eRapport

Characterizing in time and space the metastatic process of hormone receptor positive breast cancer

Prosjekt
Prosjektnummer
2019057
Ansvarlig person
Hege Elisabeth Giercksky Russnes
Institusjon
Oslo universitetssykehus HF
Prosjektkategori
Åpen prosjektstøtte
Helsekategori
Cancer
Forskningsaktivitet
4. Detection and Diagnosis
Rapporter
2024
Patients with ER positive breast cancers have a lower risk of relapse within the first five years compared to those with ER negative disease. However, after 5-year, while ER- cancers very rarely relapse, almost 50% of ER+ relapses have yet to occur. The main objective of this project is to understand time-dependent risk for disease progression.The main objective of this project is to understand time-dependent dissemination and tumor evolution with the aim of identifying predictors of late relapse of ER+ breast cancer. A particular focus is to define the potential role of liquid biopsies for tailoring treatment and monitoring disease. Key questions we will seek to answer: Is the metastatic process driven by different mechanisms in patients with different time to relapse? Do the evolutionary processes differ in these patients? Can the evolutionary process be predicted at time of diagnosis or is it revealed by later features discovered in minimal residual disease? To answer this, the study was designed as four work packages where the activity started in 2019. This project has performed extensive testing of methodology to be able to identfy molecular alterations in minor cell populations, even single tumor cells. A master thesis (Julie S. Monrad) in June 2021 identified suitable techniques, and now we are finalizing this work by analysing single cell sequencing data from the isolated cells. To understand more about evolution, we have finalized a work where corresponding primary tumors an lymph nodes are investigated at singel cell level (by CyTOF and Hyperion), this is just accepted for publication. The understand more about the clinical importance of liquid biopsies in ER+ breast cancer we have finished the blood analyses in the ICON trial; here we found that in peripheral blood (CellSearch analyses, inculding PD-L1), patients with Luminal A subtype hade more frequently circulating tumor cells. it was also a trend towards this being a prognostic marker, but the number of patients included in the trial is a little too small to conclude. We are continuing dataanalyses in this project with regard to late relapse and predictive biomarkers. This project has in addition also been important to identify technology and methodology to identify minimal residual disease in cancer patients suitable as diagnostic tests.

NEI

2023
Patients with ER positive breast cancers have a lower risk of relapse within the first five years compared to those with ER negative disease. However, after 5-year, while ER- cancers very rarely relapse, almost 50% of ER+ relapses have yet to occur. The main objective of this project is to understand time-dependent risk for disease progressionThe main objective of this project is to understand time-dependent dissemination and tumor evolution with the aim of identifying predictors of late relapse of ER+ breast cancer. A particular focus is to define the potential role of liquid biopsies for tailoring treatment and monitoring disease. Key questions we seek to answer are: Is the metastatic process driven by different mechanisms in patients with different time to relapse? Do the evolutionary processes differ in these patients? Can the evolutionary process be predicted at time of diagnosis or is it revealed by later features discovered in minimal residual disease? To answer this, the study is designed as four work packages where the activity started in 2019 (April). The activity in 2023 has been: WP1: The comparison of single cell identification and extraction methods, have been complemented by single-cell RNA sequencing and in 2023 we have worked with establishing novel data pipelines for extracting more extensive information from the data. This has delayed publications, and two manuscripts are under preparation. Detection and capture of disseminated tumor cells (DTCs) is still not solved, the work in this field is now continued in a separate project. WP2: Due to technical challenges in analysing both DNA and RNA in micrometastatic cells, we strengthened in 2022 and 2023 the work on single-cell analyses on metastatic cells in lymph nodes – paper is under submission. WP3: The clinical importance of liquid biopsies in ER+ breast cancer: Blood samples from patients in the ICON trial are run on CellSearch to identify circulating tumor cells (CTC), including PD-L1 as a marker for the cells to evaluate the PD-L1 expression of both tumor cells and immune cells prior to and after anti-PD-L1 treatment. The result of the trial was published in 2023, and the work on clinical impact of CTC detection was presented at an international conference (6th ATCT conference), manuscript is submitted. WP4: Several biomarkers with clinical interest are identified, and separate projects are identified in 2023. The largest project is funded by the Norwegian cancer Association (DECODE-BC, 2023-2027).

No research stays abroad.

