Node-negative Lung Adenocarcinoma Research Articles

P1.25-08 Surgical Outcomes in Patients with Resected Node-negative Lung Adenocarcinoma of 2 cm or Smaller

P1.25-08 Surgical Outcomes in Patients with Resected Node-negative Lung Adenocarcinoma of 2 cm or Smaller

Role of ground-glass opacity in pure invasive and lepidic component in pure solid lung adenocarcinoma for predicting aggressiveness

ObjectiveLung adenocarcinoma often includes noninvasive components with postoperative lepidic morphology on pathologic specimens that appear on preoperative high-resolution computed tomography (HRCT) images as ground-glass opacity (GGO). We aimed to disclose the role of GGO on the aggressiveness of pathologically confirmed pure invasive tumors in patients with early-stage lung adenocarcinoma. MethodsThe prognosis of 932 patients with clinical stage 0-IA and pathologic node-negative lung adenocarcinoma who underwent lobectomy at 3 institutions between 2010 and 2016 was investigated according to the status of GGO and lepidic components. ResultsThe recurrence-free survival (RFS) of patients with pathologically confirmed pure invasive tumors was worse without (n = 81) than with (n = 43) GGO (69.7%; 95% confidence interval [CI], 57.3%-79.2% vs 90.5%; 95% CI, 76.6%-96.3%, P = .028). The RFS of patients with radiologically confirmed pure solid tumors was worse without (n = 81), than with (n = 173) a lepidic component (69.7%; 95% CI, 57.3%-79.2% vs 85.3%; 95% CI, 77.2%-90.7%, P = .0012). Multivariable Cox regression analysis of overall survival and RFS revealed that pure solid and pure invasive tumors, respectively, determined by HRCT and pathologic assessment together comprised an independent prognostic factor like vascular or pleural invasion for patients with early-stage lung adenocarcinoma. ConclusionsTumors of non–small cell lung cancer with pure solid and pure invasive components were more aggressive than those with some GGO and lepidic components. Complementary HRCT and pathologic findings can predict the malignant aggressiveness of adenocarcinoma.

Prognostic influence of a ground-glass opacity component in hypermetabolic lung adenocarcinoma.

We evaluated the oncological role of a ground-glass opacity (GGO) component in hypermetabolic lung adenocarcinoma with a high maximum standardized uptake value. Between 2008 and 2017, we retrospectively reviewed the data of surgically resected clinically node-negative lung adenocarcinomas with a hypermetabolic activity. Furthermore, they were classified based on the presence of GGO. The prognostic significance of a GGO in hypermetabolic tumours was evaluated using the Cox proportional-hazards model. The overall survival (OS) was estimated by the Kaplan-Meier method using a log-rank test. Of the 1134 surgically resected clinically node-negative lung adenocarcinoma, 603 cases with hypermetabolic activity (maximum standardized uptake value ≥3.0 mg/dl) were evaluated. Among them, there were 120 (20%) cases in the With GGO group and 483 (80%) in the Solid group. The 5-year OS of patients with hypermetabolic lung adenocarcinoma was significantly different between the With GGO and Solid groups (83.1% vs 59.4%, P < 0.001). After stratifying by the presence of GGO, maximum standardized uptake value and maximum tumour size were independently significant prognosticators in the Solid group by multivariable analysis; however, no clinical factors were associated with survival among the With GGO group. The 5-year OS was favourable despite the solid component size among the With GGO group (T1a + T1b: 85.5%, T1c: 80.0%, T2a or more: 84.2%, P = 0.904). For the Solid group, survival diminished drastically with increasing tumour size (T1a + T1b: 68.7%, T1c: 62.8%, T2a or more: 48.0%, P < 0.001). The prognosis of lung adenocarcinoma with GGO was favourable even in hypermetabolic tumours. Accordingly, the presence of GGO should be considered as an important parameter in the next clinical T classification.

