Periodic Reporting for period 3 - LIMA (Liquid biopsies and Imaging for improved cancer care)
Berichtszeitraum: 2021-01-01 bis 2022-06-30
Patients with advanced cancer are typically treated using a combination of methods. If possible, surgical removal is attempted first, followed by chemotherapy to eradicate any remaining disease. Each step increases the chances of patients to survive the disease, but also increases their risk of severe side effects that may result in poor quality of life or even death.
To strike an appropriate balance between cure and quality of life, it is important to know in advance which individual patients will respond to chemotherapy and who will not. Physicians therefore sometimes switch the order of treatments, performing chemotherapy first, and surgery second. This is called “neoadjuvant chemotherapy”. It allows the tumor to be monitored on medical images during the chemotherapy in order to intervene quickly if the medication is ineffective.
Unfortunately, current methods to measure tumor response have limited accuracy. This is caused in part because medical images cannot visualize microscopic disease and because not all parts of the tumor respond equally well to the same medication.
A consortium of hospitals and industry has joined forces in the LIMA project to tackle this problem. They will develop new methods to increase the chances of cure without compromising quality of life. To allow results to be translated to patients as soon as possible, the study has been designed to follow the current clinical routine of doctors as closely as possible.
In patients with breast cancer and rectal cancer, magnetic resonance imaging (MRI) will be employed to study the biology of the tumor before and during the treatment using state-of-the-art technology. MRI uses magnetic fields and radio waves to create very detailed pictures of the tumor, its functional behaviour and chemical composition. Secondly, blood samples of the same patients will be analysed before and during treatment to automatically look for microscopic tumor cells and their characteristics. Finally, all available information will be combined with clinical information using machine learning techniques to predict as soon as possible after the start of the treatment whether the treatment will eradicate all cancer.
To strike an appropriate balance between cure and quality of life, it is important to know in advance which individual patients will respond to chemotherapy and who will not. Physicians therefore sometimes switch the order of treatments, performing chemotherapy first, and surgery second. This is called “neoadjuvant chemotherapy”. It allows the tumor to be monitored on medical images during the chemotherapy in order to intervene quickly if the medication is ineffective.
Unfortunately, current methods to measure tumor response have limited accuracy. This is caused in part because medical images cannot visualize microscopic disease and because not all parts of the tumor respond equally well to the same medication.
A consortium of hospitals and industry has joined forces in the LIMA project to tackle this problem. They will develop new methods to increase the chances of cure without compromising quality of life. To allow results to be translated to patients as soon as possible, the study has been designed to follow the current clinical routine of doctors as closely as possible.
In patients with breast cancer and rectal cancer, magnetic resonance imaging (MRI) will be employed to study the biology of the tumor before and during the treatment using state-of-the-art technology. MRI uses magnetic fields and radio waves to create very detailed pictures of the tumor, its functional behaviour and chemical composition. Secondly, blood samples of the same patients will be analysed before and during treatment to automatically look for microscopic tumor cells and their characteristics. Finally, all available information will be combined with clinical information using machine learning techniques to predict as soon as possible after the start of the treatment whether the treatment will eradicate all cancer.
During the first reporting period (M1-M18):
Focus was on setting up the workflows for liquid biopsy measurement (ct-DNA and CTCs) as well as setting up the MRI imaging protocols to be used in the two clinical trials which will be run for breast and rectal cancer, respectively. In addition, the protocols for both clinical trials have been drafted and submitted.
During the second reporting period (M19-M36):
Focus was on setting up the clinical trials for breast and rectal cancer. For this purpose IRB approval has been obtained as well as arranging all contracts required for data sharing during the duration of the LIMA project within the consortium and also through a public database after the LIMA project has ended. This took quite more time than originally anticipated as is described in more detail in the report. In summary clinical Trial progress was delayed by two factors: contract negotiations delayed the start of the clinical trials and COVID-19 brought patient recruitment down to zero in the first pandemic wave and was and still is relative small currently. A 6 month extension has been submitted to the EU to address the delay due to COVID-19 for both clinical trials. Official decision on the amendment is expect on March 12, 2021.
During the third reporting period (M37-M54) the work focussed on the execution and data analysis of the clinical trials for breast and rectal cancer.
The patient recruitment for the LIMA clinical trials continued to be massively impacted due to the COVID-19 pandemic. The 6 months extension was used to extend the period for patient recruitment and inclusion for the clinical trials. Breast cancer trial managed to include 61 patients, whereas the rectal clinical trial managed to include 15 patients. The patient inclusion period was stretched to the absolute maximum, thereby impacting the time available for sample analysis and data analysis.
Conclusions:
• Conventional clinical predictors of residual disease in breast cancer are very strong. Follow-up research to quantify the complementary value of MRI and liquid biopsies will therefore require much larger study cohorts and focus on specific patient subgroups.
• Patient numbers in rectal clinical trial were too low for a significant statistical analysis of the results.
Exploitable results:
• A standard operating procedure for CTC workflow combining technologies from Angle and ALS.
• Contributions of ALS in the LIMA project have resulted in the development of CellCelector RC system for single cell isolation and CellCelector Nanowell slides and contributed to the development of CellCelector Nanowell plates and CellCelector Flex.
• Stilla reported the development of several tools and mutation panels (breast and rectal cancer mutation detection panels) to implement and validate 6-color Crystal Digital PCR detection assays.
