Immuno-SBC · Disentangling the relationship between autoimmunity, cancer treatment, and risk of subsequent breast cancer

Approximately 1 in 5 newly diagnosed cancers is a second or subsequent cancer related to treatment for a first cancer. Second breast cancers (SBCs) are the most commonly diagnosed. Those who develop SBCs have reduced treatment options and worse outcomes than comparable individuals with first primary breast cancers. There are over 12 million female cancer survivors in the EU, of whom at least 15% will develop an SBC. A better understanding of the etiology and risk factors for SBC is therefore essential. There is an intriguing and poorly understood negative association between systemic autoimmune diseases and breast cancer, repeatedly documented in distinct populations. My preliminary data further suggests that systemic autoimmune disease interacts with chemotherapy receipt to modify the risk of SBCs. However, no research groups have interrogated the interaction among autoimmunity, cancer treatment, and SBC risk. I propose to address this gap by bringing together population-based studies, multi-omic tools, and innovative statistical modelling. I have proposed three complementary Scientific Aims to understand the epidemiological and biological relevance of autoimmune disease in SBC. In Aim 1, I will use a novel approach to link large cohorts of cancer survivors with medical data to capture the course of autoimmune disease after cancer and its relationship with SBC risk. In Aim 2, I will use germline genotyping data to define ""autoimmune states"" reflecting the true range of sub-clinical autoimmune phenotypes. In Aim 3, I will test the association between autoimmune state and SBC risk, and the interaction with chemotherapy. This project thus introduces a novel paradigm for understanding of the etiology of treatment-associated cancers. Given the fundamental importance of immune state in cancer outcomes, and the number of people at risk of SBC, this project will have a profound impact on cancer survivorship research.""