Posted December 22, 2021

Christopher Li, M.D., Ph.D., Fred Hutchinson Cancer Research Center
Arul Chinnaiyan, M.D., Ph.D., University of Michigan

Basal-like breast cancer (BLBC) accounts for up to 70% of triple-negative breast cancer (TNBC), and is more common among younger, African-American, and Hispanic women. Because BLBC is particularly aggressive and lacks targeted therapies, this leads to a poorer prognosis (compared to other forms of breast cancer) and recurrences tend to occur within the first 5 years. A test to predict a patient's risk of BLBC recurrence does not exist in the clinical setting, and given the poor prognosis, there is an urgent need for such a test. With a Fiscal Year 2011 Breast Cancer Research Program Collaborative Innovators Award, Dr. Li and Dr. Chinnaiyan aimed to identify tumor characteristics that are associated with BLBC recurrence and therefore may be useful for distinguishing patients with BLBC who will develop a recurrence from those who will not. This additional knowledge may ultimately inform targeted therapies as well as follow-up care for patients with BLBC.

In a recent publication in Clinical Cancer Research, Dr. Li, Dr. Chinnaiyan and their research teams studied BLBC tumors to discover and validate cellular characteristics that are predictive of cancer recurrence. For this research, the team matched recurrent and non-recurrent BLBC tumors (n=67 per group) from a cohort of patients in Washington state based on age, diagnosis year, stage, and treatment. Analysis of the tumor samples from each group using RNA sequencing revealed key differences between patients with BLBC who had recurrence and those who had not. The team found that tumors from patients who had developed a recurrence had increased growth factor signaling and stem cell-like features (cancer cell intrinsic factors), while tumors from recurrence-free patients showed high immune cell infiltration and movement of macrophages (tumor microenvironment factors). Importantly, these results agree with recent findings indicating that robust tumor-immune cell infiltration and higher expression of immune-related genes is associated with better clinical outcomes for patients with TNBC and BLBC. These differences are key for the identification of prognostic biomarkers and development of a prognostic gene panel.

The team set out to develop a set of genes associated with prognosis through a multi-step procedure focused on gene expression levels and association with recurrence. The 21 top-ranked genes were selected for their panel (referred to as BRAVO-DX), and the panel was then validated in five independent cohorts of patients with breast cancer including large cohorts such as The Cancer Genome Atlas. The team demonstrated that the panel outperformed existing prognostic markers and was strongly predictive of recurrence-free survival in patients with BLBC. The researchers also developed a smaller 12-gene set (referred to as BRAVO-IMMUNE) comprised of a subset of the BRAVO-DX panel focused on tumor-immune characteristics, which was highly prognostic for overall survival as well. This panel could further stratify patients with BLBC and highlight those who would benefit from immunological therapeutic strategies.

Dr. Li and Dr. Chinnaiyan's work presents a breakthrough in the identification of cancer cell characteristics that are predictive of clinical outcomes in BLBC, a particularly aggressive breast cancer subtype. While these findings require further validation, they indicate that the BRAVO-DX gene signature is a strong predictor of recurrence-free survival in patients with BLBC. In addition to predicting recurrence, the cells� intrinsic and immune characteristics identified in this study may serve as biomarkers for identifying specific mechanisms to target during BLBC treatment. Given the poor prognosis for patients with BLBC, there is a critical need to identify those who will respond to standard chemotherapy from those who may require alternate forms of therapy due to the likelihood of recurrence. The identification of prognostic biomarkers and the BRAVO-DX panel provide potential for earlier identification of beneficial treatments, which could drastically improve breast cancer patient survival.

Publication:

Li CI, Zhang Y, Cieslik M, Wu Y-M, Xiao L, Cobain E, Tang M-TC, Cao X, Porter P, Guenthoer J, Robinson DR, and Chinnaiyan AM. 2021. Cancer cell intrinsic and immunologic phenotypes determine clinical outcomes in basal-like breast cancer. Clinical Cancer Research. 27(11):3079-3093. doi: 10.1158/1078-0432.CCR-20-3890.

Link:

Public and Technical Abstracts:  Advancing Our Understanding of the Etiologies and Mutational Landscapes of Basal-Like, Luminal A, and Luminal B Breast Cancers

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