Priscilla Brastianos, MD

2012-2013 BCRF Project:
(made possible by generous support from Wilson Sporting Goods)
Conquer Cancer Foundation/ASCO 2012 Young Investigator Award

Brain metastasis is a common complication in breast cancer and reportedly occurs in up to 30% of patients with metastatic breast cancer. Of patients with clinically significant brain metastases, the majority dies because of the progression of their brain metastases. Most clinical trials in the US exclude patients with brain metastases. An understanding of the molecular mechanisms of brain metastasis and better treatment approaches are urgently needed.

Cancer arises primarily from the acquisition of alterations in the DNA of cells. Knowledge of these genetic alterations has led to groundbreaking discoveries in targeted therapies for cancer. Among these are trastuzumab (Herceptin®), which targets Her2/neu in HER2+ breast cancer, and PLX4032, which targets BRAF in melanoma (a form of skin cancer). The recognition in the efficacy of targeted therapies, along with the dramatic decrease in sequencing costs, has led to a surge in studies to understand the genetic changes of cancer. Most of these efforts do not include metastatic disease despite the devastating clinical sequelae of this disease. Dr. Brastianos's hypothesis is that tumors undergo multiple genetic alterations that drive a primary tumor to metastasize to the brain.

The purpose of Dr. Brastianos's study is to detect the changes in the DNA of metastatic brain tumors. To achieve these goals, she has established prospective tumor collections at several institutions in the US and internationally. Using the most powerful state-of-the art sequencing technologies at the Broad Institute, a joint genomics institute of Harvard University and Massachusetts Institute of Technology, Dr. Brastianos intends to sequence at least 120 brain metastases from breast cancer and match them whenever possible with their primary tumors. She anticipates that through comprehensively characterizing the genomics of brain metastases, her team will determine the critical genes that mediate metastasis in breast cancer. They hope that an understanding of the molecular pathways that drive brain metastasis will enable the development of rational therapeutics for this disease that continues to have a dismal prognosis.

Mid-year Progress: Dr. Brastianos has already acquired and extracted DNA from 425 consented brain metastases through collaborations with researchers at Massachusetts General Hospital, University of California in San Francisco, Vall d'Hebron University in Spain, and Seoul National University College of Medicine in Korea. Of these samples, 180 have matched primary and normal tissue, and 90 of these are breast cancers. This effort may be the largest collection of brain metastases to date. Dr. Brastianos and colleagues are in the process of identifying more available consented tumors and they have initiated prospective collections at each of these institutions. The neurosurgical colleagues within their own institutions are collecting three to five brain metastases prospectively per week. Dr. Brastianos has also identified an additional 550 paraffin-embedded brain metastases to be utilized for their validation set for one of the aims of this research. Although the sequencing of cancer samples is now being performed at many centers, this represents a unique collection of matched samples that will permit a statistically rigorous interrogation of brain metastases for the first time. Dr. Brastianos is also using the same genomic pipelines to determine both mutations and copy-number changes that she recently used to characterize the genomics of meningiomas in which they identified recurrent oncogenic mutations in AKT1 and SMO in a subset of these tumors. This work is currently in press for the journal Nature Genetics.

In addition, Dr. Brastianos has already submitted the whole exomes of 120 brain metastases for sequencing, with sequencing now complete on 65 brain metastases matched with their primary tumors and normal DNA. She has completed the analysis of the whole exomes of 21 brain metastases, matched with their primary tumors and normal DNA. The mean target coverage across their samples (including paraffin-embedded samples) ranges between 75-120X, and over 70% of target bases are covered over 30X. Dr. Brastianos is in the process of analyzing the rest of the data. Thus far, her team has identified 11 mutations that are recurrently and significantly mutated in the brain metastases that were not present in their matched primary tumors. These are likely to include both driver and passenger events. Dr. Brastianos is in the process of completing the analysis of the rest of the sequences samples, to determine the recurrence of genetic events across a larger number of samples and are on pace forher proposed research schedule.