2022
Patients with ER positive breast cancers have a lower risk of relapse within the first five years compared to those with ER negative disease. However, after 5-year, while ER- cancers very rarely relapse, almost 50% of ER+ relapses have yet to occur. The main objective of this project is to understand time-dependent risk for disease progression.The main objective of this project is to understand time-dependent dissemination and tumor evolution with the aim of identifying predictors of late relapse of ER+ breast cancer. A particular focus is to define the potential role of liquid biopsies for tailoring treatment and monitoring disease. Key questions we will seek to answer: Is the metastatic process driven by different mechanisms in patients with different time to relapse? Do the evolutionary processes differ in these patients? Can the evolutionary process be predicted at time of diagnosis or is it revealed by later features discovered in minimal residual disease? To answer this, the study is designed as four work packages where the activity started in 2019 (April). The activity in 2022 has been: WP1: During spring 2021, the extraction of the nucleic acids from single-cells identified and procured by four different methods were performed. A part of this work, the comparison of single cell identification and extraction methods, were completed as a Master thesis (Julie S. Monrad) in June 2021. In 2022 we did additional testing of methodology by adding single-cell RNA sequencing to identify the impact the processing of cells can have on gene expression measurements. The manuscript is under preparation. During this work it has been regular (appr. weekly) meetings with collaborator Lucy Yates at Cambridge. Methodology for detection and capture disseminated tumor cells (DTCs): the follow-up study of women in the Oslo2 trial has started with the first sampling was performed in Q4 2021. This has been continued in 2022, the evaluation of the first results are expected in Q2/3. WP2: Sequencing of DNA/RNA from micrometastases have been delayed. The activity has been thus focused on two subprojects: tumor evolution study with microdissection of pre-invasive, invasive and metastatic cells from selected patients. We perform all histopathology work and Wellcome Sanger Institute performs the data generation and sequencing in accordance to the plan. Further, we have strengthened the work on single-cell analyses on metastatic cells in lymph nodes – and have included characterisation of alterations in the corresponding primary tumor as well (by CyTOF and Hyperion), the analyses of this is ongoing. WP3: The clinical importance of liquid biopsies in ER+ breast cancer: Blood samples from patients in the ICON trial are run on CellSearch, including PD-L1 as a marker for the cells to evaluate the PD-L1 expression of both tumor cells and immune cells prior to and after anti-PD-L1 treatment. Manuscript in preparation. WP4: Biomarkers for validation in separate projects are expected to be identified in 2023.

No

2021
Patients with ER positive breast cancers have a lower risk of relapse within the first five years compared to those with ER negative disease. However, after 5-year, while ER- cancers very rarely relapse, almost 50% of ER+ relapses have yet to occur. The main objective of this project is to understand time-dependent risk for disease progression.The main objective of this project is to understand time-dependent dissemination and tumor evolution with the aim of identifying predictors of late relapse of ER+ breast cancer. A particular focus is to define the potential role of liquid biopsies for tailoring treatment and monitoring disease. Key questions we will seek to answer: Is the metastatic process driven by different mechanisms in patients with different time to relapse? Do the evolutionary processes differ in these patients? Can the evolutionary process be predicted at time of diagnosis or is it revealed by later features discovered in minimal residual disease? To answer this, the study is designed as four work packages where the activity started in 2019 (April). The extensive testing of methodology done in 2019 continued into 2020, but during 2020 tumor cell identification and single-cell selection has been optimized and the first cases from breast cancer patients are now undergoing sequencing by the main collaborator in Cambridge, UK. This includes selections of multiple small regions/groups of tumor cells from the primary tumor (procured by laser microscopy), almost 300 tumor cells from bone marrow (micrometastases) and tumor regions from a later metastasis. During spring 2021, the extraction of the nucleic acids from these samples were performed, but as the output was low and the quality parameters were inferior, the sequencing of the samples have been stalled until the sequencing pipeline can be optimized. A part of this work, the comparison of single cell identification and extraction methods, were completed as a Master thesis (Julie S. Monrad) in June 2021. A manuscript is now under preparation. During this work it has been regular (appr. weekly) meetings with collaborator Lucy Yates at Cambridge. The activity in 2021 has in addition been: WP1: Methodology for detection and capture disseminated tumor cells (DTCs): the follow-up study of women in the Oslo2 trial has started with the first sampling was performed in Q4 2021. This will continue in 2022. WP2: Sequencing of DNA/RNA from micrometastases have been delayed (see comment above). The activity has been thus focused on two subprojects: tumor evolution study with microdissection of pre-invasive, invasive and metastatic cells from selected patients. We perform all histopathology work and Wellcome Sanger Institute performs the data generation and sequencing in accordance to the plan. Further, we have strengthened the work on single-cell analyses on metastatic cells in lymph nodes – and have included characterisation of alterations in the corresponding primary tumor as well (by CyTOF and Hyperion). WP3: The clinical importance of liquid biopsies in ER+ breast cancer: Blood samples from patients in the ICON trial are run on CellSearch, inculding PD-L1 as a marker for the cells to evaluate the PD-L1 expression of both tumor cells and immune cells prior to and after anti-PD-L1 treatment. Manuscript in preparation. WP4: Clinico-pathological parameters related to time-to-relapse in large patient cohorts/datasets. With collaborators G. Ursin and A. Johansson, we have found a combination of molecular and clinical/pathological parameters to identify a group of patients where the risk of relapse do not decline over time, published in Feb. 2021. We have also included a substudy of women with different ethnical background (published in Jan. 2022).

