scholarly journals Real-world association of HER2/ERBB2 concordance with trastuzumab clinical benefit in advanced esophagogastric cancer

2021 ◽  
Author(s):  
Stacey M Stein ◽  
Jeremy Snider ◽  
Siraj M Ali ◽  
Rebecca A Miksad ◽  
Brian M Alexander ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Benefit ◽  
Copy Number ◽  
Treatment Discontinuation ◽  
Her2 Status ◽  
First Line ◽  
Time To Treatment ◽  
World Association ◽  
Esophagogastric Cancer ◽  
Erbb2 Amplification

Aim: To assess concordance between HER2 status measured by traditional methods and ERBB2 amplification measured by next-generation sequencing and its association with first-line trastuzumab clinical benefit in patients with advanced esophagogastric cancer. Methods: Retrospective analysis of HER2/ ERBB2 concordance using a deidentified USA-based clinicogenomic database. Clinical outcomes were assessed for patients with HER2+ advanced esophagogastric cancer who received first-line trastuzumab. Results: Overall HER2/ ERBB2 concordance was 87.5%. Among patients who received first-line trastuzumab, concordant HER2/ ERBB2 was associated with longer time to treatment discontinuation (adjusted hazard ratio [aHR]: 0.63; 95% CI: 0.43–0.90) and overall survival (aHR: 0.51; 95% CI: 0.33–0.79). ERBB2 copy number ≥25 (median) was associated with longer time to treatment discontinuation (aHR: 0.56; 95% CI: 0.35–0.88) and overall survival (aHR: 0.52; 95% CI: 0.30–0.91). Conclusion: HER2/ ERBB2 concordance and higher ERBB2 copy number predicted clinical benefit from trastuzumab.

scholarly journals Targeting EGFR in Esophagogastric Cancer

2020 ◽  
Vol 10 ◽  
Author(s):  
Steven B. Maron ◽  
James Xu ◽  
Yelena Y. Janjigian
Keyword(s):  
Overall Survival ◽  
Clinical Benefit ◽  
Routine Care ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Metastatic Setting ◽  
Esophagogastric Cancer ◽  
Phase Iii Trials ◽  
Related Mortality

Esophagogastric cancer (EGC) remains a major cause of cancer-related mortality. Overall survival in the metastatic setting remains poor, with few molecular targeted approaches having been successfully incorporated into routine care to-date: only first line anti-HER2 therapy in ERBB2-expressing tumors, second line anti-VEGFR2 therapy with ramucirumab in unselected patients, and pembrolizumab in PD-L1 expressing or MSI-H patients. EGFR inhibitors were extensively studied in EGC, including phase III trials with cetuximab (EXPAND), panitumumab (REAL3), and gefitinib (COG). All three trials were conducted in unselected populations, and therefore, failed to demonstrate clinical benefit. Here, we review previous attempts at targeting EGFR in EGC and potential future biomarkers for targeting this pathway in patients with EGFR-amplified tumors.

Association of response to first-line chemotherapy with the efficacy of atezolizumab in patients with metastatic urothelial carcinoma.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 409-409
Author(s):  
Deniz Tural ◽  
Omer Fatih Olmez ◽  
Ahmet Taner Sümbül ◽  
Mehmet Artac ◽  
Nail Ozhan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Bladder Cancer ◽  
Clinical Benefit ◽  
Progressive Disease ◽  
Univariate Analysis ◽  
First Line ◽  
Exact Test ◽  
Best Response ◽  
Metastatic Urothelial Carcinoma ◽  
Line Chemotherapy

