Ethnic difference of driver mutation frequencies and correlations between driver mutations and histologic subtypes in lung adenocarcinoma.

CRA7506 Background: The ability to detect driver mutations like EGFR and EML4-ALK in tumor specimens from patients with lung cancer and administer agents targeting those molecular lesions has revolutionized the management of adenocarcinoma of the lung. The availability of multiplexed assays to detect mutations permits the identification of multiple driver mutations from tumors at diagnosis. The number of molecular lesions and new agents to target them continues to grow. To exploit this, we created the LCMC to determine 10 driver mutations in tumors from 1,000 patients and to give the results to clinicians for care and entry onto targeted therapeutic trials based on these findings. Methods: The 14 member LCMC is prospectively enrolling patients to test tumors from patients with lung adenocarcinoma in CLIA laboratories for KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, and NRAS using standard multiplexed assays and fluorescence in situ hybridization (FISH) for ALK rearrangements and MET amplifications. All are stage IIIB/IV, PS 0-2, have available tissue, and signed consent. Results: 830 patients have been registered with 50 enrolling monthly. We detected a driver mutation in 60% (252/422, 95% CI 55 to 65%) of tumors thus far. Mutations found: KRAS 107 (25%, 95% CI 21 to 30%), EGFR 98 (23%, 95% CI 19 to 27%), ALK rearrangements 14 (6%, 95% CI 4 to11%), BRAF 12 (3%, 95% CI 1 to 5%), PIK3CA 11 (3%, 95% CI 1 to 5%), MET amplifications 4 (2%, 95% CI 0.5 to 5%), HER2 3, (1%, 95% CI 0.1 to 2%), MEK1 2 (0.4%, 95% CI 0.1 to 2%), NRAS 1 (0.2%, 95% CI 0.01 to 1%), AKT1 0 (0%, 95% CI 0 to 1%). 95% of molecular lesions were mutually exclusive. Conclusions: We detected an actionable driver mutation in 60% of tumors from prospectively studied patients with lung adenocarcinoma. Results of EGFR mutation testing are given to treating physicians to select erlotinib as initial treatment per NCCN and ASCO guidelines. Patients with other driver mutations are offered participation in LCMC-linked trials of agents targeting the mutation identified, e.g. crizotinib with EML4-ALK. At half of LCMC sites, multiplexed testing for all mutations is now routine practice in their pathology departments. Supported by 1RC2CA148394-01.

Lung adenocarcinoma is histologically diverse but has distinct histologic growth patterns. There is no consensus on the clinical benefit of this histologic model. We aimed to evaluate the differences in the distribution of the preoperative primary tumor positron emission tomography (PET)/computed tomography (CT) standardized uptake values (SUVs) and survival in the lung adenocarcinoma subtypes. We retrospectively evaluated the data of 107 patients with resected lung adenocarcinoma who had preoperative PET/CT between 2005 and 2017 in a single center. Patients had lepidic, acinar, papillary, micropapillary, and solid histologic subtypes. We compared fluorodeoxyglucose SUVs and survival data of histologic subtypes. The median age of the patients was 62 years (40-75), 76.4% were male, the median SUVmax was 9.4 (1-36.7), and the median follow-up time was 29 months (3-135 months). The median overall survival (OS) was 71 months and the median progression-free survival (PFS) was 33 months. SUVmax was significantly different in histologic subtypes: values for papillary, micropapillary, solid, acinar, and lepidic subtypes were 9.7, 8, 12, 9.1, and 3.9, respectively (p = 0.000). Solid predominant adenocarcinoma had significantly higher SUVmax than the other subtypes (p = 0.001). Lepidic predominant adenocarcinoma had significantly lower SUVmax than the other subtypes (p = 0.000). There was no significant difference in OS between histologic subtypes (p = 0.66), but PFS was significantly different between the groups (p = 0.017), and the solid subtype had a shorter PFS than the other histologic subtypes. Lung adenocarcinoma consists of a diverse group of diseases. Different SUVmax values are seen in different histologic subtypes of nonmetastatic lung adenocarcinoma. Solid predominant types have high SUVmax values while lepidic predominant types have lower SUVmax values. The solid subtype had a shorter PFS than the other histologic subtypes.