MCM4 as a prognostic biomarker of early-stage lung cancer.

e21033 Background: Prognostic biomarker in early-stage lung cancer is less well defined. Despite early detection, one-third of patients with completely resected early-stage lung cancer without lymph node involvement have a recurrence. Our main objective is to investigate potential biomarkers useful in classification and predicting prognosis of this early-stage lung cancer, particularly in lymph node-negative subgroup. Methods: In discovery phase, we performed proteomic profiling on 60 lung cancer tissues to distinguish solid versus non-solid adenocarcinoma. Relative protein quantification was analyzed using Tandem Mass Tag mass spectrometry. In validation phase, tumor tissues from an additional cohort were analyzed by immunohistochemistry in conjunction with quantitative image analysis to confirm the differential expression of significantly altered proteins, including MCM2, MCM4, MCM6, SCAMP3, DPP4 and MYH11. Prognostic potentials of each biomarker were analyzed with univariate and multivariate analyses. Results: Quantitative proteomic analysis of predominantly solid versus non-solid adenocarcinoma tissues showed 30 differentially expressed proteins consisting of 13 increased and 17 decreased proteins found in solid compared with non-solid adenocarcinoma. Four most increased proteins (MCM2, MCM4, MCM6, and SCAMP3) and two most decreased proteins (DPP4 and MYH11) were selected for immunostaining in the validation cohort of 204 patients with resected adenocarcinoma without lymph node involvement. 57 out of 204 (27.9%) patients had recurrent disease. The high expression level of MCM4 was the strongest signature for disease recurrence (HR 4.85, 95%CI 2.78-8.47, p &lt; 0.0001) and remained significant under multivariate analyses adjusted for TNM stage, histologic subtypes, lymphovascular invasion, tumor necrosis, and adjuvant chemotherapy. Recurrence-free survival (RFS) was significantly shorter in patients with high MCM4 compared with low MCM4 (5-y RFS 50% vs 84%, p &lt; 0.0001) and remained highly significant within stage IA (5-y RFS 69% vs 93%, p &lt; 0.0001), or stage IB and II (5-y RFS 36% vs 69%, p = 0.001). High expression of MCM4 correlated with other poor prognosis factors including smoking (p = 0.001), stage (p = 0.003), lymphovascular invasion (p = 0.036), visceral pleural invasion (p = 0.005), tumor necrosis (p &lt; 0.0001) and solid histology (p &lt; 0.0001). Conclusions: High MCM4 expression serves as an important prognostic biomarker predicting recurrence in early-stage node-negative lung adenocarcinoma.

Prognostic stratification of pathological node-negative lung adenocarcinoma by carcinoembryonic antigen level.

Carcinoembryonic antigen (CEA) is a well-known tumour marker for lung adenocarcinoma (AC). This study was conducted to evaluate the clinical characteristics and prognosis of patients with pathological node-negative lung AC who have a high preoperative level of CEA. Among 2124 patients with lung AC between 2003 and 2016, 858 patients were enrolled. CEA levels were dichotomized as normal (≤5 ng/ml) or high (>5 ng/ml). According to the levels of CEA between 6 and 12 months after surgery, patients were divided into a normalized and a remained-high group. Propensity score matching was used to compare 80 patients without adjuvant chemotherapy (ACT) with 39 patients with ACT. Kaplan-Meier survival analysis with the log-rank test and Cox proportional hazards regression analysis were performed for recurrence-free survival (RFS) and overall survival (OS). The multivariable analysis showed that high maximum standardized uptake value and T2 stage were more common in patients with high levels of CEA. The median follow-up period was 52.8 months (range 6-169 months). The 5-year RFS and OS rates were 89.3% and 68.9% and 92.8% and 77.2% in normal patients and patients with high levels of CEA, respectively, with a statistically significant difference. The 5-year RFS was 79.4% and 39.2% in the normalized and remained-high groups after surgery, respectively (P = 0.011). The 5-year RFS and OS rates were 68.9% and 62.2% and 80.1% and 82.9% in patients without and with ACT, respectively. After propensity score matching, RFS was not significantly different between patients without and with ACT (P = 0.500); however, OS was significantly better in patients with ACT than in those without ACT (P = 0.001). The clinicopathological characteristics, RFS and OS of patients with lung AC might be well discriminated by preoperative CEA levels. In patients with node-negative disease and high CEA levels, those with normalized CEA levels had a significantly better prognosis than those with persistently high CEA levels.

Occult mediastinal lymph node metastasis in FDG-PET/CT node-negative lung adenocarcinoma patients: Risk factors and histopathological study.

