ABSTRACT
We report a case of concomitant EML4-ALK and TPM3-ROS1 fusion in non-small cell lung cancer (NSCLC) in a 47-year-old Chinese man and review the clinical characteristics of this type double of fusion. The patient presented with a local tumor of the left upper lobe and underwent thoracoscopy. Postoperative surgical pathologic staging revealed T1a N0 M0 stage IA. Histological examination of the tumor showed lung adenocarcinoma. Ventana ALK (D5F3) assay of the left lung tissue was ALK negative; however, immunohistochemical assay was positive for ROS1 protein. Using next generation sequencing, we found that the tumor had concomitant EML4-ALK and TPM3-ROS1 fusion. No recurrence was observed during seven months of follow-up. Precise diagnostic techniques allow the detection of concomitant ROS1 fusion and other driver genes, including ALK or EGFR; therefore oncologists should consider this rare double mutation in NSCLC patients. Further exploration of treatment models is required to provide additional therapeutic options.
Subject(s)
Adenocarcinoma/genetics , Lung Neoplasms/genetics , Oncogene Proteins, Fusion/genetics , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins/genetics , Tropomyosin/genetics , Adenocarcinoma/pathology , Adenocarcinoma/surgery , Adenocarcinoma of Lung , ErbB Receptors/genetics , High-Throughput Nucleotide Sequencing , Humans , Lung Neoplasms/pathology , Lung Neoplasms/surgery , Male , Middle Aged , Mutation , Neoplasm StagingABSTRACT
ROS1 rearrangement occurs in 1-2% of non-small cell lung cancer (NSCLC) cases. These patients would benefit from treatment with the anaplastic lymphoma kinase inhibitor, crizotinib; however, resistance to crizotinib inevitably develops in such patients despite an initial response. The mechanism of acquired resistance to crizotinib in patients with NSCLC with ROS1 rearrangement has not yet been identified. Herein, we report a case of a 66-year-old woman diagnosed with adenocarcinoma. PCR revealed no EGFR or ALK mutations. After the patient underwent several rounds of chemotherapy, crizotinib was administered. The disease explosively progressed six months later. A novel PIK3CA gene point mutation (p.L531P) was detected by next generation sequencing. This case is the second report of bypass activation conferred crizotinib resistance in a patient with NSCLC with ROS1-rearrangement, but is the first to confirm that activation of the mTOR signaling pathway leads to acquired crizotinib resistance.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Class I Phosphatidylinositol 3-Kinases/genetics , Lung Neoplasms/drug therapy , Point Mutation , Aged , Carcinoma, Non-Small-Cell Lung/genetics , Crizotinib , Drug Resistance, Neoplasm , Female , Humans , Lung Neoplasms/genetics , Protein-Tyrosine Kinases/genetics , Proto-Oncogene Proteins/genetics , Pyrazoles/therapeutic use , Pyridines/therapeutic use , Sequence Analysis, DNAABSTRACT
Anaplastic lymphoma kinase (ALK) rearrangement responds to ALK tyrosine kinase inhibitors (TKIs) in lung cancer. Many cases ultimately acquire resistance to crizotinib. Resistance, including ALK-dominant or ALK non-dominant, mechanisms have been described. Transformation to small-cell lung cancer is rare. Herein, we report a 49-year-old man diagnosed with adenocarcinoma, who was negative for EGFR and ALK genes as detected by reverse transcription polymerase chain reaction, and was treated with crizotinib. A new biopsy showed a small-cell lung cancer after disease progression. Then, next-generation sequencing (NGS) was carried out and detected a TP53 gene mutation, an ALK rearrangement, and no loss of the retinoblastoma gene (RB). Although a regimen for small-cell lung cancer may be one treatment option, a heterogeneous tumor may exist at the time of diagnosis and manifest during the course of disease.
