Linda Sofie Lindström

Most breast cancer patients are diagnosed with hormone-dependent (estrogen receptor-positive, ER+) breast cancer and endocrine treatment is standard of care. A unique feature of ER+ disease is that the risk to develop distant metastasis remains stable beyond 5-10 years after diagnosis, and half or more of all metastases will be diagnosed after this initial follow-up. The tumor biological factors underlying long-term risk are poorly understood, and it will remain a considerable clinical challenge in the foreseeable future. We will investigate the influence of standard clinical markers, their intra-tumor heterogeneity, and the heterogeneous ER+ tumor microenvironment, to identify tumor characteristics influencing long-term risk and benefit from endocrine treatment. Novel deep-learning methods will be used and in depth spatial analysis will enable understanding of tumor biology down to single-cell level. We will use unique and large clinical trials with patients randomized to endocrine treatment versus not with complete long-term follow-up. The distinction of long-term risk is essential, since accurate risk prediction allows for individualized treatment, decreases anxiety, and supports aggressive treatment for patients at high risk of fatal disease. Our study has the potential to answer vital questions about the influence of the tumor microenvironment and intra-tumor heterogeneity for long-term risk in ER+ breast cancer, helped by the interdisciplinary expertise in our team.

Breast cancer is a very heterogeneous disease with varying ability to spread and time to eventual spread. Most women are diagnosed with hormone-sensitive cancer, which means that the tumor is dependent on estrogen to grow. We and other researchers have shown that women with hormone-sensitive breast cancer have a long-term risk of developing widespread incurable disease, sometimes several decades after diagnosis, and that only half benefit from anti-hormonal treatment. However, the disease mechanisms behind this are not clear, which is a clinical challenge, as it is necessary to be able to predict long-term risk for individualized treatment. We will therefore investigate which tumor characteristics, both clinically used and newly formed, as well as intra-tumor heterogeneity, i.e. tumor cells with opposite characteristics within the same tumor, affect the long-term risk of dying from breast cancer. This is by comparing tumor characteristics in women who have died of their disease and women who have survived in a unique way in large clinical breast cancer studies with long follow-up and detailed tumor biology information. We will use innovative methods where we analyze images from tumor microscopy and genomic information using so-called artificial intelligence and deep learning. Our project intends to provide increased knowledge about the mechanisms behind long-term risk by identifying tumor characteristics that predict who has a high risk of dying from their disease as well as patients who have long-term, transient or no benefit from anti-hormonal treatment. The analyzes take place in large randomized studies in close collaboration with pathologists and oncologists, and the knowledge should therefore be able to be used in the near future. It may be important for improved information to women with breast cancer, for the possibility of planning clinical trials to reduce late recurrences, and for the planning of return visits after breast cancer treatment.

Breast cancer is a very heterogeneous disease with different ability to spread and time to possible spread. Of the women who develop breast cancer, about one in four women will die. Most women are diagnosed with hormone-sensitive cancer, which means that the tumor is dependent on estrogen to grow, but only 50% of women benefit from hormonal treatment. Different tumor characteristics (breast cancer markers) determine what treatment a woman should receive. However, these do not predict patients' long-term risk of dying from their disease. Which is important to realize as breast cancer is common in mid-life and carries a risk of many lost female years. We have shown that patients who have tumor cells with different expressions, ie intra-tumor heterogeneity of estrogen (a breast cancer marker) within their tumor have twice the risk of dying from breast cancer. Our aim is therefore to investigate whether intra-tumor heterogeneity of the clinically used breast cancer markers and other tumor characteristics affect a patient's risk of dying from breast cancer. This is done by uniquely comparing intra-tumor heterogeneity of tumor properties (at the protein level and gene level) in women who have died of their disease and women who have survived in a unique way in large clinical cancer studies with long follow-up and detailed information. Our project aims to provide increased knowledge about factors that affect survival by identifying tumor characteristics that predict which patients have a high risk of dying from their disease and patients who do not benefit from hormonal treatment. Given that the markers are analyzed in large randomized studies and in close interdisciplinary collaboration with pathologists and oncologists, the knowledge, if it proves interesting, should be able to be used in the near future. This can be of great importance for women with breast cancer, and provide the opportunity for customized treatments and controls for women with a high risk of late recurrence of the disease.

Breast cancer is a very heterogeneous disease with different ability to spread and time to possible spread. Of the women who develop breast cancer, about one in four women will die. Most women are diagnosed with hormone-sensitive cancer, which means that the tumor is dependent on estrogen to grow, but only 50% of women benefit from hormonal treatment. Different tumor characteristics (breast cancer markers) determine what treatment a woman should receive. However, these do not predict patients' long-term risk of dying from their disease. Which is important to realize as breast cancer is common in mid-life and carries a risk of many lost female years. We have shown that patients who have tumor cells with different expressions, ie intra-tumor heterogeneity of estrogen (a breast cancer marker) within their tumor have twice the risk of dying from breast cancer. Our aim is therefore to investigate whether intra-tumor heterogeneity of the clinically used breast cancer markers and other tumor characteristics affect a patient's risk of dying from breast cancer. This is done by uniquely comparing intra-tumor heterogeneity of tumor properties (at the protein level and gene level) in women who have died of their disease and women who have survived in a unique way in large clinical cancer studies with long follow-up and detailed information. Our project aims to provide increased knowledge about factors that affect survival by identifying tumor characteristics that predict which patients have a high risk of dying from their disease and patients who do not benefit from hormonal treatment. Given that the markers are analyzed in large randomized studies and in close interdisciplinary collaboration with pathologists and oncologists, the knowledge, if it proves interesting, should be able to be used in the near future. This can be of great importance for women with breast cancer, and provide the opportunity for customized treatments and controls for women with a high risk of late recurrence of the disease.