KRASG12C Mutation Is Associated with Increased Risk of Recurrence in Surgically Resected Lung Adenocarcinoma

7522 Background: Lung adenocarcinoma (ADC) is a distinct biologic entity with unique gene amplifications (Weir B, Nature 2008). Yet, comprehensive transcriptomic analysis, including microRNAs, specific to lung ADC are lacking. Methods: Using mRNA expression data from a discovery cohort of 154 patients with histologically proven early stage (I and II) lung ADC, signatures of oncogenic pathway and tumor microenvironment status were applied and further organized by hierarchical clustering to develop a metagene model. Further, using in vitro assays in a large cohort of lung ADC cell lines (n = 42) with corresponding mRNA and microRNA data, novel microRNAs associated with a poor prognosis and their relationship to cisplatin resistance was elucidated. Results: In the discovery cohort of 154 patients with early stage disease, activation of oncogenic pathways associated with wound healing (angiogenesis), chromosomal instability, and STAT signaling were associated with an increased risk of recurrence (p<0.001). Utilizing the extremes of survival to identify cohorts of patients as high and low risk phenotypes, using bayesian regression, a 100 gene signature (‘metagene') that captured the diversity of signaling pathways unique to patients at increased risk of recurrence was identified and validated in an independent cohort (n = 364) of lung ADC samples with 78.3% accuracy. Kaplan Meier survival analysis and multivariate analysis further confirmed the independent prognostic value of the 100 gene signature (p= 0.007). Using in vitro cell proliferation assays, predicted high risk lung ADC cell lines were identified as being more resistant to cisplatin therapy than those predicted to be low risk (p=0.001). In a novel manner, we also identified several microRNAs (miR-215, miR-98, miR- 643, let-7b, miR-665, miR-629) associated with a high risk of recurrence and more importantly cisplatin resistance. Conclusions: mRNA and microRNA profiles reflect unique aspects of individual tumors and may characterize histology-specific tumor heterogeneity in lung ADC, providing an opportunity to better characterize the oncogenic process and refine therapeutic options. No significant financial relationships to disclose.

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The tumor microenvironment in EGFR-driven loco-regional lung adenocarcinoma can predict higher risk of recurrence.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.8521 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 8521-8521

Author(s):

Maya Khalil ◽

Ahmed Elkhanany ◽

Yuanquan Yang ◽

Sean Glenn ◽

Antonios Papanicolau-Sengos ◽

...

Keyword(s):

Adjuvant Therapy ◽

Lung Adenocarcinoma ◽

Cox Regression ◽

Disease Free Survival ◽

Egfr Mutations ◽

Risk Of Recurrence ◽

Increased Risk ◽

Significant Difference ◽

The Impact ◽

Egfr Mutated

8521 Background: The role of EGFR tyrosine kinase inhibitors (TKIs) as adjuvant therapy in EGFR-mutated NSCLC is still controversial. Identifying biomarkers associated with increased risk of recurrence may help stratify pts & guide adjuvant therapy. We hypothesized that tumor immune microenvironment (TME) alterations could predict disease-free survival (DFS) in these pts. Methods: The Cancer Genome Atlas (TCGA) lung Adenocarcinoma (LUAD) data at Genomic Data Common (GDC) was accessed for pt phenotype, updated outcome & normalized gene expression profile (RNA seq). Immune landscape data was obtained from PANCAN. We chose to focus on 54 key TME genes, identified from a commercially available immune report card from OmniSeq (Inc.). Pt groups were divided via K-mean clustering. Group comparison was done via Likelihood Ratio (LR, categorical), Mann Whitney (continuous), log-rank (survival) & Cox regression (outcome). Bonferroni correction was used to correct for multiple comparisons. Results: 877 pts with LUAD were identified, 32 of whom had EGFR mutations and were at stages I to III. The mutations were mostly in the TK domain, involving exons 18 (12%), 19 (27%), 20 (6%), & 21 (33%). Only 3% harbored the T790M mutation. None of the pts received adjuvant TKI. Analysis of the impact of individual genes on DFS yielded a group of 8 genes whose high expression was associated with improved DFS: IL10 (HR 0.58, p 0.029), BTLA (HR 0.66, p 0.07), CD8A (HR 0.6252, p 0.099), CD39 (HR 0.454, p 0.037), CCR2 (HR 0.729, p 0.039), CSF1R (HR 0.70, p 0.087), ICOS (HR 0.66, p 0.062), & CD4 (HR 0.67, p 0.059). K-mean clustering of the pts using these genes demonstrated 2 groups with distinct immune profiles. Group 1 was characterized by higher leukocyte and stromal fractions, lymphocyte infiltration score, macrophage regulation, TGF-ß response, & T cell richness with less proliferation, pointing towards a more “inflamed” phenotype. Significant difference between the two groups in the immune subtypes was found (LR 10, p = 0.039). 90% of pts in the inflamed group had tumors with IFN-γ dominant, inflammatory, and TGF-ß dominant subtypes, while 45% of the “non-inflamed” group had lymphocyte depleted & wound healing signatures. DFS was significantly longer in the inflamed group (median DFS 1480 vs 772 days, p = 0.002). Conclusions: In pts with resected EGFR-mutated LUAD, an inflamed TME is associated with prolonged DFS. Identifying these pts may help select those who would benefit from adjuvant therapy.