BackgroundThe aim of this study was to investigate predictive factors of occult mediastinal lymph node metastasis (MLNM) in preoperative 18F‐fluorodeoxy‐glucose PET/CT node‐negative lung adenocarcinoma patients.MethodsWe reviewed the clinical data and PET/CT parameters of 360 consecutive pulmonary adenocarcinoma patients who were scheduled to undergo anatomical pulmonary resection and systemic mediastinal node dissection. The nodal metastasis was pathologically defined and all resected tumors were classified according to the 2011 IASLC/ATS/ERS classification. Univariate and multivariate analysis were conducted to evaluate the associations between clinicopathological variables and MLNM.ResultsOf all 360 patients, 54 (15.0%) had pathological N2 diseases. The serum CEA level, nodule type, hilar nodal SUVmax, tumor SUVmax, size, location and histologic subtype were associated with MLNM significantly on univariate analysis. On multivariate analysis, CEA ≥ 5.0 ng/mL (P < 0.001), solid nodule (P = 0.012), tumor SUVmax ≥ 3.7 (P < 0.027), hilar nodal SUVmax ≥ 2.0 (P < 0.001) and centrally located tumor (P = 0.035) were independent risk factors for MLNM. The area under the ROC curve (AUC) for tumor SUVmax and hilar nodal SUVmax in predicting MLNM was 0.764 and 0.730, respectively, and the combined use of five factors yielded a higher AUC of 0.885.ConclusionIncreased primary tumor and hilar lymph node SUVmax, solid nodule, centrally located tumor and increased CEA level predicted the increased risk of mediastinal lymph node metastasis. Combined use of these factors improved the diagnostic capacity for predicting N2 disease preoperatively. Invasive mediastinal staging should be considered for patients with these risk factors, even those with a negative mediastinum on PET/CT.

Factors associated with distant recurrence following R0 lobectomy for pN0 lung adenocarcinoma

ObjectiveWe investigated factors associated with distant recurrence, disease-free survival (DFS), and overall survival (OS) following R0 lobectomy for pathologic node-negative (pN0) lung adenocarcinoma. MethodsWe performed a retrospective analysis of a prospectively maintained database of patients with pT1-3N0M0 non–small cell lung cancer. Exclusion criteria included metachronous lung cancer, sublobar/incomplete resection, nonadenocarcinoma histology, and induction/adjuvant therapy. The primary outcome was distant recurrence; secondary outcomes were DFS and OS. Associations between variables and outcomes were assessed by Fine–Gray competing-risk regression for distant recurrence and Cox proportional hazard models for DFS and OS. ResultsOf 2392 patients identified with pT1-3N0M0 lung adenocarcinoma, 893 met the inclusion criteria. Median follow-up was 35.0 months (range, 0.1-202 months). Thirteen percent of patients developed recurrence (n = 115), of which 86% (n = 99) were distant. The 5-year cumulative incidence of distant recurrence was 14% (95% confidence interval [CI], 11%-17%). On multivariable analysis, pT2a (hazard ratio [HR], 2.84; 95% CI, 1.56-5.16; P = .001) and pT2b/3 (HR, 6.53; 95% CI, 3.17-13.5; P < .001) tumors were associated with distant recurrence. Recent surgery was associated with decreased distant recurrence (HR, 0.43; 95% CI, 0.20-0.91; P = .028), and lymphovascular invasion was strongly associated with distant recurrence (HR, 1.62; 95% CI, 1.00-2.63; P = .05). DFS was independently associated with pT stage (P < .001) and lymphovascular invasion (P = .004). ConclusionsIn patients undergoing R0 lobectomy with pN0 lung adenocarcinoma, pT stage and lymphovascular invasion were associated with distant recurrence and decreased DFS. These observations support the inclusion of these patients in future clinical trials investigating adjuvant targeted and immunotherapies.

P2.05-020 Prognostic Factors in Patients with Completely Resected Subsolid Node-Negative Lung Adenocarcinoma of 3cm or Smaller

The operative method in ground glass pulmonary nodules is controversial. The prognostic value of histological subtypes in resected node-negative small-sized lung adenocarcinoma has not been widely investigated. This study aim to investigate the prognostic factors in patients with resected small ground glass nodules with consolidation/tumor (C/T) ratio of 0.5 or less determined by chest computed tomography.