• Combining the technologies of Stilla and DiaDx improved performance in detecting mutations from ctDNA and this technological synergy makes the detection of mutations even more efficient.
• Agena highlights the development of new panels and analysis tools.
• For Philips, LIMA initiated activities to address the unmet clinical need for full multi-modality data integration and representation.
• UMCU reports the deep-learning based MRI model will be investigated in follow-up study for its potential role to reduce the number of surgeries on patients with pathological complete response.
Dissemination:
• 4 papers published, 2 accepted for publication, 4 manuscripts in preparation
• Conference visits were hampered by COVID-19 pandemic. In total 4 posters and 3 oral presentations were presented at conferences.
Focus was on setting up the workflows for liquid biopsy measurement (ct-DNA and CTCs) as well as setting up the MRI imaging protocols to be used in the two clinical trials which will be run for breast and rectal cancer, respectively. In addition, the protocols for both clinical trials have been drafted and submitted.
During the second reporting period (M19-M36):
Focus was on setting up the clinical trials for breast and rectal cancer. For this purpose IRB approval has been obtained as well as arranging all contracts required for data sharing during the duration of the LIMA project within the consortium and also through a public database after the LIMA project has ended. This took quite more time than originally anticipated as is described in more detail in the report. In summary clinical Trial progress was delayed by two factors: contract negotiations delayed the start of the clinical trials and COVID-19 brought patient recruitment down to zero in the first pandemic wave and was and still is relative small currently. A 6 month extension has been submitted to the EU to address the delay due to COVID-19 for both clinical trials. Official decision on the amendment is expect on March 12, 2021.
During the third reporting period (M37-M54) the work focussed on the execution and data analysis of the clinical trials for breast and rectal cancer.
The patient recruitment for the LIMA clinical trials continued to be massively impacted due to the COVID-19 pandemic. The 6 months extension was used to extend the period for patient recruitment and inclusion for the clinical trials. Breast cancer trial managed to include 61 patients, whereas the rectal clinical trial managed to include 15 patients. The patient inclusion period was stretched to the absolute maximum, thereby impacting the time available for sample analysis and data analysis.
Conclusions:
• Conventional clinical predictors of residual disease in breast cancer are very strong. Follow-up research to quantify the complementary value of MRI and liquid biopsies will therefore require much larger study cohorts and focus on specific patient subgroups.
• Patient numbers in rectal clinical trial were too low for a significant statistical analysis of the results.
Exploitable results:
• A standard operating procedure for CTC workflow combining technologies from Angle and ALS.
• Contributions of ALS in the LIMA project have resulted in the development of CellCelector RC system for single cell isolation and CellCelector Nanowell slides and contributed to the development of CellCelector Nanowell plates and CellCelector Flex.
• Stilla reported the development of several tools and mutation panels (breast and rectal cancer mutation detection panels) to implement and validate 6-color Crystal Digital PCR detection assays.
• Combining the technologies of Stilla and DiaDx improved performance in detecting mutations from ctDNA and this technological synergy makes the detection of mutations even more efficient.
• Agena highlights the development of new panels and analysis tools.
• For Philips, LIMA initiated activities to address the unmet clinical need for full multi-modality data integration and representation.
• UMCU reports the deep-learning based MRI model will be investigated in follow-up study for its potential role to reduce the number of surgeries on patients with pathological complete response.
Dissemination:
• 4 papers published, 2 accepted for publication, 4 manuscripts in preparation
• Conference visits were hampered by COVID-19 pandemic. In total 4 posters and 3 oral presentations were presented at conferences.
LIMA will produce a comprehensive database of imaging and corresponding tissue and blood draw information from an unselected series of breast and rectal cancer patients before, during and after their treatment. This dataset will be important for future research in the medical sector, pharmacy, and education.
LIMA offers to interpret and combine advanced imaging features and new information on the molecular properties of tumors in a consistent and reproducible manner. This work can contribute to a more personalized treatment plan for patients.
If successful, the project will have a considerable impact on the patients and the healthcare systems. E.g. integration of new data sources like advanced imaging features and blood-based biomarkers in therapy response assessment, provides the opportunity to both improve disease free and overall survival outcomes. Furthermore, it will result in reduced burden, less side effects for the patients, and increased cost-effectiveness of targeted therapies.
The project has already economic impact among the SME’s involved in the project:
• There is a relevant increase in the number of people employed.
• During the running of the project, Stilla completed their next funding round of 16 M€, enable further growth of the company.
• Furthermore ALS has developed its CellCelector Dx for diagnostic applications in the project and even: first of these systems already have been sold in the market.
LIMA offers to interpret and combine advanced imaging features and new information on the molecular properties of tumors in a consistent and reproducible manner. This work can contribute to a more personalized treatment plan for patients.
If successful, the project will have a considerable impact on the patients and the healthcare systems. E.g. integration of new data sources like advanced imaging features and blood-based biomarkers in therapy response assessment, provides the opportunity to both improve disease free and overall survival outcomes. Furthermore, it will result in reduced burden, less side effects for the patients, and increased cost-effectiveness of targeted therapies.
The project has already economic impact among the SME’s involved in the project:
• There is a relevant increase in the number of people employed.
• During the running of the project, Stilla completed their next funding round of 16 M€, enable further growth of the company.
• Furthermore ALS has developed its CellCelector Dx for diagnostic applications in the project and even: first of these systems already have been sold in the market.