Ipsilateral breast metastasis from lung adenocarcinoma harboring anaplastic lymphoma kinase or ROS1 rearrangement and significant response after targeted therapy: report of two cases.
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ABSTRACT:
SUBMITTER: Zheng J
PROVIDER: S-EPMC7401736 | biostudies-literature | 2020 Jul
REPOSITORIES: biostudies-literature
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Ipsilateral breast metastasis from lung adenocarcinoma harboring anaplastic lymphoma kinase or ROS1 rearrangement and significant response after targeted therapy: report of two cases.
Zheng Jing J Zhou Jian-Ya JY Bao Zhang Z Shen Qian Q Cao He H Zhou Jian-Ying JY
Chinese medical journal 20200701 14
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Project description:BackgroundIt has not been determined if adjuvant chemotherapy would be helpful for completely resected early-stage lung adenocarcinoma even with unfavorable genetic markers. As the positive anaplastic lymphoma kinase (ALK) rearrangement is associated with aggressive clinical feature in lung adenocarcinoma, we evaluated the treatment outcomes of completely resected stage IA lung adenocarcinoma according to initial ALK status.MethodsThis is a retrospective cohort study including 309 patients with surgically resected stage IA lung adenocarcinoma from February 2010 to December 2013. Patients were screened for ALK rearrangement using immunohistochemistry. A positive ALK status was defined as an immunohistochemistry score of 2+ or more. Both disease-free survival (DFS) and the initial recurrence pattern were analyzed according to ALK status.ResultsTwenty-three (7.4%) patients had ALK-positive adenocarcinoma. During the median follow-up of 35.8 months, recurrence developed in 34 (11.0%) patients. The patients with ALK-positive tumor had significantly lower 5-year DFS rate (62.4%) compared to those with ALK-negative tumor (86.5%; P=0.038). The multivariable analysis showed that ALK rearrangement was associated with a higher risk of disease recurrence (adjusted hazard ratio =2.64; 95% confidence interval, 1.08-6.44). In addition, patient with ALK-positive tumor showed more frequent recurrence in regional lymph nodes compared with those with ALK-negative tumor (83.3% vs. 28.6%; P=0.031).ConclusionsIn patients with completely resected stage IA lung adenocarcinoma, ALK rearrangement was associated with unfavorable DFS and more frequent regional lymph node metastasis. Therefore, careful surveillance for recurrence should be performed in this subset of patients.
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Project description:Purpose:To develop a radiogenomics classifier to assess anaplastic lymphoma kinase (ALK) gene rearrangement status in pretreated solid lung adenocarcinoma noninvasively. Materials and Methods:This study consisted of 140 consecutive pretreated solid lung adenocarcinoma patients with complete enhanced CT scans who were tested for both EGFR mutations and ALK status. Pre-contrast CT and standard post-contrast CT radiogenomics machine learning classifiers were designed as two separate classifiers. In each classifier, dataset was randomly split into training and independent testing group on a 7:3 ratio, accordingly subjected to a 5-fold cross-validation. After normalization, best feature subsets were selected by Pearson correlation coefficient (PCC) and analysis of variance (ANOVA) or recursive feature elimination (RFE), whereupon a radiomics classifier was built with support vector machine (SVM). The discriminating performance was assessed with the area under receiver-operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results:In classifier one, 98 cases were selected as training data set, 42 cases as independent testing data set. In classifier two, 87 cases were selected as training data set, 37 cases as independent testing data set. Both classifiers extracted 851 radiomics features. The top 25 pre-contrast features and top 19 post-contrast features were selected to build optimal ALK+ radiogenomics classifiers accordingly. The accuracies, AUCs, sensitivity, specificity, PPV, and NPV of pre-contrast CT classifier were 78.57%, 80.10% (CI: 0.6538-0.9222), 71.43%, 82.14%, 66.67%, and 85.19%, respectively. Those results of standard post-contrast CT classifier were 81.08%, 82.85% (CI: 0.6630-0.9567), 76.92%, 83.33%, 71.43%, and 86.96%. Conclusion:Solid lung adenocarcinoma ALK+ radiogenomics classifier of standard post-contrast CT radiomics biomarkers produced superior performance compared with that of pre-contrast one, suggesting that post-contrast CT radiomics should be recommended in the context of solid lung adenocarcinoma radiogenomics AI. Standard post-contrast CT machine learning radiogenomics classifier could help precisely identify solid adenocarcinoma ALK rearrangement status, which may act as a pragmatic and cost-efficient substitute for traditional invasive ALK status test.
