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Sung YE, Kim M. Revisiting ALK (D5F3) immunohistochemistry: Insights into focal staining and neuroendocrine differentiation. Thorac Cancer 2024; 15:2175-2184. [PMID: 39257160 PMCID: PMC11496193 DOI: 10.1111/1759-7714.15445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 08/26/2024] [Accepted: 08/28/2024] [Indexed: 09/12/2024] Open
Abstract
BACKGROUND Screening for anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC) is crucial for identifying patients eligible for targeted therapy. The FDA-approved ALK (D5F3) immunohistochemistry (IHC) assay, used with the OptiView Amplification Kit, demonstrates excellent sensitivity and specificity in detecting these patients. However, the clinical significance of resulting focal positivity remains unclear, and ALK (D5F3) expression unrelated to ALK fusion is observed in some cases of neuroendocrine differentiation. This study aims to validate these findings with molecular testing and contribute to the accurate interpretation of ALK (D5F3) IHC results. METHODS A total of 1619 patients diagnosed with NSCLC and neuroendocrine carcinoma were evaluated using ALK (D5F3) IHC. For cases with strong but focal expression and those with diffuse strong positivity in neuroendocrine differentiation, ALK fluorescence in situ hybridization (FISH) and/or next-generation sequencing (NGS) tests were performed. RESULTS Seven out of 1109 adenocarcinomas (0.6%) and six out of 289 squamous cell carcinomas (2.1%) exhibited strong focal ALK (D5F3) expression. Nine out of 209 neuroendocrine carcinomas (4.3%) showed homogeneously strong ALK (D5F3) expression. All these cases, including adenocarcinoma with neuroendocrine differentiation and combined small cell carcinoma, were negative for ALK fusions by FISH and/or NGS. CONCLUSION This study demonstrates that strong but focal ALK (D5F3) immunostaining and strong expression in neuroendocrine differentiation may not indicate ALK fusion. By considering these findings, we can improve the accuracy of patient selection for targeted therapy by minimizing false-positive interpretations of ALK (D5F3) staining.
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MESH Headings
- Humans
- Anaplastic Lymphoma Kinase/genetics
- Anaplastic Lymphoma Kinase/metabolism
- Male
- Female
- Immunohistochemistry/methods
- Middle Aged
- Carcinoma, Neuroendocrine/pathology
- Carcinoma, Neuroendocrine/genetics
- Carcinoma, Neuroendocrine/metabolism
- Lung Neoplasms/genetics
- Lung Neoplasms/pathology
- Lung Neoplasms/metabolism
- Aged
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/metabolism
- Biomarkers, Tumor/metabolism
- Biomarkers, Tumor/genetics
- Adult
- In Situ Hybridization, Fluorescence/methods
- Cell Differentiation
- Aged, 80 and over
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Affiliation(s)
- Yeoun Eun Sung
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
| | - Meejeong Kim
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of MedicineThe Catholic University of KoreaSeoulSouth Korea
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Tao J, Wu Z, Huang R, Li J, Xu T, Gao Y, Jia W, Chen H. Primary Lung Squamous Cell Carcinoma With Intestinal Metastasis: A Case Report and Literature Review. THE CLINICAL RESPIRATORY JOURNAL 2024; 18:e13817. [PMID: 39118303 PMCID: PMC11310267 DOI: 10.1111/crj.13817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 07/16/2024] [Accepted: 07/19/2024] [Indexed: 08/10/2024]
Abstract
Lung squamous cell carcinoma (LUSC) is characterized by a high rate of metastasis and recurrence, leading to a poor prognosis for affected patients. Intestinal metastasis of LUSC is a rare clinical occurrence. Treatment options for LUSC patients with intestinal metastasis are limited, and no standard therapy guidelines exist for managing these cases. In this review, we discuss the clinical features, diagnosis, and treatment of LUSC patients with intestinal metastasis and present a rare case of LUSC with intestinal metastasis. We describe a patient who presented with a severe cough and chest pain and diagnosed with LUSC and bone tumor. Initially, the primary LUSC and bone tumor were controlled with standard treatments. However, the primary LUSC reoccurred shortly after treatment, this time with intestinal metastasis, for which effective treatments are lacking. Our observation from the case suggests that LUSC metastasizing to intestinal tract is associated with a poorer prognosis.
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Affiliation(s)
- Jin Tao
- Department of Cardiothoracic SurgerySchool of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical CollegeChengduChina
| | - Zhiqiang Wu
- Department of Cardiothoracic SurgerySchool of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical CollegeChengduChina
| | - Rongfei Huang
- Department of PathologySchool of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical CollegeChengduChina
| | - Jun Li
- Department of GastroenterologySchool of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical CollegeChengduChina
| | - Tiewei Xu
- Department of Cardiothoracic SurgerySchool of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical CollegeChengduChina
| | - Yujie Gao
- Department of StomatologySchool of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical CollegeChengduChina
| | - Weikun Jia
- Department of Cardiothoracic SurgerySchool of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical CollegeChengduChina
| | - Hu Chen
- Department of Cardiothoracic SurgerySchool of Clinical Medicine and The First Affiliated Hospital of Chengdu Medical CollegeChengduChina
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Poei D, Ali S, Ye S, Hsu R. ALK inhibitors in cancer: mechanisms of resistance and therapeutic management strategies. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:20. [PMID: 38835344 PMCID: PMC11149099 DOI: 10.20517/cdr.2024.25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/18/2024] [Accepted: 05/08/2024] [Indexed: 06/06/2024]
Abstract
Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified as potent oncogenic drivers in several malignancies, including non-small cell lung cancer (NSCLC). The discovery of ALK inhibition using a tyrosine kinase inhibitor (TKI) has dramatically improved the outcomes of patients with ALK-mutated NSCLC. However, the emergence of intrinsic and acquired resistance inevitably occurs with ALK TKI use. This review describes the molecular mechanisms of ALK TKI resistance and discusses management strategies to overcome therapeutic resistance.
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Affiliation(s)
- Darin Poei
- Department of Internal Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Sana Ali
- Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Shirley Ye
- Department of Internal Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Robert Hsu
- Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
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Wang Y, Song Y, Wang R, Wu Y, Li M, Xu K, He R, Wang Z, Li Q, Kong FM(S, Wang T. Clinical factors and major pathological response after neoadjuvant chemoimmunotherapy in potentially resectable lung squamous cell carcinoma. Front Oncol 2024; 14:1265228. [PMID: 38680859 PMCID: PMC11045983 DOI: 10.3389/fonc.2024.1265228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 03/18/2024] [Indexed: 05/01/2024] Open
Abstract
Objective Major pathological response (MPR) helps evaluate the prognosis of patients with lung squamous cell carcinoma (LUSC). However, the clinical factors that affect the achievement of MPR after neoadjuvant chemoimmunotherapy (NCIO) in patients with LUSC remain unclear. This study aimed to explore the clinical factors affecting the MPR after NCIO in patients with potentially resectable LUSC. Methods This retrospective study included patients with stage IIB-IIIC LUSC who underwent surgical resection after receiving NCIO at a center between March 2020 and November 2022. In addition to the postoperative pathological remission rate, sex, age, body mass index (BMI), smoking history, TNM stage, hematological and imaging test results, and other indicators were examined before NCIO. According to the pathological response rate of the surgically removed tumor tissue, the patients were split into MPR and non-MPR groups. Results In total, 91 LUSC patients who met the study's eligibility criteria were enrolled: 32 (35%) patients in the non-MPR group and 59 (65%) in the MPR group, which included 43 cases of pathological complete remission (pCR). Pre-treatment lymphocyte level (LY) (odds ratio [OR] =5.997), tumor burden (OR=0.958), N classification (OR=15.915), radiographic response (OR=11.590), pulmonary atelectasis (OR=5.413), and PD-L1 expression (OR=1.028) were independently associated with MPR (all P < 0.05). Based on these six independent predictors, we developed a nomogram model of prediction having an area under the curve (AUC) of 0.914 that is simple to apply clinically to predict the MPR. The MPR group showed greater disease-free survival (DFS) than the non-MPR group, according to the survival analysis (P < 0.001). Conclusion The MPR rate of NCIO for potentially resectable LUSC was 65%. LY, tumor burden, N classification, radiographic response, pulmonary atelectasis, and PD-L1 expression in patients with LUSC before NCIO were the independent and ideal predictors of MPR. The developed nomogram demonstrated a good degree of accuracy and resilience in predicting the MPR following NCIO, indicating that it is a useful tool for assuring customized therapy for patients with possibly resectable LUSC.
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Affiliation(s)
- Ye Wang
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, Shenyang, Liaoning, China
- School of Graduate, Dalian Medical University, Dalian, China
| | - Yingqiu Song
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, Shenyang, Liaoning, China
| | - Runze Wang
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, Shenyang, Liaoning, China
| | - Yu Wu
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, Shenyang, Liaoning, China
- School of Graduate, Dalian Medical University, Dalian, China
| | - Mo Li
- Department of Breast Surgery, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Ke Xu
- Department of Thoracic Surgery, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Rong He
- Department of Thoracic Surgery, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Zheng Wang
- Department of Thoracic Surgery, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Qingqing Li
- Department of Endoscopy, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, China
| | - Feng-Ming (Spring) Kong
- Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
- Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Tianlu Wang
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, Shenyang, Liaoning, China
- Faculty of Medicine, Dalian University of Technology, Dalian, China
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Liu W, Huo G, Chen P. Clinical benefit of pembrolizumab in treatment of first line non-small cell lung cancer: a systematic review and meta-analysis of clinical characteristics. BMC Cancer 2023; 23:458. [PMID: 37202730 DOI: 10.1186/s12885-023-10959-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Accepted: 05/13/2023] [Indexed: 05/20/2023] Open
Abstract
OBJECTIVE Pembrolizumab has become an integral first line therapeutic agent for non-small cell lung cancer (NSCLC), but its potential predictive role in clinical and molecular characteristics remains to be clarified. Accordingly, we performed a systematic review and meta-analysis to evaluate the clinical benefit of pembrolizumab in treatment of first line NSCLC and to select individuals with the greatest potential benefit from pembrolizumab therapy, in order to obtain a more accurate treatment of NSCLC in immunotherapy. METHODS Mainstream oncology datasets and conferences were searched for randomized clinical trials (RCTs) published before August 2022. RCTs involved individuals with first line NSCLC treated with pembrolizumab monotherapy or in combination with chemotherapy. Two authors independently selected the studies, extracted data, and assessed the risk of bias. The basic characteristics of the included studies were recorded, along with 95 percent confidence intervals (CI) and hazard ratios (HR) for all patients and subgroups. The primary endpoint was overall survival (OS), and secondary endpoints was progression-free survival (PFS). Pooled treatment data were estimated using the inverse variance-weighted method. RESULTS Five RCTs involving 2,877 individuals were included in the study. Pembrolizumab-based therapy significantly improved OS (HR 0.66; CI 95%, 0.55-0.79; p < 0.00001) and PFS (HR 0.60; CI 95%, 0.40-0.91; p = 0.02) compared with chemotherapy. OS was substantially enhanced in individuals aged < 65 years (HR 0.59; CI 95%, 0.42-0.82; p = 0.002), males (HR 0.74; CI 95%, 0.65-0.83; p < 0.00001), with a smoking history (HR 0.65; CI 95%, 0.52-0.82; p = 0.0003), with PD-L1 tumor proportion score (TPS) < 1% (HR 0.55; CI 95%, 0.41-0.73; p < 0.0001) and TPS ≥ 50% (HR 0.66; CI 95%, 0.56-0.76; p < 0.00001), but not in individuals aged ≥ 75 years (HR 0.82; CI 95%, 0.56-1.21; p = 0.32), females (HR 0.57; CI 95%, 0.31-1.06; p = 0.08), never smokers (HR 0.57; CI 95%, 0.18-1.80; p = 0.34), or with TPS 1-49% (HR 0.72; CI 95%, 0.52-1.01; p = 0.06). Pembrolizumab significantly prolonged OS in NSCLC patients, regardless of histology type (squamous or non-squamous NSCLC), performance status (PS) (0 or 1), and brain metastatic status (all p < 0.05). Subgroup analysis revealed that pembrolizumab combined with chemotherapy had more favorable HR values than pembrolizumab monotherapy in improving the OS of individuals with different clinical and molecular features. CONCLUSION Pembrolizumab-based therapy is a valuable option for first line treating advanced or metastatic NSCLC. Age, sex, smoking history and PD-L1 expression status can be used to predict the clinical benefit of pembrolizumab. Cautiousness was needed when using pembrolizumab in NSCLC patients aged ≥ 75 years, females, never smokers, or in patients with TPS 1-49%. Furthermore, pembrolizumab in combination with chemotherapy may be a more effective treatment regimen.
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Affiliation(s)
- Wenjie Liu
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Gengwei Huo
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Peng Chen
- Department of Thoracic Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China.
