RESUMO
BACKGROUND: Patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) respond to ALK inhibitors. Clinically, the presence of ≥15% cells with rearrangements identified on break-apart fluorescence in situ hybridization (FISH) classifies tumors as positive. Increases in native and rearranged ALK copy number also occur. METHODS: In total, 1426 NSCLC clinical specimens (174 ALK-positive specimens and 1252 ALK-negative specimens) and 24 ALK-negative NSCLC cell lines were investigated. ALK copy number and genomic status were assessed by FISH. RESULTS: Clinical specimens with 0% to 9%, 10% to 15%, 16% to 30%, 31% to 50%, and >50% ALK-positive cells were identified in 79.3%, 8.5%, 1.4%, 2.7%, and 8.1%, respectively. An increased native ALK copy number (≥3 copies per cell in ≥40% of cells) was detected in 19% of ALK-positive tumors and in 62% of ALK-negative tumors. In ALK-negative tumors, abundant, focal amplification of native ALK was rare (0.8%). Other atypical patterns occurred in approximately 6% of tumors. The mean native ALK copy number ranged from 2.1 to 6.9 copies in cell lines and was not correlated with crizotinib sensitivity (50% inhibitory concentration, 0.34-2.8 µM; r = 0.279; P = .1764). Neither native or rearranged ALK copy number nor the percentage of positive cells correlated with extra-central nervous system progression-free survival in ALK-positive patients who were receiving crizotinib. CONCLUSIONS: Overall, 8.5% of tumors fell below the established positivity threshold by ≤5%. Further investigation of ALK by other diagnostic techniques in such cases may be warranted. Native ALK copy number increases alone were not associated with sensitivity to ALK inhibition in vitro. However, rare, complex patterns of increased native ALK in patients should be studied further; because, otherwise, atypical rearrangements contained within these may be missed.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Crizotinibe , Variações do Número de Cópias de DNA , Intervalo Livre de Doença , Rearranjo Gênico , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/genética , Pirazóis/farmacologia , Piridinas/farmacologia , Receptores Proteína Tirosina Quinases/metabolismoRESUMO
RATIONALE: The development of lung cancer (LC) is accompanied by field changes in the airway mucosa that may have prognostic importance. OBJECTIVES: To compare patients with prevalent LC to control subjects regarding their histologic dysplasia scores and chromosomal aneusomy as measured by fluorescence in situ hybridization (FISH). METHODS: The most advanced bronchial histology lesion was assessed from each of 44 LC cases and 90 cancer-free control subjects using a four-color FISH probe set encompassing the chromosome 6 centromere, 5p15.2, 7p12 (epidermal growth factor receptor), and 8q24 v-myc myelocytomatosis viral oncogene homolog (MYC) sequences. Histology grades were coded as dysplasia (moderate or severe) or carcinoma in situ (CIS). MEASUREMENTS AND MAIN RESULTS: CIS was the highest histologic grade for 32 subjects, and dysplasia was the highest grade for 102 subjects (54 moderate, 48 severe). Chromosomal aneusomy was seen in 64% of the LC cases, but in only 31% of the control subjects (odds ratio [OR], 4.68; 95% confidence interval [CI]. 1.97-11.04). Among those with any level of dysplasia, the OR for positive FISH and LC was 2.28 (95% CI, 0.75-6.86). Among those with CIS, the OR for positive FISH and LC was 5.84 (95% CI, 1.31-26.01). CONCLUSIONS: Chromosomal aneusomy is associated with LC. Prospective examination of aneusomy as a precursor lesion that predicts LC is needed.
Assuntos
Brônquios/patologia , Carcinoma in Situ/genética , Aberrações Cromossômicas , Células Epiteliais/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Adulto , Idoso , Biomarcadores , Brônquios/citologia , Broncoscopia , Carcinoma in Situ/patologia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Hibridização in Situ Fluorescente , Neoplasias Pulmonares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , FumarRESUMO
Lenalidomide is a more potent and less toxic oral analog of thalidomide. The drug is indicated for treatment of multiple myeloma and other hematologic disorders and has rarely been associated with pulmonary toxicity. We describe a 73-year-old woman who received lenalidomide therapy for multiple myeloma. Nine weeks after starting the drug, she developed progressive dyspnea, cough, and constitutional symptoms, and was found to be hypoxic. A computed tomography scan of the chest showed bilateral interstitial infiltrates. Bronchoalveolar lavage was negative for infection, but transbronchial biopsy showed an organizing pneumonia. The patient was diagnosed with lenalidomide-induced interstitial lung disease after other causes were excluded. Clinical and radiologic resolution occurred after lenalidomide was discontinued and a tapering course of corticosteroids was begun. Use of the Naranjo adverse drug reaction probability indicated a high probability (score of 7) that this adverse drug reaction was caused by lenalidomide. Lenalidomide inhibits prostaglandin E(2) (PGE(2)) secretion by cells. If fibroblast PGE(2) synthesis is impaired in the lung, the mitogenic action of cysteinyl leukotrienes may be unmasked, promoting fibroblast proliferation and collagen synthesis, eventually leading to interstitial lung disease. Another potential mechanism may be an immunologic one similar to that seen in the interstitial pulmonary process in patients with hypersensitivity pneumonitis. To our knowledge, only one other case of lenalidomide-induced pulmonary toxicity has been reported in the literature. Although lenalidomide-induced pulmonary toxicity is uncommon, clinicians should consider this potential adverse drug reaction in the differential diagnosis in patients receiving lenalidomide who present with symptoms of interstitial lung disease for which alternative causes have been excluded.
Assuntos
Antineoplásicos/efeitos adversos , Dinoprostona/antagonistas & inibidores , Doenças Pulmonares Intersticiais/induzido quimicamente , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Idoso , Terapia Combinada , Diagnóstico Diferencial , Feminino , Humanos , Lenalidomida , Pulmão/efeitos dos fármacos , Pulmão/patologia , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/patologia , Mieloma Múltiplo/terapia , Talidomida/efeitos adversos , Resultado do TratamentoRESUMO
Lung carcinoma development is accompanied by field changes that may have diagnostic significance. We have previously shown the importance of chromosomal aneusomy in lung cancer progression. Here, we tested whether genomic gains in six specific loci, TP63 on 3q28, EGFR on 7p12, MYC on 8q24, 5p15.2, and centromeric regions for chromosomes 3 (CEP3) and 6 (CEP6), may provide further value in the prediction of lung cancer. Bronchial biopsy specimens were obtained by LIFE bronchoscopy from 70 subjects (27 with prevalent lung cancers and 43 individuals without lung cancer). Twenty six biopsies were read as moderate dysplasia, 21 as severe dysplasia and 23 as carcinoma in situ (CIS). Four-micron paraffin sections were submitted to a 4-target FISH assay (LAVysion, Abbott Molecular) and reprobed for TP63 and CEP 3 sequences. Spot counts were obtained in 30-50 nuclei per specimen for each probe. Increased gene copy number in 4 of the 6 probes was associated with increased risk of being diagnosed with lung cancer both in unadjusted analyses (odds ratio = 11, p<0.05) and adjusted for histology grade (odds ratio = 17, p<0.05). The most informative 4 probes were TP63, MYC, CEP3 and CEP6. The combination of these 4 probes offered a sensitivity of 82% for lung cancer and a specificity of 58%. These results indicate that specific cytogenetic alterations present in preinvasive lung lesions are closely associated with the diagnosis of lung cancer and may therefore have value in assessing lung cancer risk.