The histologic heterogeneity of lung adenocarcinoma is well known. Many histologic subtypes have been described, and recently their prognostic and predictive value has emerged. Laser capture microdissection may aid in the isolation of cancer cells from distinct subtypes of lung adenocarcinoma, thus enabling the description of their specific molecular features. Characterization of epidermal growth factor receptor (EGFR) mutations in histologic subtypes of lung adenocarcinoma has become an important issue. The purpose of this study was to analyze EGFR mutations in exons 18-21 in single histologic subtypes of lung adenocarcinoma after laser capture microdissection. A revision and reclassification of a series of 208 non-small cell lung cancers was conducted, and 62 adenocarcinomas with a total of 119 histologic component subtypes were identified. Laser capture microdissection of each subtype was performed. EGFR mutations in exons 18-21 were detected using polymerase chain reaction single-strand conformation polymorphism and direct DNA sequencing. EGFR mutations were detected only in 3 out of the 62 adenocarcinomas analyzed. Two adenocarcinomas harbored EGFR mutations in exon 19 (the E746-T751 deletion VA insertion and the LREAT deletion) and one adenocarcinoma the EGFR exon 21 L858R missense point mutation. EGFR mutations were observed in all component subtypes. This suggests that, in a patient with lung adenocarcinoma, EGFR mutations are not associated with particular component histologic subtypes and probably occur at an early stage of tumorigenesis. Notably, 2 out of the 3 mutated adenocarcinomas had a bronchioloalveolar component, whereas the third mutated adenocarcinoma had a papillary subtype. Although we detected EGFR mutations only in 3 out of 62 adenocarcinomas and EGFR mutations were present in every subtype of each mutated adenocarcinoma, our research might represent a basis for further studies in characterizing molecular profiles of different component subtypes of lung adenocarcinoma.

Objective: To analyze the clinical features and prognostic factors of different histological subtypes of lung adenocarcinoma. Methods: Data from 370 lung adenocarcinoma patients who underwent surgical resection for pathologically supported adenocarcinoma in our hospital between 2000 and 2003 were retro- spectively reviewed. The Kaplan-Meier method was used to estimate patient survival, and Cox’s proportional hazards model was performed for multivariate analysis. Results: The 5-year overall survival rate was 25.26%, and the mean survival time was 3.89 years. In multivariate analysis, histological subtype, incised margin residual, TNM stage, tumor size, and adjuvant chemotherapy were identified as independent survival predictors. The 5-year survival rate in bronchioloalveolar adenocarcinoma (BAC) patients was 41.30%, higher than in patients with other subtypes of lung adenocarcinoma (P=0.002). No significant difference was found in the prognosis among patients with different subtypes of adenocarcinoma without a BAC component. Conclusion: Ade-nocarcinoma with a BAC component is an independent subtype of lung adenocarcinoma. Its prognosis lies between those of BAC and adenocarcinoma without BAC. Histological subtype, incised margin residual, TNM stage, tumor size, and adjuvant chemotherapy are independent survival predictors.

Objective: Solid and micropapillary pattern are highly invasive histologic subtypes in lung adenocarcinoma and are associated with poor prognosis while the biopsy sample is not enough for the accurate histological diagnosis. This study aims to assess the correlation and predictive efficacy between metabolic parameters in (18)F-fluorodeoxy glucose positron emission tomography/computed tomography ((18)F-FDG PET-CT), including the maximum SUV (SUV(max)), metabolic tumor volume (MTV), total lesion glycolysis (TLG) and solid and micropapillary histological subtypes in lung adenocarcinoma. Methods: A total of 145 resected lung adenocarcinomas were included. The clinical data and preoperative (18)F-FDG PET-CT data were retrospectively analyzed. Mann-Whitney U test was used for the comparison of the metabolic parameters between solid and micropapillary subtype group and other subtypes group. Receiver operating characteristic (ROC) curve and areas under curve (AUC) were used for evaluating the prediction efficacy of metabolic parameters for solid or micropapillary patterns. Univariate and multivariate analyses were conducted to determine the prediction factors of the presence of solid or micropapillary subtypes. Results: Median SUV(max) and TLG in solid and papillary predominant subtypes group (15.07 and 34.98, respectively) were significantly higher than those in other subtypes predominant group (6.03 and 10.16, respectively, P<0.05). ROC curve revealed that SUV(max) and TLG had good efficacy for prediction of solid and micropapillary predominant subtypes [AUC=0.811(95% CI: 0.715~0.907) and 0.725(95% CI: 0.610~0.840), P<0.05]. Median SUV(max) and TLG in lung adenocarcinoma with the solid or micropapillary patterns (11.58 and 22.81, respectively) were significantly higher than those in tumors without solid and micropapillary patterns (4.27 and 6.33, respectively, P<0.05). ROC curve revealed that SUV(max) and TLG had good efficacy for predicting the presence of solid or micropapillary patterns [AUC=0.757(95% CI: 0.679~0.834) and 0.681(95% CI: 0.595~0.768), P<0.005]. Multivariate logistic analysis showed that the clinical stage (Stage Ⅲ-Ⅳ), SUV(max) ≥10.27 and TLG≥7.12 were the independent predictive factors of the presence of solid or micropapillary patterns (P<0.05). Conclusions: Preoperative SUV(max) and TLG of lung adenocarcinoma have good prediction efficacy for the presence of solid or micropapillary patterns, especially for the solid and micropapillary predominant subtypes and are independent factors of the presence of solid or micropapillary patterns.

