Classical versus non-classical EGFR mutations: Erlotinib response and impact of renal insufficiency

2020 ◽  
pp. 107815522096489
Author(s):  
Emir Celik ◽  
Nilay Sengul Samanci ◽  
Mehmet Karadag ◽  
Nebi Serkan Demirci ◽  
Duygu Ilke Cikman ◽  
...  
Keyword(s):  
Renal Insufficiency ◽  
Cox Regression ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
Effective Treatment Option ◽  
Cox Regression Analysis ◽  
Group 3 ◽  
Classical Mutation ◽  
Group 1

Introduction Erlotinib is an effective treatment option for EGFR-mutant non-small cell lung cancer. It is important to predict patients who will respond better to erlotinib. We designed this study to investigate the effect of renal insufficiency (RI) on erlotinib treatment outcomes. Methods All patients receiving erlotinib were stratified into 3 groups. Group 1 consisted of non-RI subjects with classical epidermal growth factor receptor (EGFR) mutations, Group 2 consisted of those with RI (Estimated glomerular filtration rate <60 mL/min) and classical EGFR mutations, and Group 3 consisted of those with non-classical EGFR mutations. Results 82 patients were included in the study. Median progression-free survival (PFS) in patients with classical mutation was approximately 6 months shorter in those with RI, although not statistically significant. Median overall survival (OS) in Group 1, 2 and 3 was 34.1 months, 35.2 months, and 15 months, respectively and although not statistically significant, median OS was 20 months shorter in Group 3. Univariate and multivariate cox-regression analysis revealed shorter PFS and OS in males and those with ECOG ≥2 while PFS and OS were longer in those with recurrent lung tumors and generating rash during erlotinib treatment. There was no difference between RI and non-RI patients in terms of adverse events except for fatigue and appetite loss. Conclusions This research showed OS in patients with and without RI was comparable. Although not statistically significant, PFS in patients with classical mutation was approximately 6 months shorter in those with RI patients.

scholarly journals mTOR Pathway Expression as Potential Predictive Biomarker in Patients with Advanced Neuroendocrine Tumors Treated with Everolimus

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1201 ◽  
Author(s):  
Fabio Gelsomino ◽  
Andrea Casadei-Gardini ◽  
Francesco Caputo ◽  
Giulio Rossi ◽  
Federica Bertolini ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Mtor Pathway ◽  
Cox Regression Analysis ◽  
Pathway Expression ◽  
Group 2 ◽  
Tissue Specimens ◽  
Group 1

Background. Everolimus (Eve), which is a mammalian target of Rapamicin (mTOR) inhibitor, is part of the therapeutic armamentarium of neuroendocrine tumors (NETs). Currently, there are no validated biomarkers predicting Eve efficacy in NETs. In this study, we explore whether the expression of phosphorilated (p)-mTOR and p70S6-kinase (S6K), a downstream effector of mTOR, correlates with the outcome of patients with NET that were treated with Eve. Methods. Tissue specimens that were derived from NETs treated with Eve at our Institution were examined for the expression levels of p-mTOR and p-S6K by immunohistochemistry. Response rate (RR), progression-free survival (PFS), and overall survival (OS) were analyzed in two groups: p-mTOR/p-S6K positive (group 1) and p-mTOR/p-S6K negative (group 2). Univariate and multivariate Cox regression analysis were performed. Results. Twenty-four patients with advanced NETs that were treated with Eve were included in the analysis. Eight out 24 (33.3%) patients were both p-mTOR and p-S6K positive. A better median PFS and OS in group 1 (18.2 and 39.9 months) as compared to group 2 (13 and 32.4 months) was depicted, with a toxicity profile that was comparable with data literature. Conclusions. Our study suggests that the activation of mTOR pathway can predict better outcomes in patients with NET treated with Eve. However, these results warrant further confirmation in a prospective setting.

scholarly journals Lymphadenectomy after neoadjuvant chemoradiation for esophageal adenocarcinoma: what is the optimal lymph nodes dissection?

