International study of advanced prostate cancer genome finds potential targets for drug therapy

The finding, reported by a Stand Up to Cancer-Prostate Cancer Foundation Dream Team in the May 21 edition of the journal Cell, is based on an analysis of tumor samples from 150 men with metastatic prostate cancer that no longer responded to standard hormone-blocking therapy. Eight institutions from the United States and Europe contributed tumor samples to the project.

"This study provides a strong argument that the genomics driving advanced prostate cancer is fundamentally different than primary prostate cancer, and that knowledge of these genomic differences may be immediately clinically actionable for patients with advanced disease," said Eliezer Van Allen, MD, of Dana-Farber Cancer Institute, a first author of the study.

While previous studies have surveyed the genomic characteristics of tumors confined to the prostate gland, the new study is the first to focus on metastatic hormone resistant prostate cancers, which can be difficult to treat because they often develop resistance to standard treatments.

The researchers found that nearly all the tumors had at least one genetic aberration known to drive cancers. The most common, found in nearly two-thirds of the samples, were abnormalities in genes responsible for the androgen receptor -- a cell structure that sends growth signals in response to the male hormone androgen. This wasn't a surprise since the hallmark of castration-resistant disease is that it no longer responds to conventional androgen-blocking therapies. But many other aberrations were found as well.

About a quarter of patients had mutations in the DNA repair genes including BRCA1 or BRCA2 genes, which are known to increase the risk of breast and ovarian cancer. Drugs known as PARP inhibitors have already been approved for BRCA-positive ovarian cancer, suggesting that PARP inhibitors may prove effective in prostate cancers with this type of aberration.

In addition, the researchers found that 8 percent of patients had an inherited genetic alteration. This suggests that genetic counseling may be appropriate for patients with prostate cancer.

"This is a landmark paper in several respects," said Philip Kantoff, MD, leader of the Lank Center for Genitourinary Oncology and chief of Solid Tumor Oncology at Dana-Farber, a senior author of the study. "It represents a model of collaboration between cancer centers, represents a monumental operational, technical and computational achievement and finally represents the value of precision medicine in finding actionable mutations."

Other Dana-Farber contributors to the study include Levi Garraway, MD, PhD, a co-senior author, Mary-Ellen Taplin, MD, Mark Pomerantz, MD, and Massimo Loda, MD, director of Dana-Farber's Center for Molecular Oncologic Pathology.

In the next phase of the study, researchers will genetically sequence tumor cells from at least 500 patients and follow the course of their disease. With this data in hand, researchers will track how patients with specific genetic abnormalities respond to certain treatments, improving doctors' ability to treat the disease.