Adenocarcinoma is the most common type of lung cancer, and pre-operative biopsy plays an important role to determine its major subtypes. As proposed by the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS), and European Respiratory Society (ERS) in 2011, the predominant histological subtype of adenocarcinoma is an indicator of outcomes and recurrence rate. However, the value of CT-guided core biopsy in predicting the predominant subtype and detecting the presence of an aggressive subtype of adenocarcinoma, peripheral sub-solid nodule, has less been discussed. We retrospectively reviewed 318 consecutive peripheral sub-solid nodules that underwent percutaneous CT-guided lung biopsy and surgical resection, between October 2015 and December 2018 and were diagnosed as adenocarcinoma with histological subtype. The subtyping results from biopsy and surgical pathology were compared to evaluate the concordance rate. The overall concordance rate between biopsy and surgical pathology in determining the predominant histological subtype was 64%. Better concordance was found in small tumors (≤ 2cm), in predicting either predominant histology (χ2 = 7.091, P = 0.008) or high grade adenocarcinoma, micropapillary and/or solid subtype, MIP-SOL (χ2 = 22.301, P < 0.001). The analysis of ground glass opacity (GGO) component (C/T ratio) obtained significantly higher accuracy in the pure GGO group than in the other two groups in predicting predominant histology or high grade adenocarcinoma (χ2 = 17.560, P < 0.001 and χ2 = 61.938, P < 0.001, respectively). CT-guided core biopsies provide additional value in predicting the histological subtype of lung adenocarcinoma after surgical resection, especially in small tumors (≤ 2cm) or an initially pure GGO group.

BackgroundAccording to the International Multidisciplinary Classification of Lung Adenocarcinoma (LAD) by International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society (IASLC/ATS/ERS) in 2011, the diagnosis of LAD is changing from simple morphology into a comprehensive multidisciplinary classification. The aim of this study is to detect the expression of Notch-1 and analyze its clinicopathological or prognostic significance in different histological subtypes of Lung Adenocarcinomas (LADs).MethodsWestern blot and Semi-quantitative Reverse transcription-polymerase chain reaction (RT-PCR) assays, as well as immunohisitochemistry, were performed to detect the expression of Notch-1 in LAD cells and tissue samples. Kaplan-Meier and multivariate Cox regression analyses were performed to evaluate the correlation of Notch-1 expression with clinicopathological factors and prognosis of LAD patients.ResultsThe expression level of Notch-1 protein in LAD cell lines or tissues was significantly lower than that in normal human bronchial epithelial cell line (16HBE) or nontumor tissues (P < 0.05). By statistical analyses, it was observed that negative Notch-1 expression was significantly associated with advanced clinical stage (P = 0.001) and lymph node metastasis (P = 0.026) in LAD patients. Also, the recurrence rate of Notch-1-positive group was higher than the Notch-1-negative group (P = 0.001), and patients with positive Notch-1 expression have a prolonged progression of overall survival (P = 0.033). More interestingly, the expression of Notch-1 protein was often observed to be negative in solid predominant adenocarcinoma (SPA) tissues, but highly expressed in papillary predominant adenocarcinoma (PPA) and micropapillary predominant adenocarcinoma (MPA) tissues. Kaplan-Meier survival analysis showed that patients with positive Notch-1 expression had a prolonged progression of overall survival compared with those with negative Notch-1 expression (P = 0.033). The median survival time of Notch-1-positive or negative patients was 64.6 months (95% CI: 31.497-97.703 months) or 36.0 months (95% CI: 12.132-59.868 months).ConclusionsNotch-1 could be used as a predictable biomarker to be detected in different pathological and histological subtypes in LAD for diagnosis or prognosis.

The Underlying Tumor Genomics of Predominant Histologic Subtypes in Lung Adenocarcinoma.

