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Comprehensive Genetic Profiling Unravels Molecular Targets in Prostate Cancer

Holt, Chuck

doi: 10.1097/01.COT.0000577096.71826.2f
Opinion
Free
genomics, prostate cancer

genomics, prostate cancer

While there have been advancements in the discoveries and approvals of novel therapies targeting prostate cancer, the disease remains incurable, especially in patients with advanced and metastatic tumors. According to the American Cancer Society, patients with localized prostate cancer have a 5-year survival rate of nearly 100 percent, but only 30 percent of patients with tumors that have progressed and spread to other areas of the body will live that long.

“Although these new drugs, such as abiraterone, enzalutamide, and apalutamide, are approved for different phases of advanced prostate cancer, disease progression on these drugs is literally universal,” said Neeraj Agarwal, MD, Professor of Medicine at the University of Utah and physician-scientist at Huntsman Cancer Institute, both in Salt Lake City. “To be able to improve survival and quality of life in these patients after they are progressing on those drugs is really the biggest challenge that we have in the clinic.”

To inform targeted therapy options and also identify targets for the development of new drugs for advanced and metastatic prostate cancer, Agarwal led a team of researchers who used comprehensive genomic profiling (CGP) to analyze thousands of tissue samples looking for genomic alterations (GAs) and signatures of genomic instability, including genome-wide loss of heterozygosity (gLOH), microsatellite instability (MSI) status, and tumor mutational burden (TMB).

Working in collaboration with scientists from eight other institutions around the globe, the researchers analyzed nearly 3,500 unique tumor samples, including 1,660 primary site tumors and 1,816 metastatic site tumors from unmatched patients, and found that the majority harbored alterations in targetable genes. The results from the genomic analysis were published in the JCO Precision Oncology (2019; doi:10.1200/PO.18.00283).

“This is the largest-ever report of prostate cancer tumors tested by CGP,” Agarwal told Oncology Times. “More than half of the patients (57%) were found to have alterations in targetable genes for which we have drugs already in the clinic, either approved for other cancers or available to various clinical trials. These findings have the potential to increase the number of patients with advanced prostate cancer who may pursue these treatment options, most before clinical trial.”

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Informative Genes

National Comprehensive Cancer Network (NCCN) guidelines recommend physicians integrate genetic testing for patients with advanced prostate cancer tumors into their clinical practice. The recently updated guidelines call for germline testing for every patient with metastatic prostate cancer and high-risk, localized, non-metastatic disease (NCCN Guidelines: Prostate [Version 2.2019]).

Mismatch repair (MMR) and homologous recombination deficiency (HRD) are the most informative types of gene mutations in prostate cancer. MMR genes include MSH2, MSH6, MLH1, and PMS2. Responsible for a hereditary, non-polyposis colorectal cancer called Lynch syndrome, they are found in fewer than 5 percent of prostate tumors. HRD genes include BRCA2, BRCA1, ATM, and other genes altered in about 25 percent of advanced prostate tumors. There are no FDA-approved therapies for patients with HRD mutations, although the therapeutic efficacy of PARP inhibitors is being studied in clinical trials (Genetics of Prostate Cancer (PDQ) NCI: https://www.cancer.gov/types/prostate/hp/prostate-genetics-pdq).

In the study by Agarwal, et al, frequently identified GAs included TP53 (44%), PTEN (32%), TMPRSS2-ERG (31%), and AR (23%). GAs the team considered potentially targetable were frequently identified in DNA repair, phosphatidylinositol 3-kinase, and RAS/RAF/MEK pathways. DNA repair pathway GAs included homologous recombination repair (23%), Fanconi anemia (5%), CDK12 (6%), and mismatch repair (4%). Specific DNA damage response alterations were associated with genome-wide loss of heterozygosity, the researchers wrote, adding that correlation of DNA repair GAs with gLOH identified genes associated with homologous recombination repair deficiency.

The real-world data from the routine, prospective CGP not only allowed the researchers to evaluate GAs and genomic signatures in primary and metastatic prostate cancer, but also to identify GAs that are enriched in metastatic site tumors. BRCA1/2, ATR, and FANCA alterations were associated with high gLOH, the researchers reported, whereas CDK12-altered tumors were infrequently gLOH high. Median TMB was a low 2.6 mutations/Mb. While a subset of cases (3%) had high TMB, of which 71 percent also had high MSI.

According to the researchers, metastatic site tumors were observed to be enriched for the 11q13 amplicon (CCND1/FGF19/FGF4/FGF3) and GAs in AR, LYN, MYC, NCOR1, PIK3CB, and RB1, compared with primary tumors. The discovery of GAs enriched in metastatic site tumors, they wrote, suggests therapeutic strategies for metastatic prostate cancer can and should be developed. What's more, the genomic signatures identified in the study, including MSI, TMB, and genome-wide loss of heterozygosity, “will further refine biomarker development for poly (ADP-ribose) polymerase (PARP) inhibitors and immunotherapies,” wrote the study's authors.

“I think this is a very exciting time for clinicians and investigators pursuing drug discovery for patients with advanced prostate cancer,” Agarwal said, noting that the study was not possible to conduct prior to the recent advent of CGP. “The continuously evolving technology, which was not available until a couple of years ago, is allowing us to unravel molecular targets in prostate tumors. And I think that is going to lead to an explosion in drug development and, hopefully, FDA approval of novel drugs for our patients in the very near future.”

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Looking Ahead

It's important for physicians and patients researching treatments for advanced prostate cancer online to understand that some drugs utilized in the clinical trial are not yet approved by the FDA for patients with advanced prostate cancer and thus are not readily available, Agarwal explained. “It's not like they can go to their primary doctor or oncologist and ask for them. The key is to look for the clinical trial.”

As far as further research is concerned, the first step is to genomically profile more contemporary cancer tumor tissue or to genomically profile the circulating tumor DNA. The ctDNA technology is increasingly affordable for community-based clinics, he noted.

“And then the second area of research is to be focused on improving access because most cancer patients do not have access to clinical trials utilizing these targeted therapies against altered genes in their tumors,” he said.

Meanwhile, Agarwal and his fellow researchers are eager to see how big of an impact their landmark genomic analysis of primary and metastatic prostate cancer tumors will have in the ongoing battle against the disease.

“Based on this discovery of more than half of the patients having high rates of targetable mutations in their tumors, we can expect many of the novel molecularly targeted therapies to be getting approved in the near future, thus expanding the treatment armament manyfold,” he concluded.

Chuck Holt is a contributing writer.

Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
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