For certain types of cancer, the use of drugs that target specific mutations in individual tumors — a treatment strategy known as precision medicine — is increasingly becoming part of the standard of care. People with tumors of the lung, breast, and colon, for example, now routinely have their tumor DNA analyzed to help determine the best course of treatment.
But for other types of cancer, much less is known about the genetic alterations that enable individual people’s tumors to grow and spread. One of these diseases is prostate cancer, which is routinely treated with surgery or radiation rather than drugs when it’s caught at an early stage.
Investigators are studying the gene changes that drive advanced prostate cancer.
Until now, very little has been known about the gene changes that drive the more advanced form of the disease, known as metastatic castration-resistant prostate cancer (MCRPC), and few targeted drugs are available.
In a study reported last week in the journal Cell, a multicenter team of investigators — including eight from Memorial Sloan Kettering — performed genetic analysis of 150 tumor samples taken from sites of metastases (tumor spread) in the lymph nodes, liver, and bones of patients with MCRPC to look for mutations that drive the disease. This analysis provided useful information about which targeted drugs may be effective for many of these cancers.
Focusing on Advanced Cancers
“One unique aspect of this study is that we used image-guided biopsies to obtain tumor samples from sites where the cancer had spread around the body,” says physician-scientist Charles Sawyers, Chair of MSK’s Human Oncology and Pathogenesis Program and one of the senior authors of the study. Previous studies had looked at the genetic alterations in early-stage prostate cancer, but no useful findings emerged from that research.
Surprisingly, however, in the current study the investigators found that about 90 percent of men with MCRPC have tumors with genetic mutations that, once detected, could help guide treatment with targeted therapies. The US Food and Drug Administration has already approved some of these drugs for other types of cancer, while other treatments are showing promise in late-stage clinical trials.
The study found that about 90 percent of MCRPC tumors had mutations that could be targeted with drugs.
The most common genetic alterations, found in nearly two-thirds of the men, were mutations in the androgen receptor (AR) gene. The gene produces a protein that enables cells to respond to testosterone and other male hormones, and was already an important target for advanced prostate cancer (the drugs abiraterone and enzalutamide work by blocking its action).
“Patients whose tumors carry AR mutations may be good candidates for these drugs, or may want to consider going into clinical trials that test them in combination with other, experimental drugs,” Dr. Sawyers says.Back to top
Hereditary Genes Play a Role in Some Cancers
Nearly 20 percent of men in the study had mutations in genes involved in DNA repair, such as BRCA1 and BRCA2. Mutations in these genes are associated with inherited breast and ovarian cancer and have also been linked to an increase in prostate cancer. “Women with ovarian cancer who have these mutations now routinely receive a new type of drug called a PARP inhibitor. They also respond well to cisplatinum chemotherapy,” Dr. Sawyers explains. “Those drugs are not part of the usual thinking in taking care of men with metastatic prostate cancer, but now we think they should be, for this subset of men.”
Like many breast and ovarian cancers, some prostate cancers have mutations in DNA repair genes.
He points out another interesting component of the finding: “We know that BRCA mutations run in families, but only about half of the men whose tumors had this mutation had the inherited form of the gene,” he says. “It’s not entirely clear what that means yet, and it’s something we’ll continue to look at.”
In addition to the BRCA2 and AR mutations, the investigators also found other, more rare mutations in smaller percentages of men in the study. These mutations also may also respond to treatment with targeted drugs.Back to top
A Collaborative Effort
“This study suggests that clinical genomic sequencing could impact treatment decisions in a significant number of patients with [MCRPC],” says the University of Michigan’s Arul Chinnaiyan, who was co-senior author and principal investigator of the study and is a past recipient of the Paul Marks Prize from MSK.
Dr. Sawyers and Dr. Chinnaiyan are co-leaders of the Stand Up To Cancer—Prostate Cancer Foundation Dream Team, which partially funded the study.
Dr. Sawyers explains that some hurdles remain before genomic testing of metastatic prostate tumors becomes part of the routine standard of care. “There’s a bit of a learning curve in being able to obtain biopsies from some of these sites in the body,” he says. “We benefited greatly from the expertise of the interventional radiologists at all the centers that participated in this research. But we’re committed to getting the message out about this research and helping other hospitals learn how to do this.”
“It’s also possible that we may be able to get this genetic information from looking at circulating plasma DNA in the blood, rather than tissue removed from a solid tumor. This ‘liquid biopsy’ is very promising technology that we will continue to explore,” he adds.
Learn more about the study in this article from the Wall Street Journal.Back to top