Guest LCSC Info Posted January 23, 2012 Share Posted January 23, 2012 Some New Insights About T790M Mutations and Resistance to Oral EGFR Inhibitors http://blog.lungevity.org/2012/01/20/t7 ... -behavior/ January 20th, 2012 - by Dr. Jack West A few months ago, a lifelong never-smoking patient with an adenocarcinoma in my clinic came to see me for management of her advanced lung cancer. I sent some of her tumor material for potential molecular markers, which revealed that she had both an activating EGFR mutation (exon 19 deletion) and a de novo (prior to the start of treatment) T790M mutation associated with resistance (see review of markers in this summary). Because I didn’t know what kind of result we might see by treating her first line with an EGFR tyrosine kinase inhibitor (TKI) like Tarceva (erlotinib), we initiated chemo as her first therapy. She did well for a while before progressing, and at that point I promptly started her on Tarceva-based therapy (actually as part of a clinical trial). I was gratified when, just a couple of weeks later, she relayed that her cough and chest pain, both clearly from her cancer, improved greatly within just a few weeks. However, her CT scan done several weeks later revleaed a more complex result: dramatic improvement of the disease in her chest, with modest but convincing progression in the form of new bone metastases. Thanks to a new publication in the Journal of Clinical Oncology a group of investigators in Taiwan, we now have some new insights on T790M, the mutation known as the leading cause of “acquired resistance” (loss of response after an initial good response) to an EGFR TKI. The investigators looked for both “activating” EGFR mutations (the ones known for being associated with a high probability of a good and often very prolonged response to EGFR TKI therapy) and T790M mutations in patients in Taiwan. This group was clearly representative more of the lung cancer population in Asia more than North America or Europe: predominantly (about 75%) never-smokers, adenocarcinoma subtype in over 90%. Patient could have been evaluated before (107 patients) or after EGFR TKI therapy (87 patients) using three different methods: DNA sequencing, MALDI-TOF, and next generation sequencing. Discussion of the details of these approaches is really outside of the scope of needed discussion here: basically, direct gene sequencing is the usual mutation detection technique, MALDI-TOF is a less commonly used novel approach done at some specialty centers, and next generation sequencing is the “gold standard” that really clarifies who has what and is exquisitely sensitive at detecting mutations even if that is in only a small percentage of cells. The investigators reported that MALDI-TOF was far more sensitive at picking up mutations than direct sequencing, and that MALDI-TOF detection correlated well well with next generation sequencing (again, the “gold standard” test). This was true for detecting activating mutations in EGFR TKI-naive patients (mutations detected in 37% vs. 44% of patients with direct sequencing vs. MALDI-TOF, respectively), but the difference in detection sensitivity was even more striking for T790M, which was detected in 3% vs. 25% of patients by direct sequencing vs. MALDI-TOF, respectively. In the EGFR TKI treated population (potentially selected for high probability of having a response to an EGFR TKI, or possibly enriched for being already known to have a mutation before going on an EGFR TKI), EGFR activating mutation frequency before they had started an EGFR TKI therapy was 55% with direct sequencing vs. 77% with MALDI-TOF; T790M was detected in 3% and 32% of these patients with direct sequencing and MALDI-TOF, respectively. Finally, among the twelve patients who had tissue testing for EGFR activating and T790M resistance mutation following their completion of EGFR TKI therapy, direct sequencing detected activating mutations in 9 patients (75%) and a T790M mutation in 4 patients (33%), while MALDI-TOF detected an EGFR activating mutation in all twelve patients (100%) and a T90M mutation in 10 of them (83%). These molecular markers were correlated with outcomes on an EGFR TKI, as you might expect. Those with an EGFR mutation and no resistance mutation had the longest progression-free survival (PFS), followed by those who had both an activating EGFR mutation and a T790M resistance mutation, with patients who had no activating or resistance mutation having the least favorable PFS, as shown in the figure below: (click on blog link above to view image) Importantly, there were no differences in outcomes by overall survival, nor were there differences in the response rate based on initial T790M status. So, what are the potential implications of these findings? The fact that the MALDI-TOF technique of mutation detection is not readily available (I don’t know of any commercial lab that uses it) is a limiting factor, but these results highlight that the specific technique for molecular marker detection is critical. Presumably. this is because a significant subset of patients will have only a relatively small proportion of cancer cells exhibiting the mutation in question, and the techniques vary in their sensitivity of detecting small numbers of copies of the mutated genes. These results illustrate that the T790M mutations are not rare prior to the start of EGFR TKI therapy, even if they are difficult to detect with readily available lab techniques, and are associated with a shorter PFS than we see in patients with an activating EGFR mutation and no T790M mutation. Among the small number of patients evaluated here, the clear majority have a T790M mutation after having been treated for a while on EGFR TKI therapy.. But to add some caveats to this work, it’s important to recognize that this research focuses on a relatively small number of Taiwanese patients with a low incidence of smoking, almost entirely patients with adenocarcinomas, amd that our findings, or at least the prevalence of the various mutations, would likely be fundamentally different if looking at a North American or European population. Therefore, I am personally inclined to be cautious before presuming that the findings from this study population apply far more broadly. Still, the results offer valuable new information and show that patients with an initial T790M mutation can actually still respond to an EGFR TKI, but that we might expect that their duration of response will be shorter. I would say that my own patient’s case was consistent with that, more or less. I presume that her chest disease is driven more by her EGFR activating mutation than the T790M resistance mutation, but that her bone disease is more resistant because the T790M mutation may be present in more copies there. Perhaps one more piece of the puzzle. Quote Link to comment Share on other sites More sharing options...
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