BCRF Investigator Discovers New Subgroups of Breast Cancer

Findings show structural variations in tumor cell DNA could indicate risk of recurrence or reveal tumor vulnerabilities as targets for new treatments

Breast cancers are generally classified based on hormone receptor status (the presence of estrogen and progesterone receptors) and HER2 status (levels of the HER2 protein). This information can indicate how aggressive the cancer is and inform treatment strategies. But this classification system is relatively broad and does not paint a full picture of how normal cells are transformed and become cancerous—a process called cancer initiation.

BCRF investigator Dr. Christina Curtis has a longstanding interest in cancer initiation with her recent studies focusing on the DNA within normal cells compared to tumor cells. Her team recently identified three distinct structural variations in tumor cells’ DNA and, notably, these differences did not align with specific breast cancer subtypes. These important results, published in Nature, show that these DNA variations occur early in breast cancer development and are maintained as the tumor grows and metastasizes.

Going beyond subtype to refine tumor classification

Researchers are continually working to understand how the machinery within normal cells is altered, allowing them to grow uncontrollably, form tumors, and metastasize. Constructing a comprehensive picture of these changes could reveal cancer cell vulnerabilities—a key step to then develop personalized treatment plans for patients. Dr. Curtis has led herculean efforts to drill down on the intricacies of breast cancer tumors to more precisely classify them beyond the widely used subtype classification.

Previously, her team employed cutting-edge machine learning techniques to compare DNA from healthy cells with DNA and RNA from matched breast tumors. From this research, they identified 11 genomically distinct breast cancer subgroups:

• Eight subgroups of estrogen receptor–positive disease
• Two subgroups of triple-negative breast cancer (TNBC)
• One HER2-positive subgroup

Classifying breast cancer into 11 subgroups could enable more precise patient stratification. It could also help doctors determine which patients require aggressive treatment early on and which patients require post-treatment monitoring to prevent recurrence. For example, patients in four of the eight estrogen receptor–positive subgroups were much more likely to experience a recurrence compared to the other groups, even 10 or 20 years after diagnosis. Such information could be used to guide long-term treatment and follow-up decisions for these patients.

Because the 11 subgroups had varied prognoses, the Curtis team was keen to take a deeper dive to devise more precise ways to guide patient care.

About the new study

Dr. Curtis and her team turned their attention to the genomic architecture of breast tumor cells, specifically examining what happens to the cell DNA itself that promotes cancer formation. They examined mutations and structural variations in DNA from nearly 2,000 breast cancers in various stages of development—from stage 0 (ductal carcinoma in situ) to stage 4 (metastatic breast cancer)—and identified three distinct DNA structural changes that crossed the boundaries of the 11 subgroup classification.  

• The DNA variants for high-risk, hormone receptor–positive subgroups strongly overlapped with those for the HER2-positive subgroup. The variants were the result of complex but localized amplifications in cancer-associated genes, and genetic material could also be found as small DNA circles called extrachromosomal DNA (ecDNA) that contained a multitude of oncogenes. Interestingly, other studies have implicated ecDNAs as key drivers of cancer growth perhaps because they can ignore normal cell regulation.

• TNBC tumors, which are known to be very aggressive, were found to be genomically unstable, accumulating alterations across the genome but not limited to specific oncogenes. A subset of these also showed signs of being deficient in their ability to repair DNA damage. 

• Hormone receptor–positive, HER2-negative breast cancers with an average risk of recurrence had fairly stable genomes.

Each of the structural variations—amplification of oncogenes and ecDNA presence, unstable genomes versus stable genomes—were present in the earliest stages of the disease and were preserved as the tumors grew and spread.

What this means for patients

Understanding how breast tumors arise and how they can resist therapy and recur will ultimately lead to precise personalization of patients’ breast cancer care. For example, tumors that rely on DNA amplifications and formation of ecDNA might be vulnerable to compounds that target their respective drivers. While other approaches may be developed to directly target the processes that promote these DNA changes.  

This research provides details on breast cells’ evolution into breast tumors, including the key structural DNA variants that occur early in some breast cells and set them on a path toward becoming a tumor. These findings emphasize the importance of intervening early in the course of the disease and can potentially help to inform treatment decisions. Ongoing research is focused on finding ways to leverage these results to uncover tumor vulnerabilities that may provide opportunities for early interventions.