PRECISION

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.

To enable the establishment of this ambitious, international team, Cancer Research UK partnered with the Dutch Cancer Society to fund PRECISION through Cancer Grand Challenges.

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:

1. To understand what drives or prevents the progression of DCIS to invasive breast cancer 2. To understand how we can distinguish harmless from hazardous DCIS
2. To understand when active surveillance (a watch and wait approach) for low-risk DCIS is safe.

PRECISION pursued an ambitious long-term strategy to address research gaps hindering progress in the field of DCIS. To this end, the team created innovative patient-derived DCIS intraductal mouse models and single-cell sequencing technologies to analyse historically collected tissues, previously thought to be unusuable 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.

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.   

PRECISION uncovered biological and clinical clues as to what may make DCIS progress. The team identified that DCIS size, growth patterns and HER2 status, as well as a combination of COX-2 levels and adipocyte size in the microenvironment, could potentially be used to discriminate between harmless and hazardous lesions.

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 understanding of DCIS and may have future implications for breast cancer screening and follow-up.

PRECISION also identified the molecular mechanisms behind the phenomena that having fewer menstrual cycles is associated with decreased breast cancer risk. The same mechanisms that clear mutated cells also drive expansion of any surviving mutant cells. Uncovering this double-edged sword allows a better understanding of cancer risk.

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.

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.

PRECISION has developed multiple risk stratification tools, which hold promise for future strategies to prevent the overtreatment of DCIS, with the potential to spare many thousands of women worldwide from undergoing unnecessary and invasive treatment.