3 Clinical need and practice
3.1 Epidermal growth factor receptor tyrosine kinase (EGFR‑TK) mutation testing is indicated in adults with previously untreated, locally advanced or metastatic non-small-cell lung cancer (NSCLC). Clinical trials have shown that patients with EGFR‑TK mutation-positive tumours gain more benefit from treatment with EGFR‑TK inhibitors than from standard chemotherapy treatment. Conversely, patients with EGFR‑TK mutation-negative tumours gain more benefit from standard chemotherapy than from EGFR‑TK inhibitors.
3.2 Multiple tests and test strategies for EGFR‑TK mutation testing are currently used in NHS laboratories in England. The aim of this evaluation was to identify which tests and test strategies for EGFR‑TK mutation testing in adults with previously untreated, locally advanced or metastatic NSCLC are clinically and cost effective for informing first-line treatment decisions as currently recommended by NICE.
3.3 NSCLC is the most common type of lung cancer in England and Wales, accounting for around 72% of all lung cancer cases. It can be further categorised by histological subtype; the 3 main types being squamous cell carcinoma, adenocarcinoma and large-cell carcinoma.
3.4 The prevalence of EGFR‑TK mutations in NSCLC varies widely with population ethnicity, with reported prevalence of EGFR‑TK mutations in adenocarcinoma ranging from 10.4% in a study of Italian patients (Marchetti et al. 2005) to 50% in a study of Japanese patients (Kosaka et al. 2004). The estimated proportion of EGFR‑TK mutations in NSCLC in England and Wales is 16.6% (Rosell et al. 2009).
3.5 NICE clinical guideline 121 (Lung cancer: the diagnosis and treatment of lung cancer) recommends that patients with suspected lung cancer should be urgently referred for a chest X‑ray. If the results suggest lung cancer, a contrast-enhanced CT scan of the chest, upper abdomen and lower neck is performed. Further investigations to confirm a diagnosis and to provide information on the stage of the disease are then carried out. These investigations generally include a biopsy for histological confirmation and subtyping, but may also include positron emission tomography-computed tomography, endobronchial ultrasound-guided transbronchial needle aspiration, endoscopic ultrasound-guided fine needle aspiration or non-ultrasound-guided transbronchial needle aspiration.
3.6 When biopsy is successful, DNA extraction and mutation analysis can be carried out on the biopsy tissue (which is generally stored as formalin-fixed paraffin-embedded tissue) to determine whether the tumour is EGFR‑TK mutation-positive or -negative. If biopsy tissue is not available, DNA extracted from cytology samples can be used for mutation analysis. Other molecular tests may be performed as clinically indicated.
3.7 Participants at a European multidisciplinary workshop 'EGFR testing in NSCLC: from biology to clinical practice' (2009) emphasised the importance of standardisation and validation of EGFR‑TK mutation tests and recommended that testing should only be undertaken in a quality-assured, accredited setting. However, there was no consensus on which laboratory test should be used for clinical decision-making. Participants agreed that the decision to request EGFR‑TK mutation testing should be made by the treating physician and that results should be reported within 7 working days of request. Conversely, guidelines from the Royal College of Pathologists recommend that, to minimise turnaround time, molecular diagnostic tests should be ordered by the pathologist reporting on the histology of the tumour.
3.8 Treatment options for NSCLC include gefitinib and erlotinib, which are EGFR‑TK inhibitors indicated for patients with EGFR‑TK mutation-positive tumours. NICE's technology appraisal guidance 192 (Gefitinib for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer) and technology appraisal guidance 258 (Erlotinib for the first-line treatment of locally advanced or metastatic EGFR‑TK mutation-positive non-small-cell lung cancer) recommend gefitinib and erlotinib respectively as options for the first-line treatment of locally advanced or metastatic NSCLC in people whose tumour tests positive for an EGFR‑TK mutation. Other treatment options for NSCLC include chemotherapy regimens. NICE clinical guideline 121 recommends that chemotherapy should be offered to people with stage III or IV NSCLC and a good performance status (WHO 0, 1 or Karnofsky score 80–100) with the aim of improving survival, disease control and quality of life. Treatment with curative intent is not possible for these people. First-line chemotherapy should be a combination of a single third-generation drug (docetaxel, gemcitabine, paclitaxel or vinorelbine) and a platinum drug (carboplatin or cisplatin). People who are unable to tolerate a platinum combination may be offered single-agent chemotherapy with a third-generation drug. NICE technology appraisal guidance 181 (Pemetrexed for the first-line treatment of non-small-cell lung cancer) recommends pemetrexed plus cisplatin as a first-line treatment for locally advanced or metastatic NSCLC, if the histology of the tumour has been confirmed as adenocarcinoma or large-cell tumour.