Nora Sahnane1, Milo Frattini2, Barbara Bernasconi3, Francesco Zappa4, Giovanna Schiavone5, Luciano Wannesson5, Paola Antonelli6, Piera Balzarini7, Fausto Sessa3, Luca Mazzucchelli2, Maria Grazia Tibiletti8, Vittoria Martin2. 1. Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy. Electronic address: n.sahnane@gmail.com. 2. Institute of Pathology, Locarno, Switzerland. 3. Department of Surgical and Morphological Sciences, University of Insubria, Varese, Italy. 4. Department of Oncology, Clinica Luganese, Lugano, Switzerland. 5. Oncology Institute of Southern Switzerland, Mendrisio, Switzerland. 6. Department of Oncology, Ospedale di Busto Arsizio, Busto Arsizio, Italy. 7. Department of Pathology, University of Brescia, Brescia, Italy. 8. Unit of Pathology, Ospedale di Circolo di Varese, Varese, Italy.
Abstract
INTRODUCTION: In lung adenocarcinoma (ADC), anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements are mutually exclusive with epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. However, the existence of double-positive (DP) patients have been sporadically described. We identified DP cases in therapy-naive ALK-rearranged ADC and characterized the biology of these tumors to better understand the clinical response to tyrosine kinase inhibitors (TKIs). MATERIALS AND METHODS: We selected 42 ALK-positive ADCs from a multicentric series of 301 cases of ADCs. A mutational analysis was performed using Sanger and/or pyrosequencing to address exons 18-21 of EGFR and codons 12-13 of the KRAS gene. In addition, the KRAS and EGFR copy number was investigated using fluorescent in situ hybridization. DP patients were treated with TKIs, and their response was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria. RESULTS: Eight of 42 ALK-positive ADCs (19%) demonstrated a concomitant mutation in the EGFR (3 cases) or KRAS (5 cases) genes and were classified as DP. All DP cases displayed copy number gains in the EGFR or KRAS gene because of polysomy or gene amplification. In the latter cases, a mutant allele-specific imbalance was observed. Four patients were treated with TKIs. The 2 EGFR-mutant DP patients demonstrated a better response to crizotinib compared with erlotinib. The 2 KRAS-mutant DP patients experienced opposite responses to crizotinib. CONCLUSION: The incidence of DP ADC is not negligible. Patients with ALK/EGFR might benefit more from crizotinib compared with erlotinib administration, although the efficacy of TKIs in patients with ALK/KRAS remains unclear. An integrated targeted therapy should be considered for patients with DP ADC.
INTRODUCTION: In lung adenocarcinoma (ADC), anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangements are mutually exclusive with epidermal growth factor receptor (EGFR) and Kirsten ratsarcoma viral oncogene homolog (KRAS) mutations. However, the existence of double-positive (DP) patients have been sporadically described. We identified DP cases in therapy-naive ALK-rearranged ADC and characterized the biology of these tumors to better understand the clinical response to tyrosine kinase inhibitors (TKIs). MATERIALS AND METHODS: We selected 42 ALK-positive ADCs from a multicentric series of 301 cases of ADCs. A mutational analysis was performed using Sanger and/or pyrosequencing to address exons 18-21 of EGFR and codons 12-13 of the KRAS gene. In addition, the KRAS and EGFR copy number was investigated using fluorescent in situ hybridization. DPpatients were treated with TKIs, and their response was evaluated according to the Response Evaluation Criteria in Solid Tumors criteria. RESULTS: Eight of 42 ALK-positive ADCs (19%) demonstrated a concomitant mutation in the EGFR (3 cases) or KRAS (5 cases) genes and were classified as DP. All DP cases displayed copy number gains in the EGFR or KRAS gene because of polysomy or gene amplification. In the latter cases, a mutant allele-specific imbalance was observed. Four patients were treated with TKIs. The 2 EGFR-mutant DPpatients demonstrated a better response to crizotinib compared with erlotinib. The 2 KRAS-mutant DPpatients experienced opposite responses to crizotinib. CONCLUSION: The incidence of DP ADC is not negligible. Patients with ALK/EGFR might benefit more from crizotinib compared with erlotinib administration, although the efficacy of TKIs in patients with ALK/KRAS remains unclear. An integrated targeted therapy should be considered for patients with DP ADC.
Authors: Giuseppe Lo Russo; Martina Imbimbo; Giulia Corrao; Claudia Proto; Diego Signorelli; Milena Vitali; Monica Ganzinelli; Laura Botta; Nicoletta Zilembo; Filippo de Braud; Marina Chiara Garassino Journal: Oncotarget Date: 2017-04-26