scholarly journals Evolving Management Strategies for Metastatic Esophageal and Gastroesophageal Junction Adenocarcinoma

2018 ◽  
Vol 14 (2) ◽  
pp. 82
Author(s):  
Satya Das ◽  
Michael K Gibson ◽  
◽  
Keyword(s):  
Growth Factor ◽  
Esophageal Adenocarcinoma ◽  
Checkpoint Inhibitors ◽  
Gastroesophageal Junction ◽  
Management Strategies ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Biologic Agents ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Area Of Interest

Metastatic or unresectable esophageal and gastroesophageal junction adenocarcinoma represent a devastating disease with 5-year survival rate of <5%. Although cytotoxic chemotherapy with platinum doublet based regimens is initially effective, patients inevitably progress. Patients often decline rapidly after this initial progression, making later lines of therapy a challenge to successfully administer. There have been multiple efforts to incorporate biologic agents, targeting pathways known to be dysregulated in esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma, into existing chemotherapy backbones. Other than therapeutics targeting human epidermal growth factor receptor-2 (HER2) and vascular endothelial growth factor receptor (VEGFR), other strategies have failed. Given the mixed success of biologic agents, along with the promise of immunotherapy to generate durable and sometimes complete responses, immune-agent based trials are a major area of interest for patients with this disease. Checkpoint inhibitors blocking programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) have demonstrated modest single-agent efficacy in patients with progressive esophageal adenocarcinoma and gastroesophageal junction adenocarcinoma. However, other approaches such as novel checkpoint combinations, vaccine-based approaches and autologous T cells hold more promise to change the trajectory of disease.

scholarly journals REAL-LIFE CLINICAL UTILITY OF RAMUCIRUMAB FOR THE TREATMENT OF PATIENTS WITH DISSEMINATED GASTRIC ADENOCARCINOMA: PRELIMINARY REVIEW OF THE EXPERIENCE OF BLOKHIN RUSSIAN CANCER RESEARCH CENTRE

2017 ◽  
pp. 30-38 ◽  
Author(s):  
N. S. Besova ◽  
T. A. Titova ◽  
V. A. Gorbunova ◽  
O. O. Gordeeva ◽  
A. A. Tryakin ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Single Agent ◽  
Real Life ◽  
Growth Factor Receptor ◽  
Research Centre ◽  
Combination Group ◽  
Preliminary Review ◽  
National Medical ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Endothelial Growth Factor

Angiogenesis   has  become  an  important  target  in  the  treatment  of  solid  tumors  and  anti-angiogenic   agents   are a  promising  approach  to  cancer  therapy.  Ramucirumab, an  anti-angiogenic   agent   specifically  targeting  vascular endothelial  growth factor receptor-2  (VEGFR-2). In April 2014, the FDA approved ramucirumab as a single  agent  or in combination with paclitaxel  for treatment of advanced gastric or gastroesophageal junction adenocarcinoma (GC) that has progressed on or after prior fluoropyrimidine – or platinumcontaining chemotherapy based on data of REGARD and RAINBOW trials.We evaluated the progression free (PFS), overall survival (OS) and safety of ramucirumab in patients (pts) with advanced GC in routine clinical practice From June 2016  to 20 Sep 2017  40 pts with advanced GC were treated with ramucirumab in the second line treatment as single  agent (8 pts) or in combination with paclitaxel  (26 pts) in N.N.Blokhin National medical research center of oncology.Median PFS (MPFS) and median OS (MOS) was 1,8  and 7,6 mons for monotherapy group. For combination group MPFS was 5,02  mons, MOS was not reached. Ramucirumab had an acceptable safety profile Our data are similar to the data of REGARD and RAINBOW trials.

scholarly journals Results of the use of ramucirumab in combination with paclitaxel or ramucirumab monotherapy as the second line treatment in patients with disseminated HER2-negative gastric or cardioesophageal junction adenocarcinoma: experience of N.N. Blokhin russian cancer research center of the ministry of health of Russia