1279P - Factors predicting worse outcomes in patients with N0 lung adenocarcinoma of 3cm or smaller

Background: The role of adjuvant chemotherapy for patients with stage I non-small cell lung cancer remains unknown. The prognostic value of histological subtypes in resected node-negative small-sized lung adenocarcinoma has not been widely investigated. This study investigated the prognostic factors in patients with node-negative lung adenocarcinoma of 3cm or smaller to find potential candidates for adjuvant chemotherapy. Methods: A total of 746 patients with completely resected node-negative lung adenocarcinoma of 3cm or smaller were included in the study. Prognostic factors for overall survival or probability of freedom from recurrence (FFR) were investigated. Results: The 5-year overall survival and recurrence-free rates were 86.8% and 84.8%, respectively. During follow-up, 59 (7.9%) patients developed recurrence. Univariate analysis showed that micropapillary/solid predominant group had significantly lower probability of FFR (P = 0.001) in node-negative lung adenocarcinoma of 3cm or smaller. Older age (P = 0.007), greater tumor size (P = 0.006), and micropapillary/solid predominant group (P = 0.031) had significantly lower probability of FFR in multivariate analysis. Conclusions: The new adenocarcinoma classification has significant impact on recurrence in node-negative lung adenocarcinoma of 3cm or smaller. Patients with micropapillary/solid predominant pattern have significant higher risk for recurrence. Legal entity responsible for the study: None Funding: None Disclosure: All authors have declared no conflicts of interest.

Prognostic Factors in Completely Resected Node-Negative Lung Adenocarcinoma of 3 cm orSmaller.

The role of adjuvant chemotherapy for patients with stage I NSCLC remains unknown. The prognostic value of histological subtypes in resected node-negative small lung adenocarcinoma has not been widely investigated. This study investigated the prognostic factors in patients with node-negative lung adenocarcinoma 3 cm orsmaller to find potential candidates for adjuvant chemotherapy. A total of 726 patients with completely resected node-negative lung adenocarcinoma 3 cm or smaller were included in the study. Prognostic factors for overall survival or probability of freedom from recurrence (FFR) were investigated. During follow-up, recurrence developed in 59 patients (8.1%). Univariate analysis showed that the micropapillary/solid predominant pattern group was associated with a significantly lower probability of FFR (p=0.001) in node-negative lung adenocarcinoma 3 cm orsmaller. Those with greater tumor size (p= 0.001) andthe micropapillary/solid predominant pattern group (p= 0.035) had a significantly lower probability of FFR in multivariate analysis. For tumors 2 cm or smaller, the micropapillary/solid predominant pattern group had a trend toward a lower probability of FFR (p= 0.053) in multivariate analysis. Presence of the solid pattern was a prognostic factor for lower probability of FFR (p= 0.001) in multivariate analysis. The new adenocarcinoma classification has significant impact on recurrence in node-negative lung adenocarcinoma 3 cm or smaller. Patients with the micropapillary/solid predominant pattern have a significantly higher risk for recurrence. For tumors 2 cm or smaller, presence of the solid pattern was a prognostic factor for higher probability of recurrence. This information is useful for patient stratification for adjuvant therapy.

Visceral Pleural Invasion Does Not Affect Recurrence or Overall Survival Among Patients With Lung Adenocarcinoma ≤ 2 cm: A Proposal to Reclassify T1 Lung Adenocarcinoma

T1 (≤ 3 cm) tumors with visceral pleural invasion (VPI) are upstaged to T2a (stage IB) in the TNM classification. We investigated the effect of VPI on the cumulative incidence of recurrence (CIR) and overall survival (OS) of lung adenocarcinoma (ADC) ≤ 2 cm (T1a) and 2 to 3 cm (T1b). OS and CIR among patients with or without VPI were examined by tumor size (≤ 2 and 2-3 cm) in 777 patients with node-negative lung ADC ≤ 3 cm who underwent resection. Among patients with tumors ≤ 2 cm, VPI was not associated with either increased CIR (P = .90) or decreased OS (P = .11). Among patients with tumors 2 to 3 cm in size, the presence of VPI was associated with increased CIR (P = .015) and decreased OS (P &lt; .001), even after adjusting for histologic subtype. When stage I lung ADCs ≤ 3 cm were regrouped as either new stage IA (≤ 2 cm with or without VPI, 2-3 cm without VPI) or new stage IB (2-3 cm with VPI), there was a statistically significant difference in 5-year CIR and OS between new stage IA and new stage IB tumors (CIR, 18% vs 40% [P = .004]; OS, 76% vs 51% [P &lt; .001]). VPI stratifies prognosis in patients with lung ADC 2 to 3 cm but not in those with tumors ≤ 2 cm. Our proposed regrouping of a new stage IB better stratifies patients with poor prognosis, similar to published outcomes in patients with stage II disease, who may benefit from adjuvant chemotherapy.

