Acinar Predominant Adenocarcinoma Research Articles

Robotic left apicoposterior bisegmentectomy for non–small cell lung cancer

Robotic left apicoposterior bisegmentectomy for non–small cell lung cancer

Clinicopathological features of patients with RET fusion-positive non-small cell lung cancer

Objective: To investigate the clinicopathological features, treatment and prognosis of patients with RET fusion positive non-small cell lung cancer (NSCLC). Methods: A total of 1 089 NSCLCs were retrieved at Affiliated Hospital of Jiangnan University from August 2018 to April 2020. In all cases, multiple gene fusion detection kits (fluorescent PCR method) were used to detect the gene status of RET, EGFR, ALK, ROS1, KRAS, BRAF and HER2; and immunohistochemical method was used to detect the expression of PD-L1 and mismatch repair related proteins. The correlation between RET-fusion and patients' age, gender, smoking history, tumor stage, grade, pathologic type, and PD-L1, mismatch repair related protein expression was analyzed. Results: There were 22 cases (2.02%) detected with RET fusion-positive in 1 089 NSCLC patients, in which 11 males and 11 females; and the median age was 63.5 years. There were 20 adenocarcinomas, including 11 acinar predominant adenocarcinoma (APA), five solid predominant adenocarcinoma (SPA) and four lepidic predominant adenocarcinoma (LPA); There were one case each of squamous cell carcinoma (non-keratinizing type) and sarcomatoid carcinoma (pleomorphic carcinoma). There were 6 and 16 patients with RET fusion-positive who were in stage Ⅰ-Ⅱ and Ⅲ-Ⅳ respectively, and 16 cases with lymph node metastasis, 11 cases with distant metastasis. Among RET fusion-positive cases, one was detected with HER2 co-mutation. The tumor proportion score of PD-L1≥1% in patients with RET fusion positive lung cancer was 54.5% (12/22). Defects in mismatch repair protein expression were not found in patients with RET fusion positive NSCLC. Four patients with RET fusions positive (two cases of APA and two cases of SPA) received pratinib-targeted therapy, and two showed benefits from this targeted therapy. Conclusions: The histological subtypes of RET fusions positive NSCLC are more likely to be APA or SPA. RET fusion-positive NSCLC patients are associated with advanced clinical stage, lymph node metastases, and they may benefit from targeted therapy with RET-specific inhibitors.

Luptând cu boala la 83 de ani: supravieţuire în cazul infecţiei cu SARS-CoV-2 la o pacientă cu adenocarcinom pulmonar PD-L1 negativ, care a răspuns la tratament anti-PD-1 – prezentare de caz

Background. During the novel coronavirus pandemic, the median overall survival of lung cancer patients has decreased from 7.9 months to 6.7 months. In the TERAVOLT analysis of patients with COVID-19 and thoracic cancers gathered from eight countries, 33% died and 76% needed hospital admission, with an age above 65 years old and presence of any comorbidities being negative prognostic factors. Lung cancer remains a leading cause of cancer-related death worldwide, despite the progress made with targeted therapies and immunotherapy. We present the case of an el­der­ly pa­tient diagnosed with metastatic pulmonary ade­no­car­ci­noma who, despite cardiovascular comorbidities and a negative expression of PD-L1, showed response to nivo­lu­mab (anti-PD-1) therapy and had a good clinical out­come after SARS-CoV-2 infection. Methodology. In January 2019, an 80-year-old female was diagnosed with acinar-predominant adenocarcinoma of the lung, stage IVA, with lung metastasis. She underwent sur­gi­cal treatment, consisting of atypical resection of the left inferior lobe. The tumor tested negative for ALK/EGFR mutations and PD-L1 expression. The pa­tient had a history of treated thyroid neoplasm and several car­dio­vas­cu­lar disorders. Due to her good per­for­mance status, she received first-line chemotherapy with a platinum-based regimen and bevacizumab for one year, until progression was noted following the ima­­­gis­­tic evaluation by computed tomography (CT). Im­mu­no­therapy with nivolumab was started in Fe­bruary 2020. Results. Under nivolumab therapy, the tu­mor showed an initial pseudoprogression, followed by partial response, according to iRECIST criteria. The pa­tient tolerated well the treatment. In December 2020, she tested positive for SARS-CoV-2 infection, with severe symp­toms and CT findings of bilateral ground-glass opa­ci­ties. After specific treatment, with favourable out­come, she was able to continue the nivolumab the­ra­py. Discussion. Anti-PD-L1/PD-1 antibodies (e.g., nivo­lu­mab) act by binding on the programmed death-1 (PD-1) recep­tor found on T cells and blocking its in­te­rac­tion with its ligands, programmed death ligand 1 and 2 (PD-L1 and PD-L2). Those ligands mediate an inhibition of active T-cell proliferation and surveillance of tumors. Tumors can efficiently evade immune responses by ex­pres­sing PD-L and activating this negative regulatory path­way. Although the expression of programmed death ligand 1 (PD-L1) on tumor cells is used in clinical practice as a predictive biomarker for the response to the therapy with anti-PD-L1/PD-1 antibodies, histopathological examinations revealed several examples of how PD-L1 expression can be a misleading marker. It is possible to have a good response to the aforementioned therapy in a PD-L1 negative patient or a lack of response in a PD-L1 positive one. Conclusions. This case illustrates the management of an elderly cancer patient with lung cancer and SARS-CoV-2 infection. The favourable response to nivolumab therapy reinforces the need for new biomarkers and more accurate testing assays in the clinical practice, in order to accurately predict the tumor response to anti-PD-1 antibodies.