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Increased risk of recurrence in resected EGFR -positive pN0M0 invasive lung adenocarcinoma

Thoracic Cancer ◽

10.1111/1759-7714.12866 ◽

2018 ◽

Vol 9 (12) ◽

pp. 1594-1602 ◽

Cited By ~ 4

Author(s):

Masaoki Ito ◽

Yoshihiro Miyata ◽

Kei Kushitani ◽

Tomoharu Yoshiya ◽

Yuichiro Kai ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Risk Of Recurrence ◽

Increased Risk ◽

Invasive Lung Adenocarcinoma

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Thrombophilia and risk of VTE recurrence according to the age at the time of first VTE manifestation

VASA ◽

10.1024/0301-1526/a000447 ◽

2015 ◽

Vol 44 (4) ◽

pp. 313-323 ◽

Cited By ~ 6

Author(s):

Lea Weingarz ◽

Marc Schindewolf ◽

Jan Schwonberg ◽

Carola Hecking ◽

Zsuzsanna Wolf ◽

...

Keyword(s):

Factor V Leiden ◽

Cox Proportional Hazards ◽

First Episode ◽

Factor V ◽

Factor V Leiden Mutation ◽

Younger Patients ◽

Risk Of Recurrence ◽

G20210a Mutation ◽

Increased Risk ◽

The Impact

Abstract. Background: Whether screening for thrombophilia is useful for patients after a first episode of venous thromboembolism (VTE) is a controversial issue. However, the impact of thrombophilia on the risk of recurrence may vary depending on the patient’s age at the time of the first VTE. Patients and methods: Of 1221 VTE patients (42 % males) registered in the MAISTHRO (MAin-ISar-THROmbosis) registry, 261 experienced VTE recurrence during a 5-year follow-up after the discontinuation of anticoagulant therapy. Results: Thrombophilia was more common among patients with VTE recurrence than those without (58.6 % vs. 50.3 %; p = 0.017). Stratifying patients by the age at the time of their initial VTE, Cox proportional hazards analyses adjusted for age, sex and the presence or absence of established risk factors revealed a heterozygous prothrombin (PT) G20210A mutation (hazard ratio (HR) 2.65; 95 %-confidence interval (CI) 1.71 - 4.12; p < 0.001), homozygosity/double heterozygosity for the factor V Leiden and/or PT mutation (HR 2.35; 95 %-CI 1.09 - 5.07, p = 0.030), and an antithrombin deficiency (HR 2.12; 95 %-CI 1.12 - 4.10; p = 0.021) to predict recurrent VTE in patients aged 40 years or older, whereas lupus anticoagulants (HR 3.05; 95%-CI 1.40 - 6.66; p = 0.005) increased the risk of recurrence in younger patients. Subgroup analyses revealed an increased risk of recurrence for a heterozygous factor V Leiden mutation only in young females without hormonal treatment whereas the predictive value of a heterozygous PT mutation was restricted to males over the age of 40 years. Conclusions: Our data do not support a preference of younger patients for thrombophilia testing after a first venous thromboembolic event.

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Combining Carcinoembryonic Antigen and Platelet to Lymphocyte Ratio to Predict Brain Metastasis of Resected Lung Adenocarcinoma Patients

BioMed Research International ◽

10.1155/2017/8076384 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 3

Author(s):

Wei Wang ◽

Chao Bian ◽

Di Xia ◽

Jin-Xi He ◽

Ping Hai ◽

...

Keyword(s):

