Findings Reveal Not All Post-DCIS Breast Cancers Grow from the Initial DCIS Lesion

A new study by the global Cancer Grand Challenges PRECISION team, including researchers from the University of Texas MD Anderson Cancer Center, changes the long-held belief that all invasive breast cancers result from ductal carcinoma on the spot (DCIS) originate from the original DCIS lesion. The results, published today in Natural geneticsdemonstrate that approximately one in five invasive cancers was not genetically linked to the original DCIS.

The results provide a deeper understanding of the biology of DCIS, serving as a foundation for future studies to better identify DCIS cases most likely to progress and to determine appropriate intervention strategies for women with DCIS.

“By analyzing the largest cohort of DCIS of its kind in the world, we found that a subset of invasive breast cancers after initial DCIS are unrelated to primary DCIS,” said co-lead author Tapsi Kumar, Ph.D., graduate student in genetics. “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.

DCIS, which indicates the presence of abnormal cells inside the 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 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 therapy, and hormone therapy that will ultimately provide little benefit.

The Cancer Grand Challenges PRECISION team was created to develop better tools to distinguish between high and low risk DCIS and thus prevent overtreatment for many women. In collaboration with Kumar, the work at MD Anderson was led by Nicholas Navin, Ph.D., professor of genetics and bioinformatics and computational biology, and Andy Futreal, Ph.D., chair of genomic medicine. Kumar is a member of both Navin Lab and Futreal Lab.

This study was designed to determine whether later invasive breast cancers are, in fact, related to the original DCIS. Because there are relatively few women with DCIS who later develop invasive cancer, obtaining samples for this study was a challenge. Through the global collaboration, the team was able to pool and analyze 95 pairs of samples from women who had DCIS, were treated, and then 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 DCIS and invasive cancer.

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

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

These results demonstrate that approximately one in five cases of invasive cancer following DCIS are not true recurrences, but rather 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 uncover risk factors in women with DCIS who may develop a recurrence or new cancer.

“Our study indicates that we can no longer view DCIS solely as a precursor, but rather as a risk factor for the development of invasive breast cancer later in life,” says lead author Elinor Sawyer, MBBS , Ph.D., of King’s College. London in the UK. “This important new information about the biology and behavior of DCIS, along with other findings, could change how we manage and treat the disease in clinics in the future.”

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