PRECISION - supplementary award
Cancer Research UK
Netherlands Cancer Institute
Background Ductal carcinoma in situ (DCIS) now represents 20-25% of all breast neoplasia. This is due to large-scale detection by widely adopted population-based breast cancer screening programs . As a result, thousands of women are confronted with DCIS each year: more than 8,000 in the UK, 2,300 in the Netherlands, and over 50,000 in the US. Conventional management includes surgery, supplemented by radiotherapy and/or endocrine therapy, but overtreats the majority of DCIS as ~1% recur annually and breast cancer mortality is ~3% at 20 years. Uncertainty as to which DCIS lesions will progress to invasive cancer or, after excision, which will return with recurrent DCIS or invasive breast cancer drives this overtreatment. Distinguishing DCIS that may progress to lethal disease from the majority of harmless DCIS is therefore an urgent need to save thousands of women with low risk DCIS the burden of radical treatment without any survival benefit.  Aim We aim to reduce the burden of overtreatment of DCIS (surgery, radiation therapy, hormonal therapies) through the development of novel tests that promote informed and shared decision-making between patients and clinicians, without compromising the excellent outcomes for DCIS management presently achieved.  Methods First, three large retrospective DCIS cohorts (and supplementary sources) will be collected enabling subsequent in depth molecular studies. Second, extensive genomic characterisation, immune profiling and imaging analysis will be performed. In vivo and in vitro modelling will be performed to study the biology of DCIS in detail. Finally, all clinical, immune, and molecular data will be incorporated into a clinical risk prediction model. This risk prediction model can be validated in three prospective DCIS trials. Specifically, in the current project we will a.) collect tissue and blood samples from these trials and b.) start validation of the biomarkers detected in the retrospective series.  How the results of this research will be used  The discoveries from our laboratory studies, including a risk stratification model, will be cross-validated in prospective trials of DCIS active surveillance versus conventional treatment (the LORIS, LORD and COMET trials). As such, the main result of this study will be that we can identify a group of women for which active surveillance for DCIS could be a safer alternative to intensive treatment. Ultimately, this may also contribute to a more reassuring perception of risk regarding non-life threatening precancerous lesions in general, reducing anxiety and preserving quality of life.
2.6 Resources and infrastructure (aetiology)