Cu dota igcc slides 6 2-15
•Download as PPTX, PDF•
0 likes•476 views
This study aims to evaluate a novel radioimmunoconjugate, 64Cu-DOTA-Trastuzumab, for assessing HER2 expression in gastric cancer patients via PET/CT imaging. The study hypothesizes that 64Cu-DOTA-Trastuzumab PET may better localize HER2-overexpressing gastric tumors by overcoming tumor heterogeneity, and more accurately measure functional HER2 expression compared to current IHC and FISH methods. The clinical trial will compare 64Cu uptake measured by PET/CT to IHC and FISH results from surgical specimens to determine if the novel imaging agent improves detection of patients eligible for trastuzumab therapy.
Recommended
Recommended
More Related Content
What's hot
What's hot (20)
Similar to Cu dota igcc slides 6 2-15
Similar to Cu dota igcc slides 6 2-15 (20)
Cu dota igcc slides 6 2-15
- 1. Audrey H Choi, MD1, Joseph Kim, MD1, James R Bading, MD2, David M Colcher, PhD2, Sangjun Lee, PhD1, Vincent Chung, MD3, Jinha Park, MD, PhD4 Departments of 1Surgery, 2Cancer Immunotherapeutics and Tumor Immunology, 3Medical Oncology and 4Radiology City of Hope National Medical Center, Duarte, CA USA Evaluation of a Novel Trastuzumab-Linked Radioimmunoconjugate for In Vivo Assessment of HER2 Expression in Gastric Cancer
- 2. Disclosures • The authors have no relevant disclosures
- 3. Introduction • Gastric cancer is the 2nd most common cause of cancer-related death worldwide1 • Poor prognosis for patients with advanced disease (median 7 months) • Lack of effective systemic therapies • Advances in targeted therapies have improved gastric cancer outcomes and extended overall survival beyond 1 year • Trastuzumab for Gastric Cancer (ToGA) trial: phase III RCT comparing trastuzumab plus chemotherapy (median OS 13.8 mo) versus chemotherapy alone (median OS 11.1 mo, p=0.005)2 1Kamangar et al, J Clin Oncol 2006 2Bang et al, Lancet 2010.
- 4. The challenge of accurately quantifying HER2 • Trastuzumab is a humanized monoclonal antibody against the HER2 receptor – Known to be an effective treatment in cancers with HER2 overexpression • However, HER2 expression has been difficult to assess and quantify – ToGA: only eligible to receive trastuzumab if HER2 overexpression by immunohistochemical staining (IHC) or HER2 gene amplication by fluorescence in situ hybridization (FISH) • 22% screened patients met the HER2 criteria – City of Hope: 10% of advanced gastric cancer patients meet criteria
- 5. Current methods of HER2 assessment may underestimate trastuzumab-eligible patients • Tumor-level heterogeneity of HER2 has been linked to discordant pathology scoring1,2 • Additionally, trastuzumab has been reported to benefit patients who are HER2-negative by IHC and FISH3 • These findings have several important implications: • Accuracy of IHC and FISH to identify HER2- overexpressing tumors may be limited by tumor heterogeneity and/or limitations of the tests themselves • Alternatively, there may be additional unidentified molecular markers that predict response to trastuzumab better than HER2 assessment by IHC or FISH 1Potts et al, Laboratory Investigation 2012 2Lewis et al, Am J Clin Path 2005 3Paik et al, J Clin Oncol 2007
- 6. A Novel Radioimmunoconjugate • 64Cu-DOTA-Trastuzumab – Clinical grade trastuzumab conjugated to the chelating agent DOTA (tetra- azacyclododecanetetra- acetic acid) and labeled with 64Cu radioisotope • This compound has been shown to accurately detect HER2-positive breast cancer tissue by positron emission tomography (PET) in patients with metastatic breast cancer at our institution1 Figure 1. 64Cu-DOTA-Trastuzumab PET of a breast cancer patient classified as HER2- negative by biopsy and IHC/FISH 1Mortimer et al, J Nucl Med 2014
- 7. Hypothesis • 64Cu-DOTA-Trastuzumab PET may better localize HER2-overexpressing gastric cancer – Potentially overcoming the problem of tumor heterogeneity – Non-invasive radiographic “biopsy” • 64Cu-DOTA-Trastuzumab PET can more accurately measure functional HER2 expression than IHC/FISH
- 8. Objective • Clinical trial (NCT01939275) to evaluate 64Cu- DOTA-Trastuzumab for assessing in vivo HER2 expression with modified PET/CT imaging of gastric cancer patients.
