Nadine M. Tung, 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

Using tumor samples from the INFORM trial, the research team applied artificial intelligence to analyze tumor characteristics before treatment. They have found that among tumors with low levels of immune cell activity, those with more uniform immune cells responded significantly better to chemotherapy. In fact, these tumors responded as well as those with high levels of immune activity, offering a new way to identify patients who may benefit from treatment even when traditional indicators suggest otherwise. In parallel, the team analyzed genetic material from the tumors and blood samples. Tumors that had acquired more mutations were found to be more resistant to chemotherapy, while two blood-based markers were associated with improved response to the chemotherapy drug cisplatin.

What’s next

In the upcoming year, Drs. Tung and Schnitt will further compare tumor tissue before and after chemotherapy to identify changes that allow some cancer cells to survive. This is especially important for women with inherited BRCA1 or BRCA2 mutations, since these mutations usually make tumors more sensitive to chemotherapy. However, sometimes the tumor can acquire additional genetic changes that restore the function of the BRCA gene, essentially masking the inherited mutation in the cancer cells. This makes it more challenging to treat, since it may become resistant to PARP inhibitors, a type of drug often used in patients with BRCA mutations. Learning how tumors develop this type of resistance could guide better treatment decisions in the future.