No

2020
Patients with ER positive breast cancers have a lower risk of relapse within the first five years compared to those with ER negative disease. However, after 5-year, while ER- cancers very rarely relapse, almost 50% of ER+ relapses have yet to occur. The main objective of this project is to understand time-dependent risk for disease progression.The main objective of this project is to understand time-dependent dissemination and tumor evolution with the aim of identifying predictors of late relapse of ER+ breast cancer. A particular focus is to define the potential role of liquid biopsies for tailoring treatment and monitoring disease. Key questions we will seek to answer: Is the metastatic process driven by different mechanisms in patients with different time to relapse? Do the evolutionary processes differ in these patients? Can the evolutionary process be predicted at time of diagnosis or is it revealed by later features discovered in minimal residual disease? To answer they, the study is designed as four work packages where the activity started in 2019 (April). The extensive testing of methodology done in 2019 continued into 2020, but during 2020 tumor cell identification and single-cell selection has been optimized and the first cases from breast cancer patients are now undergoing sequencing by the main collaborator in Cambridge, UK. This includes selections of multiple small regions/groups of tumor cells from the primary tumor (procured by laser microscopy), almost 300 tumor cells from bone marrow (micrometastases) and tumor regions from a later metastasis. There have been regular meetings between the collaborative groups from Oslo, Stockholm, Cambridge and Leuven (virtual). The activity in 2020 has been as follows: WP1: Methodology for detection and capture disseminated tumor cells (DTCs): by combining FACS sorting and micromanipulation we now have managed to select and isolate single tumor cells among thousands of bone marrow cells. The second part of this WP has also been initiated; the follow-up study of women in the Oslo2 trial has started and the first sampling will occur Q3 in 2021. WP2: High-resolution, multi-level molecular analyses of primary tumors, metastases and liquid biopsies: Together with collaborators from UK and Bergen we have identified suitable candidates for detailed molecular analyses (i.e. the samples described in WP1), and these are now processed for sequencing in UK. WP3: The clinical importance of liquid biopsies in ER+ breast cancer: Blood samples from patients in the ICON trial are run on CellSearch, we have added PD-L1 as a marker for the cells to evaluate the PD-L1 expression of both tumor cells and immune cells prior to and after anti-PD-L1 treatment. The dataset is now completed and being analysed. WP4: Clinico-pathological parameters related to time-to-relapse in large patient cohorts/datasets. With G. Ursin and A. Johansson we have found the combination of molecular and clinical/pathological parameters to identify a group of patients where the risk of relapse do not decline over time. This work has been published (Feb. 2021) and a follow-up analysis is planned.

