Changing the narrative around ductal carcinoma in situ and breast cancer risk

In 2015, Cancer Grand Challenges set the Lethal versus Non-lethal Cancers challenge with the aim of finding ways to distinguish between lethal cancers that need treating and non-lethal cancers that don’t. Since 2017, the PRECISION team, led by Professor Jelle Wesseling of The Netherlands Cancer Institute (NKI), has been addressing this challenge in ductal carcinoma in situ (DCIS).

DCIS is the presence of abnormal cells within the breast milk ducts. By definition, these abnormal cells are non-invasive, but in a small number of cases they can develop into ipsilateral (same breast) invasive breast cancer. 

Despite the chances of progression to breast cancer being low, DCIS is often referred to as early breast cancer and therefore treated as such. Part of PRECISION’s efforts has been to refine this narrative. 

In a new multinational study of over 47,000 women with DCIS from the Netherlands, UK and US who had received the standard of care in their respective countries, the team reported that the 10-year cumulative incidence of ipsilateral invasive breast cancer after DCIS was 3.2%. The findings were published in the British Medical Journal. 

“I think our most important finding is that invasive ipsilateral cancer after DCIS is really a rare event and so it's even more important that we find out who are the women that are at risk. DCIS itself is not life threatening, and we don't want to treat all women intensively, unnecessarily.”

Professor Marjanka Schmidt of the NKI, co-investigator in PRECISION and lead author of the paper.

The finding was part of a study that set out to determine the association of DCIS size and margin status with the risk of developing ipsilateral invasive breast cancer. These two clinical factors are often used in the clinic to stratify the risk of DCIS lesions and determine the course of treatment. 

Currently, treatment is generally recommended for all women with DCIS and may include surgery, radiation and hormone therapy. Doctors may use the grade of DCIS to help decide on the best treatment approach. 

But in most cases, women will have undergone treatment for DCIS that would have not progressed to cancer. To reduce the burden of overtreatment, there is an urgent need to find ways to distinguish the cases of DCIS that are at high risk of developing into invasive breast cancer from those that are at low risk. 

The team combined data from four patient cohorts – one from the Netherlands, one from the UK and two from the US – comprising 47,695 women diagnosed with DCIS between 1999 and 2017 who had received either breast conserving surgery or mastectomy, often followed by radiotherapy or hormone treatment, or both.

They found only a weak association between DCIS size and margin status and the risk of subsequent invasive breast cancer in the same breast, concluding that clinical features such as these were limited in discriminating between low- and high-risk DCIS.

“We concluded that these associations are not large enough to, in clinical practice, drive the decisions around who we should treat and who we should not treat." 

Marjanka

The study is the largest of its kind to date to explore the value of prognostic risk factors after DCIS, made possible by the international collaborations established between the research groups in PRECISION and the large-scale funding of the Cancer Grand Challenges initiative. 

“By combining and comparing the multiple patient cohorts, we saw that the risk of subsequent invasive breast cancer in the same breast is very similar for the UK, US and the Netherlands, and other clinical variables are actually very comparable too. Although the cohorts have been collected in a different way and the treatments are somewhat different between countries, the actual risks amongst women are very similar,” adds Dr Esther Lips of the NKI, PRECISION co-investigator and senior author on the paper.

The vision for the Lethal versus Non-lethal Cancers challenge was to be able to identify changes that distinguish a non-lethal from a potentially lethal tumour and then determining how these changes can be detected accurately. 

This work from the PRECISION team really emphasises the need of solving this challenge in DCIS, and raises important considerations for the clinical management of DCIS.

“Everything we knew about DCIS in daily practice prior to PRECISION was largely based on relatively small, often biased series that could not yield the impact to inform guidelines in the clinic,” says Jelle.

“While we want to preserve the excellent treatment outcomes for women with high-risk DCIS, we need to know exactly which women are at high risk. And I think this paper shows that some key clinically used factors, such as size and margin status, are in fact not really indicative of the risk. Even though it makes a slight difference, it doesn't have clinical utility.”

Professor Jelle Wesseling, team lead of PRECISION

Alongside the team’s research, the collaborative work of the PRECISION team has sparked important conversations across national borders amongst researchers, patient advocates and clinicians around defining DCIS and raising awareness about breast cancer risk. 

Understanding the risk is particularly important for women with DCIS who face the decision of whether or not to pursue treatment.

“Women need much more information about their individual future risks before they make treatment decisions, but the dilemma is that clinicians and scientists still can’t safely distinguish which DCIS will progress and which will not.” 

Hilary Stobart, a patient advocate on PRECISION

“The international PRECISION team is working hard to resolve this dilemma by working together to find a combination of biomarkers which will safely distinguish those women who have DCIS which needs treating and those who do not. This large ‘real-world’ international study is an important step towards that goal, so that women and their clinicians will be able to make informed treatment decisions and potentially avoid overtreatment. It has been a great privilege to be a patient advocate working with the PRECISION team.”

The findings underline the need for new prognostic markers, and PRECISION has been exploring several avenues with the aim of finding biological markers that can be used as tools to assess breast cancer risk following a DCIS diagnosis.

The PRECISION team is funded by Cancer Research UK and the KWF Dutch Cancer Society. 

“In a multidisciplinary team, PRECISION tries to identify risk factors to predict whether a woman with DCIS needs treatment or not. Being able to tailor treatments to an individual’s risk, with the aim to prevent overtreatment, fits very well with KWF’s main goals to stimulate better treatment for every type of cancer and to aim for a better quality of life for patients.” 

Carla van Gils, director of the KWF Dutch Cancer Society.

Read the full paper in the British Medical Journal.

Article written by Bethan Warman, with thanks to Esther Lips, Marjanka Schmidt, Jelle Wesseling and Hilary Stobart for their input.