P56.03 Prognostic Value of Tumor Spread Through Air Spaces in Patients With Lung Adenocarcinoma after Radical Surgery

Tumor spread through air spaces (STAS) has been identified as an invasive pattern in lung adenocarcinoma (ADC), but the correlations between clinicopathologic features and STAS and the prognostic value of STAS have not been well studied in all stages of ADC with a lager sample size. The purpose of this study was to investigate these correlations and evaluate the prognostic value of STAS in patients with ADC after radical surgery. 988 patients with completely resected lung adenocarcinomas were reviewed. Recurrence-free survival (RFS) was defined as the time between the date of surgery to the date of disease recurrence or the last follow-up. Pearson’s chi-square test or Fisher exact test was used for comparing the relationship between STAS and clinicopathological features. The log-rank test was used to identify potential prognostic factors and multivariate Cox regression models were used to explore independent prognostic factors. Of the 988 patients, STAS was found in 328 (33.2%) patients. STAS was significantly frequent in patients with ever smoking (P=0.049), micropapillary-predominant (MPA) and solid-predominant adenocarcinoma (SPA) (P<0.001), N1-3 diseases (P<0.001), stage Ⅱ-Ⅲ (P<0.001), the presence of VPI (P<0.001), the presence of LVI (P<0.001) and the presence of NI (P<0.001). Univariate analysis revealed that patients with the presence of STAS had a significantly worse RFS in patients with stage Ⅰ(P=0.002), N0 diseases (P<0.001) and intermediate grade lung adenocarcinoma (Acinar-Predominant Adenocarcinoma; APA/ Papillary-Predominant Adenocarcinoma; PPA/Invasive Mucinous Adenocarcinoma; IMA) (P<0.001), but not in patients with stage Ⅱ-Ⅲ(P=0.96), N1-3 disease (P=0.90) and high grade lung adenocarcinoma (MPA/SPA) (P=0.35). Multivariate analysis demonstrated that STAS was an independent prognostic factor for RFS in patients with stage Ⅰ(P=0.018) and N0 diseases (P=0.011). Specially, STAS had independent prognostic significance for RFS in patients with intermediate grade lung adenocarcinoma (APA/PPA/IMA) of N0 diseases (P=0.009). Moreover, STAS status was a significantly prognostic factor for RFS in patients of N0 diseases after lobectomy (P=0.004) and sublobar resection (P=0.03) in univariate analysis. Multivariate analysis found that STAS status remained an independent predictor for RFS in patients of N0 diseases after lobectomy (P=0.008), but not in patients after sublobar resection (P=0.062). The presence of STAS is a significant risk factor for recurrence in N0 and stage ⅠADC patients. Moreover, it will significantly increase the risk of recurrence for patients with intermediate grade lung adenocarcinoma of N0 diseases. The presence of STAS is a high risk factor for recurrence in N0 patients after lobectomy or sublobar resection.

Assessment of relationships among clinicopathological characteristics, morphological computer tomography features, and tumor cell proliferation in stage I lung adenocarcinoma.

BackgroundSurgically resected stage I lung adenocarcinoma (ADC) has wide variation in prognosis. It is significant to identify high-risk patients and optimize therapeutic strategy. This study aimed to investigate the relationships among histological grade, serum tumor marker index (TMI), morphological computer tomography (CT) features, and a well-established prognosticator cell proliferation (Ki-67) in stage I ADC.MethodsPreoperative CT was performed in 182 patients with stage I ADC confirmed by pathology. The Ki-67 expression was acquired by immunohistochemistry. TMI was the square root of standardized serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA 21-1) values. Tumor shadow disappearance rate (TDR) and other morphological CT features were interpreted by two radiologists. Histological grade, TMI, CT features were statistically evaluated to explore the associations with Ki-67 expression.ResultsIn univariate analysis, gender, smoking history, pack-year, histological grade, TNM stage (IA and IB), serum CEA and CYFRA 21-1 status, TMI status, as well as TDR, long-axis diameter, short-axis diameter, lobulation, spiculation, attenuation types, vacuolation, vascular invasion, vascular convergence, thickened bronchovascular bundles, pleural attachment and peripheral fibrosis were significantly associated with Ki-67 expression (all P<0.05). Solid-predominant ADC had the highest Ki-67 expression, followed by micropapillary, papillary and acinar-predominant ADC, while lepidic-predominant ADC had the lowest Ki-67 expression (P<0.001). TDR was negatively correlated with Ki-67 (r =−0.478, P<0.001). Multivariate logistic regression analysis revealed that gender, histological grade, TDR and attenuation types were independent factors associated with Ki-67 expression.ConclusionsKi-67 expression differed distinctly according to ADC histological subtypes. High Ki-67 expression is independently associated with male patients of stage I ADC with worse differentiation, lower TDR and solid tumors, which might be of prognostic value for poor prognosis in stage I ADC.

