Abstract
Almost 90% of patients with metastatic castration-resistant prostate cancer have a clinically actionable genetic alteration, according to a recently published study. Among these patients, researchers found that 65% had genetic changes that could be targeted by investigational or FDA-approved drugs currently used for other cancers, leading to new individualized treatment strategies.
A mainstay of metastatic prostate cancer treatment is the suppression of hormones that fuel tumor cells. However, almost all men with advanced prostate cancer develop resistance to these androgen-depleting therapies.
Recently, researchers showed that nearly 90% of patients with metastatic castration-resistant prostate cancer (mCRPC) have a genetic alteration that could be targeted by other clinical treatments. The findings suggest individualized approaches for these patients (Cell 2015;161:1215–28).
“This will have a major impact on how we move forward in [treating] this disease,” says Johann de Bono, MD, a principal investigator in the study and head of the Division of Clinical Studies at the Institute of Cancer Research in London, UK. “Ninety-nine percent of our trials involve no patient preselection. With this information, we can now subdivide these patients, as we've done with breast and lung cancers.”
In this first multicenter, international clinical trial, researchers conducted whole-exome and transcriptome sequencing of bone or soft-tissue biopsy samples from 150 patients living with mCRPC. Results showed that 62.7% of the patients who had a genetic alteration had androgen receptor mutations, a finding in line with current understanding of the disease.
More compelling, researchers found that of the nearly 90% of patients with genetic alterations, 65% had anomalies (other than androgen receptor mutations) that could be targeted by investigational or FDA-approved drugs currently used for other cancers. Among these alterations, almost 23% occurred in DNA repair pathways. For instance, some tumors had BRCA1 or BRCA2 mutations, which, in ovarian and breast cancers, have shown sensitivity to PARP inhibitors, drugs that interfere with DNA repair and prevent tumor cells from dividing.
In addition, researchers mapped more than a half dozen previously unknown genetic changes, such as mutations in the Wnt signaling pathway, which leads to regulation of cell development and migration, and a PIK3CB mutation with cancer-activating effects similar to PIK3CA. They also found that 8% of patients with mCRPC had germline mutations.
“This is a very important study on a number of fronts,” says Karen Knudsen, PhD, director of the Sidney Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, PA, who was not involved in the study. “It's the first large study looking at the incurable stage of the disease, where the unmet clinical need is. The large cohort gives us confidence and a much clearer picture of the drivers of disease, and they've uncovered new potential drivers that are targetable.”
When the study is completed, researchers will have mapped and sequenced the tumors of 500 patients with mCRPC. Amassing such data, says de Bono, will lead to more targeted—and more affordable—sequencing.
“It will be critical to follow up with clinical trials that correlate clinical outcomes with molecular alterations,” says Arul M. Chinnaiyan, MD, PhD, a senior author on the study and director of the Michigan Center for Translational Pathology at the University of Michigan in Ann Arbor. “The longer-term goal is to have this information ahead of time and be able to direct patients in a more precise way to the best therapy.”
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