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Effects of Lipid Metabolism-Related Genes PTGIS and HRASLS on Phenotype, Prognosis, and Tumor Immunity in Lung Squamous Cell Carcinoma. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2023; 2023:6811625. [PMID: 36703911 PMCID: PMC9873467 DOI: 10.1155/2023/6811625] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 12/21/2022] [Accepted: 01/02/2023] [Indexed: 01/19/2023]
Abstract
Background Lipid metabolism reprogramming played an important role in cancer occurrence, development, and immune regulation. The aim of this study was to identify and validate lipid metabolism-related genes (LMRGs) associated with the phenotype, prognosis, and immunological characteristics of lung squamous cell carcinoma (LUSC). Methods In the TCGA cohort, bioinformatics and survival analysis were used to identify lipid metabolism-related differentially expressed genes (DEGs) associated with the prognosis of LUSC. PTGIS/HRASLS knockdown and overexpression effects on the LUSC phenotype were analyzed in vitro experiments. Based on the expression distribution of PTGIS/HRASLS, LUSC patients were divided into two clusters by consensus clustering. Clinical information, prognosis, immune infiltration, expression of immune checkpoints, and tumor mutation burden (TMB) level were compared between the TCGA and GSE4573 cohorts. The genes related to clustering and tumor immunity were screened by weighted gene coexpression network analysis (WGCNA), and the target module genes were analyzed by functional enrichment analysis, protein-protein interaction (PPI) analysis, and immune correlation analysis. Results 191 lipid metabolism-related DEGs were identified, of which 5 genes were independent prognostic genes of LUSC. PTGIS/HRASLS were most closely related to LUSC prognosis and immunity. RT-qPCR, western blot (WB) analysis, and immunohistochemistry (IHC) showed that the expression of PTGIS was low in LUSC, while HRASLS was high. Functionally, PTGIS promoted LUSC proliferation, migration, and invasion, while HRASLS inhibited LUSC proliferation, migration, and invasion. The two clusters' expression and distribution of PTGIS/HRASLS had the opposite trend. Cluster 1 was associated with lower pathological staging (pT, pN, and pTNM stages), better prognosis, stronger immune infiltration, higher expression of immune checkpoints, and higher TMB level than cluster 2. WGCNA found that 28 genes including CD4 and IL10RA were related to the expression of PTGIS/HRASLS and tumor immune infiltration. PTGIS/HRASLS in the GSE4573 cohort had the same effect on LUSC prognosis and tumor immunity as the TCGA cohort. Conclusions PTGIS and HRASLS can be used as new therapeutic targets for LUSC as well as biomarkers for prognosis and tumor immunity, which has positive significance for guiding the immunotherapy of LUSC.
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Yang W, Li T, Bai Y, Long Y, Gao M, Wang T, Jing F, Zhang F, Tao H, Ma J, Wang L, Hu Y. Efficacy and safety of pembrolizumab versus sintilimab treatment in patients with advanced squamous lung cancer: A real-world study in China. Front Oncol 2023; 13:1147903. [PMID: 37124534 PMCID: PMC10130366 DOI: 10.3389/fonc.2023.1147903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 03/29/2023] [Indexed: 05/02/2023] Open
Abstract
Importance Both pembrolizumab and sintilimab have been approved by the Chinese State Drug Administration (NMPA) for the first-line treatment of patients with advanced squamous lung cancer. The differences of the two drugs in efficacy and safety are unclear. Objectives To compare the real-world efficacy and safety of first-line treatments in patients with advanced squamous lung cancer. Materials and methods This was a retrospective review of patients with advanced squamous carcinoma who received sintilimab or pembrolizumab in combination with chemotherapy as first-line therapy between June 2018 and April 2022 in the Chinese PLA Hospital. The primary objective was to compare the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) between the two groups. Secondary objectives were to compare the disease control rate (DCR) and to analyze adverse events (AEs) between the two groups. Results A total of 164 patients were enrolled, including 63 patients (38.4%) in the sintilimab-combined chemotherapy group and 101 patients (61.6%) in the pembrolizumab-combined chemotherapy group. The ORR was 65.10% in the sintilimab group and 61.40% in the pembrolizumab group (P=0.634). The DCR was 92.10% and 92.10% in the sintilimab and pembrolizumab groups, respectively (P=0.991). The median PFS was 22.2 months for patients treated with sintilimab group compared with 16.5 months for patients treated with pembrolizumab group[hazard ratio (HR) = 0.743; 95% confidence interval (CI): 0.479-1.152; P = 0.599]. Patients treated with pembrolizumab did not achieve a median OS, and patients treated with sintilimab had a median OS of 30.7 months. In the sintilimab group, the incidence of all treatment-related adverse events (TRAEs) was 92.1% (58/63), and the incidence of grade 3-4 TRAEs of 42.9% (27/63). In the pembrolizumab group, the incidence of all TRAEs was 90.1% (91/101), and the incidence of grade 3-4 TRAEs was 37.6% (38/101). Conclusion In the clinical treatment of Chinese patients with advanced squamous lung cancer, first-line treatment with sintilimab in combination with chemotherapy provided similar efficacy to pembrolizumab in combination with chemotherapy, and the treatment-related adverse effect profiles were comparable between the two groups, including similar rates of grade 3-4 and all adverse events.
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Affiliation(s)
- Wenyu Yang
- School of Medicine, Nankai University, Tianjin, China
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center, The General Hospital of the People's Liberation Army, Beijing, China
| | - Tao Li
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center, The General Hospital of the People's Liberation Army, Beijing, China
| | - Yibing Bai
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center, The General Hospital of the People's Liberation Army, Beijing, China
| | - Yaping Long
- School of Medicine, Nankai University, Tianjin, China
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center, The General Hospital of the People's Liberation Army, Beijing, China
| | - Ming Gao
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center, The General Hospital of the People's Liberation Army, Beijing, China
| | - Ting Wang
- School of Medicine, Nankai University, Tianjin, China
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center, The General Hospital of the People's Liberation Army, Beijing, China
| | - Fangfang Jing
- Department of Oncology, The First Medical Center, The General Hospital of the People's Liberation Army, Beijing, China
| | - Fan Zhang
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center, The General Hospital of the People's Liberation Army, Beijing, China
| | - Haitao Tao
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center, The General Hospital of the People's Liberation Army, Beijing, China
| | - Junxun Ma
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center, The General Hospital of the People's Liberation Army, Beijing, China
| | - Lijie Wang
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center, The General Hospital of the People's Liberation Army, Beijing, China
- *Correspondence: Lijie Wang, ; Yi Hu,
| | - Yi Hu
- Department of Medical Oncology, Senior Department of Oncology, The Fifth Medical Center, The General Hospital of the People's Liberation Army, Beijing, China
- *Correspondence: Lijie Wang, ; Yi Hu,
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Li F, Liu Y, Xu K, Yao Q, Li Q, Wu H. Squamous cell lung carcinoma with gastrointestinal metastasis: a case report and review of literature. Front Oncol 2023; 13:1138871. [PMID: 37152036 PMCID: PMC10160372 DOI: 10.3389/fonc.2023.1138871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 03/24/2023] [Indexed: 05/09/2023] Open
Abstract
Squamous cell lung carcinoma (LUSC) originates from squamous cells and has a high rate of metastasis and recurrence. The lack of effective genetic targets and specific therapies has resulted in a poor prognosis for patients with LUSC. Gastrointestinal metastasis of LUSC is a rare occurrence in clinical practice. Patients with gastrointestinal metastasis usually have worse overall survival and the process of diagnosis is more complicated than those with metastasis elsewhere. What's more, there are no helpful guidelines for treating patients with a clinically confirmed diagnosis of gastrointestinal metastasis, which means the treatment method is limited. Here, we review the clinical features, diagnosis, and treatment of LUSC patients with gastrointestinal metastasis and report a rare case of LUSC accompanied by gastrointestinal metastasis. The patient was admitted to the hospital with coughing and hemoptysis. A tumor was found in his lung, and lesions were initially controlled with standard treatment. The patient's tumor re-occurred again shortly for which treatment was lacking. Without effective treatment methods, the disease was difficult to control. Our learnings from the case demonstrate that LUSC metastasizes to secondary lymphoid organs of the gastrointestinal tract, usually with a poor prognosis.
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Affiliation(s)
- Feifei Li
- Sichuan Cancer Hospital & Institute Sichuan Cancer Center, School of Medicine University of Electronic Science and Technology, Chengdu, Sichuan, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical BioResource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, Guangxi, China
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Yiqiang Liu
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Ke Xu
- Sichuan Cancer Hospital & Institute Sichuan Cancer Center, School of Medicine University of Electronic Science and Technology, Chengdu, Sichuan, China
| | - Quan Yao
- Sichuan Cancer Hospital & Institute Sichuan Cancer Center, School of Medicine University of Electronic Science and Technology, Chengdu, Sichuan, China
| | - Qiang Li
- Sichuan Cancer Hospital & Institute Sichuan Cancer Center, School of Medicine University of Electronic Science and Technology, Chengdu, Sichuan, China
- *Correspondence: Hong Wu, ; Qiang Li,
| | - Hong Wu
- Sichuan Cancer Hospital & Institute Sichuan Cancer Center, School of Medicine University of Electronic Science and Technology, Chengdu, Sichuan, China
- Department of Oncology & Cancer Institute, Sichuan Academy of Medical Sciences, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- Department of Laboratory Medicine and Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan, China
- *Correspondence: Hong Wu, ; Qiang Li,
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Li S, Li W, Ma T, Fu S, Gao X, Qin N, Wu Y, Zhang X, Wang J, Pan Y, Liu Z. Assessing the efficacy of immunotherapy in lung squamous carcinoma using artificial intelligence neural network. Front Immunol 2022; 13:1024707. [PMID: 36518765 PMCID: PMC9742243 DOI: 10.3389/fimmu.2022.1024707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 11/07/2022] [Indexed: 11/29/2022] Open
Abstract
Background At present, immunotherapy is a very promising treatment method for lung cancer patients, while the factors affecting response are still controversial. It is crucial to predict the efficacy of lung squamous carcinoma patients who received immunotherapy. Methods In our retrospective study, we enrolled lung squamous carcinoma patients who received immunotherapy at Beijing Chest Hospital from January 2017 to November 2021. All patients were grouped into two cohorts randomly, the training cohort (80% of the total) and the test cohort (20% of the total). The training cohort was used to build neural network models to assess the efficacy and outcome of immunotherapy in lung squamous carcinoma based on clinical information. The main outcome was the disease control rate (DCR), and then the secondary outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results A total of 289 patients were included in this study. The DCR model had area under the receiver operating characteristic curve (AUC) value of 0.9526 (95%CI, 0.9088-0.9879) in internal validation and 0.9491 (95%CI, 0.8704-1.0000) in external validation. The ORR model had AUC of 0.8030 (95%CI, 0.7437-0.8545) in internal validation and 0.7040 (95%CI, 0.5457-0.8379) in external validation. The PFS model had AUC of 0.8531 (95%CI, 0.8024-0.8975) in internal validation and 0.7602 (95%CI, 0.6236-0.8733) in external validation. The OS model had AUC of 0.8006 (95%CI, 0.7995-0.8017) in internal validation and 0.7382 (95%CI, 0.7366-0.7398) in external validation. Conclusions The neural network models show benefits in the efficacy evaluation of immunotherapy to lung squamous carcinoma patients, especially the DCR and ORR models. In our retrospective study, we found that neoadjuvant and adjuvant immunotherapy may bring greater efficacy benefits to patients.
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Affiliation(s)
- Siqi Li
- Department of Thoracic Surgery, Beijing Chest Hospital/Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, Beijing, China
| | - Wei Li
- Department of Thoracic Surgery, Beijing Chest Hospital/Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, Beijing, China
| | - Tianyu Ma
- Department of Thoracic Surgery, Beijing Chest Hospital/Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, Beijing, China
| | - Siyun Fu
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Xiang Gao
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Na Qin
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Yuhua Wu
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Xinyong Zhang
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Jinghui Wang
- Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China,Cancer Research Center, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China,*Correspondence: Jinghui Wang, ; Zhidong Liu, ; Yuanming Pan,
| | - Yuanming Pan
- Cancer Research Center, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, China,*Correspondence: Jinghui Wang, ; Zhidong Liu, ; Yuanming Pan,
| | - Zhidong Liu
- Department of Thoracic Surgery, Beijing Chest Hospital/Beijing Tuberculosis and Thoracic Tumor Research Institute, Capital Medical University, Beijing, China,*Correspondence: Jinghui Wang, ; Zhidong Liu, ; Yuanming Pan,
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10
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袁 月, 王 征, 聂 鑫, 张 萍, 李 琳. [A Case of Advanced Lung Squamous Cell Carcinoma with CLIP1-ALK Fusion Gene]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2022; 25:696-700. [PMID: 36172736 PMCID: PMC9549425 DOI: 10.3779/j.issn.1009-3419.2022.102.29] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 06/22/2022] [Accepted: 06/23/2022] [Indexed: 11/19/2022]
Abstract
Anaplastic lymphoma kinase (ALK) fusion gene is an important tumor driver gene of non-small cell lung cancer, accounting for about 5% of patients with non-small cell lung cancer, of which 97% are patients with lung adenocarcinoma. Since the first discovery of echinoderm microtubule associated protein-like 4 (EML4)-ALK fusion in patients with lung adenocarcinoma in 2007, a variety of ALK fusion partners have been detected. CLIP1-ALK fusion gene was detected by next generation sequencing (NGS) in this patient with advanced lung squamous cell carcinoma, and Alectinib and Ensartinib were taken orally on May 5, 2021. Aletinib was effective for this patient but the patients died on September 30, 2021. This is a report of lung squamous cell carcinoma patients with CLIP1-ALK fusion gene treated with ALK inhibitors.
