Many patients are reluctant to undergo rebiopsy of their tumours since it is invasive. At the same time, most oncologists feel that this procedure may yield information about mutations occurring during treatment that can affect response. Treatment with tyrosine kinase inhibitors (TKIs) directed to the epidermal growth factor receptor (EGFR) is known to increase progression-free survival (PFS) to median value of 12 months in patients with EGFR mutated non-small cell lung cancer (NSCLC) but resistance to treatment may also develop. To date several mechanisms have been described by which resistance to EGFR TKIs is acquired, but the data are sparse, and T790M mutations in the tumour are thought to play a role. New findings were presented at European Multidisciplinary Conference in Thoracic Oncology (EMCTO), held 9-11 May, 2013 in Lugano, Switzerland that detailed the mutations acquired during TKI treatment in a retrospective cohort of patients with NSCLC. These findings support rebiopsy as a valuable tool for directing treatment in these patients.
Dr Justine Kuiper of the Department of Pulmonary Diseases and colleagues at the VU University Medical Center in Amsterdam, the Netherlands, conducted a retrospective analysis to define the EGFR mutation spectrum in 63 patients with NSCLC whose tumours became resistant to treatment with TKIs. They analysed medical records that included biopsies taken before and after TKI treatment in patients with either EGFR mutation or who had demonstrated a duration of response to TKIs of more than 24 weeks. All patients were treated with TKIs. Additionally one, two or three lines of chemotherapy were given to 24 (38%), 6 (10%) and 2 (3%) patients prior to TKI and 8 (13%), 7 (11%), 2 (3%) and 1 (2%) patients received one, two, three or five lines of chemotherapy, respectively, following TKI treatment. The objective response rate to TKI treatment was 61.9% according to RECIST criteria and the median PFS was 12.3 months (range: 1.4 – 43.2).
Comparison of pre- and post-TKI biopsies showed that the frequency of T790M mutation was 47.6% following TKI treatment, which was considered to be consistent with other reports. Two patients lost T790M and exon 21 mutations that were recorded prior to treatment. Thirteen patients developed mutations in EGFR exon 19, and mutations in T790M plus exon 19 were observed in 17 patients following TKI treatment. Transformation to small cell lung cancer occurred in one patient, which is less than reported in the literature; this patient showed an exon 19 deletion in the pre-TKI treatment biopsy. One patient with an exon 18 plus exon 21 mutations prior to TKI treatment developed a KRAS mutation afterwards but the authors in that case could not exclude the existence of a second primary tumour.
The study by Kuiper et al illustrated that rebiopsy can be a powerful tool, especially in patients who become resistant to TKI treatment, that yields information on altered tumour characteristics that may direct treatment decision and define the mechanisms behind the development of resistance.
The study discussant, Dr Luis Paz-Ares, said that currently known mechanisms of acquired resistance to EGFR TKIs are secondary EGFR mutations (T790M), MET amplification, HGF high levels, HER2 amplification, downstream effectors (PTEN loss, PI3K and BRAF mutations), small-cell lung cancer (SCLC) transformation, epithelial to mesenchimal transition (EMT), DRG: BRCA1 mRNA levels, FAS and NFKB signaling, VEGF/VEGFR, and IGFR1, IGFBP. He questioned if re-biopsy should be done in patients in the regular clinic after progression of the disease. There is no much data available, but also no much morbidity associated to it from clinicians perspective. It could be done in case of trial opportunities, but also some patients treatment could be tailored to the pheno- or genotype, especially in case of SCLC transformation, where widely available cisplatin and etoposide are effective. Alternatives to explore further in this setting are liquid biopsies and functional imaging.
EMCTO is organised in partnership between the European Society for Medical Oncology (ESMO), The European Society for Radiotherapy and Oncology (ESTRO), the European Society of Thoracic Surgeons (ESTS) and the European Respiratory Society (ERS), and the European Thoracic Oncology Platform (ETOP). The five partners have created a programme that integrated perspectives from the different disciplines and demonstrated how the multidisciplinary team can combine knowledge for personalised treatment of the whole range of thoracic oncology tumours.