NO

2019
Patients with ER positive breast cancers have a lower risk of relapse within the first five years compared to those with ER negative disease. However, after 5-year, while ER- cancers very rarely relapse, almost 50% of ER+ relapses have yet to occur. The main objective of this project is to understand time-dependent risk for disease progression.The main objective of this project is to understand time-dependent dissemination and tumor evolution with the aim of identifying predictors of late relapse of ER+ breast cancer. A particular focus is to define the potential role of liquid biopsies for tailoring treatment and monitoring disease. Key questions we will seek to answer: Is the metastatic process driven by different mechanisms in patients with different time to relapse? Do the evolutionary processes differ in these patients? Can the evolutionary process be predicted at time of diagnosis or is it revealed by later features discovered in minimal residual disease? To answer they, the study is designed as four work packages where the activity in 2019 started in April. A full-time engineer was involved in the project, with some assistance from personnel trained in single-cell detection, which has been crucial for all the technical laboratory work. As this project depend on high-quality DNA and RNA from archival samples as well as from single tumor cells from old bone marrow samples, methodology testing have been the main focus in 2019. There have been several challenges, where a few have been solved but some will be focused on in 2020 as well. A post-doc was employed in December 2019, which will be important for the next phase of the project. There have been several meetings between the collaborative groups from Oslo, Stockholm, Cambridge and Leuven, both in Oslo and in Cambridge. The activity in 2019 has been as follows: WP1: Refine methodology for detection and capture of tumor cells in liquid biopsies: There has been a major focus on refining methodology for detection and capture circulating and disseminated tumor cells (CTCs, DTCs). When using existing capturing techniques (immunocytochemistry and micromanipulation), we found RNA quality to been too low for further analyses. Together with collaborators in UK and Belgium we have developed a modified procurement technique which looks promising (changing the staining and manipulation technique), but more testing is needed (incl. laser capture microdissection). Further, we have tested enrichment by CellSearch (peripheral blood) and are now collecting CTCs from the ICON trial samples by CellSearch and have also started testing subsequent procurement by DepArray. WP2: High-resolution, multi-level molecular analyses of primary tumors, metastases and liquid biopsies: This part is waiting for optimal technique (WP1), but together with collaborators from UK and Bergen we have been working with data analyses of the NeoTax cohort to identify suitable candidates for detailed molecular analyses. L. Yates has received UK funding (1.000.000 UK Pounds) for molecular analyses of Norwegian samples involved in this project. WP3: The clinical importance of liquid biopsies in ER+ breast cancer: Blood samples from patients in the ICON trial are run on CellSearch, we are at the adding PD-L1 as a marker for the cells to evaluate the PD-L1 expression of both tumor cells and immune cells prior to and after anti-PD-L1 treatment. The dataset will be complete in 2020. WP4: Clinico-pathological parameters related to time-to-relapse in large patient cohorts/datasets. With G. Ursin and A. Johansson we are now completing a manuscript describing the dynamics of risk for relapse with regard to subsets of breast cancer using population-based registry data (The Cancer Registry of Norway).

Nei

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Deltagere
  • Thierry Voet Prosjektdeltaker
  • Peter Van Loo Prosjektdeltaker
  • Nikolas Stoecklein Prosjektdeltaker
  • Lisa Ryden Prosjektdeltaker
  • Anna Johansson Prosjektdeltaker
  • Moritz Gerstung Prosjektdeltaker
  • Irma Fredriksson Prosjektdeltaker
  • Peter Campbell Prosjektdeltaker
  • Lucy Yates Prosjektdeltaker
  • Julie Monrad Prosjektdeltaker
  • Inger Riise Bergheim Prosjektdeltaker
  • Giske Ursin Prosjektdeltaker
  • Therese Sørlie Prosjektdeltaker
  • Kristine Kleivi Sahlberg Prosjektdeltaker
  • Bjørn Naume Prosjektdeltaker
  • Randi Margit Ruud Mathiesen Prosjektdeltaker
  • Per Eystein Lønning Prosjektdeltaker
  • Ole Christian Lingjærde Prosjektdeltaker
  • Anita Langerød Prosjektdeltaker
  • Mette Langaas Prosjektdeltaker
  • Jon Amund Kyte Prosjektdeltaker
  • Vessela N. Kristensen Prosjektdeltaker
  • Stian Knappskog Prosjektdeltaker
  • Anne-Lise Børresen-Dale Prosjektdeltaker
  • Elin Borgen Prosjektdeltaker
  • Anna Bofin Prosjektdeltaker
  • Inga Hansine Rye Postdoktorstipendiat (finansiert av denne bevilgning)
  • Hege Elisabeth Giercksky Russnes Prosjektleder
  • Ingrid Bakka Prosjektdeltaker
  • My Anh Tu Sveli Prosjektdeltaker
  • Anthony Mathelier Prosjektdeltaker
  • Lisa Rydén Internasjonal samarbeidspartner

eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT

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