Understanding the genetic drivers of rare forms of breast cancer to improve the accuracy of diagnosis and to develop novel treatment approaches.  

Impact

The molecular make-up and clinical behavior of rare subtypes of breast cancer are often distinct from those of more common subtypes. Little is known about rare "special types" of breast cancer which account for up to 25 percent of all invasive breast cancers. Dr. Reis-Filho’s research focuses on defining  the genetic drivers that promote the growth of these rare cancers. In the current study, his team is investigating the basis for the aggressiveness and poor response to chemotherapy of a rare type of breast cancer called metaplastic breast cancer. He and his colleagues will use cutting-edge technologies to characterize the cellular composition of the immune tumor microenvironment and how it may mediate treatment response in metaplastic breast cancers. The results of his studies have the potential to identify new molecular targets to tailor the treatment for these patients. 

Progress Thus Far

Dr. Reis-Filho and his team have found that some rare forms of breast cancer differ from more common forms in their epigenetic alterations—the way genes are switched on and off. However, in metaplastic breast cancers, a rare type of triple-negative breast cancer, epigenetic alterations do not explain their resistance to treatment with chemotherapy and PARP inhibitors. His research has revealed that metaplastic breast cancers have unexpected defects in the way the cancer cells repair their DNA—this may be associated with its agressiveness and resistance to therapies. They are conducting whole-genome sequencing of 33 metaplastic breast cancers to determine if genetic alterations affecting non-coding regions of the genome could be drivers of metaplastic breast cancers.

What’s next

In the next year, his team will expand their analysis of the samples to include single cell RNA sequencing in combination with spatial assessment of the tumor immune cell microenvironment. Examination at the single cell level will help to define how metaplastic breast cancer cells originate, differentiate, become genetically unstable, and subsequently impact their microenvironment. Dr. Reis-Filho hopes these studies will reveal the basis of diversity of metaplastic breast cancers and their microenvironment and help to optimize the treatment for these patients.