Study Suggests Limited Intraindividual Genomic Diversity in Metastatic Prostate Cancer

Investigators at the University of Washington and the Fred Hutchinson Cancer Research Center are now reporting that a single biopsy may provide enough information to oncologists to guide precision therapy in men with metastatic prostate cancer. 

In a study published in the journal Nature Medicine, researchers showed that a single metastatic lesion provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and subsequently may be useful for selecting treatments based on predicted molecular vulnerabilities.  

“We can feel generally confident, at least with prostate cancer, that if you did sample a single tumor, you could make clinical decisions based on what you find.,” said study lead author Pete Nelson, MD, oncologist with the Seattle Cancer Care Alliance and cancer researcher at Fred Hutchinson, in a news release.  

To compare the molecular characteristics of different tumors, the researchers studied metastatic tumors from 176 men who had died of prostate cancer and previously agreed to donate their tumors posthumously to research. The team examined various types of mutations and alterations in how strongly particular genes were dialed up or down. They found tremendous variation across patients; however, tumors within individuals were quite similar.

Dr. Nelson’s team identified a few potential leads for specific drug regimens. Cells respond to testosterone via the androgen receptor (AR), which turns on an array of genes known as the AR signature. Though all the men in the study had undergone androgen deprivation therapy (ADT), more than two-thirds of the men had tumors with a high AR signature. Interestingly, tumor cells with this AR signature appeared to grow more slowly compared to tumor cells from other men in which these same genes were active at lower levels. This suggests that men whose metastases exhibit a very high AR signature could be candidates for a new strategy currently being tested in a phase II clinical trial at Seattle Cancer Care Alliance. The strategy involves alternating high doses of testosterone with suppressive therapy.

The team also found that men with somatic aberrations in Fanconi anemia (FA)-complex genes or in ataxiatelangiectasia mutated (ATM) serine/threonine kinase, exhibited significantly longer treatment-response durations to carboplatin compared to men without defects in genes encoding DNA repair proteins.

Dr. Nelson previously collaborated on a study showing that almost 25% of men with metastatic prostate cancer had tumors with mutations in DNA-repair genes. Drugs aimed at treating other types of tumors that lack the ability to repair DNA, such as the poly (ADP-ribose) polymerase (PARP) inhibitor drug olaparib (Lynparza), are already available for use. PARPs are enzymes involved in DNA damage repair. Inhibition of PARPs is a promising strategy for targeting cancers with defective DNA damage repair. A recent clinical trial with olaparib showed dramatic responses in men whose prostate tumors had DNA-repair defects.

While assessment of a single metastatic lesion can provide enough information in selecting various treatment options, it’s not always easy to obtain biopsy samples due to frequent bone metastases, etc. Tumors often shed cells and snippets of DNA into the bloodstream. Nelson and his colleagues are working to develop a much less invasive, blood-based test to detect those free-floating cells or molecules in order to one day replace biopsies of metastases.