2021 ◽  
Author(s):  
Yahua Wu ◽  
Mingqiang Lin ◽  
Mengyan Zhang ◽  
Tianxiu Liu ◽  
Zhiping Wang ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymph Nodes ◽  
Esophageal Adenocarcinoma ◽  
Cox Regression ◽  
Neoadjuvant Chemoradiotherapy ◽  
Cox Regression Analysis ◽  
Risk Of Death ◽  
Group 3 ◽  
Lymph Nodes Dissection ◽  
Group 1

Abstract Background The optimal lymph nodes dissection (LND) for esophageal adenocarcinoma (EAC) patients who underwent neoadjuvant chemoradiotherapy (NCRT) is controversial. Methods Patients were selected from Surveillance Epidemiology and End Results database. Multivariable Cox analysis was used to identify predictors of overall survival (OS). Restricted Cubic Splines (RCS) was used to examine the relationship between the number of LND and OS. Result 2,019 patients with non-metastatic EAC underwent NCRT were stratified into three groups according to LND using X-tile software: group 1: 1–8, group 2: 9–14, group 3: ≥15. In Multivariable Cox Regression analysis, the death risk was reduced by 22% (P = 0.001), 43% (P < 0.001) respectively, for patients in groups 2, 3 compared with those in group 1. The results were similar for patients with pathological lymph node-negative (ypN0) EAC patients. But for pathological lymph node-positive (ypN+) patients, a significantly reduced hazard was present only in group 3 (P < 0.001). RCS exhibited a nonlinear relationship between the number of lymph nodes removed and OS for ypN0 EAC (P = 0.002). The risk of death sharply dropped until around 24 nodes removed and then started to steadily increase afterward. However, for ypN + EAC, it showed a linear relationship between LND and OS (P = 0.205), with a better OS when an increase in the number of lymph nodes removed. Conclusions For ypN0 patients, the optimal LND was approximately 24 lymph nodes, with the number of lymph nodes removed beyond 24 nodes did not provide additional benefit. However, for ypN + patients, a more extensive lymphadenectomy could favor survival.

Exploratory evaluation of pharmacodynamic biomarkers and pharmacokinetics (PK) of ziv-aflibercept (Z) + FOLFIRI in a phase II study of Japanese patients (pts) with metastatic colorectal cancer (mCRC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 799-799 ◽  
Author(s):  
Takayuki Yoshino ◽  
Naotoshi Sugimoto ◽  
Kentaro Yamazaki ◽  
Takeshi Kajiwara ◽  
Yoshito Komatsu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cox Regression ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Tumor Stroma ◽  
Japanese Patients ◽  
Protein Biomarkers ◽  
Cox Regression Analysis ◽  
Pharmacodynamic Biomarkers ◽  
Potential Biomarkers

799 Background: Z + 5-fluorouracil/levofolinate/irinotecan (FOLFIRI) is a 2nd-line treatment for mCRC. There are no established biomarkers that predict response to this treatment. This study aimed to identify such biomarkers. Methods: 62 pts with mCRC received Z (4 mg/kg) + FOLFIRI every 2 weeks. 78 potential protein biomarkers (e.g., cytokines) were chosen for analysis based on their roles in angiogenesis, tumor progression, and tumor-stroma interaction. Plasma levels of biomarkers at baseline and pre-dose 3 (Day 1 of Cycle 3) were measured in all pts by enzyme-linked immunosorbent assays. Relationships between these levels and efficacy endpoints were assessed. PK data were calculated. Results: 10 potential biomarkers had a ±30% change from baseline to pre-dose 3 (adjusted P < .001); the greatest changes were in placental growth factor (median: 4,716%) and vascular endothelial growth factor receptor 1 (2,171%). Baseline levels of 8 potential biomarkers correlated with overall survival (OS; see table) in a univariate Cox regression analysis; none correlated with progression-free survival or maximum tumor shrinkage. Pre-dose 3 levels did not correlate with any efficacy endpoints. Conclusions: Preliminary data show that these 8 biomarkers could be associated with OS. No significant drug interactions were found. Clinical trial information: NCT01882868. [Table: see text]

scholarly journals Myocardial Metabolic Response Predicts Chemotherapy Curative Potential on Hodgkin Lymphoma: A Proof-of-Concept Study

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 971
Author(s):  
Cecilia Marini ◽  
Matteo Bauckneht ◽  
Anna Borra ◽  
Rita Lai ◽  
Maria Isabella Donegani ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Cox Regression ◽  
Metabolic Response ◽  
Progression Free Survival ◽  
Disease Relapse ◽  
Cox Regression Analysis ◽  
Normal Tissues ◽  
Pet Ct ◽  
Genome Sharing