Deep CNN Model Using CT Radiomics Feature Mapping Recognizes EGFR Gene Mutation Status of Lung Adenocarcinoma.

To recognize the epidermal growth factor receptor (EGFR) gene mutation status in lung adenocarcinoma (LADC) has become a prerequisite of deciding whether EGFR-tyrosine kinase inhibitor (EGFR-TKI) medicine can be used. Polymerase chain reaction assay or gene sequencing is for measuring EGFR status, however, the tissue samples by surgery or biopsy are required. We propose to develop deep learning models to recognize EGFR status by using radiomics features extracted from non-invasive CT images. Preoperative CT images, EGFR mutation status and clinical data have been collected in a cohort of 709 patients (the primary cohort) and an independent cohort of 205 patients. After 1,037 CT-based radiomics features are extracted from each lesion region, 784 discriminative features are selected for analysis and construct a feature mapping. One Squeeze-and-Excitation (SE) Convolutional Neural Network (SE-CNN) has been designed and trained to recognize EGFR status from the radiomics feature mapping. SE-CNN model is trained and validated by using 638 patients from the primary cohort, tested by using the rest 71 patients (the internal test cohort), and further tested by using the independent 205 patients (the external test cohort). Furthermore, SE-CNN model is compared with machine learning (ML) models using radiomics features, clinical features, and both features. EGFR(-) patients show the smaller age, higher odds of female, larger lesion volumes, and lower odds of subtype of acinar predominant adenocarcinoma (APA), compared with EGFR(+). The most discriminative features are for texture (614, 78.3%) and the features of first order of intensity (158, 20.1%) and the shape features (12, 1.5%) follow. SE-CNN model can recognize EGFR mutation status with an AUC of 0.910 and 0.841 for the internal and external test cohorts, respectively. It outperforms the CNN model without SE, the fine-tuned VGG16 and VGG19, three ML models, and the state-of-art models. Utilizing radiomics feature mapping extracted from non-invasive CT images, SE-CNN can precisely recognize EGFR mutation status of LADC patients. The proposed method combining radiomics features and deep leaning is superior to ML methods and can be expanded to other medical applications. The proposed SE-CNN model may help make decision on usage of EGFR-TKI medicine.

Diagnostic and therapeutic ERβ, HER2, BRCA biomakers in the histological subtypes of lung adenocarcinoma according to the IASLC/ATS/ERS classification

Several studies revealed that non–small cell lung cancers (NSCLCs) frequently express ER, PR, HER2 and carry BRCA mutation. However, these markers in histological subtypes of lung adenocarcinoma have not been thoroughly investigated. We retrospectively evaluated a total of 640 lung adenocarcinoma samples for ERα, ERβ, PR and HER2 expression by immunohistochemistry and western-blotting, for EGFR and BRCA mutation by real-time PCR and sequencing. Furthermore, HER2 amplification and mutation were explored in samples harboring immunopositivity HER2 using fluorescence in situ hybridization and real-time PCR, respectively. The micropapillary and invasive mucinous predominant adenocarcinoma were frequently detected the higher level of cytoplasmic ERβ (64.9% and 56.6%), HER2 (68.1% and 60.1%) protein expression. But, amplification of HER2 was detected in only three cases (3/110, 2.7%) and 26 HER2 mutations in 110 cases were identified (23.6%) in the HER2 immunopositivity patients. Logistic regression analysis showed that cytoplasmic ERβ (P = 0.032) and HER2 (P = 0.015) expression were independently associated with EGFR mutation. 8 patients (8/640, 1.25%) harbored pathogenic BRCA mutations, 6 with germline BRCA mutations and 2 with somatic BRCA1 mutations were detected with lacking ERβ, PR and HER2 expression. Acinar predominant adenocarcinoma had the higher percentage of BRCA mutations than other subtypes. A systematic examination of ERβ, HER2 and BRCA biomarkers could potentially be useful to diagnosis and identify patients with the histological subtypes of lung adenocarcinoma, who might benefit from the further individualized treatment of anti-hormone, anti-HER2 and/or PARP inhibitors therapeutics.

Targeted Sequencing Analysis of Predominant Histological Subtypes in Resected Stage I Invasive Lung Adenocarcinoma.