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Affiliation(s)
- 月 袁
- 100730 北京，国家老年医学中心，中国医学科学院老年医学研究所，北京医院肿瘤内科Department of Oncology, Beijing Hospital; National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing 100730, China
- 100730 北京，中国医学科学院，北京协和医学院研究生院Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - 征 王
- 100730 北京，国家老年医学中心，中国医学科学院老年医学研究所，北京医院病理科Department of Pathology, Beijing Hospital; National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing 100730, China
| | - 鑫 聂
- 100730 北京，国家老年医学中心，中国医学科学院老年医学研究所，北京医院肿瘤内科Department of Oncology, Beijing Hospital; National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing 100730, China
| | - 萍 张
- 100730 北京，国家老年医学中心，中国医学科学院老年医学研究所，北京医院肿瘤内科Department of Oncology, Beijing Hospital; National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing 100730, China
| | - 琳 李
- 100730 北京，国家老年医学中心，中国医学科学院老年医学研究所，北京医院肿瘤内科Department of Oncology, Beijing Hospital; National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing 100730, China
- 100730 北京，中国医学科学院，北京协和医学院研究生院Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
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11
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Patil T, Nie Y, Aisner DL, Camidge DR. Case Report: Significant Clinical Benefit From Pemetrexed-Based Therapy in ROS1- and ALK-rearranged Lung Cancer With Adenosquamous Histology. Front Oncol 2022; 11:788245. [PMID: 35070994 PMCID: PMC8777186 DOI: 10.3389/fonc.2021.788245] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 12/06/2021] [Indexed: 11/13/2022] Open
Abstract
Pemetrexed (used as a platinum doublet or as a maintenance regimen) is an established therapy for patients with advanced non-squamous non-small-cell lung cancer (NSCLC). In addition, certain gene rearrangements (e.g., ALK, ROS1, RET) appear to especially benefit from the use of pemetrexed. Inferior outcomes with pemetrexed compared to other chemotherapies in patients with NSCLC demonstrating squamous histology removed these patients from the labeled indication for the drug. While most squamous cases do not harbor driver oncogenes, rare exceptions exist. Whether the poor outcomes with pemetrexed extend to NSCLC with squamous component harboring driver oncogenes remains unexplored. In this case series, we describe two patients with adenosquamous histology harboring an ROS1 and ALK gene arrangement, respectively, who derived significant benefit from pemetrexed-based therapy. These cases suggest that the value of pemetrexed may need to be re-explored in adenosquamous NSCLC harboring such alterations.
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Affiliation(s)
- Tejas Patil
- Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States
| | - Yunan Nie
- Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States
| | - Dara L. Aisner
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States
| | - David Ross Camidge
- Division of Medical Oncology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States
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12
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Li W, Zhang J, Wang Z, Li L, Ma J, Zhou X, Wang J, Liang Z, Ying J, Experts from the RATICAL study. Guidelines for clinical practice of ALK fusion detection in non-small-cell lung cancer: a proposal from the Chinese RATICAL study group. JOURNAL OF THE NATIONAL CANCER CENTER 2021; 1:123-131. [PMID: 39036803 PMCID: PMC11256616 DOI: 10.1016/j.jncc.2021.07.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 12/24/2022] Open
Abstract
The presence of anaplastic lymphoma kinase (ALK) rearrangement defines a molecular subtype of non-small cell lung cancer (NSCLC). ALK inhibitors (ALKIs) confer significant clinical benefits in patients with ALK-positive advanced NSCLC; therefore, it is of great clinical significance to select accurate, rapid, and appropriate ALK testing methods to screen for patients who are suitable for anti-ALK treatment. In recent years, great progress has been made in the development and clinical application of ALKIs, as well as in our understanding of acquired drug resistance mechanisms. Meanwhile, new ALK companion diagnostic platforms have been developed and applied in clinical practice. Although many studies have shown that there is a high rate of concordance among these platforms, new problems continue to appear during testing. To maximize the benefit for patients, accurate testing results can be obtained by first selecting the appropriate testing method and then formulating, optimizing, and complying with the standardized testing process in accordance with the testing population and specimen types. With the ongoing accumulation of clinical practice data, experience from quality control of ALK testing, and results from multicenter research, an updated expert consensus is necessary. The experts who participated in the discussion and development of this guideline have a rich background in theoretical and clinical testing experience, which ensures the practical value of the information presented in this guideline.
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Affiliation(s)
- Wenbin Li
- Departments of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jing Zhang
- Departments of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhijie Wang
- Departments of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lin Li
- Departments of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jie Ma
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450000, China
| | - Xiaoyang Zhou
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
| | - Jie Wang
- Departments of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhiyong Liang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Jianming Ying
- Departments of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Experts from the RATICAL study
- Departments of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Departments of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Molecular Pathology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou 450000, China
- Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
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13
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Pelosi G, Eng MB, Eng MV, Uccella S, Forest F, Leone G, Barberis M, Rahal D, Bossi P, Finzi G, Marchiori D, De Luca M, Sessa F, Harari S, Spinelli M, Viola P, Macrì P, Maria S, Rizzo A, Picone A, Pattini L. Coexpression of ΔNp63/p40 and TTF1 Within Most of the Same Individual Cells Identifies Life-Threatening NSCLC Featuring Squamous and Glandular Biphenotypic Differentiation: Clinicopathologic Correlations. JTO Clin Res Rep 2021; 2:100222. [PMID: 34746884 PMCID: PMC8551500 DOI: 10.1016/j.jtocrr.2021.100222] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 08/21/2021] [Indexed: 11/15/2022] Open
Abstract
Introduction Double occurrence of TTF1 and ΔNp63/p40 (henceforth, p40) within the same individual cells is exceedingly rare in lung cancer. Little is known on their biological and clinical implications. Methods Two index cases immunoreactive for both p40 and TTF1 and nine tumors selected from The Cancer Genome Atlas (TCGA) according to the mRNA levels of the two relevant genes entered the study. Results The two index cases were peripherally located, poorly differentiated, and behaviorally unfavorable carcinomas, which shared widespread p40 and TTF1 decoration within the same individual tumor cells. They also retained SMARCA2 and SMARCA4 expression, while variably stained for p53, cytokeratin 5, and programmed death-ligand 1. A subset of basal cells p40+/TTF1+ could be found in normal distal airways. Biphenotypic glandular and squamous differentiation was unveiled by electron microscopy, along with EGFR, RAD51B, CCND3, or NF1 mutations and IGF1R, MYC, CCND1, or CDK2 copy number variations on next-generation sequencing analysis. The nine tumors from TCGA (0.88% of 1018 tumors) shared the same poor prognosis, clinical presentation, and challenging histology and had activated pathways of enhanced angiogenesis and epithelial-mesenchymal transition. Mutation and copy number variation profiles did not differ from the other TCGA tumors. Conclusions Double p40+/TTF1+ lung carcinomas are aggressive and likely underrecognized non-small cell carcinomas, whose origin could reside in double-positive distal airway stem-like basal cells through either de novo-basal-like or differentiating cell mechanisms according to a model of epithelial renewal.
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Affiliation(s)
- Giuseppe Pelosi
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy.,Inter-Hospital Pathology Division, Istituto di Ricovero e Cura a Carattere Scientifico (IRCSS) MultiMedica, Milan, Italy
| | - Matteo Bulloni Eng
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
| | - Martina Vescio Eng
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
| | - Silvia Uccella
- Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Fabien Forest
- Department of Pathology, University Hospital Center (CHU), North Hospital, Saint Etienne, France
| | - Giorgia Leone
- Pathology Service, Humanitas Istituto Clinico Catanese, Catania, Italy
| | - Massimo Barberis
- Histopathology and Molecular Diagnostics Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCSS) European Institute of Oncology, Milan, Italy
| | - Daoud Rahal
- Department of Pathology, Humanitas Clinical and Research Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCSS), Milan, Italy
| | - Paola Bossi
- Department of Pathology, Humanitas Clinical and Research Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCSS), Milan, Italy
| | - Giovanna Finzi
- Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Deborah Marchiori
- Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Marco De Luca
- Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Fausto Sessa
- Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Sergio Harari
- Department of Medical Sciences and Community Health, University of Milan, Milan, Italy.,Division of Pneumology, San Giuseppe Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCSS) MultiMedica, Milan, Italy
| | - Manuela Spinelli
- Cellular Pathology Department, Worcester Royal Hospital, Worcester, United Kingdom
| | - Patrizia Viola
- Cellular Pathology Department, Hammersmith Hospital, London, United Kingdom
| | - Paolo Macrì
- Division of Oncologic Thoracic Surgery, Humanitas Istituto Clinico Catanese, Catania, Italy
| | - Stefania Maria
- Division of Oncologic Thoracic Surgery, Humanitas Istituto Clinico Catanese, Catania, Italy
| | - Antonio Rizzo
- Pathology Service, Humanitas Istituto Clinico Catanese, Catania, Italy
| | - Antonio Picone
- Department of Oncology, Humanitas Istituto Clinico Catanese, Catania, Italy
| | - Linda Pattini
- Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milan, Italy
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Li S, Zhang P, Wang T, Wang J, Duan J. Brigatinib treated ALK positive lung squamous cell carcinoma after failed chemotherapy: A case report. Thorac Cancer 2021; 12:3273-3276. [PMID: 34647426 PMCID: PMC8636200 DOI: 10.1111/1759-7714.14133] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 08/16/2021] [Accepted: 08/17/2021] [Indexed: 11/27/2022] Open
Abstract
The definitive efficacy of anaplastic lymphoma kinase (ALK) inhibitors in ALK positive lung squamous cell carcinoma (sqCC) patients remain unclear. Here, we report a case in which brigatinib had a therapeutic effect on ALK‐positive lung squamous cell carcinoma. The patient in this report was diagnosed with ALK‐positive lung squamous cell carcinoma with brain metastases, and received brigatinib after failure of first‐line chemotherapy. Response duration was approximately 11 months, with tolerable side effects. In conclusion, a good clinical effect was achieved in a patient with ALK positive lung squamous cell carcinoma who received treatment with an ALK inhibitor.
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Affiliation(s)
- Shuluan Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Pei Zhang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tianyu Wang
- Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Jie Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jianchun Duan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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15
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Meng Q, Dong Y, Tao H, Shi L, Tong L, Tang J, Zhang S, Liu Z. ALK-rearranged squamous cell carcinoma of the lung. Thorac Cancer 2021; 12:1106-1114. [PMID: 33565277 PMCID: PMC8017260 DOI: 10.1111/1759-7714.13818] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 12/15/2020] [Accepted: 12/15/2020] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND ALK rearrangement is a very rare subset of squamous cell carcinoma (SCC) and one of the clinical features in patients is lack of data. Here, we report eight patients diagnosed with SCC of the lung harboring ALK rearrangement. METHODS We collected primary NSCLC samples at the Beijing Chest Hospital between January 2012 and December 2018 for Ventana (D5F3) immunohistochemical detection. Among the 148 patients was diagnosed ALK-rearranged non small cell lung cancer (NSCLC), only eight cases was SCC. We collected patients information from electronic patent records (EPRs). RESULTS The eight cases of SCC were diagnosed by immunohistochemistry (IHC). Two were given crizotinib as second-line therapy. One patient had stable disease (SD) and progression-free survival (PFS) of six months. The other patient had progressive disease (PD) but PFS was only one month. The side effects were tolerable. This report identified 31 cases of ALK rearrangement in SCC patients from a literature search (including the eight patients in this study). These fusion genes are often seen in a younger age group (mean age: 55.6 years) and non-smokers (18/31, 58.1%). A total of 20 cases received an ALK inhibitor as first- or second-line treatment which included 11 with a partial response (PR), four with SD, and five with PD. The DCR and ORR was 75.0% (15/20) and 55.0% (11/20), respectively. The median duration time of therapy was 6.4 ± 4.4 months. CONCLUSIONS Patients with ALK-rearranged SCC obtained clinical benefit from ALK-inhibitor therapy, especially those who were non-smokers and whose tumors had been identified by IHC+/FISH+.
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Affiliation(s)
- Qiyi Meng
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Yujie Dong
- Department of Pathology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Hong Tao
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Liang Shi
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Li Tong
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Junfang Tang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Shucai Zhang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
| | - Zhe Liu
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China
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16
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Hofman P. Detecting Resistance to Therapeutic ALK Inhibitors in Tumor Tissue and Liquid Biopsy Markers: An Update to a Clinical Routine Practice. Cells 2021; 10:168. [PMID: 33467720 PMCID: PMC7830674 DOI: 10.3390/cells10010168] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 12/16/2022] Open
Abstract
The survival of most patients with advanced stage non-small cell lung cancer is prolonged by several months when they are treated with first- and next-generation inhibitors targeting ALK rearrangements, but resistance inevitably emerges. Some of the mechanisms of resistance are sensitive to novel ALK inhibitors but after an initial tumor response, more or less long-term resistance sets in. Therefore, to adapt treatment it is necessary to repeat biological sampling over time to look for different mechanisms of resistance. To this aim it is essential to obtain liquid and/or tissue biopsies to detect therapeutic targets, in particular for the analysis of different genomic alterations. This review discusses the mechanisms of resistance to therapeutics targeting genomic alterations in ALK as well as the advantages and the limitations of liquid biopsies for their identification.
