scholarly journals Her2-Targeted Therapy Induces Autophagy in Esophageal Adenocarcinoma Cells

2018 ◽  
Vol 19 (10) ◽  
pp. 3069 ◽  
Author(s):  
Félice Janser ◽  
Olivia Adams ◽  
Vanessa Bütler ◽  
Anna Schläfli ◽  
Bastian Dislich ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Esophageal Adenocarcinoma ◽  
Acquired Resistance ◽  
Therapy Resistance ◽  
Her2 Status ◽  
Autophagic Flux ◽  
Cancer Type ◽  
Cancer Resistance ◽  
Her2 Positive ◽  
Autophagy Inhibition

Esophageal adenocarcinoma (EAC) is a highly lethal cancer type with an overall poor survival rate. Twenty to thirty percent of EAC overexpress the human epidermal growth factor receptor 2 (Her2), a transmembrane receptor tyrosine kinase promoting cell growth and proliferation. Patients with Her2 overexpressing breast and gastroesophageal cancer may benefit from Her2 inhibitors. Therapy resistance, however, is well documented. Since autophagy, a lysosome-dependent catabolic process, is implicated in cancer resistance mechanisms, we tested whether autophagy modulation influences Her2 inhibitor sensitivity in EAC. Her2-positive OE19 EAC cells showed an induction in autophagic flux upon treatment with the small molecule Her2 inhibitor Lapatinib. Newly generated Lapatinib-resistant OE19 (OE19 LR) cells showed increased basal autophagic flux compared to parental OE19 (OE19 P) cells. Based on these results, we tested if combining Lapatinib with autophagy inhibitors might be beneficial. OE19 P showed significantly reduced cell viability upon double treatment, while OE19 LR were already sensitive to autophagy inhibition alone. Additionally, Her2 status and autophagy marker expression (LC3B and p62) were investigated in a treatment-naïve EAC patient cohort (n = 112) using immunohistochemistry. Here, no significant correlation between Her2 status and expression of LC3B and p62 was found. Our data show that resistance to Her2-directed therapy is associated with a higher basal autophagy level, which is not per se associated with Her2 status. Therefore, we propose that autophagy may contribute to acquired resistance to Her2-targeted therapy in EAC, and that combining Her2 and autophagy inhibition might be beneficial for EAC patients.

DETECT III: A multicenter, randomized, phase III study to compare standard therapy alone versus standard therapy plus lapatinib in patients (pts) with initially HER2-negative metastatic breast cancer but with HER2-positive circulating tumor cells (CTC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS1146-TPS1146
Author(s):  
Carsten Hagenbeck ◽  
Carola Anna Melcher ◽  
Johann Wolfgang Janni ◽  
Andreas Schneeweiss ◽  
Peter A. Fasching ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Targeted Therapy ◽  
Clinical Benefit ◽  
Standard Treatment ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Her2 Status ◽  
Her2 Positive ◽  
Phase Iii Study

TPS1146 Background: HER2 status may change over the course of disease in breast cancer pts. Approx. 20-30% of pts with initially HER2-negative breast cancer have HER2-positive metastasis (Zidan et al. 2005; Tewes et al. 2009). Determining HER2 status on CTC is one option to re-evaluate HER2 status at the time metastasis is diagnosed. Currently it is unclear if HER2-targeted therapy based on the assessment of HER2 status of CTC reveals a clinical benefit. Methods: This is a randomized, open-label, two arm phase III study to investigate the clinical efficacy of lapatinib, as a HER2-targeted therapy in initially HER2-negative metastatic breast cancer pts with HER2-positive CTC at the time of distant disease. As only half of the pts with HER2-negative metastatic breast cancer show CTC-positivity and of those approx. 32% will exhibit HER2-positive CTC (Fehm et al. 2010), screening of about 1420 pts is required to enroll 228 pts. Main inclusion criteria: metastatic breast cancer with HER2-negative primary tumor tissue and/or biopsies from metastatic sites or locoregional recurrences, evidence of ≥1 HER2-positive CTC and ≥1 measurable metastatic lesion according to RECIST. Eligible pts will be randomized 1:1 to receive standard treatment vs. standard treatment plus lapatinib. Standard chemo- or endocrine therapy must be approved in combination with lapatinib or been investigated in prior clinical trials. Primary endpoint is progression free survival. Secondary endpoints include overall response rate, clinical benefit rate, overall survival and dynamic of CTC. The DETECT III trial is one of the first trials where treatment is based on phenotypic characteristics of CTC. If this trial succeeds in proving efficacy of lapatinib in pts with initially HER2-negative metastatic breast cancer but HER2-positive CTC, this will establish a new strategy in the treatment of metastatic breast cancer.