Objective: Lung adenocarcinoma (LADC) is classified into five main histological subtypes with distinct clinicopathologic characteristics: lepidic-predominant adenocarcinoma (LPA), acinar-predominant adenocarcinoma (APA), papillary-predominant adenocarcinoma (PPA), micropapillary-predominant adenocarcinoma (MPA) and solid-predominant adenocarcinoma (SPA). However, the mutational profiles of predominant histological subtypes have not been well defined. In this study, we aimed to reveal the genomic landscape of 5 main histological subtypes.Patients and Methods: We performed next-generation sequencing (NGS) in a cohort of 86 stage I invasive adenocarcinoma (IAC) patients, using a customized panel including 168 cancer-associated genes.Results: Our analysis identified a total of 302 genomic alterations. Five subtypes showed different mutation profiles with LPA, APA, PPA, MPA and SPA had an average mutation rate of 1.95 (range: 0-5), 2.56 (range: 1-6), 3.5 (range: 1-7), 3.75 (range: 1-8) and 6.05 (range: 2-12), respectively (p=4.17e-06).Driver mutations occurred in 96.55% (83/86) of all patients. EGFR (73.3%), KRAS (9.3%), ALK (4.7%) and MET (4.7%) are the most commonly mutated lung cancer driver genes, TP53 is the top mutated tumor suppressor gene. SPA patients harbored more driver mutations and higher frequency of TP53 than LPA patients. Interestingly, LRP1B mutations, which has been reported to be associated with high tumor mutation burden and better response to immunotherapy, were only detected from 5 SPA patients (p=0.001). No patients from other four cohorts harbored LRP1B mutations.Conclusions: We revealed distinctive mutation landscape of the 5 major histological subtypes of LADC, evident by distinctive average mutation rate with SPA and LPA having the highest and lowest average mutation rate, respectively. SPA patients showed higher mutation rate of LRP1B and higher rates for PD-L1 positivity, indicating that SPA patients may have better response to immunotherapy.

Excellent Prognosis of Patients With Invasive Lung Adenocarcinomas During Surgery Misdiagnosed as Atypical Adenomatous Hyperplasia, Adenocarcinoma In Situ, or Minimally Invasive Adenocarcinoma by Frozen Section

Our previous study revealed that intraoperative frozen section (FS) analysis could differentiate invasive lung adenocarcinoma (LUAD) accurately from preinvasive lesions. However, few articles have analyzed the clinical impact of FS errors such as underestimation of invasive adenocarcinomas (IACs), and whether complementary therapy is needed remains controversial. What is the prognosis of patients undergoing limited resection for invasive LUAD misdiagnosed as atypical adenomatous hyperplasia (AAH), adenocarcinoma insitu (AIS), or minimally invasive adenocarcinoma (MIA) by intraoperative FS analysis? From 2012 through 2018, data on 3031 patients undergoing sublobar resection of AAH, AIS, or MIA diagnosed by FS analysis were collected. The concordance rate between FS analysis and final pathologic results was evaluated. To assess the clinical significance of a discrepancy between FS and final pathologic results, patients with final pathologic results of IAC were identified for prognostic evaluation. When AAH, AIS, and MIA were classified together as a group, the overall concordance rate between FS and final pathologic results was 93.7%, and 192 patients (6.3%) received an upgraded diagnosis from the final pathologic results. Misdiagnosed IACs consisted of 94 patients (48.9%) with lepidic-predominant adenocarcinoma, 77 patients (40.1%) with acinar predominant adenocarcinoma, 19 patients (9.9%) with papillary predominant adenocarcinoma, one patient with solid predominant adenocarcinoma, and one patient with invasive mucinous adenocarcinoma. Among these patients, no positive N1 or N2 lymph node findings were observed. Moreover, the 5-year recurrence-free survival was still 100%, although the final pathologic results turned out to be IAC. Patients undergoing limited resection of invasive LUAD misdiagnosed as AAH, AIS, or MIA by FS analysis showed excellent prognoses. Sublobar resection guided by FS diagnosis would be adequate for these underestimated cases of invasive LUAD.

Targeted sequencing analysis of predominant histological subtypes in resected stage I invasive lung adenocarcinoma.

e21067 Background: Lung adenocarcinoma (LADC) is classified into 5 main histological subtypes with distinct clinicopathologic characteristics: lepidic-predominant adenocarcinoma (LPA), acinar-predominant adenocarcinoma (APA), papillary-predominant adenocarcinoma (PPA), micropapillary component (MPC) and solid-predominant adenocarcinoma (SPA). However, the mutational profiles of predominant histological subtypes have not been well defined. In this study, we aimed to reveal the genomic landscape of the 5 main histological subtypes. Methods: Surgically resected tumor samples were obtained from 86 patients with pathological stage I invasive lung adenocarcinoma who underwent surgery between January 2015 and December 2018. No patient had received preoperative chemotherapy or radiotherapy. Capture-based targeted sequencing was performed in a cohort of 86 stage I invasive adenocarcinoma (IAC) patients spanning 5 subtypes using a panel consisting of 168 lung cancer-related genes. Results: Our analysis identified a total of 302 genomic alterations. Five subtypes showed distinct mutation profiles with LPA, APA, PPA, MPC and SPA had an average mutation rate of 1.95 (range: 0–5), 2.56 (range: 1–6), 3.5 (range: 1–7), 3.75 (range: 1-8) and 6.05 (range: 2-12), respectively (p = 4.17e-06). In this cohort, 96.55% (83/86) of all patients had mutations in classic lung cancer drivers with EGFR (73.3%), KRAS (9.3%), ALK (4.7%) and MET (4.7%) being the most commonly mutated drivers. TP53 is the top mutated tumor suppressor gene. It has been reported that SPA and MPC have unfavorable prognosis comparing to the rest subtypes. Interestingly, LRP1B mutations, which has been reported to be associated with high tumor mutation burden and better response to immunotherapy, were only detected from 5 SPA patients (p = 0.001). No MPC patients from this cohort harbored LRP1B mutations. Conclusions: We revealed distinctive mutation landscape of the 5 major histological subtypes of LADC, evident by distinctive average mutation rate with SPA and PLA having the highest and lowest average mutation rate, respectively. Furthermore, we also showed that SPA patients harboring LRP1B mutations may benefit from immunotherapy.