Genome sharing between cancer and normal tissues might imply a similar susceptibility to chemotherapy toxicity. The present study aimed to investigate whether curative potential of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) is predicted by the metabolic response of normal tissues in patients with Hodgkin lymphoma (HL). METHODS: According to current guidelines, 86 patients with advanced-stage (IIB-IVB) HL, prospectively enrolled in the HD0607 trial (NCT00795613), underwent 18 F-fluorodeoyglucose PET/CT imaging at diagnosis and, at interim, after two ABVD courses, to decide regimen maintenance or its escalation. In both scans, myocardial FDG uptake was binarized according to its median value. Death and disease relapse were recorded to estimate progression-free survival (PFS) during a follow-up with median duration of 43.8 months (range 6.97–60). RESULTS: Four patients (4.6%) died, while six experienced disease relapse (7%). Complete switch-off of cancer lesions and cardiac lighting predicted a favorable outcome at Kaplan–Mayer analyses. The independent nature and additive predictive value of their risk prediction were confirmed by the multivariate Cox regression analysis. CONCLUSION: Susceptibility of HL lesions to chemotherapy is at least partially determined by factors featuring the host who developed it.

scholarly journals Clinical relevance of kallikrein-related peptidase 6 (KLK6) and 8 (KLK8) mRNA expression in advanced serous ovarian cancer

2016 ◽  
Vol 397 (12) ◽  
pp. 1265-1276 ◽  
Author(s):  
Nancy Ahmed ◽  
Julia Dorn ◽  
Rudolf Napieralski ◽  
Enken Drecoll ◽  
Matthias Kotzsch ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mrna Expression ◽  
Cox Regression ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Predictive Marker ◽  
Residual Tumor ◽  
Mrna Levels ◽  
Serous Ovarian Cancer ◽  
Cox Regression Analysis

Abstract Most members of the kallikrein-related peptidase family have been demonstrated to be dysregulated in ovarian cancer and modulate tumor growth, migration, invasion, and resistance to chemotherapy. In the present study, we assessed the mRNA expression levels of KLK6 and KLK8 by quantitative PCR in 100 patients with advanced serous ovarian cancer FIGO stage III/IV. A pronounced correlation between KLK6 and KLK8 mRNA expression (rs = 0.636, p < 0.001) was observed, indicating coordinate expression of both peptidases. No significant associations of clinical parameters with KLK6, KLK8, and a combined score KLK6+KLK8 were found. In univariate Cox regression analysis, elevated mRNA levels of KLK6 were significantly linked with shortened overall survival (OS) (hazard ratio [HR] = 2.07, p = 0.007). While KLK8 values were not associated with patients’ outcome, high KLK6+KLK8 values were significantly associated with shorter progression-free survival (HR = 1.82, p = 0.047) and showed a trend towards significance in the case of OS (HR = 1.82, p = 0.053). Strikingly, in multivariable analysis, elevated KLK6 mRNA values, apart from residual tumor mass, remained an independent predictive marker for poor OS (HR = 2.33, p = 0.005). As KLK6 mRNA and protein levels correlate, KLK6 may represent an attractive therapeutic target for potent and specific inhibitors of its enzymatic activity.

scholarly journals High expression of fibroblast activation protein (FAP) predicts poor outcome in high-grade serous ovarian cancer

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Min Li ◽  
Xue Cheng ◽  
Rong Rong ◽  
Yan Gao ◽  
Xiuwu Tang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cox Regression ◽  
Paraffin Section ◽  
Progression Free Survival ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Systematic Analysis ◽  
Cox Regression Analysis ◽  
Genes Expression ◽  
High Level

Abstract Background High-grade serous ovarian cancer (HGSOC) is a fatal form of ovarian cancer. Previous studies indicated some potential biomarkers for clinical evaluation of HGSOC prognosis. However, there is a lack of systematic analysis of different expression genes (DEGs) to screen and detect significant biomarkers of HGSOC. Methods TCGA database was conducted to analyze relevant genes expression in HGSOC. Outcomes of candidate genes expression, including overall survival (OS) and progression-free survival (PFS), were calculated by Cox regression analysis for hazard rates (HR). Histopathological investigation of the identified genes was carried out in 151 Chinese HGSOC patients to validate gene expression in different stages of HGSOC. Results Of all 57,331 genes that were analyzed, FAP was identified as the only novel gene that significantly contributed to both OS and PFS of HGSOC. In addition, FAP had a consistent expression profile between carcinoma-paracarcinoma and early-advanced stages of HGSOC. Immunological tests in paraffin section also confirmed that up-regulation of FAP was present in advanced stage HGSOC patients. Prediction of FAP network association suggested that FN1 could be a potential downstream gene which further influenced HGSOC survival. Conclusions High-level expression of FAP was associated with poor prognosis of HGSOC via FN1 pathway.

