scholarly journals Author Correction: PTEN is a predictive biomarker of trastuzumab resistance and prognostic factor in HER2-overexpressing gastroesophageal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daiju Yokoyama ◽  
Shigeo Hisamori ◽  
Yasunori Deguchi ◽  
Tatsuto Nishigori ◽  
Hiroshi Okabe ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Predictive Biomarker ◽  
Trastuzumab Resistance ◽  
Gastroesophageal Adenocarcinoma

scholarly journals PTEN is a Predictive Biomarker of Trastuzumab Resistance and Prognostic Factor in HER2-overexpressing Gastroesophageal Adenocarcinoma

2021 ◽  
Author(s):  
Daiju Yokoyama ◽  
Shigeo Hisamori ◽  
Yasunori Deguchi ◽  
Tatsuto Nishigori ◽  
Hiroshi Okabe ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Mtor Inhibitor ◽  
Gastroesophageal Junction ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Pten Expression ◽  
Trastuzumab Resistance ◽  
Effective Treatment Option ◽  
Pten Loss

Abstract IntroductionPoor Trastuzumab (Tmab) response in human epidermal growth factor receptor 2-overexpressing gastric or gastroesophageal junction adenocarcinoma (HER2-GEA) is reported to be associated with loss of phosphatase and tensin homolog (PTEN) expression.MethodsIn a multicenter, retrospective observational study, pathological samples of HER2-GEA patients receiving Tmab-combined chemotherapy were immunohistochemically analyzed for PTEN expression. Primary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The effect of PI3K pathway inhibitors on HER2-GEA cell lines were evaluated in in-vitro.ResultsAmong 145 HER2-GEA patients, 29 formed the PTEN-loss group and 116 the PTEN-positive group. In patients with target region, DCR was significantly lower in PTEN-loss than in PTEN-positive patients (67% and 87%, respectively, p=0.049). Multivariate analysis demonstrated that PTEN loss was significantly associated with shorter PFS (HR=1.63, p=0.035) and OS (HR=1.83, p=0.022). PTEN knockdown did not affect the cytostatic effect of 5-FU and cisplatin, while Tmab combined with PI3K/mTOR inhibitor NPV-BEZ235 suppressed the proliferation of PTEN knockdown cells which were resistant to Tmab alone.ConclusionIn HER2-GEA patients, PTEN loss is a predictive biomarker of Tmab resistance and prognostic factor. Molecular-targeted therapy with PI3K/mTOR inhibitor would be an effective treatment option for HER2-GEA with PTEN loss.

scholarly journals PTEN is a predictive biomarker of trastuzumab resistance and prognostic factor in HER2-overexpressing gastroesophageal adenocarcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daiju Yokoyama ◽  
Shigeo Hisamori ◽  
Yasunori Deguchi ◽  
Tatsuto Nishigori ◽  
Hiroshi Okabe ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Mtor Inhibitor ◽  
Gastroesophageal Junction ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Pten Expression ◽  
Trastuzumab Resistance ◽  
Pten Loss

AbstractPoor trastuzumab (Tmab) response of patients with human epidermal growth factor receptor 2-overexpressing gastric or gastroesophageal junction adenocarcinoma (HER2-GEA) is associated with the inhibition of phosphatase and tensin homolog (PTEN) expression. In this multicenter, retrospective observational study, pathological samples of patients with HER2-GEA receiving Tmab-combined chemotherapy were immunohistochemically analyzed for PTEN expression. The primary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). We assessed the effect of conventional chemotherapy and Tmab alone or combined with PI3K pathway inhibitors in vitro in HER2-GEA cells with or without PTEN expression. Twenty-nine and 116 patients were in the PTEN-loss and PTEN-positive groups, respectively. In patients with the target region, DCR was significantly lower in PTEN-loss patients than in PTEN-positive patients (67% and 87%, respectively, p = 0.049). The multivariate analysis demonstrated that PTEN loss was significantly associated with shorter PFS (HR = 1.63, p = 0.035) and OS (HR = 1.83, p = 0.022). PTEN knockdown did not affect the cytostatic effect of 5-FU and cisplatin, whereas Tmab combined with the PI3K/mTOR inhibitor NPV-BEZ235 suppressed PTEN-knockdown cell proliferation. In patients with HER2-GEA, PTEN loss is a predictive biomarker of Tmab resistance and prognostic factor. Molecular-targeted therapy with a PI3K/mTOR inhibitor would be effective for HER2-GEA with PTEN loss.

KRASandBRAFMutations in Advanced Colorectal Cancer Are Associated With Poor Prognosis but Do Not Preclude Benefit From Oxaliplatin or Irinotecan: Results From the MRC FOCUS Trial

2009 ◽  
Vol 27 (35) ◽  
pp. 5931-5937 ◽  
Author(s):  
Susan D. Richman ◽  
Matthew T. Seymour ◽  
Philip Chambers ◽  
Faye Elliott ◽  
Catherine L. Daly ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Factor ◽  
Braf Mutation ◽  
Poor Prognosis ◽  
Advanced Colorectal Cancer ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Poor Prognostic Factor ◽  
Minimal Impact ◽  
The Impact