Clinicopathological features, survival outcomes, and appropriate surgical approaches for stage I acinar and papillary predominant lung adenocarcinoma.

BackgroundWhether prognosis differs between lung acinar predominant adenocarcinoma (ACN) and papillary predominant adenocarcinoma (PAP) patients remains controversial. Furthermore, the appropriate surgical plan for each subtype is undetermined.MethodsData of stage I ACN or PAP patients from 2004 to 2015 were retrospectively reviewed by SEER*Stat 8.3.5. The primary outcome was overall survival (OS) and lung cancer specific survival (LCSS).Results1531 patients (PAP, 484; ACN, 1047) were included. ACN patients had better OS (P = .001) and LCSS (P = .003) than PAP patients. Among stage I ACN patients, lobectomy with mediastinal lymph node dissection (Lob) (P = .001) or segmentectomy (Seg) (P = .003) provided a better OS than wedge resection (Wed). And ACN patients who received Lob had a equivalent LCSS, compared to those who received Seg (P = .895). For patients with PAP in stage I, those who received Lob tended to have a better prognosis than that received Seg (HR of OS, 0.605, 95% CI: 0.263‐1.393; HR of LCSS, 0.541, 95% CI: 0.194‐1.504) or Wed (HR of OS, 0.735, 95% CI: 0.481‐1.123; HR of LCSS, 0.688, 95% CI: 0.402‐1.180).ConclusionsAmong patients with lung adenocarcinoma in stage I, those with ACN have a better OS and LCSS than that with PAP. For patients with stage I ACN, Seg and Lob, rather than Wed, seem to be an equivalent treatment choice; however, Seg is the prior option because it could preserve more lung function than Lob. For patients with PAP, Lob tends to be a better choice than Wed and Seg, although the prognostic difference between them is nonsignificant.

Use of a prognostic risk score that aggregates the FDG-PET/CT SUVmax, tumor size, and histologic group for predicting the prognosis of pStage I lung adenocarcinoma.

pStage I includes clinicopathologically diverse groups. This study aimed to identify the prognostic factors for pStage I lung adenocarcinoma. We retrospectively reviewed 208 patients with pStage I adenocarcinomas who underwent curative resection in our institute between 2006 and 2013. The maximum standardized uptake value (SUVmax) on [F18]-fluoro-deoxy-D-glucose positron emission tomography-computed tomography (PET/CT) was evaluated. Adenocarcinomas were categorized into the following histologic groups: group 0 (minimally invasive adenocarcinoma and lepidic predominant adenocarcinoma), group 1 (papillary predominant adenocarcinoma), and group 2 (acinar predominant adenocarcinoma and all the remaining subtypes). We assessed the relationship between disease-free survival (DFS) and clinicopathological factors. Multivariate analysis of DFS demonstrated that SUVmax > 3.0 (p < 0.001), total tumor size > 20mm (p = 0.016), and histologic groups (p < 0.05) were independent prognostic factors. The prognostic risk score (PRS) was calculated using the following equation: PRS = SUVmax (≤ 3.0: 0 point, > 3.0: 2 points) + total tumor size (≤ 20mm: 0 point, > 20mm: 1 point) + histologic group (group 0: 0 point, group 1: 1 point, group 2: 2 points). Patients were divided into the following three risk groups: low-risk (PRS 0-2 points, n = 136), intermediate-risk (PRS 3-4 points, n = 49), and high-risk groups (PRS 5 points, n = 13). The 5-year DFS rates were 93.2%, 50.6%, and 30.8% for the low-, intermediate-, and high-risk groups, respectively (p < 0.001). The PRS aggregating the FDG-PET/CT SUVmax, total tumor size, and histologic group predicts the prognosis of pStage I lung adenocarcinoma.

