Micropapillary: A component more likely to harbour heterogeneous EGFR mutations in lung adenocarcinomas.
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ABSTRACT:
SUBMITTER: Cai YR
PROVIDER: S-EPMC4820702 | biostudies-other | 2016 Apr
REPOSITORIES: biostudies-other
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Project description:BackgroundGene expression profiling has consistently identified three molecular subtypes of lung adenocarcinoma that have prognostic implications. To facilitate stratification of patients with this disease into similar molecular subtypes, we developed and validated a simple, mutually exclusive classification.MethodsMutational status of EGFR, KRAS, and TP53 was used to define seven mutually exclusive molecular subtypes. A development cohort of 283 cytology specimens of lung adenocarcinoma was used to evaluate the associations between the proposed classification and clinicopathologic variables including demographic characteristics, smoking history, fluorescence in situ hybridization and molecular results. For validation and prognostic assessment, 63 of the 283 cytology specimens with available survival data were combined with a separate cohort of 428 surgical pathology specimens of lung adenocarcinoma.ResultsThe proposed classification yielded significant associations between these molecular subtypes and clinical and prognostic features. We found better overall survival in patients who underwent surgery and had tumors enriched for EGFR mutations. Worse overall survival was associated with older age, stage IV disease, and tumors with co-mutations in KRAS and TP53. Interestingly, neither chemotherapy nor radiation therapy showed benefit to overall survival.ConclusionsThe mutational status of EGFR, KRAS, and TP53 can be used to easily classify lung adenocarcinoma patients into seven subtypes that show a relationship with prognosis, especially in patients who underwent surgery, and these subtypes are similar to classifications based on more complex genomic methods reported previously.
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Project description:In contrast to other primary epidermal growth factor receptor (EGFR) mutations in lung adenocarcinomas, insertions in exon 20 of EGFR have been generally associated with resistance to EGFR-tyrosine kinase inhibitors. Their molecular spectrum, clinicopathologic characteristics, and prevalence are not well established. Tumors harboring EGFR exon 20 insertions were identified through an algorithmic screen of 1,500 lung adenocarcinomas. Cases were first tested for common mutations in EGFR (exons 19 and 21) and KRAS (exon 2) and, if negative, further analyzed for EGFR exon 20 insertions. All samples underwent extended genotyping for other driver mutations in EGFR, KRAS, BRAF, ERBB2/HER2, NRAS, PIK3CA, MEK1, and AKT by mass spectrometry; a subset was evaluated for ALK rearrangements. We identified 33 EGFR exon 20 insertion cases [2.2%, 95% confidence interval (CI), 1.6-3.1], all mutually exclusive with mutations in the other genes tested (except PIK3CA). They were more common among never-smokers (P < 0.0001). There was no association with age, sex, race, or stage. Morphologically, tumors were similar to those with common EGFR mutations but with frequent solid histology. Insertions were highly variable in position and size, ranging from 3 to 12 bp, resulting in 13 different insertions, which, by molecular modeling, are predicted to have potentially different effects on erlotinib binding. EGFR exon 20 insertion testing identifies a distinct subset of lung adenocarcinomas, accounting for at least 9% of all EGFR-mutated cases, representing the third most common type of EGFR mutation after exon 19 deletions and L858R. Insertions are structurally heterogeneous with potential implications for response to EGFR inhibitors.
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Project description:PURPOSE:To determine if clinical and CT characteristics of surgically resected lung adenocarcinomas can distinguish those harboring ALK rearrangements from EGFR mutations. MATERIALS AND METHODS:Patients who had surgical resection and histologically confirmed lung adenocarcinoma were enrolled, including 41 patients with ALK rearrangements and 66 patients with EGFR mutations. Eighteen categorical and six quantitative CT characteristics were used to evaluate the tumors. Differences in clinical and CT characteristics between the two groups were investigated. RESULTS:Age (P=0.003), histological subtypes (P<0.001), pathological stage (P=0.007), and five CT characteristics, including size (P<0.001), GGO (P=0.001), bubble-like lucency (P=0.048), lymphadenopathy (P=0.001), and tumor shadow disappearance rate (P=0.005) were significantly different between patients harboring ALK rearrangements compared to patients with EGFR mutations. When we compared histologic components, a solid pattern was more common (P=0.009) in tumors with ALK rearrangements, and lepidic and acinar patterns were more common (P<0.001 and P=0.040, respectively) in those with EGFR mutations. Backward elimination analyses revealed that age (OR=0.93; 95% CI 0.89-0.98), GGO (OR=0.14; 95% CI 0.03-0.67), and lymphadenopathy (OR=4.15; 95% CI 1.49-11.60) were significantly associated with ALK rearrangement status. CONCLUSION:Our analyses revealed that clinical and CT characteristics of lung adenocarcinomas harboring ALK rearrangements were significantly different, compared with those with EGFR mutations. These differences may be related to the molecular pathology of these diseases.
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Project description:We have examined the microRNA expression in 154 lung adenocarcinoma samples and 20 paired normal lung tissue samples and investigated the microRNA expression to clinical variables, EGFR- and KRAS- mutational status and time to progression. 174 samples are analyzed. 154 from lung adenocarcinoma tumor tissue and 20 from paired normal lung tissue samples. No replicates or control samples included.
| S-ECPF-GEOD-48414 | biostudies-other
Project description:BackgroundStudies regarding the outcomes of salvage lung resections of epidermal growth factor receptor (EGFR)-mutant advanced lung adenocarcinomas (ALAs) following treatment with EGFR tyrosine kinase inhibitors (TKIs) are limited, hence the objective of this study was to investigate such outcomes.MethodsA total of 29 patients with EGFR-mutant ALA who underwent salvage surgery after EGFR-TKI treatment from October 2013 through January 2019 were enrolled. The patients were divided into two groups according to the surgical indications. Their perioperative parameters and surgical outcomes, including progression-free survival (PFS) and overall survival (OS), were then analyzed.ResultsThe initial stages of the patients were stage IIIB (seven patients), IVA (17 patients), and IVB (five patients). Their surgical indications included residual tumor (25 patients) and progressive disease (PD) (four patients). They all underwent surgery via minimally invasive approaches and the median follow-up was 33.9 months. Within that follow-up duration, the median PFS after surgery was 36.4 months, and the median OS was still not reached. There were no significant differences in PFS or OS according to the different EGFR-TKIs used, the different durations of EGFR-TKI treatment before surgery, or the different surgical indications. However, the patients presenting with pleural seeding before EGFR-TKI treatment had significantly poorer PFS and OS than the other patients (P < 0.001).ConclusionsSalvage surgery following EGFR-TKI treatment of ALAs is a safe procedure with acceptable intra- and postoperative results. However, studies involving more cases and longer follow-up periods are needed to clarify its benefits.Key pointsSalvage surgery following EGFR-TKI treatment of ALAs is a safe procedure with acceptable intra- and postoperative results. Our results support the use of surgery following treatment with EGFR-TKIs such as afatinib in advanced lung cancer.
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