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Affiliation(s)
- Paul Hofman
- Laboratory of Clinical and Experimental Pathology, Université Côte d’Azur, CHU Nice, FHU OncoAge, Pasteur Hospital, 30 Avenue de la Voie Romaine, BP69, CEDEX 01, 06001 Nice, France; ; Tel.: +33-4-92-03-88-55; Fax: +33-4-92-88-50
- Hospital-Integrated Biobank BB-0033-00025, Université Côte d’Azur, CHU Nice, FHU OncoAge, 06001 Nice, France
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17
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Gao M, Zhou Q. [Progress in Treatment of Advanced Squamous Cell Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2020; 23:866-874. [PMID: 32798441 PMCID: PMC7583871 DOI: 10.3779/j.issn.1009-3419.2020.101.35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Lung cancer ranks first both in mobidity and motality in china and worldwild. Squamous cell lung carcinoma is distinguished from lung adenocarcinoma in diagnosis and treatment due to its unique clinical & pathological manifestations and gene mutation characteristics, as a result, it is also explored as a separate type in clinical researches. In addition to the clinical manifestations of elderly, central tumors, late staging at diagnosis, and multiple comorbidities, the lack of driver genes makes it nearly impossible for these patients to benefit from targeted therapy. However, the exploration of targeted therapy for lung squamous cell carcinoma has never stopped. Several new drugs including fibroblast growth factor receptor tyrosine kinase inhibitor and cyclin dependent kinase 4 and 6 inhibitors have been studied in multiple phase I studies specifically in patients with lung squamous cell carcinoma. However, with the development of immunotherapy, the characteristics such as complex gene mutation and high tumor mutation burden makes it possible for patients with squamous cell lung cancer to benefit from immunotherapy combined with chemotherapy. This review will provide an overview of the treatment progress in advanced squamous cell lung cancer including chemotherapy, targeted therapy and immunotherapy.
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Affiliation(s)
- Ming Gao
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou 510515, China.,Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou 510080, China
| | - Qing Zhou
- Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou 510080, China
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Gao X, Zhu J, Chen L, Jiang Y, Zhou X, Shuai J, Zhao Y. Clinical And Imageological Features Of Lung Squamous Cell Carcinoma With EGFR Mutations. Cancer Manag Res 2019; 11:9017-9024. [PMID: 31695493 PMCID: PMC6814869 DOI: 10.2147/cmar.s223021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 09/18/2019] [Indexed: 01/03/2023] Open
Abstract
Purpose To analyze the distribution of epidermal growth factor receptor (EGFR) mutations; characterize the clinical and imageological features of lung squamous cell carcinoma (LSCC) in a large population of patients; and assess correlations between clinical and imageological characteristics and clinical outcomes of LSCC patients harboring EGFR mutations. Patients and methods Three pathologists retrospectively evaluated the morphological and immunohistochemical data of 2,322 patients with LSCC resected between February 2013 and December 2017. Data on the distribution of EGFR mutations and the clinical and imageological characteristics of the patients were retrospectively collected. Correlations between the EGFR mutation status and clinical outcomes were evaluated using univariate and multivariate analyses. Results EGFR mutations were found in 3.4% of patients with LSCC and predominantly in female and non-smoking patients. Tumor lesions in patients with EGFR-positive mutations were more irregularly shaped than those in patients with EGFR-negative mutations (P = 0.045). In non-smoking patients with LSCC, the proportion of marked spiculation was significantly higher in the EGFR-positive group than in the EGFR-negative group (P = 0.043). No significant difference in recurrence-free survival was noted between LSCC patients harboring EGFR-positive and those harboring EGFR-negative mutations. No difference in metastases was observed between the EGFR-positive and EGFR-negative cohorts. Conclusion Female gender, non-smoking habit, irregularly shaped tumor, and marked spiculation might predict the presence of EGFR mutations in LSCC. The administration of tyrosine kinase inhibitors to patients with LSCC after screening for EGFR mutations based on their clinical and imageological features would likely result in a population with a greater sensitivity to afatinib.
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Affiliation(s)
- Xuejuan Gao
- Department of Physics, Xiamen University, Xiamen, People's Republic of China
| | - Junjie Zhu
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, People's Republic of China
| | - Linsong Chen
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, People's Republic of China
| | - Yan Jiang
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, People's Republic of China
| | - Xiao Zhou
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, People's Republic of China
| | - Jianwei Shuai
- Department of Physics, Xiamen University, Xiamen, People's Republic of China.,State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, Xiamen University, Xiamen, People's Republic of China
| | - Yanfeng Zhao
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital Affiliated to Tongji University, Shanghai, People's Republic of China
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19
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Mas A, Alonso R, Garrido-Gómez T, Escorcia P, Montero B, Jiménez-Almazán J, Martín J, Pellicer N, Monleón J, Simón C. The differential diagnoses of uterine leiomyomas and leiomyosarcomas using DNA and RNA sequencing. Am J Obstet Gynecol 2019; 221:320.e1-320.e23. [PMID: 31121144 DOI: 10.1016/j.ajog.2019.05.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 05/10/2019] [Accepted: 05/14/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND Although uterine leiomyomas and leiomyosarcomas are considered biologically unrelated tumors, they share morphologic and histologic characteristics that complicate their differential diagnosis. The long-term therapeutic option for leiomyoma is laparoscopic myomectomy with morcellation, particularly for patients who wish to preserve their fertility. However, because of the potential dissemination of undiagnosed or hidden leiomyosarcoma from morcellation, there is a need to develop a preoperative assessment of malignancy risk. OBJECTIVE Through an integrated comparative genomic and transcriptomic analysis, we aim to identify differential genetic targets in leiomyomas vs leiomyosarcomas using next-generation sequencing as the first step toward preoperative differential diagnosis. STUDY DESIGN Targeted sequencing of DNA and RNA coding regions for solid tumor-associated genes was performed on formalin-fixed paraffin-embedded samples from 13 leiomyomas and 13 leiomyosarcoma cases. DNA sequencing was used to identify copy number variations, single-nucleotide variants, and small insertions/deletions. RNA sequencing was used to identify gene fusions, splice variants, and/or differential gene expression profiles. RESULTS In leiomyosarcomas, tumor mutation burden was higher in terms of copy number variations, single nucleotide variants, small insertions/deletions, and gene fusions compared with leiomyomas. For copy number variations, 20 genes were affected by deletions in leiomyosarcomas, compared with 6 observed losses in leiomyomas. Gains (duplications) were identified in 19 genes in leiomyosarcomas, but only 3 genes in leiomyomas. The most common mutations (single-nucleotide variants and insertions/deletions) for leiomyosarcomas were identified in 105 genes of all analyzed leiomyosarcomas; 82 genes were affected in leiomyomas. Of note, 1 tumor previously diagnosed as leiomyosarcoma was established as inflammatory myofibroblastic tumor along this study with a novel ALK-TNS1 fusion. Finally, a differential transcriptomic profile was observed for 11 of 55 genes analyzed in leiomyosarcomas; 8.5% of initially diagnosed leiomyosarcomas showed high-confidence, novel gene fusions that were associated with these tumors. CONCLUSION Through integrated comparative genomic and transcriptomic analyses, we identified novel differential genetic targets that potentially differentiate leiomyosarcomas and leiomyomas. This provides a new insight into the differential diagnosis of these myometrial tumors.
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20
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Yang X, Peng P, Zhang L. Multiline treatment of advanced squamous cell carcinoma of the lung: A case report and review of the literature. World J Clin Cases 2019; 7:1899-1907. [PMID: 31417937 PMCID: PMC6692274 DOI: 10.12998/wjcc.v7.i14.1899] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 05/10/2019] [Accepted: 05/23/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Squamous cell carcinoma (SCC) is one the most common subtypes of non-small cell lung cancer, yet the treatment options for it remain limited. Here, we report a case of advanced SCC and review the related literature focusing on the multiline therapy method.
CASE SUMMARY We report the case of a 45-year-old man with advanced SCC who was deemed inoperable at the time of advanced SCC diagnosis. The patient had been referred to our hospital in April 2013 with complaints of a stuffy feeling in the chest, dyspnea, and pain in the right shoulder lasting for 1 mo. Physical examination found no obvious abnormalities, except for lower breath sound in the right lower lung. Laboratory data were within normal limits. Immunohistochemistry analysis of the tumor tissue showed CK5/6 (+), p63 (+), CD56 (+), and Ki-67 (+, approximately 30%), and genetic testing detected no EGFR mutation. He received a multiline treatment that included chemotherapy, radiotherapy, targeted therapy, and antiangiogenic therapy. After more than 5-year comprehensive treatment, the patient remains alive.
CONCLUSION This typical case highlights the importance of appropriate multiline therapy for those patients with advanced SCC.
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Affiliation(s)
- Xin Yang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Ping Peng
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Li Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
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21
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Jiang W, Ji M. Receptor tyrosine kinases in PI3K signaling: The therapeutic targets in cancer. Semin Cancer Biol 2019; 59:3-22. [PMID: 30943434 DOI: 10.1016/j.semcancer.2019.03.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 03/09/2019] [Accepted: 03/28/2019] [Indexed: 12/17/2022]
Abstract
The phosphoinositide 3-kinase (PI3K) pathway, one of the most commonly activated signaling pathways in human cancers, plays a crucial role in the regulation of cell proliferation, differentiation, and survival. This pathway is usually activated by receptor tyrosine kinases (RTKs), whose constitutive and aberrant activation is via gain-of-function mutations, chromosomal rearrangement, gene amplification and autocrine. Blockage of PI3K pathway by targeted therapy on RTKs with tyrosine kinases inhibitors (TKIs) and monoclonal antibodies (mAbs) has achieved great progress in past decades; however, there still remain big challenges during their clinical application. In this review, we provide an overview about the most frequently encountered alterations in RTKs and focus on current therapeutic agents developed to counteract their aberrant functions, accompanied with discussions of two major challenges to the RTKs-targeted therapy in cancer - resistance and toxicity.
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Affiliation(s)
- Wei Jiang
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Meiju Ji
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
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22
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Wang H, Sun L, Sang Y, Yang X, Tian G, Wang Z, Fang J, Sun W, Zhou L, Jia L, Tsao MS, Shi H, Lin D. A study of ALK-positive pulmonary squamous-cell carcinoma: From diagnostic methodologies to clinical efficacy. Lung Cancer 2019; 130:135-142. [PMID: 30885334 DOI: 10.1016/j.lungcan.2019.02.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 02/03/2019] [Accepted: 02/16/2019] [Indexed: 11/16/2022]
Abstract
BACKGROUND High concordance has been observed between Ventana D5F3 ALK immunohistochemistry (IHC) and fluorescence in-situ hybridization (FISH) in lung adenocarcinoma (LADC). However, whether a similar conclusion can be applied to lung squamous-cell carcinoma (LSCC) has remained unclear. We therefore evaluated the ALK (anaplastic lymphoma kinase) status and the therapeutic effect of an ALK tyrosine kinase inhibitor (TKI) in IHC- or FISH-positive LSCC. MATERIALS AND METHODS A total of 2403 LSCC patients from three institutions were screened for ALK aberration by IHC. All IHC-positive cases were subjected to FISH (with an approximately equal number of negative cases as a control group) and next-generation sequencing (NGS). Clinical efficacy was evaluated for the patients who received TKI therapy. RESULTS In 2403 cases of LSCC, 37 cases were identified as ALK-positive by IHC. After quality control, 28 cases were succeeded by FISH (six with insufficient tissue, three with lack of signals) and 13 by NGS (24 failed due to insufficient samples or poor DNA quality); the percentage of non-diagnostic tests was 24.3% (9/37) and 64.9% (24/37), respectively. Four cases (4/2394, 0.17%) analyzed by FISH were determined as ALK-positive. For the control group (40 ALK IHC), FISH demonstrated no samples with ALK gene fusion. The concordance between ALK IHC- and ALK FISH-positive results was 14.3% (4/28). In the 13 cases studied by NGS, two cases showed ALK-EML4 fusion (consistent with two FISH-positive results), and two cases were interpreted as harboring an ALK-association gene mutation. Among four patients (two FISH-positive and two IHC-positive only cases) receiving TKI therapy, two patients had stable disease and the other two had progressive disease. CONCLUSIONS The positive concordance rate of ALK IHC and FISH in LSCC is far less than that reported for LADC. Therefore, ALK IHC detection in LSCC cannot be used as a diagnostic method for ALK rearrangement.
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Affiliation(s)
- Haiyue Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Leina Sun
- Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China
| | - Yaxiong Sang
- Oncology Business Division, Beijing Novogene Bioinformatics Technology Co., Ltd, Beijing, People's Republic of China
| | - Xin Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Guangming Tian
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic OncologyⅡ, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Ziping Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic OncologyⅠ, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Jian Fang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic OncologyⅡ, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Wei Sun
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Lixin Zhou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Ling Jia
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Ming-Sound Tsao
- University Health Network/Princess Margaret Cancer Centre and University of Toronto, Toronto, Canada
| | - Huaiyin Shi
- Pathology Department, Chinese PLA General Hospital and Chinese PLA Medical School, Beijing, People's Republic of China.
| | - Dongmei Lin
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China.
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23
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Lin L, Huang F, Chen F, He Y, Hu J, Cao X. Anaplastic lymphoma kinase (ALK)-rearranged pulmonary pleomorphic carcinoma successfully treated with crizotinib. J Int Med Res 2018; 46:3491-3497. [PMID: 29310482 PMCID: PMC6134637 DOI: 10.1177/0300060517748262] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 11/23/2017] [Indexed: 01/12/2023] Open
Abstract
Pulmonary pleomorphic carcinoma (PPC) is rare, and the response of patients to conventional chemotherapy is very poor. Here we present a patient with anaplastic lymphoma kinase (ALK)-rearranged advanced PPC treated with crizotinib. Computed tomography revealed a mass in the left upper lung of a nonsmoking 60-year-old woman. Pathological findings using resected tissue were consistent with PPC stage 1A, T1bN0M0. Although the patient received adjuvant radiotherapy, the disease relapsed, quickly progressed, and remained PPC according to analysis of biopsied tissue. Although negative for epidermal growth factor receptor mutations, ALK rearrangements were detected in adenocarcinoma and spindle-cell components. The patient received crizotinib therapy and achieved a partial response for 7 months. This case indicates that patients with PPC, particularly those with adenocarcinoma, may harbor an epithelial component with the ALK rearrangement. Although the progression-free survival of patients treated with crizotinib is limited, they may obtain more benefit compared with conventional chemotherapy.