409 Background: In the current study, we evaluated whether the response first-line chemotherapy could impact atezolizumab benefit in terms of response rate and overall survival in patients with metastatic urothelial carcinoma. Methods: In this study, we present the retrospective analysis of 105 patients with urothelial cancer treated with ATZ after progression on first-line chemotherapy. The association between response to first-line chemotherapy and ATZ was assessed using Fisher’s exact test. Overall survival (OS) was estimated by using the Kaplan-Meier method. Univariate analysis was used to identify clinical and laboratory factors that significantly impact OS. Variables were retained for multivariate analysis if they had a statistical relationship with OS (p˂0.1) and then included the final model if p˂0.05. Results: Best response to first-line chemotherapy was complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) in 5(4.8%), 38(36.2%), 16(15.2%), 46(43.8%) patients, respectively. Best response to atezolizumab was CR, PR, SD, PD in 9(8.6%), 22(21%), 23(21,9%), 51(48,5%). Forty (74.1%) of patients who benefited from first-line chemotherapy also benefited from atezolizumab, while only 14 (25.9%) of patients with initial PD after first-line chemotherapy subsequently experienced clinical benefit with atezolizumab (Fisher’s exact test, p=0.001). Patients with clinical benefit from first-line chemotherapy had a higher OS. The median OS of atezolizumab were 14.8 and 3.4 months for patients with clinical benefit and progressive disease in response to first-line chemotherapy, respectively (log-rank p=0.001). In univariate analysis, Patients with clinical benefit from first-line chemotherapy, liver metastases, baseline creatinine clearance less (GFR)than 60 ml/min, Eastern Cooperative Oncology Group (ECOG) performance status (1 ≥), and hemoglobin levels below 10 mg/dl were all significantly associated with OS. Three of the adverse prognostic factors according to the Bellmunt criteria were independent factor of short survival: liver metastases (Hazard Ratio [HR]= 0.6; 95% CI 0.174-0.60; p=0.04), ECOG PS≥1 (HR= 0.36; 95% CI 0.2-0.66; p=0.001), and Hemoglobin level below 10 mg/dl (HR= 0.36; 95% CI 0.2-0.66; p <0.001). In addition, Patients with clinical benefit from first-line chemotherapy (HR= 0.39; 95% CI 0.24-0.65; p <0.001) maintained a significant association with OS in multivariate analysis. Conclusions: Our study demonstrated that clinical benefit from first-line chemotherapy was independent prognostic factor on OS in patients' use of atezolizumab as second-line treatment in metastatic bladder cancer. Furthermore, these findings are important for stratification factors for future immunotherapy study design in patients with bladder cancer who have progressed after first-line chemotherapy.

Biomarker Analyses and Final Overall Survival Results From a Phase III, Randomized, Open-Label, First-Line Study of Gefitinib Versus Carboplatin/Paclitaxel in Clinically Selected Patients With Advanced Non–Small-Cell Lung Cancer in Asia (IPASS)

2011 ◽  
Vol 29 (21) ◽  
pp. 2866-2874 ◽  
Author(s):  
Masahiro Fukuoka ◽  
Yi-Long Wu ◽  
Sumitra Thongprasert ◽  
Patrapim Sunpaweravong ◽  
Swan-Swan Leong ◽  
...  
Keyword(s):  
Overall Survival ◽  
Copy Number ◽  
Egfr Mutation ◽  
Gene Copy Number ◽  
Phase Iii ◽  
Egfr Mutations ◽  
Gene Copy ◽  
First Line ◽  
Egfr Gene ◽  
Significant Difference

