Genetic Markers in Advanced Prostate Cancer Could Explain Treatment Resistance

Genetic Markers in Advanced Prostate Cancer Could Explain Treatment Resistance

Researchers at the Mayo Clinic Center for Individualized Medicine have identified genetic markers that can predict resistance to Zytiga (abiraterone acetate) and prednisone in patients with metastatic castration-resistant prostate cancer. The new findings could enable healthcare providers to identify in advance patients who will not respond to the treatment, to select a more effective approach.

The study, “A Prospective Genome-Wide Study of Prostate Cancer Metastases Reveals Association of Wnt Pathway Activation and Increased Cell Cycle Proliferation with Primary Resistance to Abiraterone Acetate-Prednisone,” appeared in the journal Annals of Oncology.

The research, conducted between 2013 and 2015, was led by Manish Kohli, MD, and Liewei Wang, MD, PhD. The results revealed genetic markers that may predict resistance to Zytiga and prednisone, which aim to stop progression of advanced, metastatic prostate cancer.

Prostate cancer currently affects approximately one in seven men in the U.S., 10-20% of whom ultimately develop castration-resistant prostate cancer, which does not respond to standard hormone treatment. These patients’ average life expectancy is less than 19 months.

The scientists conducted molecular biology experiments analyzing DNA to study all disease-causing genes and RNA to specifically analyze the levels of each individual gene. The experiments were performed on metastasized tumors of 92 patients before any treatment. The same tests were repeated after 12 weeks.

Furthermore, the researchers used samples of patients’ tissue to grow the cancer in mice. Experimental drugs were then tested.

After 12 weeks, 32 patients did not respond to the treatment and experienced disease progression. These patients had mutations or other abnormalities in a certain cell signaling pathway, called Wnt/β-catenin, more frequently than those who responded.

Additionally, patients with higher levels of cell cycle regulatory genes — genes that control cell division and proliferation — were 2.1 times more likely to have acquired resistance.

“In this groundbreaking study, we explored thousands of genetic characteristics in each tumor, and identified specific genes – for example a set of genes called cell cycle proliferation genes – that now allow us to take an individualized approach to treatment with this drug,” Kohli said in a press release. The findings support the “development of predictive biomarker-based strategies for patients with advanced castration-resistant prostate cancer.”

The results could guide healthcare providers to prescribe individualized treatments for castration-resistant prostate cancer, which is unresponsive to standard hormone therapy. Despite the availability of several therapies, these treatments lack consistency, as they affect each patient differently.

“The discovery of these genetic signals after such an elaborate and extensive evaluation of the patients’ genetic makeup has not been previously performed,” Kohli added. “Such knowledge can empower physicians to better manage patients with advanced-stage, castration-resistant prostate cancer.”

Overall, the findings represent “an additional way to customize treatment plans based on a patient’s unique genetic makeup,” Keith Stewart, MB, ChB, said. Stewart is the director of the Mayo Clinic Center for Individualized Medicine and professor of cancer research at the Division of Hematology-Oncology at Mayo Clinic.

Future studies are needed to determine which combination of drugs is most effective to overcome drug resistance in patients with these genetic markers, the scientists concluded.

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