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Affiliation(s)
- Liping Lin
- Department of Oncology, Panyu Central Hospital, Guangzhou, China
- Cancer Institute of Panyu, Guangzhou, China
- These authors contributed equally to this work
| | - Fuxi Huang
- Department of Oncology, Panyu Central Hospital, Guangzhou, China
- Cancer Institute of Panyu, Guangzhou, China
- These authors contributed equally to this work
| | - Fang Chen
- Department of Pathology, Panyu Central Hospital, Guangzhou, China
- Cancer Institute of Panyu, Guangzhou, China
- These authors contributed equally to this work
| | - Yan He
- Department of Oncology, Panyu Central Hospital, Guangzhou, China
- Cancer Institute of Panyu, Guangzhou, China
| | - Jiazhu Hu
- Department of Oncology, Panyu Central Hospital, Guangzhou, China
- Cancer Institute of Panyu, Guangzhou, China
| | - Xiaolong Cao
- Department of Oncology, Panyu Central Hospital, Guangzhou, China
- Cancer Institute of Panyu, Guangzhou, China
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24
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Watanabe J, Togo S, Sumiyoshi I, Namba Y, Suina K, Mizuno T, Kadoya K, Motomura H, Iwai M, Nagaoka T, Sasaki S, Hayashi T, Uekusa T, Abe K, Urata Y, Sakurai F, Mizuguchi H, Kato S, Takahashi K. Clinical features of squamous cell lung cancer with anaplastic lymphoma kinase (ALK)-rearrangement: a retrospective analysis and review. Oncotarget 2018; 9:24000-24013. [PMID: 29844868 PMCID: PMC5963613 DOI: 10.18632/oncotarget.25257] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 04/06/2018] [Indexed: 12/20/2022] Open
Abstract
Anti-anaplastic lymphoma kinase (ALK)-targeted therapy dramatically improves therapeutic responses in patients with ALK-rearranged lung adenocarcinoma (Ad-LC). A few cases of squamous cell lung carcinoma (Sq-LC) with ALK rearrangement have been reported; however, the clinicopathological features and clinical outcomes following treatment with ALK inhibitors are unknown. We addressed this in the present study by retrospectively comparing the clinical characteristics of five patients with ALK-rearranged Sq-LC with those of patients with ALK-rearranged Ad-LC and by evaluating representative cases of ALK inhibitor responders and non-responders. The prevalence of ALK rearrangement in Sq-LCs was 1.36%. Progression-free survival (PFS) after initial treatment with crizotinib was significantly shorter in Sq-LC than in Ad-LC with ALK rearrangement (p = 0.033). Two ALK rearrangements assayed by fluorescence in situ hybridization (FISH)-positive/immunohistochemistry-negative cases did not respond to crizotinb, and PFS decreased following alectinib treatment of ALK-rearranged Sq-LC (p = 0.045). A rebiopsy revealed that responders to ceritinib harbored the L1196M mutation, which causes resistance to other ALK inhibitors. However, non-responders were resistant to all ALK inhibitors, despite the presence of ALK rearrangement in FISH-positive circulating tumor cells and circulating free DNA and absence of the ALK inhibitor resistance mutation. These results indicate that ALK inhibitors remain a reasonable therapeutic option for ALK-rearranged Sq-LC patients who have worse outcomes than ALK-rearranged Ad-LC patients and that resistance mechanisms are heterogeneous. Additionally, oncologists should be aware of the possibility of ALK-rearranged Sq-LC based on clinicopathological features, and plan second-line therapeutic strategies based on rebiopsy results in order to improve patient outcome.
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Affiliation(s)
- Junko Watanabe
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Tokyo 113-8431, Japan.,Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo 113-8431, Japan
| | - Shinsaku Togo
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Tokyo 113-8431, Japan.,Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo 113-8431, Japan
| | - Issei Sumiyoshi
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Tokyo 113-8431, Japan
| | - Yukiko Namba
- Department of Respiratory Medicine, Juntendo University Urayasu Hospital, Chiba 279-0001, Japan
| | - Kentaro Suina
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Tokyo 113-8431, Japan
| | - Takafumi Mizuno
- Junior Resident of Juntendo University Hospital, Tokyo 113-8431, Japan
| | - Kotaro Kadoya
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Tokyo 113-8431, Japan
| | - Hiroaki Motomura
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Tokyo 113-8431, Japan
| | - Moe Iwai
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Tokyo 113-8431, Japan.,Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo 113-8431, Japan.,Department of Pharmacy, Juntendo University School of Medicine, Tokyo 113-8431, Japan
| | - Tetsutaro Nagaoka
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Tokyo 113-8431, Japan.,Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo 113-8431, Japan
| | - Shinichi Sasaki
- Department of Respiratory Medicine, Juntendo University Urayasu Hospital, Chiba 279-0001, Japan
| | - Takuo Hayashi
- Department of Pathology, Juntendo University School of Medicine, Tokyo 113-8431, Japan
| | - Toshimasa Uekusa
- Department of Pathology, Labor Health and Welfare Organization Kanto Rosai Hospital, Kanagawa 211-8510, Japan
| | - Kanae Abe
- Oncolys BioPharma, Inc, Minato-ku, Tokyo 105-0001 Japan
| | - Yasuo Urata
- Oncolys BioPharma, Inc, Minato-ku, Tokyo 105-0001 Japan
| | - Fuminori Sakurai
- Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
| | - Hiroyuki Mizuguchi
- Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
| | - Shunsuke Kato
- Department of Medical Oncology, Juntendo University School of Medicine, Tokyo 113-8431, Japan
| | - Kazuhisa Takahashi
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Tokyo 113-8431, Japan.,Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Tokyo 113-8431, Japan
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25
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Itchins M, Hayes SA, Gill AJ, Cooper W, O'Connell R, Howell VM, Clarke SJ, Pavlakis N. Pattern of care and survival of anaplastic lymphoma kinase rearranged non-small cell lung cancer (ALK+ NSCLC) in an Australian Metropolitan Tertiary Referral Centre: A retrospective cohort analysis. Asia Pac J Clin Oncol 2018; 14:e275-e282. [PMID: 29675948 DOI: 10.1111/ajco.12877] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Accepted: 03/18/2018] [Indexed: 12/24/2022]
Abstract
AIM To report on the pattern of care and survival of anaplastic lymphoma kinase rearranged non-small cell lung cancer (ALK+NSCLC) in a real-world retrospective cohort from an Australian tertiary referral center. METHODS Individuals with a pathological diagnosis of ALK+NSCLC via immunohistochemistry and fluorescence in situ hybridization and a radiological diagnosis of stage IV disease were eligible. Patients were identified via the Pathology Department specimen database and electronic patient chart review. Data were collected and analyzed for baseline demographics, radiological pattern of disease and response to treatment, treatment sequencing, toxicity and survival. RESULTS Thirty-five patients were identified over a 7-year period from 2010 to 2016 and followed for a median of 23 months. Median overall survival (OS) in the entire cohort was immature at data cut, 46.0 months (95% confidence interval [CI], 22.53-69.47 months), with the longest surviving patient was alive 62.1 months since diagnosis. Objective radiological response rate overall across six potential treatments and six treatment lines (range 1-6) was 58.2%. Almost 50% received at-least two lines of ALK inhibitor therapy with median OS in this group estimated to be 53.4 months (95% CI, 35.1 months-not reached). Toxicity was manageable with a low rate of ≥ grade 3 toxicity (n = 7). Forty-eight percent relapsed within the CNS and 43% overall died due to CNS progression. In those with CNS diagnosis at baseline and/or progression within the CNS (n = 32), median OS was also 46.0 months (95% CI, 24.22-66.78 months). CONCLUSION This retrospective cohort analysis of a single tertiary institution experience in treating ALK+NSCLC demonstrates impressive OS and the importance and impact of careful management of CNS disease in this patient population.
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Affiliation(s)
- Malinda Itchins
- Sydney Medical School, Northern Clinical School, University of Sydney, Sydney, NSW, Australia.,Bill Walsh Translational Research Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, Australia.,Northern Cancer Institute, St Leonards Sydney, NSW, Australia
| | - Sarah A Hayes
- Sydney Medical School, Northern Clinical School, University of Sydney, Sydney, NSW, Australia.,Bill Walsh Translational Research Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Anthony J Gill
- Sydney Medical School, Northern Clinical School, University of Sydney, Sydney, NSW, Australia.,Cancer Diagnosis and Pathology Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, Australia.,NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Wendy Cooper
- Sydney Medical School, Northern Clinical School, University of Sydney, Sydney, NSW, Australia.,Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.,School of Medicine, Western Sydney University, Sydney, NSW, Australia
| | - Rachel O'Connell
- NHMRC Clinical Trial Centre, University of Sydney, Camperdown, NSW, Australia
| | - Viive M Howell
- Sydney Medical School, Northern Clinical School, University of Sydney, Sydney, NSW, Australia.,Bill Walsh Translational Research Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Stephen J Clarke
- Sydney Medical School, Northern Clinical School, University of Sydney, Sydney, NSW, Australia.,Bill Walsh Translational Research Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, Australia.,Northern Cancer Institute, St Leonards Sydney, NSW, Australia.,Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Nick Pavlakis
- Sydney Medical School, Northern Clinical School, University of Sydney, Sydney, NSW, Australia.,Bill Walsh Translational Research Laboratory, Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards, NSW, Australia.,Northern Cancer Institute, St Leonards Sydney, NSW, Australia.,Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW, Australia
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26
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Huang T, Engelmann BJ, Morgan RM, Absher KJ, Kolesar JM, Villano JL. EML4-ALK rearrangement in squamous cell carcinoma shows significant response to anti-ALK inhibitor drugs crizotinib and alectinib. Cancer Chemother Pharmacol 2018; 81:965-968. [PMID: 29610932 DOI: 10.1007/s00280-018-3571-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 03/24/2018] [Indexed: 11/28/2022]
Abstract
EML4-ALK alterations are more common in adenocarcinomas and are rarely found in squamous cell histology. In documented cases, the majority of EML4-ALK translocations are identified in squamous cell histology and occur in patients with no or light smoking history. We report an EML4-ALK4 translocation in a 50-year-old patient with squamous cell carcinoma and an 18 pack-year smoking history. The patient had a near complete response in the CNS to alectinib treatment. Our observation suggests that EML4-ALK genomic testing may be clinically useful in patients with heavy smoking history.
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Affiliation(s)
- Thomas Huang
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | | | - Rachael M Morgan
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA.,College of Pharmacy, University of Kentucky, Lexington, KY, USA
| | - Kimberly J Absher
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA.,Department of Pathology, University of Kentucky, Lexington, KY, USA
| | - Jill M Kolesar
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA.,College of Pharmacy, University of Kentucky, Lexington, KY, USA
| | - John L Villano
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA. .,Department of Medicine, University of Kentucky, Lexington, KY, USA. .,Department of Neurology, University of Kentucky, Lexington, KY, USA. .,Department of Neurosurgery, University of Kentucky, Lexington, KY, USA.
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27
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Hirsch FR, Kerr KM, Bunn PA, Kim ES, Obasaju C, Pérol M, Bonomi P, Bradley JD, Gandara D, Jett JR, Langer CJ, Natale RB, Novello S, Paz-Ares L, Ramalingam SS, Reck M, Reynolds CH, Smit EF, Socinski MA, Spigel DR, Stinchcombe TE, Vansteenkiste JF, Wakelee H, Thatcher N. Molecular and Immune Biomarker Testing in Squamous-Cell Lung Cancer: Effect of Current and Future Therapies and Technologies. Clin Lung Cancer 2018; 19:331-339. [PMID: 29773328 DOI: 10.1016/j.cllc.2018.03.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 03/12/2018] [Accepted: 03/13/2018] [Indexed: 12/18/2022]
Abstract
Patients with non-small-cell lung cancer, including squamous-cell lung cancer (SqCLC), typically present at an advanced stage. The current treatment landscape, which includes chemotherapy, radiotherapy, surgery, immunotherapy, and targeted agents, is rapidly evolving, including for patients with SqCLC. Prompt molecular and immune biomarker testing can serve to guide optimal treatment choices, and immune biomarker testing is becoming more important for this patient population. In this review we provide an overview of current and emerging practices and technologies for molecular and immune biomarker testing in advanced non-small-cell lung cancer, with a focus on SqCLC.