2018 ◽  
pp. 34-40
Author(s):  
N. S. Besova ◽  
T. A. Titova ◽  
E. V. Trusilova ◽  
V. A. Gorbunova ◽  
A. A. Tryakin ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Research Center ◽  
Combination Group ◽  
Line Treatment ◽  
Second Line ◽  
National Medical ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Endothelial Growth Factor

Background.Working out of the second line chemotherapy of advanced gastric adenocarcinoma is a promising approach to cancer therapy. Ramucirumab, an anti-angiogenic agent specifically targeting vascular endothelial growth factor receptor-2 (VEGFR-2). In April 2014, the FDA approved ramucirumab as a single agent or in combination with paclitaxel for treatment of advanced gastric or gastroesophageal junction adenocarcinoma that has progressed on or after prior fluoropyrimidineor platinum containing chemotherapy based on data of REGARD and RAINBOW trials.Materials and Methods: From June 2016 to 15Jan 201837 pts with advanced GC were treated with ramucirumabin the second line treatment as single agent (11 pts) or in combination with paclitaxel (26 pts) in N.N.Blokhin National medical research center of oncology.Results: edian PFS (MPFS) and median OS (MOS) was 1,8 and 7,6 mons for monotherapy group. For combination group MPFS was 4,0mons, MOS -10,6 mons. Ramucirumab had an acceptable safety profileConclusions:ur data are similar to the data of international randomized trials.

scholarly journals Human epidermal growth factor receptor 2 overexpression in gastric and gastroesophageal junction adenocarcinoma in patients seen at the University Teaching Hospital, Lusaka, Zambia

2020 ◽  
Vol 20 (4) ◽  
pp. 1857-64
Author(s):  
Chimwasu Kasochi ◽  
Peter Julius ◽  
Isaac Mweemba ◽  
Violet Kayamba
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Gastroesophageal Junction ◽  
Growth Factor Receptor ◽  
Her2 Overexpression ◽  
Protein Overexpression ◽  
Human Epidermal Growth Factor ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Epidermal Growth

Background: There are scanty data on the occurrence of gastric tumours overexpressing human epidermal growth factor receptor 2 (HER2) in Africa. Objective: To assess HER2 protein overexpression in gastric and gastroesophageal junction adenocarcinoma (GGEAC) samples from a single centre in Zambia. Methodology: This was a cross-sectional study of formalin-fixed paraffin-embedded blocks with GGEAC. Prepared slides were first stained with Haematoxylin and Eosin and then evaluated for HER2 protein overexpression by immunohistochem- istry. Results: A total of 57 gastric tissues were stained and evaluated for HER2 overexpression. Thirteen (23%) showed overex- pression, 41/57 (72%) had negative and 3/57 (5%) had equivocal staining. The equivocal cases were excluded from the final analysis. Of the remaining 54 tissues, 28 (52%) were from females, and 26 (48%) were from males. The mean age was 59 years (SD 15 years). HER2 overexpression was highest in moderately differentiated tumours (p=0.0005). Intestinal type tu- mours had a higher occurrenc of HER2 overexpression than diffuse or mixed sub-types (p=0.0087). HER2 overexpression was not associated with age (p=0.27), sex (p=1.00) or anatomical location (p=1.00). Conclusion: The occurrence of GGEAC HER2 overexpression in Zambian patients is similar to proportions reported elsewhere, and it is associated with moderately differentiated tumours of the intestinal type. Keywords: Gastric and Gastroesophageal junction adenocarcinoma; Human Epidermal growth factor Receptor 2 over- expression; immunohistochemistry.

scholarly journals Targeted Molecular Therapies in the Treatment of Esophageal Adenocarcinoma, Are We There Yet?