Risk Factors ◽

Brain Metastasis ◽

Lung Adenocarcinoma ◽

Carcinoembryonic Antigen ◽

Roc Curve ◽

Univariate Analysis ◽

Significant Risk ◽

Platelet To Lymphocyte Ratio ◽

Lymphocyte Ratio ◽

Increased Risk

We aimed to evaluate the role of pretreatment carcinoembryonic antigen (CEA) and platelet to lymphocyte ratio (PLR) in predicting brain metastasis after radical surgery for lung adenocarcinoma patients. The records of 103 patients with completely resected lung adenocarcinoma between 2013 and 2014 were reviewed. Clinicopathologic characteristics of these patients were assessed in the Cox proportional hazards regression model. Brain metastasis occurred in 12 patients (11.6%). On univariate analysis, N2 stage (P = 0.013), stage III (P = 0.016), increased CEA level (P = 0.006), and higher PLR value (P = 0.020) before treatment were associated with an increased risk of developing brain metastasis. In multivariate model analysis, CEA above 5.2 ng/mL (P = 0.014) and PLR ≥ 120 (P = 0.036) remained as the risk factors for brain metastasis. The combination of CEA and PLR was superior to CEA or PLR alone in predicting brain metastasis according to the receiver operating characteristic (ROC) curve analysis (area under ROC curve, AUC 0.872 versus 0.784 versus 0.704). Pretreatment CEA and PLR are independent and significant risk factors for occurrence of brain metastasis in resected lung adenocarcinoma patients. Combining these two factors may improve the predictability of brain metastasis.

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Intrathoracic anastomotic leakage after gastroesophageal cancer resection is associated with increased risk of recurrence

Journal of Thoracic and Cardiovascular Surgery ◽

10.1016/j.jtcvs.2015.04.030 ◽

2015 ◽

Vol 150 (1) ◽

pp. 42-48 ◽

Cited By ~ 17

Author(s):

Steen C. Kofoed ◽

Dan Calatayud ◽

Lone S. Jensen ◽

Frederik Helgstrand ◽

Michael P. Achiam ◽

...

Keyword(s):

Anastomotic Leakage ◽

Gastroesophageal Cancer ◽

Cancer Resection ◽

Risk Of Recurrence ◽

Increased Risk

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Clinical and Imaging Predictors of Recurrent Ischemic Stroke: A Systematic Review and Meta-Analysis

Cerebrovascular Diseases ◽

10.1159/000490422 ◽

2018 ◽

Vol 45 (5-6) ◽

pp. 279-287 ◽

Cited By ~ 8

Author(s):

Frans Kauw ◽

Richard A.P. Takx ◽

Hugo W.A.M. de Jong ◽

Birgitta K. Velthuis ◽

L. Jaap Kappelle ◽

...

Keyword(s):

Ischemic Stroke ◽

Lower Risk ◽

Meta Analysis ◽

Cochrane Library ◽

Large Artery ◽

Cortical Lesions ◽

Level Of Evidence ◽

Risk Of Recurrence ◽

Increased Risk ◽

History Of

Background: Predictors of recurrent ischemic stroke are less well known in patients with a recent ischemic stroke than in patients with transient ischemic attack (TIA). We identified clinical and radiological factors for predicting recurrent ischemic stroke in patients with recent ischemic stroke. Methods: A systematic search in PubMed, Embase, Cochrane Library, and CINAHL was performed with the terms “ischemic stroke,” “predictors/determinants,” and “recurrence.” Quality assessment of the articles was performed and the level of evidence was graded for the articles included for the meta-analysis. Pooled risk ratios (RR) and heterogeneity (I2) were calculated using inverse variance random effects models. Results: Ten articles with high-quality results were identified for meta-analysis. Past medical history of stroke or TIA was a predictor of recurrent ischemic stroke (pooled RR 2.5, 95% CI 2.1–3.1). Small vessel strokes were associated with a lower risk of recurrence than large vessel strokes (pooled RR 0.3, 95% CI 0.1–0.7). Patients with stroke of an undetermined cause had a lower risk of recurrence than patients with large artery atherosclerosis (pooled RR 0.5, 95% CI 0.2–1.1). We found no studies using CT or ultrasound for the prediction of recurrent ischemic stroke. The following MRI findings were predictors of recurrent ischemic stroke: multiple lesions (pooled RR 1.7, 95% CI 1.5–2.0), multiple stage lesions (pooled RR 4.1, 95% CI 3.1–5.5), multiple territory lesions (pooled RR 2.9, 95% CI 2.0–4.2), chronic infarcts (pooled RR 1.5, 95% CI 1.2–1.9), and isolated cortical lesions (pooled RR 2.2, 95% CI 1.5–3.2). Conclusions: In patients with a recent ischemic stroke, a history of stroke or TIA and the subtype large artery atherosclerosis are associated with an increased risk of recurrent ischemic stroke. Predictors evaluated with MRI include multiple ischemic changes and isolated cortical lesions. Predictors of recurrent ischemic stroke concerning CT or ultrasound have not been published.

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856 NODAL METASTASES AFTER NEOADJUVANT CHEMORADIATION AND R0 RESECTION IN ESOPHAGEAL ADENOCARCINOMA: PATTERNS AND PROGNOSIS

Diseases of the Esophagus ◽

10.1093/dote/doab052.856 ◽

2021 ◽

Vol 34 (Supplement_1) ◽

Author(s):

Caitlin Harrington ◽

Rebecca Carr ◽

Smita Sihag ◽

Prasad Adusumilli ◽

Manjit Bains ◽

...

