Ignite Creation Date:
2024-05-06 @ 2:17 PM
Last Modification Date:
2024-10-26 @ 1:28 PM
Study NCT ID:
NCT04277195
Status:
UNKNOWN
Last Update Posted:
2020-02-20
First Post:
2019-11-18
Brief Title:
Developing a Diagnostic Tool to Predict Response to Chemotherapy
Sponsor:
Nottingham University Hospitals NHS Trust
Organization:
Nottingham University Hospitals NHS Trust
Study Overview
Official Title:
Developing a Diagnostic Tool Using SPAG5 for Predicting Clinical Benefit From Standard Anthracycline Combination AC in Breast Cancer
Status:
UNKNOWN
Status Verified Date:
2019-11
Last Known Status:
ACTIVE_NOT_RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
SPAG5
Brief Summary:
Every year nearly 62000 people are diagnosed with breast cancer in the UK One in eight women in the UK will develop breast cancer in their lifetime
The investigators are developing an inexpensive test to accurately predict how breast cancer patients will respond to the standard chemotherapy Anthracycline AC Only 15-20 of patients have no tumour remaining following AC so a method of treatment selection is urgently needed
Breast cancers are currently treated with a combination of chemotherapy targeted therapy and surgery However breast cancers are not identical each tumours individual characteristics affect how they respond to treatment Recently the investigators discovered a new tumour characteristic a protein which is unusually active in approximately 20 of breast cancers It was found that a patient whose tumour showed high activity often respond well to AC and vice versa
AC is an aggressive treatment which can potentially cause severe side effects including a risk of permanent heart damage It is important therefore to spare those patients who will not benefit from AC the physical and emotional side-effects of this drug Currently there is no predictive test for selecting which patients will benefit from AC and which will not The investigators have shown that an accurate prediction can be made by testing the activity of a protein called SPerm associated AntiGen 5 SPAG5 in tumour tissue
The aim is to develop a clinical SPAG5 testing kit that can be used by hospital laboratories to determine the activity of SPAG5 in the tumour This information will help guide the choice of treatment and achieve better patient outcomes
In June 2018 the investigators started a three year National Institute for Health Research NIHR funded project to develop a lab test that could form the basis of a SPAG5 testing kit
The investigators are developing an inexpensive test to accurately predict how breast cancer patients will respond to the standard chemotherapy Anthracycline AC Only 15-20 of patients have no tumour remaining following AC so a method of treatment selection is urgently needed
Breast cancers are currently treated with a combination of chemotherapy targeted therapy and surgery However breast cancers are not identical each tumours individual characteristics affect how they respond to treatment Recently the investigators discovered a new tumour characteristic a protein which is unusually active in approximately 20 of breast cancers It was found that a patient whose tumour showed high activity often respond well to AC and vice versa
AC is an aggressive treatment which can potentially cause severe side effects including a risk of permanent heart damage It is important therefore to spare those patients who will not benefit from AC the physical and emotional side-effects of this drug Currently there is no predictive test for selecting which patients will benefit from AC and which will not The investigators have shown that an accurate prediction can be made by testing the activity of a protein called SPerm associated AntiGen 5 SPAG5 in tumour tissue
The aim is to develop a clinical SPAG5 testing kit that can be used by hospital laboratories to determine the activity of SPAG5 in the tumour This information will help guide the choice of treatment and achieve better patient outcomes
In June 2018 the investigators started a three year National Institute for Health Research NIHR funded project to develop a lab test that could form the basis of a SPAG5 testing kit
Detailed Description:
Approximately 16700000 people are diagnosed with breast cancer BC worldwide each year with 500000 people dying annually In the UK alone each year nearly 62000 people are diagnosed with BC with one in eight women developing BC in their lifetime Breast cancers are currently treated with a combination of chemotherapy targeted therapy and surgery However breast cancers are not identical each tumours individual characteristics affect how they respond to treatment In many cases treatment options are limited and patients are often given sub-optimal treatments which are associated with burdensome side effects For instance despite chemotherapy being offered to about 60-70 of patients with BC either alone or in combination with other targeted therapies results from a meta-analysis of 123 randomised trials including more than 100000 patients has shown that chemotherapy reduces recurrence and mortality in only 20 to 33 of patients Therefore 80-67 of patients endured this aggressive chemotherapy treatment and did not benefit unnecessarily suffering the serious physical and emotional side effects including a risk of permanent heart damage Currently there is no predictive test for selecting which patients will benefit from receiving chemotherapy and which will not
In clinical practice the decision to use chemotherapy or not depends on evaluating the risk of recurrence and prognosis by interpreting prognostic clinicopathological features including high cost multi-gene tests such as Oncotype DX Genomic Health Inc Mamma-Print Agendia and PAM50 NanoString Unfortunately almost all these molecular approaches share common issues such as insufficiently high levels of evidence overfitting of computational models and high false discovery rates Furthermore they might not be available for clinical logistical or financial reasons Therefore there is an urgent need for a cost effective reliable sensitive specific validated biomarker based approach for optimising chemotherapy treatments in patients with BC
Recently the investigators have shown that an accurate prediction can be made by testing the activity of a protein called SPerm associated AntiGen 5 SPAG5 in tumour tissue In a study published in Lancet Oncology 2016 the investigators showed that SPAG5 gene amplification as well as SPAG5 transcript and SPAG5 protein overexpression were all associated with poor clinical outcome and were independent predictors for chemotherapy response