Epidermal growth factor receptor mutation status in pulmonary adenocarcinoma: Multi-institutional data discussion at national conference of “Lung Cancer Management in Indian context”

The presence of activating mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene in adenocarcinomas of lung confers sensitivity to tyrosine kinase inhibitor therapy. The prevalence of EGFR mutations varies among different ethnicities and demographic profile. This multi-institutional data was compiled to determine the EGFR mutation status in Indians patients with lung adenocarcinoma. Cohorts represented by 4 tertiary care hospitals participated in data discussion at a national conference entitled as ‘Lung Cancer Management in Indian Context’. The clinicopathologic data and EGFR mutation rate in the patients of lung adenocarcinoma screened in these cohorts were collected and analyzed. The sample types included both surgical and cytological specimens. A variety of methods were used including immunohistochemistry, polymerase chain reaction, Sanger sequencing and next generation sequencing. A total of 3436 cases of treatment naïve lung adenocarcinoma were tested for EGFR mutations. The overall frequency of EGFR mutations observed was 30.03%. The most common baseline mutation detected was exon 19 deletion followed by L858R point mutation in exon 21. Dual mutations were observed in 6.5% of cases and were predominantly combinations of exon 19 deletion and T790M point mutation in exon 20. Incidence of EGFR mutations was higher among females and non-smokers diagnosed with lung adenocarcinomas. The most common histology in EGFR mutant cases was acinar predominant adenocarcinomas. With nearly one-third of Indian patients with lung adenocarcinoma harboring EGFR mutations, routine testing for these mutations is important to get the benefit of targeted therapy.

MUC5AC enhances tumor heterogeneity in lung adenocarcinoma with mucin production and is associated with poor prognosis.

The clinicopathological significance of Mucin5AC (MUC5AC) in lung adenocarcinoma with mucin production is still unclear. This study aimed to explore MUC5AC expression in lung adenocarcinoma with mucin production and its correlation with histological subtypes, common driver mutations and its impact on prognosis. MUC5AC and thyroid transcription factor 1 immunohistochemistry was performed on surgical samples from 90 patients with lung adenocarcinoma with mucin production. Common driver mutations including EGFR and KRAS mutations and ALK rearrangement were detected by established methods. MUC5AC was significantly associated with lymphovascular invasion (P=0.023) and tumors with intra-cytoplasmic mucin (P<0.001). Moreover, MUC5AC was more significant in invasive mucinous adenocarcinoma (P<0.001), as well as in tumors with KRAS mutations (P=0.005) and a lack of thyroid transcription factor 1 expression (P<0.001). Conversely, MUC5AC was less significantly detected in acinar predominant adenocarcinoma (P=0.036) and tumors with EGFR mutations (P=0.001). Notably, MUC5AC in non-pure mucinous subtype of lung adenocarcinoma with mucin production showed more aggressive behavior, distinct expression pattern and a lack of significant correlation with thyroid transcription factor 1 (P=0.113) when compared with pure mucinous subtype. MUC5AC-positive tumors were significantly associated with a worse prognosis compared to MUC5AC-negative tumors (P<0.001). A multivariate survival analysis showed that MUC5AC was an independent prognosis factor for poor prognosis (P=0.006). The clinicopathological features of non-pure mucinous subtype of lung adenocarcinoma with mucin production were distinct and should be distinguished from pure mucinous subtype. MUC5AC was associated with poor prognosis and could be a potential therapeutic target for this distinct type of lung adenocarcinoma that has few effective treatments.

Morule-like features in pulmonary adenocarcinoma associated with epidermal growth factor receptor mutations: two case reports with targeted next-generation sequencing analysis.

Morules, or morule-like features, can be identified in benign and malignant lesions in various organs. Morular features are unusual in pulmonary adenocarcinoma cases with only 26 cases reported to date. Here, we describe two cases of pulmonary adenocarcinoma with morule-like features in Korean women. One patient had a non-mucinous-type adenocarcinoma in situ and the other had an acinarpredominant adenocarcinoma with a micropapillary component. Both patients showed multiple intra-alveolar, nodular, whorled proliferative foci composed of atypical spindle cells with eosinophilic cytoplasm. Targeted next-generation sequencing was performed on DNA extracted from formalin-fixed paraffin-embedded samples of the tumors. Results showed unusual epidermal growth factor receptor (EGFR) mutations, which are associated with drug resistance to EGFR tyrosine kinase inhibitors, revealing the importance of identifying morule-like features in pulmonary adenocarcinoma and the need for additional study, since there are few reported cases.

Correlation Study of 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Pathological Subtypes of Invasive Lung Adenocarcinoma and Prognosis.