Tumor cell proliferation (Ki-67) expression and its prognostic significance in histological subtypes of lung adenocarcinoma

The discovery of oncogenic drivers has ushered in a new era for lung cancer, but the role of these mutations in different racial/ethnic minorities has been understudied. The Lung Cancer Mutation Consortium 1 (LCMC1) database was investigated to evaluate the frequency and impact of oncogenic drivers in lung adenocarcinomas in the racial/ethnic minority patient population. Patients with metastatic lung adenocarcinomas from 14 US sites were enrolled in the LCMC1. Tumor samples were collected from 2009 through 2012 with multiplex genotyping performed on 10 oncogenic drivers (KRAS, epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase (ALK) rearrangements, ERBB2 [formerly human epidermal growth factor receptor 2], BRAF, PIK3CA, MET amplification, NRAS, MEK1, and AKT1). Patients were classified as white, Asian, African American (AA), or Latino. The driver mutation frequency, the treatments, and the survival from diagnosis were determined. One thousand seven patients were included. Whites represented the majority (n = 838); there were 60 AAs, 48 Asians, and 28 Latinos. Asian patients had the highest rate of oncogenic drivers with 81% (n = 39), and they were followed by Latinos with 68% (n = 19), whites with 61% (n = 511), and AAs with 53% (n = 32). For AAs, the EGFR mutation frequency was 22%, the KRAS frequency was 17%, and the ALK frequency was 4%. Asian patients were most likely to receive targeted therapies (51% vs 27% for AAs). There were no significant differences in overall survival. Differences were observed in the prevalence of oncogenic drivers in lung adenocarcinomas and in subsequent treatments among racial groups. The lowest frequency of drivers was seen for AA patients; however, more than half of AA patients had a driver, and those treated with targeted therapy had outcomes similar to those of other races. Cancer 2016;122:766-772. © 2015 American Cancer Society.

8019 Background: The detection of driver mutations in the EGFR and ALK genes and targeted therapy has transformed treatment of lung cancer. The LCMC was established in 2009 to assay lung adenocarcinomas for driver genomic alterations in 10 genes and to study and treat patients by their molecular subtypes. Methods: The 14-member LCMC enrolled patients with metastatic adenocarcinoma of the lung and tested their tumors in CLIA laboratories for KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, and NRAS mutations using multiplexed assays, and for ALK rearrangements and MET amplifications using fluorescence in situ hybridization (FISH). Results: 1,102 eligible patients were enrolled; 1,007 underwent testing for at least one genomic alteration with 733 undergoing testing for all 10 genes. 600 patients were women (60%) with a median age of 63; 341 were never smokers (34%) and 589 former smokers (58%). A driver alteration was detected in 622 (62%) of the 1,007 with any genotyping, and in 465 (63%) of the 733 fully genotyped cases. Among the tumors with full genotyping, drivers were found as follows: KRAS 182 (25%), sensitizing EGFR 107 (15%), ALK rearrangements 56 (8%), other EGFR 43 (6%), two genes 29 (4%), BRAF 16 (2%), HER2 15 (2%), PIK3CA 6 (1%), MET amplification 5 (1%), NRAS 5 (1%), MEK1 1 (&lt;1%), and AKT1 0 (0%). Results were used to select targeted therapy or targeted trials in 279 patients with a driver alteration (28% of 1,007 total). Among 938 patients with clinical follow-up and treatment information, 264 with a driver alteration treated with a targeted agent had a median survival of 3.5 years; 313 with a driver who did not receive targeted therapy had a median survival of 2.4 years; while 361 without an identified driver had a median survival of 2.1 years (p&lt;0.0001). Conclusions: An actionable driver alteration was detected in 62% of tumors from patients with lung adenocarcinomas, leading to use of a targeted therapy in 28%. The patients with an identified driver treated with a targeted agent lived longer than those patients who did not receive targeted therapy. Multiplexed genomic testing can aid physicians in matching patients with targeted treatments and appropriate clinical trials.

Purpose: The aims of this study were to combine CT images with Ki-67 expression to distinguish various subtypes of lung adenocarcinoma and to pre-operatively predict the Ki-67 expression level based on CT radiomic features.Methods: Data from 215 patients with 237 pathologically proven lung adenocarcinoma lesions who underwent CT and immunohistochemical Ki-67 from January 2019 to April 2021 were retrospectively analyzed. The receiver operating curve (ROC) identified the Ki-67 cut-off value for differentiating subtypes of lung adenocarcinoma. A chi-square test or t-test analyzed the differences in the CT images between the negative expression group (n = 132) and the positive expression group (n = 105), and then the risk factors affecting the expression level of Ki-67 were evaluated. Patients were randomly divided into a training dataset (n = 165) and a validation dataset (n = 72) in a ratio of 7:3. A total of 1,316 quantitative radiomic features were extracted from the Analysis Kinetics (A.K.) software. Radiomic feature selection and radiomic classifier were generated through a least absolute shrinkage and selection operator (LASSO) regression and logistic regression analysis model. The predictive capacity of the radiomic classifiers for the Ki-67 levels was investigated through the ROC curves in the training and testing groups.Results: The cut-off value of the Ki-67 to distinguish subtypes of lung adenocarcinoma was 5%. A comparison of clinical data and imaging features between the two groups showed that histopathological subtypes and air bronchograms could be used as risk factors to evaluate the expression of Ki-67 in lung adenocarcinoma (p = 0.005, p = 0.045, respectively). Through radiomic feature selection, eight top-class features constructed the radiomic model to pre-operatively predict the expression of Ki-67, and the area under the ROC curves of the training group and the testing group were 0.871 and 0.8, respectively.Conclusion: Ki-67 expression level with a cut-off value of 5% could be used to differentiate non-invasive lung adenocarcinomas from invasive lung adenocarcinomas. It is feasible and reliable to pre-operatively predict the expression level of Ki-67 in lung adenocarcinomas based on CT radiomic features, as a non-invasive biomarker to predict the degree of malignant invasion of lung adenocarcinoma, and to evaluate the prognosis of the tumor.