- 9. Study Design – Imaging phase Gastric cancer patients identified in medical oncology, surgery clinics Surgical candidates 1. Biopsy-proven gastric CA, ≥18 yo 2. Early stage: curative-intent procedure 3. Locally-advance, metastatic: palliative procedure CT for staging Non-surgical candidates 15 mCi 64Cu-DOTA- Trastuzumab IV injection given 48 hrs prior to PET/CT 64Cu uptake (SUV) measured in tumor and adjacent non-tumor tissues
- 10. Study Design – Surgical pathology phase Surgical candidates to operating room: areas corresponding to 64Cu uptake on PET marked with suture in OR Marked specimen to pathology IHC Paraffin-embedded tissue into 4 µm sections, stained by anti- HER2 antibody FISH Paraffin-embedded tissue, HER2/CEP17ratio determined IHC/FISH results compared to SUV measured on PET/CT and pre-operative biopsy IHC/FISH (if available) Target accrual: 22 patients
- 11. Summary • Current methods of HER2 detection may underestimate the number of patients eligible for trastuzumab therapy • Our novel, non-invasive imaging method may improve localization of HER2-overexpressing tissue and aid in the identification of trastuzumab- eligible patients in gastric cancer
- 12. Thank You Clinical trial (NCT01939275) contact information: City of Hope National Medical Center Duarte, CA 91010 Principle investigator: Vincent Chung, MD Contact: (626) 471-9200; vchung@coh.org
Editor's Notes
- Gastric cancer is the second most common cause of cancer-related death worldwide, with an especially poor prognosis for patients with advanced disease at a median survival of 7 months. This has mainly been attributed to the lack of effective systemic therapies, but in recent years advances in targeted therapies have improved gastric cancer outcomes and extended overall survival beyond 1 year. The Trastuzumab for Gastric Cancer trial (ToGA) is a phase III RCT published in 2010 comparing trastuzumab plus chemotherapy versus chemotherapy alone. They showed that the addition of trastuzumab significantly improved survival.
- Trastuzumab is a humanized monoclonal antibody against the HER2 receptor. It is known to be an effective treatment against cancers with HER2 overexpression. However, HER2 expression has been difficult to assess and quantify, with varying results at different institutions. For example, in the ToGA trial, only patients who demonstrated HER2 overexpression by immunohistochemical staining or fluorescence in situ hybridization were eligible to receive trastuzumab. 22% of screened ToGA patients met the HER2 overexpression criteria, but in a review of our own institutional data, only 10% of advanced gastric cancer patients met the same criteria. NOTE: ToGA requirements: either 3+ by IHC or positive on FISH (HER2:CEP17 ratio >=2)
- Current methods of HER2 assessment may underestimate the number of patients eligible for trastuzumab therapy. Tumor-level heterogeneity of HER2 has been linked to discordant pathology scoring. Additionally, trastuzumab has been reported to benefit patients who tested negative for HER2 overexpression by IHC and FISH. These findings have several important implications. First, the accuracy of IHC and FISH for the identification of HER2-overexpressing tumors may be limited by tumor heterogeneity and/or limitations of the tests themselves. Second, there may be additional unidentified molecular markers that predict response to trastuzumab better than HER2 assessment by IHC and FISH. Full citations: Paik et al. Benefit from adjuvant trastuzumab may not be confined to patients with IHC 3+ and/or FISH-positive tumors: Central testing results from NSABP B-31. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 25, No 18S (June 20 Supplement), 2007: 511
- In order to address the first point regarding tumor heterogeneity and limitations of IHC/FISH, City of Hope has developed a novel radioimmunoconjugate called 64Cu-DOTA-trastuzumab that can be used in PET imaging for the localization of HER2-overexpressing tissue. The compound is clinical grade trastuzumab that is conjugated to a chelating agent DOTA and labeled with copper 64 radioisotope. This compound has been shown to accurately detect HER2-positive breast cancer tissue in patients with metastatic disease at our institution. This figure shows a Cu-DOTA-trastuzumab PET scan of a breast cancer patient whose breast cancer was HER2 negative by IHC/FISH. The blue arrows show PET activity in the tumor on the left chest wall. 64Cu was chosen because it has a short, but effective half life (12.7 hours), so it is well-suited for a 1-3 day imaging study. It is detected by PET DOTA was selected because have experience with this chelating agent and it has a high affinity for trastuzumab FIGURE 1. Shown clockwise are conventional axial CT, axial fused PET/CT, coronal and sagittal fused PET/CT images through a tumor in the left chest wall
- We hypothesized that the Cu-DOTA-trastuzumab PET scans may better localized HER2-overexpressing gastric cancer, potentially overcoming the problem of tumor heterogeneity. It can act as a non-invasive radiographic biopsy to potentially identify patients eligible for trastuzumab therapy. Secondly, we hypothesize that the Cu-DOTA-trastuzumab PET can more accurately measure functional HER2 expression than IHC/FISH.
- To test these hypotheses, a clinical trial was developed at City of Hope to evaluate Cu-DOTA-trastuzumab for assessing in vivo HER2 expression with modified PET/CT imaging of gastric cancer patients
- In terms of the study design, gastric cancer patients will be identified and consented in medical and surgical oncology clinics. They will undergo triple phase CT for staging to determine whether they are eligible for surgery. Surgical candidates must have biopsy-proven gastric cancer and be at least 18 years of age. Those with early stage disease will undergo curative-intent gastrectomy. For patients with locally-advance or metastatic disease, only those undergoing palliative surgical procedures will be eligible for the study. These patients will then receive Cu-DOTA-trastuzumab 48 hr prior to PET/CT. Then 64Cu uptake will be measured in tumor and adjacent non-tumor tissues.
- Surgical candidates will have the areas of the stomach corresponding to 64Cu uptake on the PET/CT marked with suture in the operating room. These specimens will be processed in pathology and tested for HER2 overexpression by both IHC and FISH. Then we will determine whether there is correlation between the SUV measured on PET/CT to the degree of IHC staining or number of HER2 copies on FISH for both the surgical specimen and pre-operative EGD biopsy if available. Target accrual of this study is 22 patients. HER2/CEP17 ratio >= 2 is considered positive Study start date: September 2014 Correlation between tumor SUV and degree of IHC (0, 1+, 2+, 3+) and HER2/CEP17 ratio