Earlier diagnosis in women at high risk of breast and ovarian cancer

Background Recent advances allow tiny amounts of cancer-derived DNA and proteins to be detected in blood.

These have been utilised to develop commercial cancer screening tests for the general population, the most advanced now being evaluated within the NHS.

Such tests, however, are unlikely to be ideal for populations at increased risk, where incidence rates of specific cancer types are extreme.

In parallel, there is need to further study the relationship between early cancer development and dynamics of circulating tumour DNA (ctDNA) in blood.

In the last five years, despite the COVID pandemic, we established collections from large cohorts of women at high risk.

We recruited to those studies >2150 women at high genetic risk and >3650 women at moderate-high risk who contribute annual blood-samples. We collected >9000 annual blood-samples and identified >80 incident cancers. In preliminary analysis, we detected ctDNA fragments in blood collected >6 months prior to cancer diagnosis.

We further collected 700 samples from women presenting with symptoms or abnormal screening mammograms.

In data from those, we detected cancer signals in 45% of women diagnosed with early-stage breast cancer, and 44%/89% of women diagnosed with early/late-stage ovarian cancers, at specificities >90% and >80%. Aims 1. Develop blood-based assays to detect early-stage breast and ovarian cancers; 2. Collect longitudinal samples prior to cancer emergence from women at high risk who go on to develop breast cancer; 3.

Study the dynamics of ctDNA levels months and years prior to cancer diagnosis; 4.

Assess the performance of early detection assays in women who present with symptoms or abnormal findings that indicate a suspicion of breast or ovarian cancer; 5.

Develop concepts and protocols for future interventional trials to implement tests for earlier diagnosis of cancer in women at high risk or with suspected symptoms.

Methods We will use infrastructure we developed to continue collecting annual samples from thousands of women at high risk, and from hundreds of women with suspected symptoms/findings.

We will optimise methods for analysing cell-free DNA and integrate with cutting-edge proteomics, to study the natural history of ctDNA before cancer diagnosis and to evaluate the performance of multi-omic methods for earlier diagnosis of breast and ovarian cancers.

How the results of this research will be used Such methods may reduce the need for risk-reducing salpingo-oophorectomy and mastectomy in women with a high risk of cancer, and allow faster/earlier diagnosis in women with abnormal findings or suspected symptoms.