Purpose The results of the Iressa Pan-Asia Study (IPASS), which compared gefitinib and carboplatin/paclitaxel in previously untreated never-smokers and light ex-smokers with advanced pulmonary adenocarcinoma were published previously. This report presents overall survival (OS) and efficacy according to epidermal growth factor receptor (EGFR) biomarker status. Patients and Methods In all, 1,217 patients were randomly assigned. Biomarkers analyzed were EGFR mutation (amplification mutation refractory system; 437 patients evaluable), EGFR gene copy number (fluorescent in situ hybridization; 406 patients evaluable), and EGFR protein expression (immunohistochemistry; 365 patients evaluable). OS analysis was performed at 78% maturity. A Cox proportional hazards model was used to assess biomarker status by randomly assigned treatment interactions for progression-free survival (PFS) and OS. Results OS (954 deaths) was similar for gefitinib and carboplatin/paclitaxel with no significant difference between treatments overall (hazard ratio [HR], 0.90; 95% CI, 0.79 to 1.02; P = .109) or in EGFR mutation–positive (HR, 1.00; 95% CI, 0.76 to 1.33; P = .990) or EGFR mutation–negative (HR, 1.18; 95% CI, 0.86 to 1.63; P = .309; treatment by EGFR mutation interaction P = .480) subgroups. A high proportion (64.3%) of EGFR mutation–positive patients randomly assigned to carboplatin/paclitaxel received subsequent EGFR tyrosine kinase inhibitors. PFS was significantly longer with gefitinib for patients whose tumors had both high EGFR gene copy number and EGFR mutation (HR, 0.48; 95% CI, 0.34 to 0.67) but significantly shorter when high EGFR gene copy number was not accompanied by EGFR mutation (HR, 3.85; 95% CI, 2.09 to 7.09). Conclusion EGFR mutations are the strongest predictive biomarker for PFS and tumor response to first-line gefitinib versus carboplatin/paclitaxel. The predictive value of EGFR gene copy number was driven by coexisting EGFR mutation (post hoc analysis). Treatment-related differences observed for PFS in the EGFR mutation–positive subgroup were not apparent for OS. OS results were likely confounded by the high proportion of patients crossing over to the alternative treatment.

scholarly journals Real-world data of fulvestrant as first-line treatment of postmenopausal women with estrogen receptor-positive metastatic breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
I. Blancas ◽  
C. Olier ◽  
V. Conde ◽  
J. L. Bayo ◽  
C. Herrero ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Estrogen Receptor ◽  
Postmenopausal Women ◽  
Real World ◽  
Clinical Benefit ◽  
Randomized Clinical Trials ◽  
First Line ◽  
Clinical Benefit Rate ◽  
Er Positive

AbstractGoals of endocrine therapy for advanced breast cancer (ABC) include prolonging survival rates, maintaining the quality of life, and delaying the initiation of chemotherapy. We evaluated the effectiveness of fulvestrant as first-line in patients with estrogen receptor (ER)-positive ABC with relapse during or after adjuvant anti-estrogenic therapy in real-world settings. Retrospective, observational study involving 171 postmenopausal women with ER-positive ABC who received fulvestrant as first-line between January 2011 and May 2018 in Spanish hospitals. With a median follow-up of 31.4 months, the progression-free survival (PFS) with fulvestrant was 14.6 months. No differences were seen in the visceral metastatic (14.3 months) versus non-visceral (14.6 months) metastatic subgroup for PFS. Overall response rate and clinical benefit rate were 35.2% and 82.8%. Overall survival was 43.1 months. The duration of the clinical benefit was 19.2 months. Patients with ECOG performance status 0 at the start of treatment showed a significant greater clinical benefit rate and overall survival than with ECOG 1–2. Results in real-world settings are in concordance with randomized clinical trials. Fulvestrant continues to demonstrate clinical benefits in real-world settings and appears be well tolerated as first-line for the treatment of postmenopausal women with ER-positive ABC.

Everolimus and sunitinib as first- and second-line treatments of patients with metastatic papillary renal cell carcinoma (pRCC): A retrospective study of the GETUG (Groupe Français d’Etude des Tumeurs Uro-Génitales).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 505-505
Author(s):  
Claude Linassier ◽  
Laurence Albiges ◽  
Christine Chevreau ◽  
Brigitte Laguerre ◽  
Stephane Oudard ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Benefit ◽  
Karnofsky Performance Status ◽  
Multivariable Analysis ◽  
Prognostic Impact ◽  
Second Line ◽  
Phase Ii Trials ◽  
First Line ◽  
Group 2 ◽  
Group 1

505 Background: pRCC accounts for 15% of all renal cancers. Two French prospective phase II trials demonstrated efficacy of both Sun and Eve in first-line treatment of metastatic disease (RAPTOR (NCT00688753) and SUPAP (NCT00541008)). Most patients (pts) usually receive the alternate drug at progression. We report the first series of drug sequencing in pRCCs. Methods: We updated clinical data of metastatic pts with pathologically documented pRCC, who were treated in firs line or more with Sun or Eve, from 2/06 to 6/15, in 24 GETUG centers. Results: 196 pts (166 men, 30 women), median aged of 61 years, with histological subtypes (HST) I (28 pts), II (122 pts) or unclassified (46 pts), were treated for metastatic pRCC in 1st-line: group 1 Su 50 mg daily 4/6 weeks (n=158 pts) ; group 2 Eve 10 mg daily (n=38 pts). 76 pts were included in the RAPTOR or SUPAP studies. The median follow-up was 59.5 months. We found no difference between the 2 groups in terms of patients’ characteristics, clinical benefit in first-line (CR+PR+SD) (71% vs 72%; p=0.95) or progression-free survival (PFS) (PFS-1: 5.7 vs 4.6 months; p=0.152). Reasons for treatment discontinuation were tumor progression (74% vs 70%) or toxicity (26 vs 30%) (p=0.58). 134 pts received the alternative drug in second-line (group 1: Eve; group 2: Sun) with similar clinical benefit (64% vs 58%; p=0.69) and median PFS (PFS-2: 3.5 vs 3.0 months p=0.98). Overall survival (OS) did not differ between the two groups (16.4 vs 17.6 months; p=0.58). Age, Karnofsky performance status < 80 (KPS-80), HST, platelet (Plts) and absolute neutrophil counts (ANC), hemoglobin and calcium levels, time from diagnosis to metastases (TTM) were studied as prognostic variables. In multivariable analysis, only Plts and KPS-80 had prognostic impact on EFS-1, whereas ANC, KPS-80 and TTM were prognostic for OS. We found a trend in favor of HST I vs non I, with no statistical difference in terms of PFS or OS. Conclusions: In this large retrospective series of metastatic pRCC pts, Sun and Eve had good compliance and similar efficacy in terms of first-, second-line PFS and overall survival.

Prospective Measurement of EBV-DNA in Plasma and Peripheral Blood Mononuclear Cells of Extranodal NK/T-Cell Lymphoma, Nasal Type.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 135-135
Author(s):  
Ritsuro Suzuki ◽  
Motoko Yamaguchi ◽  
Koji Izutsu ◽  
Go Yamamoto ◽  
Kenzo Takada ◽  
...  
Keyword(s):  
Overall Survival ◽  
Peripheral Blood ◽  
Copy Number ◽  
Mononuclear Cells ◽  
Clinical Stage ◽  
Performance Status ◽  
First Line ◽  
Dna Copy Number ◽  
Nasal Type ◽  
Ebv Dna