Abstract 350: HER3 mediates acquired resistance to HER2-targeted therapy in esophageal adenocarcinoma

2015 ◽  
Author(s):  
Eva A. Ebbing ◽  
Jan Paul Medema ◽  
Sybren L. Meijer ◽  
Kausilia K. Krishnadath ◽  
Mark I. van Berge Henegouwen ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Esophageal Adenocarcinoma ◽  
Acquired Resistance

scholarly journals HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance

2019 ◽  
Vol 11 ◽  
pp. 175883591983351 ◽  
Author(s):  
Sonia Pernas ◽  
Sara M. Tolaney
Keyword(s):  
Breast Cancer ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Mtor Inhibitors ◽  
Therapy Resistance ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

The introduction of anti-HER2 therapies to the treatment of patients with HER2-positive breast cancer has led to dramatic improvements in survival in both early and advanced settings. Despite this breakthrough, nearly all patients with metastatic HER2-positive breast cancer eventually progress on anti-HER2 therapy due to de novo or acquired resistance. A better understanding not only of the underlying mechanisms of HER2 therapy resistance but of tumor heterogeneity as well as the host and tumor microenvironment is essential for the development of new strategies to further improve patient outcomes. One strategy has focused on inhibiting the HER2 signaling pathway more effectively with dual-blockade approaches and developing improved anti-HER2 therapies like antibody–drug conjugates, new anti-HER2 antibodies, bispecific antibodies, or novel tyrosine kinase inhibitors that might replace or be used in addition to some of the current anti-HER2 treatments. Combinations of anti-HER2 therapy with other agents like immune checkpoint inhibitors, CDK4/6 inhibitors, and PI3K/AKT/mTOR inhibitors are also being extensively evaluated in clinical trials. These add-on strategies of combining optimized targeted therapies could potentially improve outcomes for patients with HER2-positive breast cancer but may also allow de-escalation of treatment in some patients, potentially sparing some from unnecessary treatments, and their related toxicities and costs.

scholarly journals Peptide Based Imaging Agents for HER2 Imaging in Oncology

2020 ◽  
Vol 19 ◽  
pp. 153601212096025 ◽  
Author(s):  
Maxwell Ducharme ◽  
Suzanne E. Lapi
Keyword(s):  
Breast Cancer ◽  
Pet Imaging ◽  
Imaging Techniques ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Her2 Status ◽  
Cancer Type ◽  
Her2 Positive ◽  
Positron Emission ◽  
Imaging Probes

Breast cancer continues to be the most lethal cancer type in women and one of the most diagnosed. Understanding Breast cancer receptor status is one of the most vital processes for determining treatment options. One type of breast cancer, human epidermal growth factor receptor 2 (HER2) positive, has approved receptor-based therapies including trastuzumab and pertuzumab that can significantly increase the likelihood of survival. Current methods to determine HER2 status include biopsies with immunohistochemical staining and/or fluorescence in situ hybridization. However, positron emission tomography (PET) imaging techniques using 89Zr-trastuzumab or 89Zr-pertuzumab are currently in clinical trials for a non-invasive, full body diagnostic approach. Although the antibodies have strong specificity to the HER2 positive lesions, challenges involving long post-injection time for imaging due to the blood circulation of the antibodies and matching of long-live isotopes leading to increased dose to the patient leave opportunities for alternative PET imaging probes. Peptides have been shown to allow for shorter injection-to-imaging time and can be used with shorter lived isotopes. HER2 specific peptides under development will help improve the diagnosis and potentially therapy options for HER2 positive breast cancer. Peptides showing specificity for HER2 could start widespread development of molecular imaging techniques for HER2 positive cancers.

