Non-invasive breast carcinomas have long been assumed to be the precursors of any invasive cancers that follow. But new findings indicate that around 1 in 5 of these subsequent cancers are unrelated to the initial lesion and instead are new primary tumours.
We met with the team behind the study to discuss the paradigm-shifting potential of these findings in the clinic.
Ductal carcinoma in situ (DCIS), the presence of abnormal but non-invasive cells in the breast milk ducts, is harmless in most people – but some people with the condition will develop invasive breast cancer (IBC). Because it’s impossible to predict whether a person will go on to develop IBC, treatment is generally recommended for all cases. As a result, thousands of people with DCIS undergo unnecessary surgery, radiation and hormone therapy each year.
To avoid this overtreatment, and the accompanying stress, adverse effects and anxiety, a deeper understanding of DCIS biology is urgently needed, and predictive markers of progression must be identified. This is the premise of our Lethal vs. Non-Lethal challenge.
Major new findings from the Cancer Grand Challenges PRECISION team take a step further in tackling this challenge. Under the current dogma, almost all cases of IBC after DCIS are believed to be related to the initial lesion and to be due to lesion progression. But the new study, published [today] in Nature Genetics, refutes this thinking. The study reveals that as many as 1 in 5 subsequent IBCs are unrelated to the initial DCIS and develop as second primary tumours.
The findings may change clinical paradigms. “Our study indicates we can no longer consider DCIS solely as a precursor but rather also a risk factor for the development of invasive breast cancer later on in life,” says Elinor Sawyer, joint senior author of the study, based at King’s College London, UK. “This important new information about DCIS biology and behaviour could change the way we manage and treat the condition in clinics in the near future.”
A tour de force in integrating diverse data
Historically, research on the progression of DCIS to IBC has been logistically challenging: the proportion of people with DCIS who later develop IBC is relatively small, and recurrent IBC often occurs long after the initial DCIS diagnosis. The Cancer Grand Challenges team has addressed this obstacle by analysing data and samples from well-annotated cohorts of people with DCIS from the UK, the US and the Netherlands, examining the largest cohort of its kind in the world.
This rich source of data has been central to the team’s paradigm-shifting insights, allowing integration of clinical, imaging, pathological and epidemiological data, in addition to multiple layers of genomic, exomic and mutational analyses down to the single-cell level. “We have such a breadth and depth of quality information backing our findings,” says team lead Jelle Wesseling, from the Netherlands Cancer Institute. “This study is the culmination of a real tour de force.”
A remaining question is why some people can develop two clonally unrelated cancers in the same breast. One possibility might be that inherited genetic changes influence whether people are more likely to develop a recurrence or a new cancer after DCIS. Alternatively, certain factors in the breast microenvironment and the surrounding tissue architecture might make some people more prone to breast tissue tumorigenesis, permitting the emergence of a second, unrelated primary tumour. Further research investigating these hypotheses is ongoing.
Avoiding the burden of unnecessary treatment
“It’s wonderful that this full team effort could have real-world implications for the way we manage DCIS in the clinic in coming years,” says Jelle.
For oncologist Elinor, the clinical goal is decreasing the use of radiotherapy, which is often administered to reduce the risk of local recurrence and progression. “If the invasive cancer is unrelated to the DCIS, radiation won’t help to prevent it, and the patient will receive no benefit,” she says.
Meanwhile, for pathologist Jelle, the goal is “understanding when it's safe to consider a watch-and-wait approach instead of conventional treatment.”
“Our findings bring us closer to understanding the risk of a particular DCIS lesion in a particular individual and knowing when it’s safe to undergo a moratorium on treatment and opt instead for active surveillance,” Jelle elaborates. “Collectively, our work could ultimately save tens of thousands of people the burden of invasive treatment with little benefit.”
The Cancer Grand Challenges PRECISION team is generously supported by Cancer Research UK and the Dutch Cancer Society.
Elinor Sawyer also receives funding from Breast Cancer Now.
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