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3077
Author(s):  
Shayan Khalafi ◽  
Albert Craig Lockhart ◽  
Alan S. Livingstone ◽  
Wael El-Rifai
Keyword(s):  
Growth Factor ◽  
Esophageal Adenocarcinoma ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Growth Factor Receptor ◽  
Western World ◽  
Term Survival ◽  
Recent Advances

Esophageal adenocarcinoma is one of the leading causes of cancer-related deaths worldwide. The incidence of esophageal adenocarcinoma has increased at an alarming rate in the Western world and long-term survival remains poor. Current treatment approaches involve a combination of surgery, chemotherapy, and radiotherapy. Unfortunately, standard first-line approaches are met with high rates of recurrence and metastasis. More recent investigations into the distinct molecular composition of these tumors have uncovered key genetic and epigenetic alterations involved in tumorigenesis and progression. These discoveries have driven the development of targeted therapeutic agents in esophageal adenocarcinoma. While many agents have been studied, therapeutics targeting the human epidermal growth factor receptor (HER2) and vascular endothelial growth factor (VEGF) pathways have demonstrated improved survival. More recent advances in immunotherapies have also demonstrated survival advantages with monoclonal antibodies targeting the programmed death ligand 1 (PD-L1). In this review we highlight recent advances of targeted therapies, specifically agents targeting receptor tyrosine kinases, small molecule kinase inhibitors, and immune checkpoint inhibitors. While targeted therapeutics and immunotherapies have significantly improved survival, the benefits are limited to patients whose tumors express biomarkers such as PD-L1 and HER2. Survival remains poor for the remainder of patients with esophageal adenocarcinoma, underscoring the critical need for development of novel treatment strategies.

HELOISE: Phase IIIb Randomized Multicenter Study Comparing Standard-of-Care and Higher-Dose Trastuzumab Regimens Combined With Chemotherapy as First-Line Therapy in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

2017 ◽  
Vol 35 (22) ◽  
pp. 2558-2567 ◽  
Author(s):  
Manish A. Shah ◽  
Rui-hua Xu ◽  
Yung-Jue Bang ◽  
Paulo M. Hoff ◽  
Tianshu Liu ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Gastroesophageal Junction ◽  
Growth Factor Receptor ◽  
Loading Dose ◽  
First Line ◽  
Human Epidermal Growth Factor ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Epidermal Growth

Purpose To compare standard-of-care (SoC) trastuzumab plus chemotherapy with higher-dose (HD) trastuzumab plus chemotherapy to investigate whether HD trastuzumab increases trastuzumab serum trough concentration (Ctrough) levels and increases overall survival (OS) in first-line human epidermal growth factor receptor 2–positive metastatic gastric or gastroesophageal junction adenocarcinoma. Patients and Methods Patients with Eastern Cooperative Oncology Group performance status 2, no prior gastrectomy, and ≥ two metastatic sites were randomly assigned at a one-to-one ratio to loading-dose trastuzumab 8 mg/kg followed by SoC trastuzumab maintenance 6 mg/kg every 3 weeks or loading-dose trastuzumab 8 mg/kg followed by HD trastuzumab maintenance 10 mg/kg every 3 weeks until progression; treatment in each arm was combined with cisplatin 80 mg/m2 plus capecitabine 800 mg/m2 twice per day in cycles 1 to 6. The primary objective was HD trastuzumab OS superiority (all randomly assigned patients [full-analysis set]). Final results are from an interim analysis for futility (boundary hazard ratio [HR] ≥ 0.95) at 125 deaths. Results At clinical cutoff, 248 patients had been randomly assigned. A marked increase in mean trastuzumab Ctrough was observed after the first HD trastuzumab cycle versus SoC trastuzumab. In the full-analysis set, median OS was 12.5 months in the SoC trastuzumab arm and 10.6 months in the HD trastuzumab arm (stratified HR, 1.24; 95% CI, 0.86 to 1.78; P = .2401). Results were similar in the per-protocol set (cycle 1 trastuzumab Ctrough < 12 µg/mL). Safety was comparable between arms. Conclusion HD trastuzumab maintenance dosing was associated with higher trastuzumab concentrations, no increased efficacy, and no new safety signals. HELOISE confirms standard-dose trastuzumab (loading dose of 8 mg/kg followed by 6 mg/kg maintenance dose every 3 weeks) with chemotherapy as the SoC for first-line treatment of human epidermal growth factor receptor 2–positive metastatic gastric or gastroesophageal junction adenocarcinoma.