Predictors of tumor progression among children with gangliogliomas

2009 ◽  
Vol 3 (6) ◽  
pp. 461-466 ◽  
Author(s):  
Mostafa El Khashab ◽  
Lynn Gargan ◽  
Linda Margraf ◽  
Korgun Koral ◽  
Farideh Nejat ◽  
...  
Keyword(s):  
Risk Factors ◽  
Tumor Progression ◽  
Cox Regression ◽  
Tumor Resection ◽  
Progression Free Survival ◽  
Initial Presentation ◽  
Subtotal Resection ◽  
Low Grade ◽  
Cox Regression Analysis ◽  
Presenting Symptoms

Object Few reports describe the outcome and prognostic factors for children with gangliogliomas. The objective of this report was to describe the progression-free survival (PFS) for children with low-grade gangliogliomas and identify risk factors for tumor progression. Methods A retrospective study was performed in children with low-grade gangliogliomas who were evaluated and treated in the neuro-oncology department between 1986 and 2006 to determine risk factors for subsequent tumor progression. Results A total of 38 children with newly diagnosed gangliogliomas were included in this report. Thirty-four children were treated with surgery alone, 3 with subtotal resection and radiation therapy, and 1 with subtotal resection and chemotherapy. The follow-up ranged from 4 months to 15.8 years (mean 5.7 ± 4.2 years [± SD]). Seven children have experienced tumor progression, and 1 child died after his tumor subsequently underwent malignant transformation. The 5-year PFS was calculated to be 81.2% using Kaplan-Meier survival analysis. Initial presentation with seizures (p = 0.004), tumor location in the cerebral hemisphere (p = 0.020), and complete tumor resection (p = 0.035) were associated with prolonged PFS. Further analysis of the above significant variables by a Cox regression model identified initial presentation with seizures as being associated with prolonged PFS (p = 0.028). Conclusions The PFS and overall survival of children with gangliogliomas are good. Tumors located in the cerebral hemispheres, the achievement of total resection, and seizures at presentation were associated with prolonged PFS. Cox regression analysis identified presenting symptoms including seizures as significant predictive factors of PFS. Prospective studies with larger numbers of children are needed to define the significant factors of tumor progression.

The Role of Surgery in IDH-Wild-Type Lower-Grade Gliomas: Threshold at a High Extent of Resection Should be Pursued

Neurosurgery ◽  
2021 ◽  
Author(s):  
Peng Wang ◽  
Chen Luo ◽  
Peng-jie Hong ◽  
Wen-ting Rui ◽  
Shuai Wu
Keyword(s):  
Cox Regression ◽  
Progression Free Survival ◽  
Extent Of Resection ◽  
Lower Grade ◽  
Wild Type ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Lower Grade Glioma ◽  
Clinical Benefits

Abstract BACKGROUND While maximizing extent of resection (EOR) is associated with longer survival in lower-grade glioma (LGG) patients, the number of cases remains insufficient in determining a EOR threshold to elucidate the clinical benefits, especially in IDH-wild-type LGG patients. OBJECTIVE To identify the effects of EOR on the survival outcomes of IDH-wild-type LGG patients. METHODS IDH-wild-type LGG patients were retrospectively reviewed. The effect of EOR and other predictor variables on overall survival (OS) and progression-free survival (PFS) was analyzed using Cox regression models and the Kaplan-Meier method. RESULTS A total of 94 patients (median OS: 48.9 mo; median follow-up: 30.6 mo) were included in this study. In the multivariable Cox regression analysis, postoperative residual volume was associated with prolonged OS (HR = 2.238; 95% confidence interval [CI], 1.130-4.435; P = .021) and PFS (HR = 2.075; 95% CI, 1.113-3.869; P = .022). Thresholds at a minimum EOR of 97.0% or a maximum residue of 3.0 cm3 were necessary to impact OS positively. For the telomerase reverse transcriptase (TERT)p-wild-type group, such an association was absent. Significant differences in survival existed between the TERTp-wild-type and mutant patients who underwent relatively incomplete resections (residual ≥2.0 cm3 + TERTp wild type: median OS of 62.6 mo [95% CI: 39.7-85.5 mo]; residual ≥2.0 cm3 + TERTp mutant: median OS of 20.0 mo [95% CI:14.6-25.4 mo]). CONCLUSION Our results support the core role of maximal safe resection in the treatment of IDH-wild-type LGGs, especially for IDH-wild-type + TERTp-mutant LGGs. Importantly, the survival benefits of surgery could only be elucidated at a high EOR cut-off point.