Abstract Abstract 135 Background: Peripheral blood of patients with extranodal NK/T-cell lymphoma, nasal type (ENKL) contains fragmented Epstein-Barr virus (EBV) DNA. Measurement of the circulating viral DNA load has been reported to be useful for the diagnosis, monitoring and prognostication of the disease. However, there are two different subjects for analysis, plasma/serum component and mononuclear cells (MNC). Most reports do not compare both samples from the same patients, and are biased by a retrospective manner of accrual. Therefore, it remains unclear which samples are more useful subjects. Materials and Methods: To evaluate clinical significance of peripheral blood EBV-DNA copy number for ENKL, we conducted a prospective study to analyze EBV-DNA with quantitative polymerase chain reaction. Inclusion criteria are as follows: (1) Diagnosis of ENKL or aggressive NK-cell leukemia by biopsy or cytology. (2) Patients without other serious complications and those tolerable for chemotherapy and/or radiotherapy. (3) No prior history of chemotherapy or radiotherapy. (4) Patients with written informed consent. Primary endpoint was a prognostic value of EBV-DNA copy number to predict 2-year overall survival. Secondary endpoints were comparison of EBV-DNA copy number and pretreatment characteristics and prognostic capability of EBV-DNA during/after treatments. Three times of analysis, pre-treatment, mid-treatment, post-treatment, at central laboratory was to be performed for each patient. Results: A total of 33 patients were registered from June 2004 to March 2007. All patients were diagnosed with ENKL and male/female ratio was 21/12. The median age was 56 years old, ranging from 18 to 81. 19 patients were in stage IE, 3 in stage IIE, and 11 in stage IV. 13 patients had B-symptom and 14 had elevated serum LDH level. ECOG performance status was low (0–2) in 29 patients, but was 3 in 2 patients. IPI was high-intermediate/high in 11. First line treatment included concurrent chemoradiotherapy in 16, radiotherapy followed by chemotherapy in 8, and chemotherapy alone in 6. Pretreatment MNC and plasma EBV-DNA were detectable in 6 and 14 patients, respectively. The maximum copy numbers were 780 copies/microgram DNA for MNC and 71000 copies/mL for plasma. Significant correlation was observed between mononuclear and plasma EBV-DNA copies (r = 0.8741, P < 0.0001). Plasma EBV-DNA well correlated with pretreatment clinical stage (P = 0.02), presence of B-symptom (P = 0.02), ECOG PS (P = 0.02), serum LDH level (P = 0.05), and soluble IL-2 receptor (P < 0.0001), but not with regional node involvement (P = 0.17), nasal vs. nasal-type (P = 0.16), and serum C-reactive protein (P = 0.29). Among 28 patients evaluable for response, 21 patients responded (CR/PR) to the first line treatment. Mean plasma EBV-DNA copy number before treatment was significantly higher in non-responders compared to responders (16472 copies/mL vs 2645 copies/mL, P = 0.02). 2-year overall survival was 69.7%. The median follow-up of patients was 2.9 years. Clinical stage, performance status, pretreatment plasma EBV-DNA and pretreatment mononuclear cell EBV-DNA were significant prognostic factors for overall survival by univariate analysis. Multivariate analysis showed clinical stage (hazard ratio = 9.0, 95% confidence interval: 1.8–45.0) and pretreatment plasma EBV-DNA (hazard ratio = 10.6, 95% confidence interval: 1.3–87.0) were significant prognostic factors. 2-year overall survival of plasma EBV-DNA positive and negative patients was 42.9% and 94.4%, respectively (Figure, P = 0.0009). Conclusions: Our study shows pretreatment plasma EBV-DNA copy number is a good indicator for both response to treatment and overall survival. Measurement of the plasma EBV-DNA is useful for prospective clinical trials and general practice. Disclosures: Oshimi: Eisai Pharmaceutical Company: Employment.

scholarly journals CDKL2 Is Associated with HER2 Status and Overall Survival in Gastric Cancer: Comparative Analysis of CDKL2 Protein Expression and Gene Copy Number

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Qiong Shao ◽  
Fang Wang ◽  
Yuxia Xu ◽  
Xu Zhang ◽  
Wenting Tang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Protein Expression ◽  
Copy Number ◽  
Epithelial Mesenchymal Transition ◽  
Mrna Level ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Her2 Status ◽  
Mesenchymal Transition

Background. Cyclin-dependent kinase-like 2 (CDKL2) is a member of the CDKL family and recognized as a novel regulator of epithelial-mesenchymal transition of breast cancer cells, but its role has not been explored in gastric cancer (GC). This study was to characterize the CDKL2 protein expression and gene copy number in relation to human epidermal growth factor receptor 2 (HER2) status, clinicopathological features, and overall survival (OS) in GC. Methods. This study detected the CDKL2 protein expression and gene copy number by immunochemistry (IHC) and fluorescent in situ hybridization (FISH), respectively, in 334 GC samples. HER2 status was determined according to established criteria. Associations of the CDKL2 protein expression and gene copy number with OS in GC were evaluated, and the association between CDKL2 mRNA expression and OS in GC was also analyzed using TCGA data. Results. The detection results suggested that 34.1% cases showed high CDKL2 protein expression; 11.4% cases had ≥5 copies of CDKL2 gene or a ratio of CDKL2 to chromosome of ≥2. The CDKL2 protein expression was markedly correlated with its gene copy number. High protein expression and high gene copy number were both significantly associated with positive HER2 status, and they both could predicted a shorter OS, although not as independent markers suggested by the multivariate Cox proportional hazard regression analysis. The TCGA data indicated that higher CDKL2 mRNA level also predicted a shorter OS in GC. Conclusions. The combined detection of the CDKL2 protein level and gene copy number could be of important value in predicting HER2 status and prognosis of patients with GC.