HER2 status in primary tumors and metastatic regional lymph nodes in patients with esophageal adenocarcinoma (EAC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4071-4071
Author(s):  
Harry H. Yoon ◽  
Qian Shi ◽  
William R. Sukov ◽  
Christopher A. Sattler ◽  
Rakhee Vaidya ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Lymph Nodes ◽  
Her2 Status ◽  
Her2 Amplification ◽  
Her2 Gene ◽  
Her2 Positive ◽  
Regional Lymph Nodes ◽  
Primary Tumors ◽  
Routine Procedures

4071 Background: Selection of patients for HER2-targeted therapy is based on HER2 analysis in primary EACs. Since EACs metastasize via regional lymph nodes, concordance of HER2 gene amplification results between primary tumors and their metastatic lymph nodes (MLN) is a clinically important issue. Methods: Resected EACs (N = 103) having at least three distinct regional MLNs (total 508 MLNs; median 4 [range 3-11]) were sectioned using routine procedures and tested for HER2 amplification by fluorescence in situ hybridization (FISH). Primary tumors were also evaluated for HER2 protein expression by immunohistochemistry (IHC) and by FISH. Amplification was defined as HER2/CEP17 ≥ 2. IHC was scored as 0, 1+, 2+, or 3+. Primaries whose HER2 status was positive by both FISH and IHC (ie, amplified and IHC3+), or negative by both (ie, nonamplified and IHC0-1+), were selected. HER2 status was compared between primaries and their MLNs (kappa). Results: Concordant HER2 results between primaries and their MLNs were found in 92% (95/103) of EACs (Table; κ = .76 [95% CI .60 - .92]). However, among patients with HER2-positive primaries, 19% (4/21) had HER2-nonamplified MLNs; among these cases, either all MLNs were HER2-nonamplified (n = 2), or both HER2-nonamplified and –amplified MLNs were present (n = 2). Among HER2-negative primary EACs, 5% (4/82) of cases had MLNs that were all HER2-amplified (n = 3) or both HER2-nonamplified and -amplified (n = 1). Conclusions: A patient subset whose primary EACs were HER2-positive (by both FISH and IHC) were unexpectedly found to lack HER2 amplification in corresponding MLNs. Conversely, a subgroup with HER2-negative primaries had HER2-amplified MLNs, and would have been deemed ineligible for HER2-targeted therapy. These preliminary data suggest that evaluating MLNs in resected EACs has the potential to better identify patients who benefit from HER2-targeted therapy. [Table: see text]

scholarly journals Colorectal Cancer: From Genetic Landscape to Targeted Therapy

2021 ◽  
Vol 2021 ◽  
pp. 1-17
Author(s):  
Mouade El Bali ◽  
Joaira Bakkach ◽  
Mohcine Bennani Mechita
Keyword(s):  
Colorectal Cancer ◽  
Targeted Therapy ◽  
Clinical Investigation ◽  
Acquired Resistance ◽  
Predictive Biomarkers ◽  
Molecular Characteristics ◽  
Molecular Heterogeneity ◽  
Molecular Pathways ◽  
Cancer Type ◽  
Genetic Landscape

Colorectal cancer (CRC) is the third most common cancer type and the second cause of death worldwide. The advancement in understanding molecular pathways involved in CRC has led to new classifications based on the molecular characteristics of each tumor and also improved CRC management through the integration of targeted therapy into clinical practice. In this review, we will present the main molecular pathways involved in CRC carcinogenesis, the molecular classifications. The anti-VEGF and anti-EGFR therapies currently used in CRC treatment and those under clinical investigation will also be outlined, as well as the mechanisms of primary and acquired resistance to anti-EGFR monoclonal antibodies (cetuximab and panitumumab). Targeted therapy has led to great improvement in the treatment of metastatic CRC. However, there has been variability in CRC treatment outcomes due to molecular heterogeneity in colorectal tumors, which underscores the need for identifying prognostic and predictive biomarkers for CRC-targeted drugs.