Purpose: To investigate the correlation between 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) metabolic parameters and clinicopathological factors in pathological subtypes of invasive lung adenocarcinoma and prognosis.Patients and Methods: Metabolic parameters and clinicopathological factors from 176 consecutive patients with invasive lung adenocarcinoma between August 2008 and August 2016 who underwent 18F-FDG PET/CT examination were retrospectively analyzed. Invasive lung adenocarcinoma was divided into five pathological subtypes:lepidic predominant adenocarcinoma (LPA), acinar predominant adenocarcinoma (APA), papillary predominant adenocarcinoma (PPA), solid predominant adenocarcinoma (SPA), and micropapillary predominant adenocarcinoma (MPA). The differences in metabolic parameters [maximal standard uptake value (SUVmax), mean standard uptake value (SUVmean), total lesion glycolysis (TLG), and metabolic tumor volume (MTV)] and tumor diameter for different pathological subtypes were analyzed. Patients were divided into two groups according to their prognosis: good prognosis group (LPA, APA, PPA) and poor prognosis group (SPA, MPA). Logistic regression was used to filter predictors and construct a predictive model, and areas under the receiver operating curve (AUC) were calculated. Cox regression analysis was performed on prognostic factors.Results: 82 (46.6%) females and 94 (53.4%) males of patients with invasive lung adenocarcinoma were enrolled in this study. Metabolic parameters and tumor diameter of different pathological subtype had statistically significant (P < 0.05). The predictive model constructed using independent predictors (Distant metastasis, Ki-67, and SUVmax) had good classification performance for both groups. The AUC for SUVmax was 0.694 and combined with clinicopathological factors were 0.745. Cox regression analysis revealed that Stage, TTF-1, MTV, and pathological subtype were independent risk factors for patient prognosis. The hazard ratio (HR) of the poor prognosis group was 1.948 (95% CI 1.042–3.641) times the good prognosis group. The mean survival times of good and poor prognosis group were 50.2621 (95% CI 47.818–52.706) and 35.8214 (95% CI 27.483–44.159) months, respectively, while the median survival time was 47.00 (95% CI 45.000–50.000) and 31.50 (95% CI 23.000–49.000) months, respectively.Conclusion: PET/CT metabolic parameters combined with clinicopathological factors had good classification performance for the different pathological subtypes, which may provide a reference for treatment strategies and prognosis evaluation of patients.

Unusual synchronous double primary treatment-na\xefve lung adenocarcinoma harboring T790M and L858R mutations in early-stage lung cancer

BackgroundConcurrent mutations of synchronous multiple primary non-small cell lung cancer (SMPNSCLC) is rare, and only a few cases have been reported. Herein, we present a case of early-stage SMPNSCLC with T790M and L858R mutations.Case presentationA 68-year-old male patient presented to the Thoracic Surgery Department due to a tumor in the right lower lung. The tumor was detected more than 5 years previously during a health examination; however, the patient ignored the problem because the clinician at that time stated that the lesion was highly likely to be benign. Chest computed topography (CT) was ordered and the images showed a well-defined tumor in the right lower lung and a faint nodular lesion over the left lower lung field. A CT-guided biopsy results showed the presence of atypical cells and positive staining of TTF-1 and CK7. Surgical intervention was performed. The right- and left-sided tumors disclosed micropapillary predominant adenocarcinoma and acinar-predominant adenocarcinoma, respectively. Both tumors were positive for TTF-1 but negative for ALK and p40. Real-time PCR analysis showed that the right-sided tumor had an epidermal growth factor receptor (EGFR) mutation presenting as point mutation T790M in exon 20, while the left-sided tumor had a point mutation L858R in exon 21 of EGFR.ConclusionsOur patient’s case suggests that tumors resembling a benign pattern with central calcification may be misdiagnosed. Thus, early screening for lung cancer is important, and intensive efforts to make a diagnosis through surgical resection or biopsies to allow for tailored optimal treatment may be preferential for the best patient outcomes.

Detection of Novel NRG1, EGFR, and MET Fusions in Lung Adenocarcinomas in the Chinese Population

IntroductionMultiple oncogene fusions beyond ALK receptor tyrosine kinase (ALK), RET, and ROS1 fusion has been described in lung cancer, especially in lung adenocarcinomas without common oncogenic mutations. Molecular inhibitors have been developed and proved effective for patients whose tumors harbor these novel alterations. MethodsA consecutive series of surgically resected lung adenocarcinomas were collected and profiled using an enrichment strategy to detect nine common oncogenic driver mutations and fusions concerning EGFR, KRAS, HER2, BRAF, MET, ALK, RET, ROS1, and FGFR. Driver-negative cases were further analyzed by a comprehensive RNA-based next-generation sequencing (NGS) fusion assay for novel fusions. ResultsIn total, we profiled 1681 lung adenocarcinomas, among which 255 cases were common driver–negative. One hundred seventy-seven cases had sufficient tissue for NGS fusions screening, which identified eight novel fusions. NRG1 fusions occurred in 0.36% of all lung adenocarcinoma cases (6 of 1681 cases), including 4 CD74-NRG1–positive cases, 1 RBPMS-NRG1–positive case, and 1 novel ITGB1-NRG1–positive case. Furthermore, another 2 novel fusions were also detected, including 1 EGFR-SHC1 fusion and 1 CD47-MET fusion, both of which were in-frame and retained the functional domain of the corresponding kinases. No fusion event was detected for NTRK, KRAS, BRAF or HER2 genes in this cohort. Detailed clinicopathologic data showed that invasive mucous adenocarcinoma (three of eight cases) and acinar-predominant adenocarcinoma (three of eight cases) were the most prevalent pathologic subtypes among novel fusions. ConclusionsFusions affecting NRG1, EGFR, and MET were detected in 0.48% of unselected lung adenocarcinomas, and NRG1 fusions ranked the most prevalent fusions in common driver-negative lung adenocarcinomas from Chinese population. RNA-based NGS fusion assay was an optional method for screening actionable fusions in common driver-negative cases.

