Prostate Cancer Consensus Panel to Script Testing Guidelines for Inherited Disease

Veda Giri, MD

Although the oncology community has made many advancements in understanding the role of germline mutations in prostate cancer, a pressing need exists for clarity in determining which genes should be included in testing panels and what steps should be taken to counsel patients at risk and their families.

Those were among the key messages that emerged from the 2019 Philadelphia Prostate Cancer Consensus Conference, where more than 100 prostate cancer experts convened with a shared goal: propose protocols for the implementation of genetic testing for inherited disease. The initiative, which the Sidney Kimmel Cancer Center at Jefferson Health in Philadelphia, Pennsylvania, hosted in October, was the follow-up to the inaugural conference in 2017 that led to the publication of a set of guidelines to aid in the management of hereditary prostate cancer.

Two years ago, the conference focused on the populations that should consider genetic counseling and genetic testing and the genes that should factor into clinical considerations. The manuscript produced as a result of the 2017 meeting, published in the Journal of Clinical Oncology, marked “the first comprehensive, multidisciplinary consensus statement to address a genetic evaluation framework for inherited [prostate cancer] in the multigene testing era,” the authors said.¹ National and international medical organizations have since embraced the guidelines.

Subsequent developments in prostate cancer provide the impetus for an update to the guidelines. “We now have not only significant expansion of multigene testing options, but also avenues of access to genetic testing, expansion of genetic testing guidelines, a greater [number] of nongenetic providers ordering tests, and rapid growth of precision medicine in clinical trials,” said Veda N. Giri, MD, director of the Jefferson Clinical Cancer Genetics Service, Men’s Genetic Risk Clinic, who cochaired the consensus meeting.

Clinicians, researchers, national organizations, thought leaders, and patient advocates congregated at the 2019 conference to trade insights on genes associated with prostate cancer risk and aggressiveness; implementation strategies for genetic testing and genetic counseling, specifically in terms of screening and risk assessment; approaches for cascade testing of family members; existing gaps in the use of genetic testing, such as in diverse populations; and methods for educating nongenetic providers about hereditary prostate cancer.

“Over the past 20 years we have seen an increase in knowledge regarding the genetic contribution to prostate cancer and in testing capabilities” Giri said. “[but] we will need to make a lot of advances in this field.”

As in 2017, the conference participants will produce a document that consolidates consensus statements from the 2019 meeting. Summaries of the presentations have been published as a supplement of The Canadian Journal of Urology International.² A final consensus manuscript will focus on the best uses of genetic tests and define subsequent resources to be developed for patients and providers.

Genetic Landscape in Prostate Cancer

Overall, germline mutations have been reported in 15% to 17% of men diagnosed with prostate cancer, including 12% of those with metastatic disease.² The ability to test for genes that might confer a heightened risk of malignancy is growing, as are the clinical implications of mutations. Patients with BRCA1/2 mutations may be candidates for treatment with PARP inhibitors, and pathogenic mutations in DNA repair mechanisms have been associated with a preferential response to platinum-containing therapies.²

“The landscape of multigene genetic testing in prostate cancer has evolved quite significantly over the past 2 years,” Saud H. Aldubayan, MB, BS, an instructor in medicine at Dana-Farber Cancer Institute in Boston, Massachusetts, said during a presentation at the conference. “In 2017, we had 3 main panels that included 12 to 14 genes. Nowadays there are at least 10 panels offered by major labs with very valuable coverage.”

In 2017, available prostate cancer multigene testing panels included genes associated with a higher risk for prostate cancer—BRCA1/2, HOXB13, and DNA mismatch repair (MMR) genes—as well as other genes suspected of conferring risk such as ATM, CHEK2, and NBN. The push to update the 2017 guidelines reflects the need for further standardized instruction in this area, particularly as more testing panels hit the market and as genetic counseling and testing practices grow more common in the prostate cancer field.

“We’re all aware that public awareness of these genetic testing issues is out there. Patients are becoming increasingly more familiar with [these tests] and they’re going to come to urologists and providers to ask them for advice on whether or not to [pursue] these things,” said presenter Michael S. Cookson, MD. “We need to know whether they’re appropriate, how to obtain these [resources], and what the results might mean.”

Like multigene testing panels in prostate cancer, guidelines for genetically conscious care in this disease setting are fairly new, particularly to urologists, said Cookson, professor and chairman of the Department of Urology and the Donald D. Albers Endowed Chair in Urology at the University of Oklahoma Health Sciences Center in Oklahoma City. He also is president-elect of the Society of Urologic Oncology.

“The first appearance of some of the advising guidance for testing men for mutations like BRCA1/2 was in the National Comprehensive Cancer Network’s [NCCN] guidelines for breast and ovarian cancer syndrome, which urologists never really went through,” Cookson said. “That was obscure, and it was curious that it would show up there before it would show up for urologists or for medical oncologists caring for men with prostate cancer.”

The NCCN did not mention BRCA1/2 in its guidelines for prostate cancer until 2017, he added.