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Project description:PurposeAnaplastic lymphoma kinase (ALK) rearrangement has been detected in colorectal carcinoma (CRC) using advanced molecular diagnostics tests including exon scanning, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). We investigated if immunohistochemistry (IHC) can be used to detect ALK rearrangement in gastrointestinal malignancies.Experimental designsTissue microarrays (TMAs) from consecutive gastric carcinoma (GC) and CRC patients who underwent surgical resection at Samsung Medical Center, Seoul, Korea were screened by IHC using ALK monoclonal antibody 5A4. IHC positive cases were confirmed by FISH, nCounter assays, and NGS-based comprehensive genomic profiling (CGP). ALK IHC was further applied to CRC patients enrolled in a pathway-directed therapeutic trial.ResultsFour hundred thirty-two GC and 172 CRC cases were screened by IHC. No GC sample was ALK IHC positive. One CRC (0.6%) was ALK IHC positive (3+) that was confirmed by ALK FISH and a novel CAD-ALK (C35; A20) fusion variant that resulted from a paracentric inversion event inv(2)(p22-21p23) was identified by CGP. One out of 50 CRC patients enrolled in a pathway-directed therapeutic trial was ALK IHC positive (3+) confirmed by ALK FISH and found to harbor the EML4-ALK (E21, A20) fusion variant by CGP. Growth of a tumor cell line derived from this EML4-ALK CRC patient was inhibited by ALK inhibitors crizotinib and entrectinib.ConclusionsALK IHC is a viable screening strategy for identifying ALK rearrangement in CRC. ALK rearrangement is a potential actionable driver mutation in CRC based on survival inhibition of patient tumor-derived cell line by potent ALK inhibitors.
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Project description:Pulmonary spindle cell carcinoma is a subtype of pulmonary sarcomatoid carcinoma and a very rare tumor type with a poor prognosis. A few case reports have documented patients with pulmonary sarcomatoid carcinoma with anaplastic lymphoma kinase rearrangement, and the efficacy and outcomes of anaplastic lymphoma kinase inhibitors remain unclear. Herein, we present the case of a 60-year-old woman with stage IVB disease who was diagnosed with a metastatic brain tumor. This patient showed high levels of programmed cell death ligand 1 expression and anaplastic lymphoma kinase rearrangement and received pembrolizumab as the first-line treatment. Three weeks later, pembrolizumab failed to reduce the size of the primary pulmonary tumor, and the patient's general condition did not improve. The patient received alectinib as the second-line treatment. Two months later, multiple brain metastases were observed. Hence, whole-brain irradiation was performed as treatment for multiple brain metastases, while another anaplastic lymphoma kinase inhibitor was administered; however, both treatments remained ineffective. The patient eventually died 9 months after the initiation of first-line treatment. The present case report describes the therapeutic course of a patient with pulmonary spindle cell carcinoma with an anaplastic lymphoma kinase rearrangement.
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Project description:Renal cell carcinoma (RCC) with anaplastic lymphoma kinase (ALK) rearrangement is rare, and the genetic profiles of the tumor have not been elucidated. Here, we report a case with recurrent papillary RCC and lung metastasis after nephrectomy for nearly 7 years. The patient first received sunitinib, whereas the drug toxicity was intolerable. Combined Immunohistology (IHC) and fluorescence in situ hybridization (FISH) revealed the patient has an ALK rearrangement, and the patient then was treated with crizotinib. The patient had good tolerance, and a partial response in the target lesions was achieved. In order to further understand the benefit of crizotinib in ALK-rearranged RCC, the patient was detected with whole exome sequencing (WES) to study her genetic profiles. Compared those of RCC cases without ALK rearrangement (nALK-RCC), the patient and nine RCC cases with ALK rearrangement (ALK-RCC) revealed unique genetic characteristics: 1) The common mutations that occurred in RCC were not found in ALK-RCC.; 2) A total of 11 co-existing mutations in ALK-RCC were found, and they occurred in nALK-RCC at a relatively low frequency. DNMT3A mutations were concurrent with ALK fusions in our case. These findings indicated a different genetic alteration pattern of ALK-RCC from nALK-RCC. Our case demonstrated the efficacy of crizotinib in an RCC patient with ALK rearrangement.