The prognostic and predictive power of SPAG5 outperforms many currently used tests including the standard cancer proliferation index Ki67 prognostic clinicopathological factors such as the American Joint Committee on Cancer AJCC stage and Nottingham Prognostic Index as well as other currently available multigene-tests including PAM-50 96-gene genomic grade index Genomic Chemo Sensitivity Predictor the Diagonal Linear Discrimination Analysis of 30-gene signature and the Adjuvant Online index
The most immediately useful aspect of our original findings is the potential ability to distinguish those patients with BC who are likely to benefit from standard Anthracycline combination AC chemotherapy regimens from those who will not Therefore our findings have the potential to deliver an accurate predictive biomarker for chemotherapy response in BC which would enable the effective tailoring of treatment to the individual patient Furthermore the analysis of SPAG5 expression could underpin the development of novel strategies for more effective management and treatment of the disease
The work undertaken by the investigators on SPAG5 testing has relied on a commercially available polyclonal antibody PAb against SPAG5 marketed by Sigma Aldrich and produced by Atlas Antibodies This has a number of problems when aiming to develop a SPAG5 based clinical test Firstly a PAb is a mixture of antibodies and so it lacks specificity and sensitivity Also as a PAb it is extracted directly from an animal constraining the supply and placing a finite limit on the availability of the antibody as the animal will die one day ending our ability to provide the test Thirdly the PAb is owned by a company and so the cost and availability of any test will be subject to that companys decision Therefore it is essential to develop a monoclonal antibody MAb that is suitable for immunohistochemistry staining of Formalin Fixed Paraffin Embedded FFPE tissue
To overcome these problems the investigators chose to develop a SPAG5 targeting MAb that can be taken through the evaluation clinical testing and regulatory approval process to become a SPAG5 clinical test Moreover once the MAb is developed the validation of previous results will be carried out on a large number of BC cases to verify the prognostic and predictive powers of the antibody In addition the predictive utility for chemo-sensitivity of SPAG5 MAb and PAb will be compared to each other and to rival Immunohistochemistry IHC tests such as Ki67 and the rival gene expression tests A bespoke gene panel will be developed for the nanoString nCounter FLEX instrument featuring genes used in PAM-50 21-gene recurrence Genomic-Chemo-Sensitivity-Predictor and the 30-gene-DLDA tests alongside SPAG5 and Ki67
In June 2018 the investigators were granted funding to pursue this work by the NIHR Invention for innovation grant program
In clinical practice the decision to use chemotherapy or not depends on evaluating the risk of recurrence and prognosis by interpreting prognostic clinicopathological features including high cost multi-gene tests such as Oncotype DX Genomic Health Inc Mamma-Print Agendia and PAM50 NanoString Unfortunately almost all these molecular approaches share common issues such as insufficiently high levels of evidence overfitting of computational models and high false discovery rates Furthermore they might not be available for clinical logistical or financial reasons Therefore there is an urgent need for a cost effective reliable sensitive specific validated biomarker based approach for optimising chemotherapy treatments in patients with BC
Recently the investigators have shown that an accurate prediction can be made by testing the activity of a protein called SPerm associated AntiGen 5 SPAG5 in tumour tissue In a study published in Lancet Oncology 2016 the investigators showed that SPAG5 gene amplification as well as SPAG5 transcript and SPAG5 protein overexpression were all associated with poor clinical outcome and were independent predictors for chemotherapy response
The prognostic and predictive power of SPAG5 outperforms many currently used tests including the standard cancer proliferation index Ki67 prognostic clinicopathological factors such as the American Joint Committee on Cancer AJCC stage and Nottingham Prognostic Index as well as other currently available multigene-tests including PAM-50 96-gene genomic grade index Genomic Chemo Sensitivity Predictor the Diagonal Linear Discrimination Analysis of 30-gene signature and the Adjuvant Online index
The most immediately useful aspect of our original findings is the potential ability to distinguish those patients with BC who are likely to benefit from standard Anthracycline combination AC chemotherapy regimens from those who will not Therefore our findings have the potential to deliver an accurate predictive biomarker for chemotherapy response in BC which would enable the effective tailoring of treatment to the individual patient Furthermore the analysis of SPAG5 expression could underpin the development of novel strategies for more effective management and treatment of the disease
The work undertaken by the investigators on SPAG5 testing has relied on a commercially available polyclonal antibody PAb against SPAG5 marketed by Sigma Aldrich and produced by Atlas Antibodies This has a number of problems when aiming to develop a SPAG5 based clinical test Firstly a PAb is a mixture of antibodies and so it lacks specificity and sensitivity Also as a PAb it is extracted directly from an animal constraining the supply and placing a finite limit on the availability of the antibody as the animal will die one day ending our ability to provide the test Thirdly the PAb is owned by a company and so the cost and availability of any test will be subject to that companys decision Therefore it is essential to develop a monoclonal antibody MAb that is suitable for immunohistochemistry staining of Formalin Fixed Paraffin Embedded FFPE tissue
To overcome these problems the investigators chose to develop a SPAG5 targeting MAb that can be taken through the evaluation clinical testing and regulatory approval process to become a SPAG5 clinical test Moreover once the MAb is developed the validation of previous results will be carried out on a large number of BC cases to verify the prognostic and predictive powers of the antibody In addition the predictive utility for chemo-sensitivity of SPAG5 MAb and PAb will be compared to each other and to rival Immunohistochemistry IHC tests such as Ki67 and the rival gene expression tests A bespoke gene panel will be developed for the nanoString nCounter FLEX instrument featuring genes used in PAM-50 21-gene recurrence Genomic-Chemo-Sensitivity-Predictor and the 30-gene-DLDA tests alongside SPAG5 and Ki67
In June 2018 the investigators were granted funding to pursue this work by the NIHR Invention for innovation grant program
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| II-LA-0417-20004 | OTHER_GRANT | None | None |
| 2125 | OTHER_GRANT | Nottingham Hospitals Charity | None |