Association between prior radical surgery (RS) and outcomes with immune checkpoint inhibitor (ICI) therapy for advanced urothelial carcinoma (aUC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 444-444
Author(s):  
Dimitrios Makrakis ◽  
Daniel Castellano ◽  
Ivan de Kouchkovsky ◽  
Joseph J. Park ◽  
Mehmet Asim Bilen ◽  
...  
Keyword(s):  
Immune Checkpoint Inhibitor ◽  
Overall Response Rate ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Similar Proportion ◽  
Multivariable Model ◽  
Free Survival ◽  
Cox Regression Analysis ◽  
Response Table ◽  
Advanced Urothelial Carcinoma

444 Background: It is unclear whether prior RS of primary tumor is associated with response and outcomes with ICI in aUC. We hypothesized that such response and outcomes would not differ based on prior RS. Methods: We performed a retrospective cohort study including patients (pts) with aUC who received ICI. We compared overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) between pts with vs without RS [cystectomy or (nephro)-ureterectomy]. Analysis was stratified based on ICI therapy line (first-line vs salvage). A separate comparison between pts with prior RS or radiation (RT) only or none was also pursued. ORR was compared between groups using logistic regression, as well OS and PFS using cox regression analysis; a multivariable model was built adjusting for calculated Bellmunt score. P<0.05 was significant. Results: We identified 984 pts from 24 institutions; 682, 704 and 673 were included in OS, PFS and ORR analyses, respectively; 54% of pts had prior RS with median age 68 at ICI initiation with RS vs 71 without RS with similar proportion of men (73-74%) and ever smokers (70-71%). The RS group had higher proportion (%) of white pts (77% vs 71%), lower % of pts with Hb<10g/dL at ICI initiation (23% vs 32%) but not significantly higher % of liver metastasis at ICI initiation (23% vs 17%). Bellmunt score with vs without RS was 16% vs 11%, 50% vs 48%, 27% vs 37%, 7% vs 4% for 0, 1, 2, and 3, respectively. ORR and PFS were not significantly different between groups, while prior RS was associated with longer OS (unadjusted HR 0.8, p=0.03). However, after adjustment for Bellmunt score, this association was not significant (table). Upon stratification based on treatment line, OS was longer with prior RS (0.7, p=0.03) for those treated with salvage ICI but this was not significant after adjusting for Bellmunt score. ORR, PFS and OS were not significantly different between pts receiving prior RT only vs RS vs none. Conclusions: Prior RS was not significantly associated with longer OS in pts with aUC receiving ICI after adjusting for Bellmunt score. Further work is needed to interrogate tumor-host immune interactions and identify biomarkers that can be prognostic and/or predictive of ICI response. [Table: see text]

scholarly journals Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 434 ◽  
Author(s):  
Ming-Ju Tsai ◽  
Jen-Yu Hung ◽  
Mei-Hsuan Lee ◽  
Chia-Yu Kuo ◽  
Yu-Chen Tsai ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
First Line ◽  
Free Survival ◽  
Younger Patients ◽  
Epidermal Growth

Patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutations usually have a good response rate (RR) and longer progression-free survival (PFS) to EGFR tyrosine kinase inhibitors (TKIs). However, the treatment efficacy to uncommon EGFR mutations remains controversial. We, therefore, performed a retrospective study, screening 2958 patients. A total of 67 patients with lung adenocarcinoma harboring uncommon EGFR mutations were enrolled and 57 patients with stage IV diseases receiving a first-line EGFR TKI were included for further analyses. The patients were classified into 27 (47%) “a single sensitizing uncommon mutation”, 7 (12%) “multiple sensitizing mutations”, 5 (9%) “a sensitizing mutation and a resistant uncommon mutation”, and 18 (32%) “other resistant uncommon mutations”. No significant difference was noted in PFS or overall survival (OS) between groups. Patients receiving different first-line EGFR TKIs had similar PFS and OS. The elder patients had a significantly poorer performance status than the younger patients but a significantly longer PFS than the younger patients (median PFS: 10.5 vs. 5.5 months, p = 0.0320). In conclusion, this is the first study to identify that elderly patients with stage IV lung adenocarcinoma harboring uncommon EGFR mutation might have a longer PFS. Large-scale prospective studies are mandatory to prove our findings.

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