Fr166 TIME TRENDS IN THE EPIDEMIOLOGY OF GASTROESOPHAGEAL JUNCTION ADENOCARCINOMA AND ESOPHAGEAL ADENOCARCINOMA: RESULTS FROM A POPULATION BASED DATABASE

2021 ◽  
Vol 160 (6) ◽  
pp. S-245
Author(s):  
Siddharth Agarwal ◽  
Lovekirat Dhaliwal ◽  
Don C. Codipilly ◽  
Ramona Lansing ◽  
Rachel E. Rhody ◽  
...  
Keyword(s):  
Esophageal Adenocarcinoma ◽  
Time Trends ◽  
Gastroesophageal Junction ◽  
Population Based ◽  
Gastroesophageal Junction Adenocarcinoma

scholarly journals Loss of Phosphatase and Tensin Homolog or Phosphoinositol-3 Kinase Activation and Response to Trastuzumab or Lapatinib in Human Epidermal Growth Factor Receptor 2–Overexpressing Locally Advanced Breast Cancers

2011 ◽  
Vol 29 (2) ◽  
pp. 166-173 ◽  
Author(s):  
Bhuvanesh Dave ◽  
Ilenia Migliaccio ◽  
M. Carolina Gutierrez ◽  
Meng-Fen Wu ◽  
Gary C. Chamness ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Epidermal Growth

Purpose Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit. Methods We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations. Results Under low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007). Conclusion Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents.

ZW25, an anti-HER2 bispecific antibody, plus chemotherapy with/without tislelizumab as first-line treatment for patients with advanced HER2-positive breast cancer or gastric/gastroesophageal junction adenocarcinoma: A phase 1B/2 trial-in-progress.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3145-TPS3145
Author(s):  
Do-Youn Oh ◽  
Hyun Cheol Chung ◽  
Young Hyuck Im ◽  
Chia Jui Yen ◽  
Yee Chao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Antitumor Activity ◽  
Gastroesophageal Junction ◽  
Single Agent ◽  
Tolerability Profile ◽  
First Line ◽  
Her2 Positive ◽  
Gastroesophageal Junction Adenocarcinoma ◽  
Treatment Naïve ◽  
Phase 1B

TPS3145 Background: ZW25 is a novel HER2-targeted antibody that binds two distinct extracellular domains of HER2, allowing for multiple mechanisms of action, including activation of ADCC and inhibition of ligand-dependent and -independent cellular growth. ZW25 is well tolerated and showed single-agent antitumor activity in patients (pts) with advanced HER2-positive cancers. Previous reports suggested that tislelizumab, an investigational anti-PD-1 antibody engineered to minimize binding of FcgR on macrophages in order to abrogate antibody-dependent phagocytosis, was generally well tolerated and had antitumor activity alone and in combination with chemotherapy in pts with advanced solid tumors. Combining HER2-targeted agents with chemotherapy has resulted in improved survival; the highly immunogenic nature of HER2 tumors has led to the development of therapies combining anti-HER2 therapies with immune checkpoint blockade. Methods: This open-label, two cohort phase 1B/2 study is designed to evaluate ZW25 plus chemotherapy ± tislelizumab as first-line therapy in pts (n≈50) with HER2-positive metastatic breast cancer (mBC; cohort 1) or advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC; cohort 2). In cohort 1, pts with HER2-positive (IHC3+ or ISH amplified) mBC must be treatment-naïve for metastatic disease and will receive intravenous (IV) ZW25 30 mg/kg plus docetaxel 75 mg/m2 IV once every 3 weeks (Q3W). In cohort 2, treatment-naïve pts with HER2-positive (IHC3+ or IHC2+ with ISH amplification) advanced GC/GEJC will receive ZW25 30 mg/kg plus tislelizumab 200 mg IV and chemotherapy (CAPOX regimen: capecitabine 1000 mg/m2 twice daily and oxaliplatin 130 mg/m2 IV) Q3W. A safety lead-in phase is designed for the first six pts in cohort 2, followed by dose expansion after a safety monitoring committee review. Primary endpoints are the safety/tolerability profile and objective response rate; secondary endpoints include duration of response, time to response, progression-free survival, disease control rate, and overall survival. Clinical trial information: Registered, NCT number pending will provide as soon as available .

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