PD-L1 Expression in Non-Small-Cell Lung Cancer Including Various Adenocarcinoma Subtypes.

Purpose: Knowledge regarding programmed death-ligand 1 (PD-L1) expression in lung cancer is limited. We aim to clarify PD-L1-positive expression in non-small-cell lung cancer (NSCLC), including adenocarcinoma subtypes.Methods: In all, 90 NSCLC specimens containing various adenocarcinoma subtypes, in addition to squamous cell carcinoma and large-cell carcinoma were selected. PD-L1 was immunohistochemically stained by murine monoclonal antibody clone 22C3.Results: When PD-L1-positive expression was defined by tumor proportion score (TPS) ≥1%, the positive cases were 0/11 in adenocarcinoma in situ, 0/12 in minimally invasive adenocarcinoma, 1/10 in lepidic predominant adenocarcinoma, 1/13 in papillary predominant adenocarcinoma, 8/14 in acinar predominant adenocarcinoma, 6/11 in solid predominant adenocarcinoma, 0/3 in micropapillary predominant adenocarcinoma, 0/4 in invasive mucinous adenocarcinoma, 4/9 in squamous cell carcinoma, and 2/3 in large-cell carcinoma. PD-L1 positivity was higher in males, smokers, advanced pathologic stages, positive vessel invasion, and positive lymphatic invasion. Postoperative survival analysis revealed that PD-L1-positive expression was a significantly worse prognostic factor in univariate analysis for recurrence-free survival (RFS).Conclusion: PD-L1-positive tumors were frequent in acinar predominant adenocarcinoma and solid predominant adenocarcinoma than other adenocarcinoma subtypes. PD-L1 expression seemed to increase according to pathologic tumor progression, suggesting a worse postoperative prognosis in NSCLC patients.

Abstract 814: Aurora kinase: A target modulating invasiveness of lung adenocarcinoma

Abstract Introduction: Lung cancer is the major cause of cancer-related deaths in United States and lung adenocarcinoma (LUAD) is its most common subtype exhibiting highly variable molecular signature. Identification of patients at high risk of developing invasive tumor is important for their better management. Experimental procedure: We obtained 53 early-stage LUAD patient's tumor samples, histopathologically classified into 32 indolent (adenocarcinoma in situ, minimally invasive and lepidic predominant adenocarcinoma) and 21 invasive (acinar predominant, papillary predominant, micropapillary predominant and solid predominant adenocarcinoma) subtypes and profiled their transcriptomes by RNA sequencing. We clustered these samples in an unsupervised manner followed by additional supervised clustering into 2 groups. Using our signature genes, we categorized 51 lung adenocarcinoma cell lines from Cancer Cell Line Encyclopedia database based on their relative invasiveness scores derived from elastic network trained in our dataset. We chose NCI-H1792, NCI-H1373, SK-LU-1 and NCI-H2009 representing high while HCC1833, Calu3 and NCI-H3255 representing low invasive signature for our in vitro functional assays. Summary: Our clustering significantly overlapped with the groups classified by histology and we defined 21 tumors as “invasive” and 32 as “non-invasive” early stage LUAD. We identified 1,322 differentially expressed genes between two groups with 526 upregulated and 796 downregulated genes in invasive tumors. Among the enriched signature genes, AURKA and AURKB were significantly upregulated in the “invasive” group. We used two potent aurora kinase inhibitors AMG 900 and PF-03814735 to determine the effect of aurora kinase inhibition on invasiveness of LUAD cells. AMG 900 and PF-03814735 significantly inhibited Aurora kinase (Aur-) A and B activity, but did not affect cell viability (IC50 ≥2μM) of all cell lines regardless of their invasiveness score. Of note, both drugs significantly suppressed wound healing, migration and invasion of all four “invasive” cell lines at much lower 100nM. Moreover, the cells with low invasive signature used in the study showed little migration and invasion thus confirming the validity of our elastic network analysis for their relative invasiveness. Conclusion: Here, we have identified a robust gene signature that distinguishes invasive to indolent non-invasive early-stage LUADs, which may lead to development of assays on clinical specimens such as biopsy to identify patients at high risk of developing invasive LUAD at an early stage. This gene signature also suggests Aur-A and B promote invasiveness in early stage LUAD. Our in vitro functional data suggest that targeting Aur-A and B could be a promising approach for management of early stage LUAD patients who are more likely to develop an invasive tumor. Citation Format: Abhilasha Sinha, Seungyeul Yoo, Hideo Watanabe, Jun Zhu, Charles A. Powell. Aurora kinase: A target modulating invasiveness of lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 814.