Stuart J. Schnitt, MD

Understanding the molecular nature of treatment response and resistance in breast cancer.

Impact

The BRCA1 and BRCA2 genes are the most affected genes in hereditary breast and ovarian cancers. Normally, BRCA1 and BRCA2 function to ensure the proper repair of DNA damage, but mutations in these genes lead to rapid accumulation of DNA errors, which leads to cancer. However, this defect also makes BRCA-mutated cells vulnerable to treatments that cause DNA damage. Cisplatin, a platinum-containing chemotherapy agent not typically used to treat breast cancer, has demonstrated good activity in BRCA mutation carriers with breast cancer and in some women with triple-negative breast cancer (TNBC). Recently, Drs. Tung and Schnitt completed the INFORM trial, which showed that while cisplatin is an active agent in BRCA mutation carriers with breast cancer, it was not more effective than the standard chemotherapy regimen. Drs. Tung and Schnitt are evaluating why some breast cancers respond to chemotherapy, including platinum chemotherapy, and other breast cancers do not.

Progress Thus Far

Drs. Schnitt and Tung are using artificial intelligence (AI) to analyze tumor tissue and blood collected as part of the INFORM trial to identify predictors of chemotherapy response. These samples represent the largest group of breast cancers from BRCA mutation carriers to undergo such an extensive molecular analysis. They have found that nearly all the breast cancers had loss of the normal copy of the relevant BRCA gene in the tumor, that they had a pattern of gene abnormalities characteristic of breast cancers that develop in BRCA mutation carriers, and that they demonstrated an inability to repair DNA damage. Additionally, they identified a subset of estrogen receptor (ER)-positive breast cancers that closely resemble TNBC molecularly. Importantly, they found that tumors more responsive to chemotherapy had more immune cells infiltrating and were significantly enriched for genes related to immune activation. Tumors that had a higher rate of proliferation and had a higher immune profile were more responsive to chemotherapy.

What’s next

In the upcoming year, Drs. Schnitt and Tung will continue with their analysis of the tumor and blood samples using AI, state-of-the-art genetic sequencing techniques, and spatial transcriptomics (a method used to assign cell types to their locations in microscopic tissue sections). They plan to refine their prediction tools by including other markers of tumor proliferation and immune activation and adding patient clinical data, such as age at diagnosis, tumor size and lymph node involvement. The markers will be validated with other clinical trial databases, such as those comparing platinum and standard chemotherapy in patients with TNBC. Although this work is being conducted in breast cancers that developed in BRCA mutation carriers, the results will also help to understand the behavior of breast cancers in women without these inherited mutations.