ObjectiveOur prospective study aims to define the correlation of EGFR(epidermal growth factor receptor) mutations with major histological subtypes of lung adenocarcinoma from resected and non-resected specimens, according to the WHO 2015 classification, in Moroccan North East Population.MethodsEpidermal growth factor receptor mutations of 150 primary lung adenocarcinoma were performed using Real-Time PCR or SANGER sequencing. SPSS 21 was used to assess the relationship between histological subtypes of lung adenocarcinoma and EGFR mutation status.Results25 mutations were detected in the series of 150 lung adenocarcinomas, most of which were found in cases with papillary, acinar, patterns than without these patterns and more frequently occurred in the cases without solid pattern than with this pattern. A significant correlation was observed between EGFR mutation and acinar (P = 0,024), papillary pattern (P = 0,003) and, negative association with a solid pattern (P < 0,001). In females, EGFR mutations were significantly correlated with the acinar pattern (P = 0,02), whereas in males with the papillary pattern (P = 0,01). Association between the histologic component and exon 19 deletions and exon 21 mutations were also evaluated and, we found a significant correlation between the papillary major pattern with exon 19 mutations (P = 0,004) and, ex21 with the acinar component (P = 0,03).ConclusionAn analysis of resected and non-resected lung ADC specimens in 150 Moroccan Northeast patients, revealed that acinar and papillary patterns may predict the presence of a mutation in the EGFR gene. While the solid major pattern may indicate a low mutation rate of the EGFR gene.

A different TRAP220 expression in distinct histologic subtypes of lung adenocarcinoma and the prognostic significance

Background The volume doubling time (VDT) is a key parameter in the differentiation of aggressive tumors from slow-growing tumors. How different histologic subtypes of primary lung adenocarcinomas vary in their VDT and the prognostic value of this measurement is unknown. Purpose To investigate differences in VDT between the predominant histologic subtypes of primary lung adenocarcinomas and to assess the correlation between VDT and prognosis. Materials and Methods This retrospective study included patients who underwent at least two serial CT examinations before undergoing operation between July 2010 and December 2018. Three-dimensional tumor segmentation was performed on two CT images and VDTs were calculated. VDTs were compared between predominant histologic subtypes and lesion types by using Kruskal-Wallis tests. Disease-free survival (DFS) was obtained in patients undergoing surgical procedures before July 2017. Univariable and multivariable Cox proportional hazards regression analyses were performed to determine predictors of DFS. Results Among 268 patients (mean age, 64 years ± 8 [standard deviation]; 143 men), there were 30 lepidic, 87 acinar, 109 papillary, and 42 solid or micropapillary predominant subtypes. The median VDT was 529 days (interquartile range, 278-872 days) for lung adenocarcinomas. VDTs differed across subtypes (P < .001) and were shortest in solid or micropapillary subtypes (229 days; interquartile range, 77-530 days). Solid lesions (VDT, 248 days) had shorter VDTs than subsolid lesions (part-solid lesions, 665 days; nonsolid lesions, 648 days) (P < .001). In the 148 patients (mean age, 64 years ± 8; 89 men) included in the survival analysis, 35 patients had disease recurrence and 17 patients died. VDT (<400 days) was an independent risk factor for poor DFS (hazard ratio, 2.6; P = .01) and higher TNM stage. Adding VDT to TNM stage improved model performance (C-index, 0.69 for TNM stage vs 0.77 for combined VDT class and TNM stage; P = .002). Conclusion Volume doubling times varied significantly according to the predominant histologic subtypes of lung adenocarcinoma and had additional prognostic value for disease-free survival. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Ko in this issue.