Title: ROCKETS-GEN: Earlier detection of ovarian cancer using novel genomic technology
Funder: Cancer Research UK

Abstract: Background: Ovarian cancer (OC) is the fifth most common cancer in women in the UK with approximately 7,000 new cases diagnosed in 2011. The majority of women (60%) have advanced disease (stage III-IV) at diagnosis. 5-year survival rates are 43% overall but over 90% for early stage tumours. High grade serous is the most common histotype (80%). Worryingly, long term survival from OC has remained static over the last decades at 30%. Earlier detection of ovarian cancer will save lives. Using next generation sequencing it is now possible to amplify small amounts of free circulating DNA in the blood to identify molecular alterations observed in tumour DNA. Somatic mutations are highly specific biomarkers of cancer and if these could be detected in circulating tumour DNA (ctDNA) this could provide a powerful non-invasive method for earlier cancer diagnosis. Aims We propose to investigate ctDNA as a diagnostic biomarker for OC by collecting plasma samples and analysing ctDNA in a nested case control design within a prospective study (ROCkeTS-GEN) that will initially recruit postmenopausal participants entering the ongoing NIHR funded ROCkeTS study and subsequently after the end of recruitment to ROCkeTS continue recruitment as an independent study. Methods : Cell free DNA will be extracted from plasma samples and sequenced using targeted sequencing for TP53 and shallow whole genome sequencing (sWGS). Any mutations identified will be validated by sequencing DNA extracted from tumour tissue obtained at the time of surgery. Sensitivity and specificity of plasma ctDNA as a biomarker for diagnosis of OC, particularly early stage OC will be established against histology or 12month follow-up as a reference standard. How the results of this research will be used: ROCkeTS-GEN will establish the diagnostic accuracy of plasma ctDNA as a biomarker for earlier diagnosis of ovarian cancer. If proven, this could be used in clinical practice to improve outcomes for women within the next 5 years

Lay abstract: Background: Ovarian cancer (OC) is the fifth most common cancer in women in the UK with approximately 7,000 new cases diagnosed in 2011. The majority of women (60%) have advanced disease (stage III-IV) at diagnosis. 5-year survival rates are 43% overall but over 90% for early stage tumours. High grade serous is the most common histotype (80%). Worryingly, long term survival from OC has remained static over the last decades at 30%. Earlier detection of ovarian cancer will save lives. Using next generation sequencing it is now possible to amplify small amounts of free circulating DNA in the blood to identify molecular alterations observed in tumour DNA. Somatic mutations are highly specific biomarkers of cancer and if these could be detected in circulating tumour DNA (ctDNA) this could provide a powerful non-invasive method for earlier cancer diagnosis. Aims We propose to investigate ctDNA as a diagnostic biomarker for OC by collecting plasma samples and analysing ctDNA in a nested case control design within a prospective study (ROCkeTS-GEN) that will initially recruit postmenopausal participants entering the ongoing NIHR funded ROCkeTS study and subsequently after the end of recruitment to ROCkeTS continue recruitment as an independent study. Methods : Cell free DNA will be extracted from plasma samples and sequenced using targeted sequencing for TP53 and shallow whole genome sequencing (sWGS). Any mutations identified will be validated by sequencing DNA extracted from tumour tissue obtained at the time of surgery. Sensitivity and specificity of plasma ctDNA as a biomarker for diagnosis of OC, particularly early stage OC will be established against histology or 12month follow-up as a reference standard. How the results of this research will be used: ROCkeTS-GEN will establish the diagnostic accuracy of plasma ctDNA as a biomarker for earlier diagnosis of ovarian cancer. If proven, this could be used in clinical practice to improve outcomes for women within the next 5 years

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS