Abstract
BackgroundEGFR and ALK alternations often contribute to human malignancies, including lung cancer. EGFR and ALK mutations are usually sensitive to EGFR-tyrosine kinase inhibitors (TKIs) and ALK-TKIs. Although generally mutually exclusive, these mutations do co-exist in rare cases. This study investigated the frequencies, clinical characteristics, therapeutic efficacies, and genetic profiles of lung cancer patients with EGFR and ALK co-mutations.MethodsPatients with concurrent EGFR and ALK mutations were included in this study, which analyzed mutation profiles and treatment histories. SPSS20.0 were used for survival analysis.ResultsAmong 271 ALK-positive (ALK-pos) and 2975 EGFR-positive (EGFR-pos) patients in our database, nine (2.6% of ALK-pos and 0.2% of EGFR-pos) patients had concurrent EGFR and ALK mutations (including three exon19 Indel + EML4-ALK, two exon19 Indel + STRN-ALK, two L858R + L1152R, one L858R + EML4-ALK, and one G719C + S768I + STRN-ALK). Eight patients had at least one type of EGFR-TKIs treatment. The median progression free survival (PFS) of these patients on first-generation EGFR-TKIs was 14.5 months (95% CI: 11 - NR). Of these eight patients, one who progressed on Gefitinib and subsequently on Osimertinib had a T790M + C797G. The other seven EGFR-TKIs resistance patients had no known resistance mutations. No patients had ALK mutations before treatment, so ALK mutations may have developed as resistance mechanisms during EGFR-TKIs therapies. EGFR-TKIs-treated patients with EGFR/ALK L1152R mutations generally had a shorter PFS than patients with other mutation combinations.ConclusionsALK and EGFR mutations coincide at a relatively low frequency in lung cancer patients. ALK mutations developed either synchronously or heterochronously with EGFR mutations. Two ALK mutations (L1152R and STRN-ALK) may co-exist with EGFR mutations at a higher frequency than others. Most EGFR/ALK co-alteration patients (other than the EGFR/ALK L1152R type) can benefit from first line EGFR-TKIs.
Highlights
Epidermal growth factor receptor (EGFR) and Anaplastic lymphoma kinase (ALK) alternations often contribute to human malignancies, including lung cancer
We found that EGFR mutation types and ALK rearrangement types (ALK-L1152R) are independent factors that associate with poor progression-free survival (PFS) in EGFR-tyrosine kinase inhibitors (TKIs) treatment (HR 3.70, 95% confidence interval (CI): 1.76–23.58, p = 0.024; and HR 4.67, 95% CI: 1.86– 33.09, p = 0.015; respectively)
Except for one patient (T790M + C797G) who progressed on Gefitinib and subsequently on Osimertinib, the other seven EGFR-TKI resistance patients had no previously known resistance mutations
Summary
EGFR and ALK alternations often contribute to human malignancies, including lung cancer. EGFR and ALK mutations are usually sensitive to EGFR-tyrosine kinase inhibitors (TKIs) and ALK-TKIs. generally mutually exclusive, these mutations do co-exist in rare cases. This study investigated the frequencies, clinical characteristics, therapeutic efficacies, and genetic profiles of lung cancer patients with EGFR and ALK co-mutations. EGFR mutations and ALK rearrangements are the two most important driving genes for NSCLC. The occurrence of an ALK rearrangement is 3 to 5% of patients with NSCLC They often have unique clinical and pathological characteristics including a younger age, no history of heavy smoking, and adenocarcinoma [10,11,12,13]. With the application of Next-generation sequencing, more low-frequency mutations, as well as concurrent mutations can be detected
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