Genomic analysis provides a deeper understanding of DCIS biology

A new study led by the global Cancer Grand Challenges PRECISION team, including researchers from the University of Texas MD Anderson Cancer Center, shifts the long-held belief that all invasive breast cancers develop after ductal carcinoma. on the spot (DCIS) arise from the original DCIS lesion. The results, published today in Natural Geneticsshow that about one in five invasive cancers was genetically unrelated to the original DCIS.

The findings provide a deeper understanding of the biology of DCIS and serve as a basis for future studies to better identify cases of DCIS that are most likely to progress and to determine appropriate intervention strategies for women with DCIS.

By analyzing the largest DCIS cohort of its kind in the world, we found that a subset of invasive breast cancers after an initial DCIS are unrelated to the primary DCIS. These data challenge our previous understanding of DCIS progression and give us a starting point to identify better predictive biomarkers to determine which DCIS lesions are most likely to progress to invasive cancer.”

Tapsi Kumar, Ph.D., co-lead author, genetics graduate student

DCIS, which indicates the presence of abnormal cells in the breast milk duct, is the most common form of pre-invasive breast cancer. The condition is harmless in most cases; less than 10% of women with DCIS will later develop an invasive cancer.

Because it is currently difficult to predict which cases of DCIS will progress, treatment is recommended in most cases to prevent the development of invasive cancer. Therefore, most patients diagnosed with DCIS are treated with a combination of surgery, radiation, and hormone therapy that will ultimately yield little benefit.

The Cancer Grand Challenges PRECISION team was created to develop better tools to differentiate high- and low-risk DCIS and thus prevent overtreatment for many women. Along with Kumar, the work at MD Anderson was led by Nicholas Navin, Ph.D., Professor of Genetics and Bioinformatics & Computational Biology, and Andy Futreal, Ph.D., Chair of Genomic Medicine. Kumar is a member of both the Navin lab and the Futreal lab.

This study aimed to determine whether subsequent invasive breast cancers are indeed related to the original DCIS. Because there are relatively few women with DCIS who later develop invasive cancer, obtaining samples for this study has been challenging. The global collaboration allowed the team to collect and analyze 95 pairs of samples from women who had DCIS, were treated and later developed invasive cancer in the same breast.

The researchers performed genomic sequencing on all samples, including single-cell DNA sequencing on a subset, to compare mutations and copy number changes between the DCIS and invasive cancer.

The combined results of these analyzes revealed that 75% of the paired samples were indeed related, meaning they shared the same genetic abnormalities and the invasive cancer that arose from the DCIS lesion.

However, the researchers also found that 18% of the paired samples were unrelated, suggesting that the invasive cancer later developed independently of the original DCIS lesion. A final 7% of the samples had ambiguous results and researchers were unable to clarify a connection.

These findings show that about one in five cases of invasive cancer after DCIS are not true recurrences, but instead represent new cancers. These results may explain why it has remained difficult for researchers to identify biomarkers that accurately predict the risk of DCIS recurrence. Future studies will build on these findings to discover risk factors for women with DCIS who are likely to develop a recurrence or a new cancer.

“Our study indicates that we can no longer view DCIS as just a precursor, but also a risk factor for developing invasive breast cancer later in life,” said senior author Elinor Sawyer, MBBS, Ph.D., of King’s College. London in the United Kingdom. “This important new information about the biology and behavior of DCIS, along with other findings, could in the future change the way we manage and treat the condition in clinics.”