scholarly journals A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML

Blood ◽  
2017 ◽  
Vol 129 (9) ◽  
pp. 1143-1154 ◽  
Author(s):  
Steven Knapper ◽  
Nigel Russell ◽  
Amanda Gilkes ◽  
Robert K. Hills ◽  
Rosemary E. Gale ◽  
...  
Keyword(s):  
Overall Survival ◽  
Inhibitory Activity ◽  
Clinical Benefit ◽  
Kinase Inhibitor ◽  
Newly Diagnosed ◽  
First Line ◽  
Standard Chemotherapy ◽  
Key Points ◽  
Line Chemotherapy

Key Points No overall clinical benefit was seen after the addition of lestaurtinib to standard chemotherapy for newly diagnosed FLT3-mutated AML. Lower rates of relapse and improved overall survival were seen in patients who achieved sustained levels of FLT3 inhibitory activity.

Prognostic effect of EIF4EBP1 on ovarian cancer: A single gene biomarker for overall survival and platinum response.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5565-5565
Author(s):  
Victor Manuel Villalobos ◽  
Yan Wang ◽  
Scooter Willis ◽  
Brian Leyland-Jones ◽  
Branimir I. Sikic
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Mrna Expression ◽  
Copy Number ◽  
Cancer Genetics ◽  
First Line ◽  
Ovarian Carcinomas ◽  
Aberrant Expression ◽  
Normal Expression ◽  
Z Scores

5565 Background: Using a novel computational approach, Gene Set Outcome Analysis (GSOA), we were able to identify an area of amplification on chromosome 8p12 that leads to worse prognosis in high grade/high stage ovarian cancer. Located within this amplicon is EIF4EBP1, an effector of DNA translation that is activated by mTOR. Methods: We utilized the MSKCC CBIO cancer genetics portal and the ovarian TCGA clinical dataset, to detect variation in mRNA expression (EXP), (z-scores thresholds ± 2) and copy number variation (CNV), determined using GISTIC 2.0, that are associated with significant differences in PFS and overall survival in grade 3 and stage III/IV ovarian cancer. Results: 6.7% of tumors exhibited upregulation of EIF4EBP1 (CNV amplified and mRNA z > 2) and poorer prognosis with OS of 30.2 vs. 43.8 months (p = 0.0007, n = 445) in tumors not upregulated. Patients with upregulated vs. normal expression showed inferior PFS with first line, platinum based therapy, 10.0 vs. 15.2 months (p = 0.0406, n = 400), respectively. An additional 4.9% of cases had downregulation of EIF4EBP1, with homozygous deletion or mRNA expression z-scores < -2. Downregulation vs. normal expression also showed worse OS of 27.0 vs. 42.1 months (p = 0.0178) and PFS of 11.0 vs. 15.0 months (p = 0.028), respectively. As these groups are mutually exclusive and show a similar trend towards poor prognosis, when combined to compare aberrant vs. normal mRNA expression and copy number, we found an OS of 28.2 vs. 44.6 months (p = <0.0001) and PFS for first line platinum therapy of 10.2 vs. 15.3 months (p = 0.0024), respectively. Conclusions: In this dataset of 445 high-risk ovarian cancer patients, 11.8% exhibited aberrant expression of EIF4EBP1. While amplification of this region showed highly significant changes in OS and PFS, inclusion of both increased and decreased EIF4EBP1 mRNA expression achieved high statistical significance, demonstrating a “Goldilocks effect”, wherein normal expression leads to better outcomes. The potential relationship of gene expression levels of EIF4EBP1 to responsiveness to mTOR inhibitors should be explored in ovarian carcinomas.

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