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Affiliation(s)
- Fred R Hirsch
- Division of Medical Oncology, University of Colorado Cancer Center, Aurora, CO.
| | - Keith M Kerr
- Department of Pathology, University of Aberdeen School of Medicine and Aberdeen Royal Infirmary, Aberdeen, Scotland
| | - Paul A Bunn
- Division of Medical Oncology, University of Colorado Cancer Center, Aurora, CO
| | - Edward S Kim
- Levine Cancer Institute, Atrium Health, Charlotte, NC
| | | | - Maurice Pérol
- Department of Medical Oncology, Centre Léon Bérard, Lyon, France
| | - Philip Bonomi
- Department of Hematology and Oncology, Rush University Medical Center, Chicago, IL
| | - Jeffrey D Bradley
- Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO
| | - David Gandara
- Department of Hematology and Oncology, UC Davis Comprehensive Cancer Center, Sacramento, CA
| | - James R Jett
- Department of Oncology, formerly of National Jewish Health, Denver, CO
| | - Corey J Langer
- Department of Thoracic Oncology, University of Pennsylvania Abramson Cancer Center, Philadelphia, PA
| | - Ronald B Natale
- Cedars-Sinai Comprehensive Cancer Center, West Hollywood, CA
| | - Silvia Novello
- Department of Oncology, University of Turin, Turin, Italy
| | - Luis Paz-Ares
- Department of Medical Oncology, Hospital Universitario Doce de Octubre, Universidad Complutense, CIBERONC and CNIO, Madrid, Spain
| | - Suresh S Ramalingam
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
| | - Martin Reck
- Lung Clinic Grosshansdorf, Airway Research Center North, Member of the German Center for Lung Research, Grosshansdorf, Germany
| | | | - Egbert F Smit
- Department of Pulmonary Diseases, VU University Medical Center, Amsterdam, The Netherlands
| | | | | | | | - Johan F Vansteenkiste
- Respiratory Oncology Unit, Department of Respiratory Medicine, University Hospital KU Leuven, Leuven, Belgium
| | - Heather Wakelee
- Department of Medicine (Oncology), Stanford Cancer Institute and Stanford University School of Medicine, Stanford, CA
| | - Nick Thatcher
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
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Socinski MA, Obasaju C, Gandara D, Hirsch FR, Bonomi P, Bunn PA, Kim ES, Langer CJ, Natale RB, Novello S, Paz-Ares L, Pérol M, Reck M, Ramalingam SS, Reynolds CH, Spigel DR, Wakelee H, Thatcher N. Current and Emergent Therapy Options for Advanced Squamous Cell Lung Cancer. J Thorac Oncol 2018; 13:165-183. [DOI: 10.1016/j.jtho.2017.11.111] [Citation(s) in RCA: 145] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 11/06/2017] [Accepted: 11/09/2017] [Indexed: 12/14/2022]
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Addeo A, Tabbò F, Robinson T, Buffoni L, Novello S. Precision medicine in ALK rearranged NSCLC: A rapidly evolving scenario. Crit Rev Oncol Hematol 2017; 122:150-156. [PMID: 29458783 DOI: 10.1016/j.critrevonc.2017.12.015] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/18/2017] [Accepted: 12/20/2017] [Indexed: 12/12/2022] Open
Abstract
IMPORTANCE The identification of anaplastic lymphoma kinase (ALK) rearrangements in 2-5% of non-small cell lung cancer (NSCLC) patients led to the rapid clinical development of its oral tyrosine kinase inhibitor (TKI). Crizotinib was the first ALK inhibitor approved and utilised in the treatment of ALK+ NSCLC patients in the second line setting first and subsequently in the first line one. Since then many other ALK inhibitors have been developed (ceritinib, alectinib, brigatinib, lorlatinib,etc) and the treatment paradigm of these patients has considerably drifted. The questions regarding their treatment at progression remains unanswered at the moment. OBJECTIVE Our review clarifies what it is the state of the art in the treatment of ALK rearranged NSCLC patients, highlights the mechanisms of primary and secondary resistance mutations and suggests a treatment algorithm based on specific primary resistance or acquired mutations. EVIDENCE REVIEW Studies that enrolled ALK+ NSCLC patients with locally advance or metastatic disease receiving treatment with ALK inhibitor, first or second line, were identified using electronic databases (MEDLINE, EMBASE, and Cochrane library). Trials were excluded if they were phase 1, enrolled less than 10 patients. FINDING Overall 1942 patients were included in our review. It confirms the role and the efficacy in first line of Alectinib but it highlights also that all the ALK inhibitors could play a crucial role during the patients' journey. Identifying the different mutations and utilising the most active ALK inhibitor depending on the "up-to-date" driven mutation is the way forward in the management of those patients. CONCLUSIONS AND RELEVANCE the review shows the rapid drifting in the management of ALK+ NSCLC patients and the importance of fully understanding and acknowledging the role of the resistance mutation, primary or acquired. We strongly advocate a comprehensive genomic approach in the management of ALK+ NSCLC patients who develop resistance mutations that are still targetable by a different ALK inhibitor.
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Affiliation(s)
- Alfredo Addeo
- Oncology Department, University Hospital Geneva, Rue Gabrielle-Perret-Gentil 4, Geneva, CH, Switzerland.
| | - Fabrizio Tabbò
- Oncology Department, San Luigi Hospital University of Turin, Orbassano, Turin, Italy
| | - Tim Robinson
- Oncology Department, Bristol University Hospital Trust, Horfield Road, Bristol, UK
| | - Lucio Buffoni
- Oncology Department, San Luigi Hospital University of Turin, Orbassano, Turin, Italy
| | - Silvia Novello
- Oncology Department, San Luigi Hospital University of Turin, Orbassano, Turin, Italy
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Clinicopathologic Features of Advanced Squamous NSCLC. J Thorac Oncol 2016; 11:1411-22. [PMID: 27296106 DOI: 10.1016/j.jtho.2016.05.024] [Citation(s) in RCA: 108] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 05/19/2016] [Accepted: 05/19/2016] [Indexed: 12/31/2022]
Abstract
Lung cancer remains the leading cause of cancer-related death worldwide. NSCLC accounts for more than 85% of all lung cancers, and the prognosis for advanced-stage disease is typically poor. In recent years, the importance of histologic subtypes of NSCLC has been recognized, and the distinction between squamous and other NSCLC histologic subtypes is now critical to patient management. Squamous cell lung cancer (sqCLC) represents approximately 25% to 30% of NSCLC. The prognosis for patients with advanced NSCLC is poorer for those with sqCLC than for those with adenocarcinoma. This is partly due to a number of clinical characteristics that distinguish sqCLC from other NSCLC histologic subtypes, such as smoking history, comorbid diseases, age, and molecular profile. Together, these factors make sqCLC an especially challenging disease to manage. Herein, we review some of the key clinicopathologic features of sqCLC. Understanding these features to optimally address many of the unique therapeutic challenges of this disease is likely to be central to ultimately improving outcomes for patients with squamous NSCLC.
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Yamamoto Y, Kodama K, Maniwa T, Takeda M, Kishima H. Anaplastic lymphoma kinase-positive squamous cell carcinoma of the lung: A case report. Mol Clin Oncol 2016; 5:61-63. [PMID: 27330767 DOI: 10.3892/mco.2016.878] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2016] [Accepted: 04/08/2016] [Indexed: 12/27/2022] Open
Abstract
It is widely known that echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) rearrangement mostly occurs in the adenocarcinoma subtype of non-small-cell lung cancer (NSCLC). Patients with squamous cell carcinoma harboring the ALK rearrangement are extremely rare. This is a case report of a squamous cell carcinoma patient with EML4-ALK rearrangement. An elderly man with a heavy smoking history presented with a mass lesion in the right main bronchus. Bronchoscopic biopsy of the tumor confirmed a diagnosis of squamous cell carcinoma, and it was proven to harbor ALK rearrangement, based on fluorescence in situ hybridization, but not epidermal growth factor receptor mutations. The patient underwent radiation therapy, with a markedly favorable response. ALK-targeted treatment may be a viable option if disease progression occurs in such a case in the future.
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Affiliation(s)
- Yoko Yamamoto
- Department of Thoracic Surgery, Yao Municipal Hospital, Yao, Osaka 581-0069, Japan
| | - Ken Kodama
- Department of Thoracic Surgery, Yao Municipal Hospital, Yao, Osaka 581-0069, Japan
| | - Tomohiro Maniwa
- Department of Thoracic Surgery, Yao Municipal Hospital, Yao, Osaka 581-0069, Japan
| | - Masashi Takeda
- Department of Pathology, Yao Municipal Hospital, Yao, Osaka 581-0069, Japan
| | - Hiroki Kishima
- Department of Surgery, Kishima Hospital Main Division, Yao, Osaka 581-0069, Japan
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Zhao W, Choi YL, Song JY, Zhu Y, Xu Q, Zhang F, Jiang L, Cheng J, Zheng G, Mao M. ALK, ROS1 and RET rearrangements in lung squamous cell carcinoma are very rare. Lung Cancer 2016; 94:22-7. [DOI: 10.1016/j.lungcan.2016.01.011] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 01/14/2016] [Accepted: 01/18/2016] [Indexed: 01/11/2023]
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Koutsoukos K, Mountzios G. Novel therapies for advanced squamous cell carcinoma of the lung. Future Oncol 2016; 12:659-67. [PMID: 26880383 DOI: 10.2217/fon.15.358] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Advanced squamous non-small-cell lung carcinoma (SqCC) has traditionally been considered the 'neglected sibling' compared with lung adenocarcinoma due to lack of effective targeted treatment options. Currently, limited progress has been made in the systemic treatment of advanced disease and combination chemotherapy remains the gold standard. However, the recent completion of the molecular characterization of SqCC revealed an interestingly complex genomic profile, comprising various genetic alterations that can potentially function as molecular targets for the development of novel targeted agents. Recent encouraging results of the use of immune checkpoint inhibitors in several neoplasms has emerged as a promising novel treatment option for advanced SqCC. Future personalized studies, enrolling SqCC patients according to specific driving mutations are underway.
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Affiliation(s)
- Konstantinos Koutsoukos
- Medical Oncology Department, Alexandra Hospital, University of Athens School of Medicine, Athens, Greece
| | - Giannis Mountzios
- Department of Medical Oncology, 251 Airforce General Hospital, 115 25, Athens, Greece
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Plönes T, Engel-Riedel W, Stoelben E, Limmroth C, Schildgen O, Schildgen V. Molecular Pathology and Personalized Medicine: The Dawn of a New Era in Companion Diagnostics-Practical Considerations about Companion Diagnostics for Non-Small-Cell-Lung-Cancer. J Pers Med 2016; 6:jpm6010003. [PMID: 26784235 PMCID: PMC4810382 DOI: 10.3390/jpm6010003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 01/12/2016] [Accepted: 01/13/2016] [Indexed: 01/04/2023] Open
Abstract
Companion diagnostics (CDx) have become a major tool in molecular pathology and assist in therapy decisions in an increasing number of various cancers. Particularly, the developments in lung cancer have been most impressing in the last decade and consequently lung cancer mutation testing and molecular profiling has become a major business of diagnostic laboratories. However, it has become difficult to decide which biomarkers are currently relevant for therapy decisions, as many of the new biomarkers are not yet approved as therapy targets, remain in the status of clinical studies, or still have not left the experimental phase. The current review is focussed on those markers that do have current therapy implications, practical implications arising from the respective companion diagnostics, and thus is focused on daily practice.
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Affiliation(s)
- Till Plönes
- Lungclinic Merheim, Department of Thoracic Surgery, Lung Clinic Cologne, Kliniken der Stadt Köln gGmbH, Cologne Merheim Hospital, Faculty of Health/School of Medicine, Witten/Herdecke, Ostmerheimerstrasse 200, 51109 Köln, Germany.
| | - Walburga Engel-Riedel
- Lungclinic Merheim, Department of Thoracic Surgery, Lung Clinic Cologne, Kliniken der Stadt Köln gGmbH, Cologne Merheim Hospital, Faculty of Health/School of Medicine, Witten/Herdecke, Ostmerheimerstrasse 200, 51109 Köln, Germany.
| | - Erich Stoelben
- Lungclinic Merheim, Department of Thoracic Surgery, Lung Clinic Cologne, Kliniken der Stadt Köln gGmbH, Cologne Merheim Hospital, Faculty of Health/School of Medicine, Witten/Herdecke, Ostmerheimerstrasse 200, 51109 Köln, Germany.
| | - Christina Limmroth
- Clinics for Internal Medicine Holweide, Hospital of Cologne, Neufelder Str. 34, 51067 Köln, Germany.
| | - Oliver Schildgen
- Institute for Pathology, Hospital of Cologne, Private University Witten/Herdecke, Ostmerheimerstrasse 200, 51109 Köln, Germany.
| | - Verena Schildgen
- Institute for Pathology, Hospital of Cologne, Private University Witten/Herdecke, Ostmerheimerstrasse 200, 51109 Köln, Germany.
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Chan ELY, Chin CHY, Lui VWY. An update of ALK inhibitors in human clinical trials. Future Oncol 2016; 12:71-81. [DOI: 10.2217/fon.15.293] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The proto-oncogenic ALK is a druggable receptor tyrosine kinase for cancer treatment. Two small molecule inhibitors of ALK, crizotinib and ceritinib, have been recently approved for the treatment of metastatic non-small-cell lung cancer, with marked improvement of progression-free survival of patients. Independent case reports also indicate their potential therapeutic activity in other ALK-rearranged cancers. Numerous single-agent and combination therapy trials are ongoing in lung and many other cancers. Results of these trials are greatly anticipated. Here, we summarize our current understanding of ALK signaling, genomic aberrations in cancer and emerging mechanisms of drug resistance. We will also provide a timely review on all ALK inhibitors and their current status of development in clinical settings.