PurposeActivating mutation of the KRAS oncogene is an established predictive biomarker for resistance to anti–epidermal growth factor receptor (anti-EGFR) therapies in advanced colorectal cancer (aCRC). We wanted to determine whether KRAS and/or BRAF mutation is also a predictive biomarker for other aCRC therapies.Patients and MethodsThe Medical Research Council Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing (MRC FOCUS) trial compared treatment sequences including first-line fluorouracil (FU), FU/irinotecan or FU/oxaliplatin in aCRC. Tumor blocks were obtained from 711 consenting patients. DNA was extracted and KRAS codons 12, 13, and 61 and BRAF codon 600 were assessed by pyrosequencing. Mutation (mut) status was assessed first as a prognostic factor and then as a predictive biomarker for the benefit of adding irinotecan or oxaliplatin to FU. The association of BRAF-mut with loss of MLH1 was assessed by immunohistochemistry.ResultsThree hundred eight (43.3%) of 711 patients had KRAS-mut and 56 (7.9%) of 711 had BRAF-mut. Mutation of KRAS, BRAF, or both was present in 360 (50.6%) of 711 patients. Mutation in either KRAS or BRAF was a poor prognostic factor for overall survival (OS; hazard ratio [HR], 1.40; 95% CI, 1.20 to 1.65; P < .0001) but had minimal impact on progression-free survival (PFS; HR, 1.16; 95% CI, 1.00 to 1.36; P = .05). Mutation status did not affect the impact of irinotecan or oxaliplatin on PFS or OS. BRAF-mut was weakly associated with loss of MLH1 staining (P = .012).ConclusionKRAS/BRAF mutation is associated with poor prognosis but is not a predictive biomarker for irinotecan or oxaliplatin. There is no evidence that patients with KRAS/BRAF mutated tumors are less likely to benefit from these standard chemotherapy agents.

Determination of hypoxia signature to predict prognosis and the tumor immune microenvironment in melanoma

2021 ◽  
Vol 17 (2) ◽  
pp. 307-316
Author(s):  
Yanhong Shou ◽  
Lu Yang ◽  
Yongsheng Yang ◽  
Xiaohua Zhu ◽  
Feng Li ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Predictive Biomarker ◽  
Independent Prognostic Factor ◽  
Immune Microenvironment ◽  
Tumor Immune Microenvironment ◽  
Hypoxia Signature

The hypoxia score is identified as an independent prognostic factor and a predictive biomarker of the immune microenvironment for melanoma.

DKN-01 in combination with pembrolizumab in patients with advanced gastroesophageal adenocarcinoma (GEA): Tumoral DKK1 expression as a predictor of response and survival.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 357-357 ◽  
Author(s):  
Samuel J. Klempner ◽  
Johanna C. Bendell ◽  
Victoria Meucci Villaflor ◽  
Laura LaNiel Tenner ◽  
Stacey Stein ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Benefit ◽  
Objective Response ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Clinical Activity ◽  
Kaplan Meier ◽  
Dkk1 Expression ◽  
Clinical Benefit Response ◽  
Gastroesophageal Adenocarcinoma

357 Background: Dickkopf-1 (DKK1) modulates Wnt signaling and contributes to an immune suppressive tumor microenvironment. DKN-01 (D), a neutralizing DKK1 antibody + pembrolizumab (P) has demonstrated safety and clinical activity in advanced GEA. We report response and survival outcomes in anti-PD-1/anti-PD-L1 naïve GEA patients by high/low tumoral DKK1 expression. Methods: We enrolled advanced anti-PD-1/PD-L1 naïve GEA patients (pts) in a Phase 1b/2a study of D + P (NCT02013154). Tumoral DKK1 mRNA expression was assessed by an in situ hybridization RNAscope assay. Objective response rate (ORR), disease control rate (DCR), progression free survival (PFS) and overall survival (OS) were compared between DKK1 high and low groups. Kaplan-Meier method and Cox-PH model was used for survival analysis and logistic regression was used for clinical benefit/response outcome. Results: 34 GEA pts were enrolled to receive 300 mg D + P. 31 GEA pts had DKK1 expression available (25 response-evaluable/RE) and 27 had both DKK1 and PD-L1 expression available (22 RE). In RE pts, DKK1 high (H-score ≥ upper-tertile [≥35]) had an ORR of 50% (5 PR/10), DCR of 80% (8/10) while DKK1 low ( < upper-tertile) had an ORR of 0% (0/15) and DCR of 20% (3/15); DKK1 high (vs. low) had an OR of 16 (95%CI: 2.2, 118.3; n = 25) and adjusted (for PD-L1 CPS ≥10 vs. < 10) OR of 17.6 (95%CI:1.6, 194.4; n = 22) for clinical benefit/response (PR/SD vs. PD). Median PFS was 22.1 weeks in DKK1 high (n = 11) vs. 5.9 weeks in DKK1 low (n = 20); HR of 0.23 (95%CI: 0.082, 0.66; n = 31). Adjusted (for PD-L1 expression) HR for DKK1 high was 0.20 (95%CI: 0.061,0.68; n = 27) for PFS. DKK1 high (n = 11) had a median OS of 31.6 weeks vs. 17.4 weeks in DKK1 low (n = 20); HR of 0.45 (95%CI: 0.16, 1.3; n = 31) and adjusted HR of 0.62 (95%CI: 0.2,1.9; n = 27). Conclusions: High levels of tumoral DKK1 expression identify advanced anti-PD-1/PD-L1 naïve GEA pts with the greatest benefit from D + P. Improvements in response/clinical benefit and PFS were observed independent of PD-L1 expression. Tumoral DKK1 as a potential predictive biomarker for DKN-01 treated GEA pts will be evaluated in future studies. Overall survival follow-up is ongoing. Clinical trial information: NCT02013154.

High Systemic Immune-Inflammation Index is an Adverse Prognostic Factor for Patients With Gastroesophageal Adenocarcinoma

2019 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Gerd Jomrich ◽  
Matthias Paireder ◽  
Ivan Kristo ◽  
Andreas Baierl ◽  
Ayseguel Ilhan-Mutlu ◽  
...  
Keyword(s):  
Prognostic Factor ◽  
Adverse Prognostic Factor ◽  
Immune Inflammation ◽  
Gastroesophageal Adenocarcinoma
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