Non-small-cell lung cancer harbouring mutations in the EGFR kinase domain |
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Authors: | Rafael Rosell Teresa Morán Enric Carcereny Vanessa Quiroga Miguel Ángel Molina Carlota Costa Susana Benlloch Miquel Tarón |
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Institution: | (1) Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA;(2) Departments of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA;(3) Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 44 Binney Street—D 1234, Boston, MA 02115, USA |
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Abstract: | Key “driver” mutations have been discovered in specific subgroups of non-small-cell lung cancer (NSCLC) patients. Activating
mutations in the form of deletions in exon 19 (del 19) or the missense mutation L858R in the tyrosine kinase domain of the
epidermal growth factor receptor (EGFR) predict outcome to EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib.
Pooled data from several phase II studies show that gefitinib and erlotinib induce responses in over 70% of NSCLC patients
harbouring EGFR mutations, with progression-free survival (PFS) ranging from 9 to 13 months and median survival of around
23 months. Two studies in Caucasian and Asian patients have confirmed that these subgroups of patients attain response rates
of 70% with erlotinib and gefitinib, including complete responses, PFS up to 14 months and median survival up to 27 months.
These landmark outcomes have been accompanied by new challenges: the additional role of chemotherapy and the management of
tumours with the secondary T790M mutation that confers resistance to EGFR TKIs. Mechanisms of resistance to reversible EGFR
TKIs should be further clarified and could be related to modifications in DNA repair. The presence of double mutations (T790M
plus either L858R or del 19) at the time of diagnosis could be much more frequent than originally thought. The sensitivity
to EGFR TKIs could be greatly influenced by the expression of genes involved in the repair of DNA double-strand breaks by
homologous recombination and non-homologous end joining. |
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