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Affiliation(s)
- Eason Leong Yin Chan
- Pharmacogenomics & Precision Therapeutics Laboratory, Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Claudia Ho Yi Chin
- Pharmacogenomics & Precision Therapeutics Laboratory, Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
| | - Vivian Wai Yan Lui
- Pharmacogenomics & Precision Therapeutics Laboratory, Department of Pharmacology & Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR
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36
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Vergne F, Quéré G, Andrieu-Key S, Descourt R, Quintin-Roué I, Talagas M, De Braekeleer M, Marcorelles P, Uguen A. ALK-rearranged squamous cell lung carcinoma responding to crizotinib: A missing link in the field of non-small cell lung cancer? Lung Cancer 2015; 91:67-9. [PMID: 26603857 DOI: 10.1016/j.lungcan.2015.11.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 09/24/2015] [Accepted: 11/05/2015] [Indexed: 02/07/2023]
Abstract
ALK-rearrangements are mainly encountered in lung adenocarcinomas and allow treating patients with anti-ALK targeted therapy. ALK-rearranged squamous cell lung carcinomas are rare tumors that can also respond to anti-ALK-targeted therapy. Nevertheless, ALK screening is not always performed in patients with squamous cell lung carcinomas making the identification and treatment of this molecular tumor subtype challenging. We intend to report a rare case of ALK-rearranged lung squamous cell carcinoma with response to crizotinib therapy. We report clinical, pathological, immunohistochemical and fluorescent in situ hybridization data concerning a patient having an ALK-rearranged squamous cell lung cancer diagnosed in our institution. The patient was a 58-year old woman with a metastatic-stage lung cancer. Histopathological and immunohistochemical analyses were performed on a bronchial biopsy sample and concluded in a non-keratinizing squamous cell lung carcinoma expressing strongly cytokeratin 5/6, p63 and p40, which are classic hallmarks of lung squamous cell carcinomas, but also cytokeratin 7 which is more commonly expressed in lung adenocarcinomas. The tumor did not express thyroid transcription factor-1. ALK rearrangement was searched because of the never-smoker status of the patient and resulted in strong positive fluorescent in situ hybridization test and ALK/p80 immunohistochemistry. The patient responded to crizotinib therapy during 213 days. Our observation points out the interest of considering ALK screening in patients with metastatic lung squamous cell carcinomas, especially in patients lacking a usual heavy-smoker clinical history. The histopathological and immunohistochemical features of this particular tumor highlighting the overlapping criteria between lung adenocarcinomas and rare ALK-rearranged squamous cell lung carcinomas could also be relevant to extend ALK screening to tumors with intermediate phenotypes between squamous cell carcinomas and adenocarcinomas and/or arising in non-smokers.
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Affiliation(s)
- Florence Vergne
- CHRU Brest, Institut de Cancérologie et Hématologie, Brest F-29220, France.
| | - Gilles Quéré
- CHRU Brest, Institut de Cancérologie et Hématologie, Brest F-29220, France.
| | - Sophie Andrieu-Key
- CHRU Brest, Service d'Anatomie et Cytologie Pathologiques, Brest F-29220, France.
| | - Renaud Descourt
- CHRU Brest, Institut de Cancérologie et Hématologie, Brest F-29220, France.
| | | | - Matthieu Talagas
- CHRU Brest, Service d'Anatomie et Cytologie Pathologiques, Brest F-29220, France; Université Européenne de Bretagne, France; Faculté de Médecine et des Sciences de la Santé Université de Brest, EA4685, Brest F-29200, France.
| | - Marc De Braekeleer
- Université Européenne de Bretagne, France; CHRU Brest, Laboratoire de Cytogénétique et Biologie de la Reproduction, Brest F-29220, France; Inserm, U1078, Brest F-29200, France.
| | - Pascale Marcorelles
- CHRU Brest, Service d'Anatomie et Cytologie Pathologiques, Brest F-29220, France; Université Européenne de Bretagne, France; Faculté de Médecine et des Sciences de la Santé Université de Brest, EA4685, Brest F-29200, France.
| | - Arnaud Uguen
- CHRU Brest, Service d'Anatomie et Cytologie Pathologiques, Brest F-29220, France; Université Européenne de Bretagne, France; Inserm, U1078, Brest F-29200, France.
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Pelosi G, Fabbri A, Papotti M, Rossi G, Cavazza A, Righi L, Tamborini E, Perrone F, Settanni G, Busico A, Testi MA, Maisonneuve P, De Braud F, Garassino M, Valeri B, Sonzogni A, Pastorino U. Dissecting Pulmonary Large-Cell Carcinoma by Targeted Next Generation Sequencing of Several Cancer Genes Pushes Genotypic-Phenotypic Correlations to Emerge. J Thorac Oncol 2015; 10:1560-9. [DOI: 10.1097/jto.0000000000000658] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Takanashi Y, Tajima S, Matsuura S, Koyama S, Takahashi T, Neyatani H. ALK-rearranged squamous cell carcinoma of the lung. Respirol Case Rep 2015; 3:105-7. [PMID: 26392858 PMCID: PMC4571740 DOI: 10.1002/rcr2.115] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 05/14/2015] [Accepted: 05/18/2015] [Indexed: 12/12/2022] Open
Abstract
The fusion gene echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) is identified in approximately 5% of non-small-cell lung cancer patients. A rare case of ALK-positive squamous cell carcinoma of the lung is reported. A 60-year-old man, an ex-smoker with a 720-packs-per-year tobacco smoking history, presented with a mass lesion in the upper lobe of the left lung on chest computed tomography. Transbronchial biopsy of the mass confirmed a diagnosis of lung squamous cell carcinoma, and it was proven to have ALK rearrangement by fluorescent in situ hybridization. The patient underwent left upper lobectomy. Hematoxylin and eosin staining of the surgical specimen demonstrated the typical morphology of pure squamous cell carcinoma. The patient has been advised to attend regular check-ups for postoperative recurrence. ALK testing and subsequent ALK-targeted treatment can be a possible option in cases of postoperative recurrence.
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Affiliation(s)
- Yusuke Takanashi
- Department of Thoracic Surgery, Fujieda Municipal General Hospital Fujieda, Shizuoka, Japan
| | - Shogo Tajima
- Department of Pathology, Graduate School of Medicine, University of Tokyo Tokyo, Japan
| | - Shun Matsuura
- Department of Respiratory Medicine, Fujieda Municipal General Hospital Fujieda, Shizuoka, Japan
| | - Shin Koyama
- Department of Thoracic Surgery, Fujieda Municipal General Hospital Fujieda, Shizuoka, Japan
| | - Tsuyoshi Takahashi
- Department of Thoracic Surgery, Fujieda Municipal General Hospital Fujieda, Shizuoka, Japan
| | - Hiroshi Neyatani
- Department of Thoracic Surgery, Fujieda Municipal General Hospital Fujieda, Shizuoka, Japan
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39
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Colato C, Vicentini C, Cantara S, Pedron S, Brazzarola P, Marchetti I, Di Coscio G, Chilosi M, Brunelli M, Pacini F, Ferdeghini M. Break-apart interphase fluorescence in situ hybridization assay in papillary thyroid carcinoma: on the road to optimizing the cut-off level for RET/PTC rearrangements. Eur J Endocrinol 2015; 172:571-582. [PMID: 25698220 DOI: 10.1530/eje-14-0930] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Chromosomal rearrangements of the RET proto-oncogene is one of the most common molecular events in papillary thyroid carcinoma (PTC). However, their pathogenic role and clinical significance are still debated. This study aimed to investigate the prevalence of RET/PTC rearrangement in a cohort of BRAF WT PTCs by fluorescence in situ hybridization (FISH) and to search a reliable cut-off level in order to distinguish clonal or non-clonal RET changes. DESIGN Forty BRAF WT PTCs were analyzed by FISH for RET rearrangements. As controls, six BRAFV600E mutated PTCs, 13 follicular adenomas (FA), and ten normal thyroid parenchyma were also analyzed. METHODS We performed FISH analysis on formalin-fixed, paraffin-embedded tissue using a commercially available RET break-apart probe. A cut-off level equivalent to 10.2% of aberrant cells was accepted as significant. To validate FISH results, we analyzed the study cohort by qRT-PCR. RESULTS Split RET signals above the cut-off level were observed in 25% (10/40) of PTCs, harboring a percentage of positive cells ranging from 12 to 50%, and in one spontaneous FA (1/13, 7.7%). Overall, the data obtained by FISH matched well with qRT-PCR results. Challenging findings were observed in five cases showing a frequency of rearrangement very close to the cut-off. CONCLUSIONS FISH approach represents a powerful tool to estimate the ratio between broken and non-broken RET tumor cells. Establishing a precise FISH cut-off may be useful in the interpretation of the presence of RET rearrangement, primarily when this strategy is used for cytological evaluation or for targeted therapy.
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Affiliation(s)
- Chiara Colato
- Department of Pathology and DiagnosticsARC-NET Research CentreUniversity of Verona, Policlinico GB Rossi, Piazzale LA Scuro, 10, Piastra Odontoiatrica (II floor), 37134 Verona, ItalyDepartment of Internal MedicineEndocrinology, and Metabolism and Biochemistry, University of Siena, Siena, ItalyDepartment of Surgery and OncologyUniversity of Verona, Verona, ItalyDivision of SurgicalMolecular and Ultrastructural, Section of Cytopathology, University Hospital of Pisa, Pisa, ItalyNuclear Medicine UnitUniversity Hospital of Verona, Verona, Italy
| | - Caterina Vicentini
- Department of Pathology and DiagnosticsARC-NET Research CentreUniversity of Verona, Policlinico GB Rossi, Piazzale LA Scuro, 10, Piastra Odontoiatrica (II floor), 37134 Verona, ItalyDepartment of Internal MedicineEndocrinology, and Metabolism and Biochemistry, University of Siena, Siena, ItalyDepartment of Surgery and OncologyUniversity of Verona, Verona, ItalyDivision of SurgicalMolecular and Ultrastructural, Section of Cytopathology, University Hospital of Pisa, Pisa, ItalyNuclear Medicine UnitUniversity Hospital of Verona, Verona, Italy
| | - Silvia Cantara
- Department of Pathology and DiagnosticsARC-NET Research CentreUniversity of Verona, Policlinico GB Rossi, Piazzale LA Scuro, 10, Piastra Odontoiatrica (II floor), 37134 Verona, ItalyDepartment of Internal MedicineEndocrinology, and Metabolism and Biochemistry, University of Siena, Siena, ItalyDepartment of Surgery and OncologyUniversity of Verona, Verona, ItalyDivision of SurgicalMolecular and Ultrastructural, Section of Cytopathology, University Hospital of Pisa, Pisa, ItalyNuclear Medicine UnitUniversity Hospital of Verona, Verona, Italy
| | - Serena Pedron
- Department of Pathology and DiagnosticsARC-NET Research CentreUniversity of Verona, Policlinico GB Rossi, Piazzale LA Scuro, 10, Piastra Odontoiatrica (II floor), 37134 Verona, ItalyDepartment of Internal MedicineEndocrinology, and Metabolism and Biochemistry, University of Siena, Siena, ItalyDepartment of Surgery and OncologyUniversity of Verona, Verona, ItalyDivision of SurgicalMolecular and Ultrastructural, Section of Cytopathology, University Hospital of Pisa, Pisa, ItalyNuclear Medicine UnitUniversity Hospital of Verona, Verona, Italy
| | - Paolo Brazzarola
- Department of Pathology and DiagnosticsARC-NET Research CentreUniversity of Verona, Policlinico GB Rossi, Piazzale LA Scuro, 10, Piastra Odontoiatrica (II floor), 37134 Verona, ItalyDepartment of Internal MedicineEndocrinology, and Metabolism and Biochemistry, University of Siena, Siena, ItalyDepartment of Surgery and OncologyUniversity of Verona, Verona, ItalyDivision of SurgicalMolecular and Ultrastructural, Section of Cytopathology, University Hospital of Pisa, Pisa, ItalyNuclear Medicine UnitUniversity Hospital of Verona, Verona, Italy
| | - Ivo Marchetti
- Department of Pathology and DiagnosticsARC-NET Research CentreUniversity of Verona, Policlinico GB Rossi, Piazzale LA Scuro, 10, Piastra Odontoiatrica (II floor), 37134 Verona, ItalyDepartment of Internal MedicineEndocrinology, and Metabolism and Biochemistry, University of Siena, Siena, ItalyDepartment of Surgery and OncologyUniversity of Verona, Verona, ItalyDivision of SurgicalMolecular and Ultrastructural, Section of Cytopathology, University Hospital of Pisa, Pisa, ItalyNuclear Medicine UnitUniversity Hospital of Verona, Verona, Italy
| | - Giancarlo Di Coscio
- Department of Pathology and DiagnosticsARC-NET Research CentreUniversity of Verona, Policlinico GB Rossi, Piazzale LA Scuro, 10, Piastra Odontoiatrica (II floor), 37134 Verona, ItalyDepartment of Internal MedicineEndocrinology, and Metabolism and Biochemistry, University of Siena, Siena, ItalyDepartment of Surgery and OncologyUniversity of Verona, Verona, ItalyDivision of SurgicalMolecular and Ultrastructural, Section of Cytopathology, University Hospital of Pisa, Pisa, ItalyNuclear Medicine UnitUniversity Hospital of Verona, Verona, Italy
| | - Marco Chilosi
- Department of Pathology and DiagnosticsARC-NET Research CentreUniversity of Verona, Policlinico GB Rossi, Piazzale LA Scuro, 10, Piastra Odontoiatrica (II floor), 37134 Verona, ItalyDepartment of Internal MedicineEndocrinology, and Metabolism and Biochemistry, University of Siena, Siena, ItalyDepartment of Surgery and OncologyUniversity of Verona, Verona, ItalyDivision of SurgicalMolecular and Ultrastructural, Section of Cytopathology, University Hospital of Pisa, Pisa, ItalyNuclear Medicine UnitUniversity Hospital of Verona, Verona, Italy
| | - Matteo Brunelli