Patterns of DNA Mutations and ALK Rearrangement in Resected Node Negative Lung Adenocarcinoma

Many studies have examined specific mutations in patients with resected lung adenocarcinoma across heterogeneous stages, comprising predominantly advanced/metastatic disease, but there is little data regarding the mutation profile of patients with early stage node negative disease. The aim of this study was to identify patterns of mutations in early stage node negative lung adenocarcinoma. A total of 204 patients who underwent resection for stage IB (sixth Ed American Joint Committee on Cancer) lung adenocarcinoma and received no neoadjuvant or adjuvant treatments were identified. Tumors were genotyped using the OncoCarta v1.0 kit (Sequenom, San Diego, CA) on the Sequenom MassARRAY platform. Fluorescence in situ hybridization for ALK rearrangement was also performed. A total of 110 (54%) patients' tumors harbored at least one mutation. KRAS, EGFR, PIK3CA, ALK, PDGFRA, AKT1, BRAF, FGFR1, and HRAS mutations were detected in tumors from 77 (37.7%), 29 (14.2%), 9 (4.4%), 2 (1%), 2 (1%), 1 (0.5%), 1 (0.5%), 1 (0.5%), and 1 (0.5%) patients respectively. Synchronous mutations (either comutations or double mutations) were identified in 18 (8.8%) patients. KRAS and PIK3CA mutations were associated with poorly differentiated tumors (p = 0.03; p = 0.02), whereas EGFR mutations were associated with well-differentiated tumors (p = 0.001). Five tumours contained EGFR mutations (one T790M and four exon 20 insertions), which are associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). Diverse patterns of mutations are seen in resected node-negative lung adenocarcinoma including an unexpectedly low rate of ALK rearrangement, EGFR mutations associated with resistance to EGFR-TKIs and a high rate of synchronous mutations. These data may influence the design of future adjuvant targeted therapy trials.

Clinical Characterization of Node-Negative Lung Adenocarcinoma: Results of a Prospective Investigation

In clinical stage IA lung adenocarcinoma, the clinical features of a truly node-negative population were prospectively investigated by means of a prospective investigational study. The clinical data and radiographic features of high-resolution computed tomography (HR-CT) were registered before operation in 169 clinical stage IA lung cancer patients who were scheduled to undergo a standard lobectomy and systemic mediastinal node dissection. The nodal metastasis was pathologically defined and the clinical factors associated with the presence of the nodal metastasis were evaluated. In 114 assessable cases with adenocarcinomas, 15 (13.1%) were node-positive. The serum carcinoembryonic antigen (CEA), retraction sign, and intratumoral air-bronchogram on HR-CT were suggested to be predictive factors for lymph node metastasis, with hazard ratios of 12.44 (p = 0.0003), 6.53 (p = 0.0533), and 0.17 (p = 0.0073), respectively. In combination with the radiologic features and serum CEA, cases with elevated serum CEA or presence of retraction sign included 15.6% of node metastasis-positive, whereas all cases with normal CEA and absence of retraction sign showed no nodal metastasis. Cases with elevated serum CEA or absence of intratumoral air-bronchogram included 24.5% of node metastasis, whereas cases with normal CEA and presence of air-bronchogram showed 4.6% of node metastasis. The tumor size and the proportion of ground-glass attenuation were not associated with the incidence of nodal metastasis. The serum CEA and HR-CT features thus allowed us to identify node-negative lung adenocarcinomas measuring 3 cm or less in size.

Clinical Characterization of Node-Negative Lung Adenocarcinoma: Results of a Prospective Investigation

Clinical Characterization of Node-Negative Lung Adenocarcinoma: Results of a Prospective Investigation

Prognostic impact of p53 protein overexpression in patients with node-negative lung adenocarcinoma

Prognostic value of p53 protein expression in node-negative lung adenocarcinoma is still controversy. The expression of p53 protein was examined immunohistochemically in lung adenocarcinoma using monoclonal antibody BP53-12. A total 131 cases of primary lung adenocarcinoma were examined. Relationship between expression of p53 protein and clinicopathologic factors were studied. Overexpression of p53 protein was found in 19 patients (14.5%). Univariate and multivariate analysis showed that overexpression of p53 protein was an independent prognostic factor in node-negative lung adenocarcinoma. p53 alteration could be a valuable predictor for prognosis in node-negative lung adenocarcinoma.