PRECISION
Led by Professor Jelle Wesseling (The Netherlands Cancer Institute, Netherlands).The challenge
In 2017, team PRECISION set out to tackle the lethal versus non-lethal cancers challenge, distinguishing between lethal cancers that need treating and non-lethal cancers that don’t, focusing on ductal carcinoma in situ (DCIS).
At the time, the condition was generally considered as a precursor to invasive breast cancer, resulting in widespread overtreatment, as up to 80% of cases would never actually progress.
By delving deeply into the biology of DCIS, the team aimed to identify factors that could distinguish between aggressive forms and those posing no threat. PRECISION hoped their discoveries would ultimately lead to new de-escalation strategies for managing DCIS, sparing many thousands of women around the world from unnecessary and intensive cancer treatment.
At a glance
PRECISION was funded by
Team and leadership
PRECISION was led by:
PRECISION assembled a team of over 60 researchers and clinicians from multiple complementary disciplines based in the Netherlands, UK and USA. Led by Professor Jelle Wesseling, a pathologist at the Netherlands Cancer Institute, the team has become a leading international force in the DCIS field over the last seven years.
Tackling the lethal versus non-lethal cancers challenge
Since the introduction of population-based screening such as mammographies for early diagnosis of breast cancer, the detection of DCIS has increased around seven-fold. But historically, it has not been possible for clinicians to discriminate between harmless forms and the 20% that pose a real threat. This uncertainty has led to the over-treatment of DCIS, with tens of thousands of women every year undergoing needless, extensive and disruptive treatment for a condition that will never do them any harm.
When PRECISION set out to address this issue, knowledge about the biology of DCIS was limited and there was no clear understanding of what drove or prevented its progression to invasive cancer. The team had three overarching aims:
- To understand what drives or prevents the progression of DCIS to invasive breast cancer
- To understand how we can distinguish harmless from hazardous DCIS
- To understand when active surveillance (a watch and wait approach) for low-risk DCIS is safe.
Central to the team PRECISION’s comprehensive and pioneering approach was the pooling together of the largest-ever international collection of data and tissue samples – from 47,000 women with DCIS in the UK, US and the Netherlands. Using this unique resource, the team saw that clinical-pathological factors used in the clinic do not hold sufficient prognostic value to predict which women might be suitable for less invasive treatment strategies. Taking advantage of additional cohorts, PRECISION identified gene expression patterns that could help to discriminate between low- and high-risk forms of DCIS. By employing an AI-based approach to analyse mammography data, the team also uncovered subtle differences in the shape and organisation of DCIS growths that could help to discriminate between harmless and hazardous lesions. The team are now working to validate the most promising potential biomarkers identified and are exploring their translation into the clinic.
Crucially, PRECISION has made significant advances in understanding the biological mechanisms of DCIS evolution and progression. Through genomic analysis of DCIS recurrence after surgery, the team made the surprising discovery that around 20% of subsequent invasive breast cancers were entirely unrelated to the initial DCIS. This suggests that DCIS is not only a precursor to invasive breast cancer, but is also a risk factor for developing new primary breast cancers. This breakthrough has resulted in significant progress in our understanding of DCIS and may have future implications for breast cancer screening and follow-up.
As part of the LORD clinical trial (run by the NKI in parallel to PRECISION’s work), the team reported that when women with perceived low-risk DCIS were given a choice between active surveillance versus conventional treatment, a striking 76% opted for active surveillance. This illustrates the shift in perception around DCIS as a precursor to invasive breast cancer and demonstrates the real-world impact of the team’s work.
Furthermore, team PRECISION has pursued an ambitious long-term strategy to address research gaps hindering progress in the field of DCIS. To this end, the team have created innovative patient-derived DCIS intraductal mouse models and single-cell sequencing technologies to analyse historically collected tissues, previously thought to be unusable for this kind of analysis. These resources, which are now available to the scientific community, will pave the way for further advancements in the DCIS field and beyond.
Looking ahead
Team PRECISION has made impressive and surprising discoveries that have fundamentally transformed the way the field thinks about DCIS. The resources generated, along with the biological insights and putative biomarkers identified, hold promise for the development of novel strategies to prevent the overtreatment of DCIS in the future. These advancements have the potential to improve the lives of thousands of women diagnosed with the condition each year worldwide – sparing many from undergoing the stress and anxiety of unnecessary treatment.