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Project description:BackgroundPatients with lung cancer are at an increased risk for venous thromboembolism (VTE). Approximately 8-15% of patients with advanced non-small-cell lung cancer (NSCLC) experience a VTE throughout the course of the disease. However, the incidence of VTE in different NSCLC molecular subtypes is rarely reported, although there are significant differences in clinical feature and prognosis. Tissue factor (TF) expressed in many solid tumors could trigger the downstream coagulation cascade and lead to thrombin generation and clot formation.MethodsIn the present study, retrospective data were obtained from electronic medical records at Henan Cancer Hospital in China between January 2015 and January 2017. Advanced lung adenocarcinoma patients with anaplastic lymphoma kinase (ALK) rearrangement, epidermal growth factor receptor (EGFR) mutation and both negative were included in the present study. The incidence of VTE of these patients was calculated. We then randomly selected ALK-rearrangement-positive and -negative lung adenocarcinoma tissues (n=29 and n=26, respectively) and detected TF protein expression via immunohistochemistry.ResultsAt a median follow up of 2.5 years, 5.85% (n=30/513) patients with advanced lung adenocarcinoma experienced VTE. Compared to patients with EGFR mutation (n=11/218, 5.05%) or both negative (n=13/266, 4.89%), patients with ALK-rearrangement were more likely to develop VTE (n=6/29, 20.69%; P=0.006, P=0.004; respectively). In ALK-rearrangement-positive tissues, 41.67% (n=10/24) had a high TF protein expression; the incidence was significantly higher than the TF protein expression in ALK-negative tissues (11.54%, n=3/26, P=0.015).ConclusionsALK-rearrangement-positive NSCLC patients are more likely to develop VTE; this might be due to a higher TF expression in tumor tissues.
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Project description:Patients with AIDS have increased risk of developing lymphomas, such as anaplastic large cell lymphoma (ALCL), which generally carry a poor prognosis. The DUSP-IRF4 genetic rearrangement in ALCL confers a favourable prognosis in HIV-negative patients; it is unknown how this interacts clinically with HIV/AIDS. A man aged 53 years presented with subcutaneous nodules on the scalp and axillae, and diffuse lymphadenopathy. Biopsy of subcutaneous nodule and lymph node showed large atypical anaplastic lymphocytes which were CD30+ and anaplastic lymphoma kinase-negative, consistent with primary systemic ALCL. In addition, he was found to be HIV-positive and diagnosed with AIDS. Genetic testing of the tissue revealed a DUSP22-IRF4 rearrangement. Complete remission was achieved with HyperCVAD and subsequent brentuximab vedotin monotherapy. We report a case of AIDS-associated primary systemic ALCL with a DUSP22-IRF4 rearrangement. AIDS-associated ALCL is an aggressive lymphoma, with a poor prognosis. However, the presence of the genetic rearrangement, previously unseen in this disease, drastically altered the disease course. This case highlights the value of genetic testing and identifies DUSP22-IRF4-associated ALCL in the setting of HIV-associated lymphoproliferative disorders.
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Project description:This retrospective study investigated the association between the pattern of disease progression and molecular mechanism of acquired resistance in a large cohort of 49 patients with ROS1-rearranged advanced non-small-cell lung cancer treated with first-line crizotinib. We found that treatment-emergent ROS1 point mutations were the major molecular mechanism of crizotinib resistance, particularly for patients who developed extracranial-only disease progression. Our findings highlight the importance of rebiopsy and gene testing for subsequent-line therapeutic management.
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Project description:BackgroundAnaplastic lymphoma kinase (ALK) rearrangements define a subgroup of lung cancer which is eligible to targeted kinase inhibition. The aim of this study is to observe the incidence rate of ALK fusion in a large cohort of Chinese digestive tract cancer patients.Patients and methodsTissue microarray (TMA) was constructed from 808 digestive tract cancer cases, including 169 esophageal squamous cell carcinoma, 182 gastric cancer and 457 colorectal cancer (CRC) cases. We tested all cases for ALK expression via a fully automated immunohistochemistry (IHC) assay. The IHC-positive cases were subjected to fluorescence in situ hybridization (FISH), real-time polymerase chain reaction (qRT-PCR), target gene enrichment and sequencing for confirmation of ALK gene rearrangement and discovery of novel fusion partner.ResultsAmong the tested cases, 2 (0.44%) CRC cases showed positive both by IHC and FISH. By qRT-PCR, EML4-ALK fusion was found in one IHC-positive CRC case. In another IHC-positive CRC case, target gene enrichment and sequencing revealed ALK was fused to a novel partner, spectrin beta non-erythrocytic 1 (SPTBN1). One gastric cancer case showed partially positive IHC result, but no fusion was found by FISH and gene sequencing.ConclusionsThe incidence rate of ALK gene fusion in Chinese CRC patients was 0.44%,but not detectable in gastric and esophageal cancers. The novel SPTBN1 -ALK fusion, together with other ALK fusion genes, may become a potential target for anti-ALK therapy.
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Project description: Not available
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