Identifying Genes of Interest

Presenters at the consensus meeting broadly supported testing for the established prostate cancer susceptibility genes of BRCA1/2 and HOXB13 and MMR genes in panels specific for the disease. MMR genes, which are associated with Lynch syndrome (LS), include MLH1, MSH2, MSH6, PMS2, and EPCAM.² Additionally, testing should be considered for gene mutations with evidence that suggests higher risk for disease (ATM, BLM) and for DNA repair genes with “predictive/ therapeutic” utility, such as CHEK2, PALB2, RAD50, RAD51D, and FANCA, according to Kathleen A. Cooney, MD, chair of the Department of Medicine at Duke University School of Medicine in Durham, North Carolina.

Genetic counseling and genetic testing can be used to identify actionable mutations that confer greater risk for prostate cancer; project the aggressiveness of disease; and subsequently inform preemptive courses of care or, alternatively, treatment decisions, Cooney said.

“There are many opportunities for us to consider genetic testing, ranging from risk assessment to prevention to prognosis, active surveillance, radiation therapy, and the implications of results for family members,” Cookson said.

If a genetic variant such as a BRCA2 mutation is associated with an increased risk of advanced disease, then definitive treatment with surgery or radiation should be favored over other strategies such as active surveillance, said Brian T. Helfand, MD, PhD, a research assistant professor in the Department of Urology at the Feinberg School of Medicine at Northwestern University in Chicago, Illinois.

Although germline mutations in the BRCA1/2 genes are believed to confer higher risk for inherited prostate cancer, BRCA2 mutations are specifically linked to more aggressive disease and worse prostate cancer—specific outcomes than BRCA1 mutations. Therefore, Helfand would not recommend active surveillance in the presence of a BRCA2 mutation.

He also cautioned against the use of active surveillance for patients with ATM mutations. Mutations in BRCA1, CHEK2, and MSH2 would warrant a discussion on the risks and benefits of active surveillance, Helfand said. He does not consider HOXB13 to be an actionable mutation; consequently, active surveillance would be safe for patients with that genetic variant.

Broader adoption of genetic counseling and genetic testing is critical for those with a known family history of prostate cancer, hereditary breast and ovarian cancer (HBOC) syndrome, and LS. Family history is the strongest risk factor for hereditary prostate cancer.² The propensity for prostate cancer is greatest for men with a first-degree relative who currently has or has had the disease. Risk is augmented for those with multiple first- or second-degree family members who have received a prostate cancer diagnosis.

“A patient’s ancestry is an important predictor of the likelihood of identifying a pathogenic variant in prostate cancer— relevant genes,” Cooney said. She added, however, that multigene panel testing “increases the chances of identifying pathogenic variants with unknown clinical significance in prostate cancer.”

2017 Conclusions

At the 2017 consensus conference, 71 experts from the United States, Canada, England, and the Netherlands anonymously responded to a series of clinical questions centered on the management of prostate cancer via an electronic audience response system.¹

The majority of 2017 panelists recommended genetic counseling and testing for men with prostate cancer whose families meet the criteria for HBOC (93%), hereditary prostate cancer (HPC; 95%), and LS (88%).

Participants also felt that genetic counseling should be provided and genetic testing should be performed in men with prostate cancer who have ≥2 blood relatives on the same side of the family with a cancer in HBOC (93%), HPC (86%), or LS (86%). Many respondents (67%) said that all men with metastatic castration-resistant prostate cancer (mCRPC) should consider genetic testing.

Nearly all experts (98%) supported testing for BRCA1/2 mutations in men with prostate cancer with ≥2 close blood relatives on the same side of the family with a cancer in the HBOC spectrum. Additionally, 97% would test MMR genes in those who meet the same criteria for the LS spectrum.

Broadly, panelists advocated for shared decision making on genetic testing for prostate cancer, with 77% agreeing that patients should engage in discussions. Confirmatory germline testing for prostate cancer predisposition was deemed appropriate for men with prostate tumor sequencing that shows mutations in cancer-risk genes (BRCA1/2, 89%; MMR genes, 88%; HOXB13, 68%; ATM, 61%).

The 2017 manuscript additionally contained recommendations for interpreting test results for early-stage/localized prostate cancer, advanced/high-risk disease, and mCRPC.

Leonard G. Gomella, MD, cochair of the Philadelphia Prostate Cancer Consensus, said he is hopeful that the updated set of guidelines derived from the 2019 meeting will be published in the first half of 2020, providing insight on the optimal use of genetic counseling and genetic testing in this disease setting.

“We recognize the fact that not all patients with prostate cancer need to undergo genetic testing and have to be more specific on which patients in which settings should be considered for testing,” said Gomella, who is chair of the Department of Urology and director of the Kimmel Cancer Center Network at Jefferson Health.

References

1. Giri VN, Knudsen KE, Kelly WK, et al. Role of genetic testing for inherited prostate cancer risk: Philadelphia Prostate Cancer Consensus Conference 2017. J Clin Oncol. 2018;36(4):414-424. doi: 10.1200/JCO.2017.74.1173.
2. Gomella LG, Knudsen KE, Giri VN, eds. Can J Urol. 2019;26(suppl 2):A1-A59. canjurol.com/pdfs/supplemets/CJU_Supplement_ Cancer_Consenus_2019.pdf. Accessed November 5, 2019.