Derailed offspring or malignant newcomers?

09-06-2022

Non-invasive 'breast cancer' has long been assumed to be a precursor of invasive breast cancer that follows. But new findings indicate that around 1 in 5 of these subsequent cancers are unrelated to the initial lesion and are instead new primary tumors. These findings are highly relevant for understanding precursor biology and developing the right treatment strategies.

New research could change the way ductal carcinoma in situ (DCIS) is treated in the clinic.

DCIS, a non-invasive breast lesion, has long been assumed to be the precursor of any invasive breast cancer that follows. But new research from the Cancer Grand Challenges PRECISION team shows that 1 in 5 of these subsequent cancers are unrelated to the initial lesion - and instead are new primary tumors.

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. Because it’s still impossible to predict whether a person will go on to develop invasive breast cancer, treatment is generally recommended for all cases, meaning thousands of people with harmless DCIS worldwide undergo unnecessary surgery, radiation, and hormone therapy each year.

Dogma refuted
New findings from the international Cancer Grand Challenges PRECISION consortium, led by Jelle Wesseling from the Netherlands Cancer Institute, take us a step further in tackling this challenge. The study, published today in Nature Genetics, refutes the current dogma in which almost all cases of breast cancer after DCIS are believed to be related to the initial lesion and develop due to the progression of this initial lesion. Instead, as many as one in five subsequent breast cancers are unrelated to the initial DCIS and develop as second primary tumors.

Related and unrelated breast cancer after ductal carcinoma in situ (DCIS)

In the top row, the DCIS and the following invasive breast cancer are related: the tumor cells have the same color. The graph on the right shows that there are many genetic changes (indicated by the different colors), which are shared between the DCIS and breast cancer. In the bottom row, the DCIS and breast cancer are unrelated, indicated by purple cells in the DCIS and orange cells in the breast cancer. The graph on the right shows that the genetic changes of the DCIS (gray, black) are different from the genetic changes of the breast cancer (green, pink).

Unrelated breast cancer
“Our results indicate that not every breast cancer originates in the primary DCIS”, says co-author Esther Lips from the Netherlands Cancer Institute. “The true recurrence risk in DCIS might be overestimated, as 20 percent of the assumed recurrences are in fact new primaries. This is highly relevant for our search for biomarkers that predict which DCIS will develop into invasive breast cancer.”

“We also compared our findings with risk estimates based on the Netherlands Cancer Registry data”, says Lips. “Based on this, we estimate that women with DCIS develop a new, unrelated breast cancer twice as often compared to the general female population. Our work confirms that DCIS should not only be considered as a precursor lesion but also as a risk factor for developing an unrelated breast cancer.”

Obstacle overcome
“This important new information about DCIS biology and behavior could change the way we manage and treat the condition in the future,” says pathologist and lead investigator Jelle Wesseling from the Netherlands Cancer Institute. For example: radiotherapy to treat DCIS will not prevent an unrelated breast cancer later on in life. “Our findings bring us closer to understanding the risk of a particular DCIS lesion in a particular individual.”

Investigating the progression of DCIS to breast cancer is a methodologically challenging effort. The proportion of people with DCIS who later develop breast cancer is relatively small, and the disease occurs up to 20 years after the initial DCIS diagnosis. In the current study, the Cancer Grand Challenges team has overcome this obstacle by analyzing data and samples from well-annotated cohorts of people with DCIS from the Netherlands, the UK, and the US – which is the largest of its kind in the world.

Genetic variants
The team integrated clinical, pathological, and epidemiological data from 95 women who developed breast cancer long after their DCIS, in addition to multiple layers of genomic, exomic, and mutational analyses up to the single-cell level. “This study is the culmination of a real tour de force,” says Jelle Wesseling.

A remaining question is why some people develop two clonally unrelated cancers in the same breast. One possibility might be that inherited genetic variants influence whether people are more likely to develop a recurrence or a new cancer after DCIS. Alternatively, certain factors in the breast microenvironment and surrounding tissue architecture might make some people more prone to breast tissue tumorigenesis, permitting the emergence of a second, unrelated primary tumor. Further research is ongoing to investigate these hypotheses.

Learn more about this and other Cancer Grand Challenges in the 2022 CGC annual progress magazine Discover, featuring NKI researchers Jelle Wesseling, Esther Lips, Jacco van Rheenen and Jos Jonkers.

The Cancer Grand Challenges PRECISION team is generously supported by Cancer Research UK and the Dutch Cancer Society.

Derailed offspring or malignant newcomers?

Figure 1 DCIS Jelle Wesseling (1)

Figure 2 DCIS Jelle Wesseling Square

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