Original StudyNonsquamous, Non-Small-Cell Lung Cancer Patients Who Carry a Double Mutation of EGFR, EML4-ALK or KRAS: Frequency, Clinical-Pathological Characteristics, and Response to Therapy
Introduction
Treatment of advanced nonsquamous (NS) non–small-cell lung cancer (NSCLC) patients has changed in recent years as a result of the definition of druggable features and the increased availability of targeted agents. Mutations of the epidermal growth factor receptor (EGFR) gene are present in approximately 15% of patients in Western countries and in 50% in Asia.1, 2 These mutations have been shown to be predictive of response to specific tyrosine kinase inhibitors (TKIs) such as gefitinib, erlotinib, or afatinib, which are used as first-line therapy in this setting.3, 4, 5 Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) translocation defines another group of patients (approximately 3%-5%)6 who are particularly sensitive to targeted therapies such as crizotinib, alectinib, and ceritinib7, 8, 9: the first is superior to chemotherapy in first- and advanced-lines of treatment, and the remaining 2 are currently under evaluation and are showing promising activity at recurrence after crizotinib.9, 10 For these reasons, it is important to determine EGFR mutations and EML4-ALK translocation before any treatment decision is made. Finally, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are present in approximately 25% of patients with NS-NSCLC11, 12; data on their ability to predict response to TKIs are conflicting and their correlation with resistance to therapy (TKIs and chemotherapy), has not been unequivocally defined.13, 14, 15 In general, EML4-ALK translocation and EGFR and KRAS mutations are considered to be mutually exclusive, as reported in several studies.16, 17, 18 However, some case reports19, 20, 21, 22, 23 and studies performed prevalently in Asian24, 25, 26 or Caucasian27, 28, 29 case series have suggested that these mutations might overlap. Moreover, little is known of the role they play in response to TKIs. In fact, in some studies it was hypothesized that this double alteration might represent a resistance mechanism to TKIs,19, 23 and others have reported an increased sensitivity to TKIs in patients with an EGFR mutation and EML4-ALK translocation.21, 22 Similarly, few data are available on concomitant KRAS mutations and EGFR or EML4-ALK alterations.
In the present study we analyzed the prevalence of overlapping mutations among EGFR, KRAS, and EML4-ALK in patients treated for NS-NSCLC and evaluated their clinical response to targeted therapies.
Section snippets
Patients and Methods
We evaluated 380 patients with NS-NSCLC who underwent nonsequential testing for EGFR and KRAS mutations and EML4-ALK translocation in medical oncology units of the wide catchment area of Romagna (Area Vasta Romagna [AVR]) between January 2010 and December 2013. All patients had a histologically or cytologically confirmed diagnosis of NS-NSCLC. The clinical-pathological characteristics of patients are listed in Table 1. The study was approved by the AVR institutional review board.
Formalin-fixed
Results
Among the 380 patients analyzed for EML4-ALK translocation and EGFR mutations, 32 (8.4%) showed an EML4-ALK translocation and 44 (11.6%) had an EGFR mutation: 27 (61.4%) had an exon 19 deletion, 13 (30.0%) an exon 21 L858R mutation (1 of which with a concomitant T790M mutation), 2 (4.6%) an exon 21 L861Q mutation, and 2 (4.6%) an exon 18 G719S mutation. KRAS mutations were evaluated in 282 patients, 92 of whom (32.6%) showed a mutation: G12C in 44 patients (48%), G12V in 19 (21%), G12D in 9
Discussion
The EGFR and KRAS mutations and the EML4-ALK translocations have long been considered mutually exclusive.16, 17, 18 However, there is increasing evidence that double mutations, albeit rare, can be concomitantly present.19, 20, 21, 22, 23 This phenomenon can, in fact, be explained by the concept of tumor heterogeneity according to which different mutations of tyrosine kinase receptors might coexist, not only in different clones of tumor cells,30 but also in the same tumor cell, as we and others
Conclusion
Our study showed that concomitant mutations involving EGFR, EML4-ALK, and KRAS are possible, albeit rare, in advanced NS-NSCLC patients and that their presence might have a detrimental effect on response to treatment. For these reasons, the mutational status of NS-NSCLC patients should be determined at the time of diagnosis to allow the best therapeutic strategy to be chosen.
Disclosure
The authors have stated that they have no conflicts of interest.
Acknowledgments
The authors thank Grainne Tierney and Ursula Elbling for editing the manuscript.
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