- Department of Pathology and DiagnosticsARC-NET Research CentreUniversity of Verona, Policlinico GB Rossi, Piazzale LA Scuro, 10, Piastra Odontoiatrica (II floor), 37134 Verona, ItalyDepartment of Internal MedicineEndocrinology, and Metabolism and Biochemistry, University of Siena, Siena, ItalyDepartment of Surgery and OncologyUniversity of Verona, Verona, ItalyDivision of SurgicalMolecular and Ultrastructural, Section of Cytopathology, University Hospital of Pisa, Pisa, ItalyNuclear Medicine UnitUniversity Hospital of Verona, Verona, Italy
| | - Furio Pacini
- Department of Pathology and DiagnosticsARC-NET Research CentreUniversity of Verona, Policlinico GB Rossi, Piazzale LA Scuro, 10, Piastra Odontoiatrica (II floor), 37134 Verona, ItalyDepartment of Internal MedicineEndocrinology, and Metabolism and Biochemistry, University of Siena, Siena, ItalyDepartment of Surgery and OncologyUniversity of Verona, Verona, ItalyDivision of SurgicalMolecular and Ultrastructural, Section of Cytopathology, University Hospital of Pisa, Pisa, ItalyNuclear Medicine UnitUniversity Hospital of Verona, Verona, Italy
| | - Marco Ferdeghini
- Department of Pathology and DiagnosticsARC-NET Research CentreUniversity of Verona, Policlinico GB Rossi, Piazzale LA Scuro, 10, Piastra Odontoiatrica (II floor), 37134 Verona, ItalyDepartment of Internal MedicineEndocrinology, and Metabolism and Biochemistry, University of Siena, Siena, ItalyDepartment of Surgery and OncologyUniversity of Verona, Verona, ItalyDivision of SurgicalMolecular and Ultrastructural, Section of Cytopathology, University Hospital of Pisa, Pisa, ItalyNuclear Medicine UnitUniversity Hospital of Verona, Verona, Italy Department of Pathology and DiagnosticsARC-NET Research CentreUniversity of Verona, Policlinico GB Rossi, Piazzale LA Scuro, 10, Piastra Odontoiatrica (II floor), 37134 Verona, ItalyDepartment of Internal MedicineEndocrinology, and Metabolism and Biochemistry, University of Siena, Siena, ItalyDepartment of Surgery and OncologyUniversity of Verona, Verona, ItalyDivision of SurgicalMolecular and Ultrastructural, Section of Cytopathology, University Hospital of Pisa, Pisa, ItalyNuclear Medicine UnitUniversity Hospital of Verona, Verona, Italy
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Duchemann B, Friboulet L, Besse B. Therapeutic management of ALK+ nonsmall cell lung cancer patients. Eur Respir J 2015; 46:230-42. [PMID: 25929953 DOI: 10.1183/09031936.00236414] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Accepted: 03/14/2015] [Indexed: 02/04/2023]
Abstract
With therapeutic approaches based on oncogene addiction offering significant anticancer benefit, the identification of anaplastic lymphoma kinase (ALK) rearrangements is a key aspect of the management of lung cancers. The EML4-ALK gene fusion is detected in 4-8% of all lung cancers, predominantly in light smokers or nonsmokers. Crizotinib, the first agent to be approved in this indication, is associated with a median progression-free survival of 10.9 months when given as first-line treatment and 7.7 months when administered after chemotherapy. Median overall survival with crizotinib in the second-line setting is 20.3 months. Second-generation ALK inhibitors are currently being evaluated, with early studies giving impressive results, notably in patients resistant to crizotinib or with brain metastases. Among available chemotherapies, pemetrexed appears to be particularly active in this population. Despite this progress, several questions remain unanswered. What detection strategies should be favoured? What underlies the mechanisms of resistance and what options are available to overcome them? What are the best approaches for progressing patients? This review provides an overview of current data in the literature and addresses these questions.
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Affiliation(s)
- Boris Duchemann
- Dept of Medical Oncology, Hopital Avicenne, Bobigny, France Paris 13 University, Paris, France
| | - Luc Friboulet
- Dept of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Benjamin Besse
- Dept of Cancer Medicine, Gustave Roussy, Villejuif, France Paris-Sud University, Paris, France
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Shiroyama T, Tanaka A, Tamiya M, Hamaguchi M, Osa A, Takeoka S, Tani E, Azuma Y, Morishita N, Suzuki H, Okamoto N, Kimura K, Kadota Y, Kawahara K, Hirashima T, Kawase I. A Rare Case of Pleomorphic Carcinoma of the Lung Harboring an Anaplastic Lymphoma Kinase (ALK) Rearrangement. Intern Med 2015; 54:2741-3. [PMID: 26521903 DOI: 10.2169/internalmedicine.54.4474] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Molecular testing for anomalies, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase (ALK) rearrangement, is part of the current standard of care for non-small cell lung cancer, particularly adenocarcinoma. ALK rearrangement occurs most frequently in adenocarcinoma cells and rarely in non-adenocarcinoma cells. We herein report a rare case of pleomorphic lung carcinoma with ALK rearrangement in both its adenocarcinoma and spindle cell components. This case suggests the possibility of ALK rearrangement in pleomorphic carcinoma.
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Affiliation(s)
- Takayuki Shiroyama
- Department of Thoracic Malignancy, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases, Japan
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Vincent MD. Promising targets and current clinical trials in metastatic squamous cell lung cancer. Front Oncol 2014; 4:320. [PMID: 25538887 PMCID: PMC4260675 DOI: 10.3389/fonc.2014.00320] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Accepted: 10/26/2014] [Indexed: 01/15/2023] Open
Abstract
Squamous cancer of the lung (SQCC), although no longer the premier variant of non-small cell lung cancer, continues to impose a heavy world-wide burden. Advanced SQCC has enjoyed little of the recent progress benefiting patients with adenocarcinoma of the lung, but that has now begun to change. This article reviews the underlying molecular pathology of SQCC, as well as potential new targets and the corresponding novel targeted agents; included are some of which may soon be approvable in this notoriously hard-to-treat indication.
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Affiliation(s)
- Mark D Vincent
- London Regional Cancer Program, Department of Medical Oncology, London Health Sciences Centre , London, ON , Canada
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Conde E, Suárez-Gauthier A, Benito A, Garrido P, García-Campelo R, Biscuola M, Paz-Ares L, Hardisson D, de Castro J, Camacho MC, Rodriguez-Abreu D, Abdulkader I, Ramirez J, Reguart N, Salido M, Pijuán L, Arriola E, Sanz J, Folgueras V, Villanueva N, Gómez-Román J, Hidalgo M, López-Ríos F. Accurate identification of ALK positive lung carcinoma patients: novel FDA-cleared automated fluorescence in situ hybridization scanning system and ultrasensitive immunohistochemistry. PLoS One 2014; 9:e107200. [PMID: 25248157 PMCID: PMC4172507 DOI: 10.1371/journal.pone.0107200] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2014] [Accepted: 08/07/2014] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Based on the excellent results of the clinical trials with ALK-inhibitors, the importance of accurately identifying ALK positive lung cancer has never been greater. However, there are increasing number of recent publications addressing discordances between FISH and IHC. The controversy is further fuelled by the different regulatory approvals. This situation prompted us to investigate two ALK IHC antibodies (using a novel ultrasensitive detection-amplification kit) and an automated ALK FISH scanning system (FDA-cleared) in a series of non-small cell lung cancer tumor samples. METHODS Forty-seven ALK FISH-positive and 56 ALK FISH-negative NSCLC samples were studied. All specimens were screened for ALK expression by two IHC antibodies (clone 5A4 from Novocastra and clone D5F3 from Ventana) and for ALK rearrangement by FISH (Vysis ALK FISH break-apart kit), which was automatically captured and scored by using Bioview's automated scanning system. RESULTS All positive cases with the IHC antibodies were FISH-positive. There was only one IHC-negative case with both antibodies which showed a FISH-positive result. The overall sensitivity and specificity of the IHC in comparison with FISH were 98% and 100%, respectively. CONCLUSIONS The specificity of these ultrasensitive IHC assays may obviate the need for FISH confirmation in positive IHC cases. However, the likelihood of false negative IHC results strengthens the case for FISH testing, at least in some situations.
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Affiliation(s)
- Esther Conde
- Laboratorio de Dianas Terapéuticas, Centro Integral Oncológico “Clara Campal”, Hospital Universitario Madrid Sanchinarro, Universidad San Pablo-CEU, Madrid, Spain
| | - Ana Suárez-Gauthier
- Laboratorio de Dianas Terapéuticas, Centro Integral Oncológico “Clara Campal”, Hospital Universitario Madrid Sanchinarro, Universidad San Pablo-CEU, Madrid, Spain
| | | | | | | | | | | | - David Hardisson
- IdiPAZ (Hospital La Paz Institute for Health Research), University Hospital La Paz, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain
| | - Javier de Castro
- IdiPAZ (Hospital La Paz Institute for Health Research), University Hospital La Paz, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain
| | | | | | - Ihab Abdulkader
- C.H.U. Santiago de Compostela, Santiago de Compostela, Spain
| | | | | | - Marta Salido
- Hospital del Mar-Parc de Salut Mar, Barcelona, Spain
| | - Lara Pijuán
- Hospital del Mar-Parc de Salut Mar, Barcelona, Spain
| | | | | | | | | | | | - Manuel Hidalgo
- Oncology Department, Centro Integral Oncológico “Clara Campal”, Hospital Universitario Madrid Sanchinarro, Universidad San Pablo-CEU, Madrid, Spain
| | - Fernando López-Ríos
- Laboratorio de Dianas Terapéuticas, Centro Integral Oncológico “Clara Campal”, Hospital Universitario Madrid Sanchinarro, Universidad San Pablo-CEU, Madrid, Spain
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Schmitz K, Schildhaus HU. Clinical significance of FGFR1 gene amplification in lung cancer patients. Lung Cancer Manag 2014. [DOI: 10.2217/lmt.14.24] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
SUMMARY Background: Lung cancer is the leading cause of cancer related death worldwide. Molecular targeted therapies are routinely used for pulmonary adenocarcinomas, harboring therapeutically tractable genomic aberrations such as EGFR mutations, ALK and ROS1 fusions. Comparable therapeutic options are still missing for squamous and small-cell lung cancer. Results: Molecular analyses revealed a significant amplification of FGFR1 in 20% of squamous and 6% of small-cell carcinomas. Preclinical and first clinical trials with FGFR inhibitors have shown that this genomic alteration is therapeutically actionable. For detection of FGFR1 amplification fluorescence in situ hybridization is a specific biomarker assay. We review evaluation strategy and criteria for FGFR1 positivity. Conclusion: FGFR1 amplification represents a promising potential target in squamous and small-cell lung cancer.
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Affiliation(s)
- Katja Schmitz
- Institute of Pathology, University Hospital Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany
| | - Hans-Ulrich Schildhaus
- Institute of Pathology, University Hospital Göttingen, Robert-Koch-Str. 40, D-37075 Göttingen, Germany
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Brega E, Brandao G. Non-Small Cell Lung Carcinoma Biomarker Testing: The Pathologist's Perspective. Front Oncol 2014; 4:182. [PMID: 25077070 PMCID: PMC4099940 DOI: 10.3389/fonc.2014.00182] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Accepted: 06/27/2014] [Indexed: 12/01/2022] Open
Abstract
Biomarker testing has become standard of care for patients diagnosed with non-small cell lung carcinoma (NSCLC). Although, it can be successfully performed in circulating tumor cells, at present, the vast majority of investigations are carried out using direct tumor sampling, either through aspiration methods, which render most often isolated cells, or tissue sampling, that could range from minute biopsies to large resections. Consequently, pathologists play a central role in this process. Recent evidence suggests that refining NSCLC diagnosis might be clinically significant, particularly in cases of lung adenocarcinomas (ADC), which in turn, has prompted a new proposal for the histologic classification of such pulmonary neoplasms. These changes, in conjunction with the mandatory incorporation of biomarker testing in routine NSCLC tissue processing, have directly affected the pathologist’s role in lung cancer work-up. This new role pathologists must play is complex and demanding, and requires a close interaction with surgeons, oncologists, radiologists, and molecular pathologists. Pathologists often find themselves as the central figure in the coordination of a process, that involves assuring that the tumor samples are properly fixed, but without disruption of the DNA structure, obtaining the proper diagnosis with a minimum of tissue waste, providing pre-analytical evaluation of tumor samples selected for biomarker testing, which includes assessment of the proportion of tumor to normal tissues, as well as cell viability, and assuring that this entire process happens in a timely fashion. Therefore, it is part of the pathologist’s responsibilities to assure that the samples received in their laboratories, be processed in a manner that allows for optimal biomarker testing. This article goal is to discuss the essential role pathologists must play in NSCLC biomarker testing, as well as to provide a summarized review of the main NSCLC biomarkers of clinical interest.
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Affiliation(s)
- Elisa Brega
- Department of Pathology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University , Montreal, QC , Canada
| | - Guilherme Brandao
- Department of Pathology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University , Montreal, QC , Canada
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