Diffusion:

Distribution of the TheraScreen® EGFR29 kit in Italy is expected to start in July 2010. To date the device is used only in 3 centres (two hospitals and one laboratory) where it has been purchased directly from the manufacturer. The usage volumes, that is the number of tests purchased or executed, are not known.

Cost, infrastructure and economic consequences:

The technology has no significant structural impact when used in a Pathology laboratory fitted with equipment for real-time PCR.
The technology impacts the workflow of a Pathology laboratory where it tends to substitute mutation analyses by direct sequencing (relative to EGFR analysis in NSCLC samples). In addition personnel with specific training in the field of molecular biology is required.

Ethical, social, legal, political and cultural impact:

None.

Evidence & Policy

Clinical evidence and safety:

We searched the EuroScan database(27 January 2010) to identify Horizon Scanning reports and Rapid Health Technology Assessments, published in English,on the TheraScreen diagnostics kit for identification of EGFR gene mutation in NSCLC patients for treatment with TKI. The search only found reports on the effects deriving from the administration of a specific drug after detection of a certain mutation. Our literature search was undertaken on three database Embase (15 February 2010), Medline (25 January 2010) and the Cochrane Library (5 February 2010), to identify studies of the technology, published from 2007 to date in English and Italian. The search did not find studies which assessed the use of the specific TheraScreen EGFR29® Diagnostic kit. We identified only one study [Mok TS, 2009] in which this test was used to address Asian patients with advanced pulmonary adenocarcinoma, non or ex smokers (subjects who had quit smoking for at least 15 years and who smoked less than 10 packets per year) to first-line treatment with TKIs.
As this is an emerging technology, an analysis of “grey literature” was also undertaken (registers, presentations, posters, etc.). We identified only one poster of a study, conducted in 2009, reporting a comparison between direct DNA sequencing and the TheraScreen EGFR29® kit, on 96 tumours (in NSCLC patients) [Angulo B, 2009]. The study compared only 88 tumours because insufficient DNA collected from 5 tumours impeded execution of both procedures, while a further 3 tumours were not analysed due to poor DNA quality. In the 88 tumours, both procedures confirmed the same results, i.e. they found 10 mutated tumours and 78 wild type tumours. According to the authors, the TheraScreen EGFR29® kit allowed to detect also 1% of mutant DNA in the specimen, while direct sequencing required at least 10%. The conclusions were however based on the comparison of the 10 mutated specimens. Given the nature of the sources and the low number of specimens observed, the conclusions may be considered of limited general application. There are no significant concerns on the safety of the technology: TheraScreen EGFR29® is a non directly invasive diagnostic test.

Economic evaluation:

At the moment the technology is available at an indicative price of € 160.00 (price without VAT declared by the manufacturer) for the analysis of a single specimen. The price of the kit in the two formats (20 and 80 tests)is not available at this time.
The test requires the availability of ordinary equipment for real-time PCR. This equipment can be used for many other analyses (molecular biology) but is not usually available as normal equipment of Pathology laboratories. In laboratories already using real-time PCR, the technology does not require dedicated and specifically trained personnel (no additional training costs are foreseen).

Ongoing research:

None.

Ongoing or planned HTA:

None.

Web link:

http://www.agenas.it/innov_sperim_sviluppo/HS-4%20%5BAgenas%5D.pdf

References and sources:

AIRTUM. I tumori in Italia, rapporto 2009. Associazione Italiana dei Registri Tumori.

AIRT Working group. I tumori in Italia – rapporto 2006. Incidenza, mortalità e stime. Epidemiologia & Prevenzione 2006; 30 (Suppl. 1): 64-65.

Angulo B, Conde E, Martinez R, et al. Comparison of Direct Sequencing and a Commercial Real-Time PCR Kit for Detection of Mutations in EGFR Gene.Poster presented at the 13th World Conference on Lung Cancer, San Francisco, 2009.

Eberhard DA, Giaccone G, Johnson BE. Biomarkers of Response to Epidermal Growth Factor Receptor Inhibitors in Non–Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial setting. J Clin Oncol 2008; 26 (6): 983-993.