Keyword(s):

Lymph Node ◽

Esophageal Adenocarcinoma ◽

Lymph Node Metastases ◽

Cox Regression ◽

Neoadjuvant Chemoradiation ◽

Nodal Metastasis ◽

Nodal Metastases ◽

Risk Of Recurrence ◽

Increased Risk ◽

Node Metastases

Abstract Although the pattern of nodal metastasis and the prognosis of number and location of positive nodes have been well described with esophageal cancer undergoing upfront surgery, little is known about nodal metastasis after neoadjuvant treatment. The aim of this study is to assess the pattern of nodal metastases in esophageal adenocarcinoma treated with neoadjuvant chemoradiation and surgery and evaluate its effect on prognosis. Methods All patients with esophageal adenocarcinoma who had undergone neoadjuvant chemoradiation and an R0 esophagectomy between 2010 and 2018 at our institution were included (n = 577). Pathology reports were reviewed for sites of lymph node metastases. Patients were excluded if nodal stations were not listed separately (n = 40). Age, sex, race, tumor location, TRG, pT stage, number of positive lymph nodes, number of positive nodal stations, and specific nodal stations were analyzed for risk of recurrence using univariable Cox regression, and significant covariates were included in multivariable Cox regression model. Results Of 537 patients, 193(36%) had pathologic nodal metastases. 153 patients(28%) had single-station disease: 135(88%) at the paraesophageal station, 16(10%) at the left gastric, 1 at the subcarinal and 1 at the paratracheal station(0.65% each). 32 patients(6.0%) had two-station and 8(1.5%) had three-station disease. The majority of patients with multiple positive nodal stations had positive nodes in the paraesophageal(90%) and/or left gastric artery stations(60%). On multivariable analysis, the number of positive nodal stations (HR 1.59, CI 1.35–1.84, p < 0.001), subcarinal (HR 2.78, CI 1.54–5.03, p < 0.001), and paraesophageal stations (HR 2.0, CI 1.58–2.54, p < 0.001) were associated with increased risk of recurrence. Conclusion Patients who have undergone neoadjuvant and R0 esophagectomy for adenocarcinoma often have lymph node metastases at time of surgery, most commonly at the paraesophageal station. The number of nodal stations, along with subcarinal and paraesophageal metastases, were associated with increased risk of recurrence.

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Primary signet ring cell histology does not portend worse survival for early stage lung cancer following lobectomy

Asian Cardiovascular and Thoracic Annals ◽

10.1177/02184923211045910 ◽

2021 ◽

pp. 021849232110459

Author(s):

Terrance Peng ◽

Anita Yau ◽

Li Ding ◽

Elizabeth A. David ◽

Sean C. Wightman ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Early Stage ◽

Signet Ring Cell ◽

Rank Test ◽

Poor Prognostic Factor ◽

Risk Of Death ◽

Increased Risk ◽

Signet Ring ◽

Ring Cell ◽

The Impact

Introduction Signet ring cell (SRC) histology is considered a poor prognostic factor in various cancers. However, primary SRC lung adenocarcinoma is rare and poorly understood. Methods The National Cancer Database was queried to identify treatment-naïve patients who received lobectomy for primary SRC or non-SRC pT1-2N0 lung adenocarcinoma <4 cm within four months of diagnosis. SRC lung adenocarcinoma was defined by ICD-O-3 code 8490, while non-SRC lung adenocarcinoma was defined by ICD-O-3 codes 8140, 8141, 8143, 8147, 8255, 8260, 8310, 8481, 8560, and 8570–8574. The Kaplan-Meier curve and log-rank test was used to compare five-year OS between SRC versus non-SRC lung adenocarcinoma cohorts. The impact of SRC histology on risk of death was assessed using the Cox proportional hazards regression model. Results 48,399 patients were included in this study: 62 with primary SRC lung adenocarcinoma and 48,337 with non-SRC lung adenocarcinoma. The mean age of the overall cohort was 67.0 ± 9.6 years. Five-year OS following lobectomy did not differ significantly between SRC lung adenocarcinoma and non-SRC lung adenocarcinoma cohorts (SRC 73.9% vs. non-SRC 69.3%, p = 0.64). SRC histology did not significantly impact risk of death within five years after lobectomy (HR 0.89, p = 0.66). Conclusions Following lobectomy for pT1-2N0 tumors <4 cm, patients with primary SRC lung adenocarcinoma do not experience worse five-year OS or increased risk of death within five years relative to those with non-SRC lung adenocarcinoma. Additional study, including exploration of emerging molecular profiling data, may serve to better define optimal treatment for this histopathologic group of lung adenocarcinomas.

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