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Sensitive methods for detection of the S768R substitution in exon 18 of the DDR2 gene in patients with central nervous system metastases of non-small cell lung cancer.

ABSTRACT: Discoidin death receptor 2 (DDR2) receptor belongs to a DDR family that shows a tyrosine kinase activity. The somatic mutations in DDR2 gene, reported in non-small cell lung cancer (NSCLC), are involved in up-regulation of cells' migration, proliferation and survival. A S768R substitution in DDR2 gene was commonly reported in squamous cell lung carcinoma. Clinical data of patients carrying the DDR2 gene mutation suggest that its presence can be independent of gender and age. The effectiveness of an oral dual-specific (Src and Abl) multikinase inhibitors-dasatinib-was observed in different cell lines and in some NSCLC patients with identified DDR2 mutation. In the present study, we have used three molecular methods (ASP-real-time PCR, ASP-DNA-FLA PCR and direct sequencing) to detect the DDR2 gene mutation in 143 patients with NSCLC metastases to the central nervous system (CNS). The prevalence of the DDR2 gene mutation was correlated with the occurrence of mutations in the EGFR, KRAS, HER2 and BRAF genes. We identified three patients (2.1% of studied group) with DDR2 mutation. The mutation was observed in two patients with low differentiated squamous cell lung cancer and in one patient with adeno-squamous cell carcinoma (ADSCC). In ADSCC patients, DDR2 mutation coexisted with G12C substitution in KRAS gene. According to the current knowledge, examination of the presence of the DDR2 gene mutation in metastatic lesion is the first such report worldwide. The information, that these driver mutations are present in CNS metastases of NSCLC, could broaden therapeutic choices in such group of patients.

SUBMITTER: Nicos M

PROVIDER: S-EPMC4180903 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abstract BACKGROUND: While immunotherapy has revolutionized the treatment for several solid tumors, pseudoprogression, radiographically defined as the initial increase in tumor volume followed by tumor shrinkage, is less clearly defined. This is particularly noteworthy for patients with central nervous system metastases, commonly seen in patients with advanced melanoma or non-small cell lung cancer treated with PD-1 or CTLA-4 inhibitors. B7-H3 (CD276) is a transmembrane protein belonging to the B7 family of costimulatory molecules. 1 Several solid tumors overexpress B7-H3, and expression appears to be closely associated with immune escape, tumor cell invasion and metastases. The incidence of pseudoprogression after B7-H3 therapy is unknown. METHOD: A 4 year old girl with central nervous system metastases of neuroblastoma underwent resection of 2 left parietal lobe lesions, the largest 1.4 cm with edema, enhancement and restricted diffusion, followed by craniospinal radiation therapy, irinotecan, temozolomide, inducing a second remission with expected MR appearance in the operative cavity. She was then registered to clinicaltrials.gov (NCT00089245) with intraventricular 131-I-anti B7-H3. One month after therapy, routine MR revealed increased nodular enhancement around both operative cavities with adjacent leptomeningeal enhancement, concerning for progressive neuroblastoma. The patient remained asymptomatic. RESULTS: A repeat brain performed 2 weeks later showed interval resolution of both the operative cavity and leptomeningeal enhancement and edema. Repeat brain and spine MR performed 6 months later shows continued remission with complete resolution of all enhancement and edema. RESULTS: Anti- B7-H3 therapy caused an immediate inflammatory reaction with spontaneous radiographic resolution and return to baseline 2 weeks later, all in the absence of concurrent steroid administration. CONCLUSION: Though the precise frequency and timeline is unclear, B7-H3 directed therapy may be added to the list of immunotherapeutic agents recognized to cause pseudoprogression. Key efforts are now being made to correlate the appearance of CNS neuroblastoma pseudoprogression with overall survival.

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Sensitive methods for detection of the S768R substitution in exon 18 of the DDR2 gene in patients with central nervous system metastases of non-small cell lung cancer.

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