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07-05-2013 | Oncology | Article

TKI resistance markers found for NSCLC patients


Free abstract

medwireNews: Korean scientists have identified several genetic markers that may explain lack of response to tyrosine kinase inhibitor (TKI) therapy in patients with epidermal growth factor receptor (EGFR)-activating, non-small-cell lung cancer (NSCLC).

The study examined the genetic profiles of 197 patients given gefitinib (90.9%) or erlotinib (9.1%) treatment at the Seoul National University Hospital. The patients had a median progression-free survival (PFS) time of 11.9 months and a response rate of 78.8%.

Although 94.4% of patients achieved 3 months of PFS, 11 patients had primary resistance to TKI therapy and progressive disease within this time period.

Notably, PFS did not significantly differ between patients with and without BIM deletion polymorphisms (11.9 vs 11.3 months). This mutation leads to a loss of function of the proapoptotic protein, which has been implicated in TKI resistance, explain S-H Lee (Seoul National University Hospital) and co-authors.

Nor did the team find a significant correlation between PFS and EGFR mutation genotype, or smoking history. But patients who had recurrence after surgery had significantly longer PFS than patients who were initially diagnosed with stage IV disease (16.0 vs 10.0 months).

Analysis of the 11 patients with primary resistance found that all but two had a large burden of disease when beginning TKI treatment and four patients had disease progression to the central nervous system.

Three of the 11 patients had co-existing genetic alterations that may explain their primary resistance. This included one patient with a de novo EGFR T790M "gatekeeper" mutation plus an exon 19 deletion, one patient with de novo MET amplification and an L858R mutation, and a patient with ALK fusion plus exon 19 deletion.

Targeted deep sequencing found TP53 mutations in three of nine patients but failed to find any "remarkable" mutations within other major oncologic genes, such as KRAS, BRAF, or PTEN.

"Although EGFR-targeted treatment in NSCLC has an outstanding record of success, our understanding of this subtype of NSCLC is not sufficient," the team concludes in the Annals of Oncology.

"Further investigation is warranted to understand the mechanism of differential responses to TKIs, which can lead to more personalized therapy."

medwireNews ( is an independent clinical news service provided by Springer Healthcare Limited. © Springer Healthcare Ltd; 2013

By Lynda Williams, Senior medwireNews Reporter

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