Fassina A, Gazziero A, Zardo D, et al. Detection of EGFR and KRAS mutations on transthoracic needle aspiration of lung nodules by high resolution melting analysis. J Clin Pathol 2009 62: 1096-1102.

Gianni L, Eiermann W, Semiglazov V et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010 Jan 30;375(9712):377-384.

Giornale Italiano di Health Technology Assessment 2008; 1(1): 15-20.

Hirsch FR, Varella-Garcia M, Bunn PA, et al. Epidermal Growth Factor Receptor in Non–Small-Cell Lung Carcinomas: Correlation Between Gene Copy Number and Protein Expression and Impact on Prognosis Journal of Clinical Oncology, Vol 21, Issue 20 (October), 2003: 3798-3807.

Jiang H. Overview of gefitinib in non-small cell lung cancer: an Asian perspective Jpn J Clin Oncol. 2009 Mar;39(3):137-50.

Johnson DH. Targeted therapy in non-small cell lung cancer: myth or reality. Lung Cancer. 2003 Aug;41 Suppl 1:S3-8.

Jørgensen JT. From blockbuster medicine to personalized medicine. Personalized medicine. 2008, Vol. 5, No. 1, Pages 55-63.

Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009 Sep 3;361(10):947-57.

Non-small Cell Lung Cancer Collaborative Group. Chemotherapy for non-small cell lung cancer. Cochrane Database Syst Rev 2000;(2):CD002139.

Sanford M, Scott LJ. Gefitinib: a review of its use in the treatment of locally advanced/metastatic non-small cell lung cancer. Drugs. 2009 Nov 12;69(16):2303-28.

Shigematsu H, Lin L, Takahashi T, et al. Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers. J Natl Cancer Inst 2005;97:339 – 46.

Yang CH, Shih JY, Chen KC, et al. Survival outcome and predictors of gefitinib antitumor activity in East Asian chemonaive patients with advanced non small cell lung cancer. Cancer. 2006 Oct 15;107(8):1873-82.

Yu J, Kane S, Wu J, et al. Mutation–specific antibodies for the detection of EGFR mutations in non-small-cell lung cancer. Clinical Cancer Research. 2009 May 1;15(9):3023-8.

www.cancer.gov National Cancer Institute - Dictionary of Cancer Terms (last access 11 February 2010).

www.eurogentest.org Definitions of Genetic Testing (Sequeiros J, Guimarães B) EuroGentest Network of Excellence Project. http://www.eurogentest.org/patient/public_health/info/public/unit3/DefinitionsGeneticTesting-3rdDraf18Jan07.xhtml. (last access 2 February 2010)

Notes:

Diagnostic tests for genetic mutations based on real-time PCR technology are an emerging technology in oncology. By contrast with direct DNA sequencing methods, these may also be executed on biological specimens with a low number of cells (e.g. needle aspiration biopsy), and present a potentially significant impact in terms of integration in clinical-hospital work flows (due to low complexity and reduced times). However these tests enable only the detection of specific mutations, already identified and described. In certain cases, this limit may have little relevance. In the specific case of NSCLC, the principal EGFR gene mutations have been identified and affect Exons 19 and 21, which together account for some 90% of the mutations discovered and Exons 18 and 20 [Yu J, 2009].
As patients with these mutations showed a greater sensitivity to TKIs drugs [Sanford M, 2009], their identification before choosing the treatment could only generate positive effects in terms of appropriateness of treatment.
The technology enables the identification of 29 EGFR gene mutations relative to Exons 18, 19, 20 and 21 in specimens taken from NSCLC patients and may have a positive impact on clinical oncology practice. However this potential may be considered expressed only performing comparative studies to evaluate the diagnostic efficacy of the new technology with respect to the technologies employed today. At now the sole source of evidence is represented by a poster presentation which cannot be considered sufficient [Angulo B, 2009].
Particular attention should be paid to the analysis of the context of use of the new technology. The structural and organisational impact on Pathological Anatomy laboratory already using real-time PCR would be minimal while it could be fairly significant otherwise, as the molecular biology skills and the equipment required are not present in all Pathological Anatomy laboratories.