Concomitant ALK translocation and other non-EGFR gene in NSCLC: knowledge in the making

Abstract

We read with great interest the two papers published recently on Annals of Oncology, regarding concomitant ALK translocation with EGFR and KRAS mutations [1.Won J.K. Keam B. Koh J. et al.Concomitant ALK translocation and EGFR mutation in lung cancer: a comparison of direct sequencing and sensitive assays and the impact on responsiveness to tyrosine kinase inhibitor.Ann Oncol. 2015; 26: 348-354Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 2.Rossi G. Baldi L. Barbieri F. et al.Concomitant EGFR and KRAS mutations in ALK rearranged lung cancer.Ann Oncol. 2015; 26: 1035-1036Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar]. Although, the use of high-sensitive methodologies (as mutant-enriched next-generation sequencing) increased the rate of lung cancer with concomitant EGFR and ALK rearrangement, these data confirming that lung cancer with ALK rearrangement show high genetic heterogeneity. Only a few years ago, we consider ALK and EGFR mutually exclusive but today we not only detect concomitant ALK and EGFR mutations [3.Baldi L. Mengoli M.C. Bisagni A. et al.Concomitant EGFR mutation and ALK rearrangement in lung adenocarcinoma is more frequent than expected: report of a case and review of the literature with demonstration of genes alteration into the same tumor cells.Lung Cancer. 2014; 86: 291-295Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar], but are able to treat these patients prolong their survival with different target agents targeting different target [4.Ricciardi G.R. Russo A. Franchina T. et al.NSCLC and HER2: between lights and shadows.J Thorac Oncol. 2014; 9: 1750-1762Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar]. At the present time, based only sporadic case report explored the role of different target agents in NSCLC when concomitant mutations are present, it is difficult to understand how is the best sequence of treatment. In our clinical experience, we found a different concomitant mutation with ALK rearranged. On September 2012, a thoracic lobectomy was carried out on a 46-year-old woman, no smoker, with a definitive histopathological examination of NSCLC with adenocarcinoma features, with lymph node involvement in one-third of resected lymph node; stage pT2a pN1: stage IIB (based on 7th edition of TNM classification). A primary assessment on pathological tissue resulted negative for EGFR mutations and weakly positive (4% of cells) for ALK gene rearranged. Considering the clinical and pathological anamnestic data of the patient, we carried out a deeply new evaluation of the tumor sample. We evaluated the mutational status of EGFR and K-RAS by bidirectional Sanger sequencing, ALK by FISH and immunohistochemistry (IHC), ROS-1-gene and RET (10q11.21) rearrangement by FISH, and expression (IHC) and amplification of HER-2 proteins. Both of EGFR was confirmed as wild type. Re-analysis for EGFR and KRAS confirmed for both the wild-type status. ROS-1-gene and RET (10q11.21) resulted negative. ALK gene rearrangement was detected by FISH (break Apart Rearrangement Probe, Abbott Molecular, Les Plaines, IL) in ∼15% of the tumor cells (Figure 1A); IHC showed a diffuse and strong positivity for ALK (clone D5F3) (Figure 1B). Forty percent of the tumor cell membranes were completely and intensely stained with anti HER-2 (Herceptest, Dako, Glostrup, DK) (Figure 1C). Furthermore, we found HER-2/Neu amplification evaluated by DDISH (Ventana, Tucson, AZ) (Figure 1D). Bidirectional Sanger sequencing was negative for HER-2 mutations. On May 2014, patients developed a progression disease with bilateral adrenal lesions and started first-line treatment with cisplatin (70 mg/mq) and pemetrexed (500 mg/mq) 1q21, for four cycles. Patients continued treatment with maintenance pemetrexed at the present time on-going. In this report, we showed for the first time, that over EGFR mutations, Her-2 gene [5.Chiari R. Duranti S. Ludovini V. et al.Long-term response to gefitinib and crizotinib in lung adenocarcinoma harboring both epidermal growth factor receptor mutation and EML4-ALK fusion gene.J Clin Oncol. 2014; 32: e30-e32Crossref PubMed Scopus (34) Google Scholar] amplification could be occur in patients with ALK translocation, confirming the heterogeneity of non-small-cell lung cancer with adenocarcinoma histology. The findings improve our knowledge about intratumor heterogeneity of non-small-cell lung cancer, in particular when ‘druggable’ or sensitive mutations are detected. These aspects could be used to explore the role of dual-inhibition with target agents, which at the present time are missed, excluding sporadic report. The authors have declared no conflicts of interest.