Use of the PRO Onc Assay (Prometheus) to measure HER2 overexpression/activation in circulating tumor cells (CTCs) in women with HER2-negative metastatic breast cancer (MBC): A Sarah Cannon Research Institute (SCRI) trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 618-618
Author(s):  
John D. Hainsworth ◽  
Howard A. Burris ◽  
Patrick Brian Murphy ◽  
Ruth E. Lamar ◽  
Mythili Shastry ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Accurate Determination ◽  
Metastatic Breast ◽  
Reference Value ◽  
Assay Method ◽  
Her2 Status ◽  
Her2 Overexpression ◽  
Her2 Positive ◽  
Improve Patient Management

618 Background: HER2- targeted therapy has markedly improved the treatment of women with HER2- positive breast cancer. FISH testing for HER2 overexpression is the most reliable assay method; treatment decisions are usually based on HER2 expression of the breast primary tumor. Accurate determination of HER2 status by testing CTCs may improve patient management by allowing ongoing assessment of HER2 status during treatment and/or identifying additional patients (pts) for HER2- targeted therapy. Methods: The PRO Onc assay uses a multiplexed immunoassay format to provide expression and activation profiling of HER2 and other signal transduction molecules. The assay can detect overexpression and activation (phosphorylation) of HER2, with sensitivity at a single CTC level. We obtained blood specimens from 57 women with metastatic HER2- negative breast cancer who were receiving standard chemotherapy. In these women, HER2 status had previously been determined by FISH (32) or 0 – 1+ IHC testing (25). All specimens were tested for the presence of CTCs; the PRO Onc assay was performed when CTCs were identified. The HER2 overexpression cutoff (>3.0 CU) was based on the reference value (average + 4SD) determined by analyzing normal blood obtained from 42 healthy donors. Results: 31 of 57 pts (54%) had CTCs identified. 6 of 31 pts (19%) had HER2 overexpressed, and 4 pts (13%) had HER2 activation without overexpression. 7 of 10 pts with HER2 overexpression/activation by PRO Onc Assay were FISH- negative; 3 were IHC- negative. Since initial HER2 determination, these 10 pts had received a median of 3 chemotherapy regimens (range 1 - 5). Conclusions: When CTCs were present, the PRO Onc assay identified HER2 overexpression or activation in 31% of women with HER2- negative MBC. The therapeutic significance of this finding is unknown. Since the predetermined threshold of ≥10% HER2- positive assay results was exceeded, this trial will proceed to a planned second portion, in which women with HER2- negative MBC (by FISH testing) and HER2 overexpression or activation in CTCs will receive a trial of HER2- targeted therapy.

scholarly journals Mixed adenoneuroendocrine carcinoma with loss of HER2 positivity after trastuzumab-based chemotherapy for HER2-positive gastric cancer: a case report

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Hiromi Nagata ◽  
Hironori Tsujimoto ◽  
Yoshihisa Yaguchi ◽  
Keita Kouzu ◽  
Yujiro Itazaki ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Rare Case ◽  
Metastatic Tumor ◽  
Endoscopic Biopsy ◽  
Her2 Status ◽  
Resected Specimen ◽  
Her2 Positive ◽  
Standard Regimen ◽  
Mixed Adenoneuroendocrine Carcinoma ◽  
Her2 Positivity

Abstract Background Trastuzumab (T-mab)-based chemotherapy is a standard regimen for human epithelial growth factor 2 (HER2)-positive gastric cancer. However, some patients have demonstrated a change in HER2 status after T-mab-based treatment of breast cancer. We report a rare case of mixed adenoneuroendocrine carcinoma with loss of HER2 positivity after T-mab-based chemotherapy for HER2-positive gastric cancer. Case presentation A 60-year-old man presented with a mass of the upper abdomen, which was diagnosed as adenocarcinoma with a HER2 score of 3+ by endoscopic biopsy. He received seven cycles of combination chemotherapy with capecitabine, cisplatin, and T-mab. Subsequently, he underwent open total gastrectomy, distal pancreatosplenectomy, and extended left hepatic lobectomy as a conversion surgery. The surgically resected specimen demonstrated both adenocarcinoma and neuroendocrine components; therefore, it was diagnosed as HER2-negative mixed adenoneuroendocrine carcinoma. Although the patient received additional chemotherapy, multiple liver metastases appeared at 3 months postoperatively and he died at 6 months postoperatively because of the rapidly progressing metastatic tumor. Conclusions We encountered a rare case of rapidly progressive mixed adenoneuroendocrine carcinoma that was negative for HER2 expression after T-mab treatment combined with chemotherapy.

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