Precision Medicine Takes Hold of Prostate Cancer Management

Since the first mention of screening for inherited risk of prostate cancer was published in the National Comprehensive Cancer Network guidelines in 2016, the applications for germline and somatic genetic testing have skyrocketed, carving out an important role in screening, diagnosis, and treatment, explained Leonard G. Gomella, MD, FACS.

“Precision medicine is here for prostate cancer. It’s not a fantasy anymore. We’re using it every day more and more,” Gomella, The Bernard W. Godwin Professor of Prostate Cancer, chairman, Department of Urology, and senior director for Clinical Affairs Director, Jefferson Kimmel Cancer Center, Thomas Jefferson University, said in a presentation at the 15th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies.¹

Genomic or genetic germline testing is done to inform treatment decisions and screening in an individual and their family members for other at-risk cancers, Gomella said. Almost all the genes that are associated with inherited prostate cancer are found in the DNA damage response and repair pathway and include ATM, CHEK2, MLH1, MSH2, MSH6, NBN, RAD51D, and BRCA1/2, the latter of which increases individual and familial risk for other hereditary cancers, including breast, ovarian, pancreatic, colon, gastric, and Lynch syndrome.

“The DNA damage response genes increase the risk of developing prostate cancer and, more importantly, aggressive, life-threatening, metastatic prostate cancer,” Gomella said, adding the disease is typically defined by a Gleason score of 8 or higher, positive nodes, metastases, and poor survival.

Notably, men with an inherited BRCA2 gene mutation have a 2.6-fold increased risk of developing aggressive prostate cancer during their lifetime, and that risk is increased 8.6-fold by the age of 65 years.

“If you identify someone who has an inherited germline mutation, you really need to pay attention to that patient,” Gomella said, adding that germline mutations are found in more than 11% of prostate cancer cases and up to 25% of metastatic castration-resistant cancers.

Additionally, HOXB13, although uncommon, is an androgen receptor gene mutation that is the most significant inherited gene for prostate cancer and one that is almost always found in aggressive cancers in family members diagnosed before the age of 55 years.

Prostate cancer–specific genetic testing panels on the market include ProstateNext by Ambry Genetics, the Prostate Cancer Panel by GeneDx and Invitae, and the Hereditary DNA Repair Panel for Prostate Cancer by NeoGenomics. General cancer panels that also screen for relevant gene mutations include Myriad’s myRisk and Color Genomics/Genome Dx’s Hereditary Cancer Panel.

The use of such panels is first informed by a patient’s family history, said Gomella, who emphasized to urologists that asking about an individual’s history of inherited prostate cancer should be augmented by any history of breast and ovarian cancer, melanoma, and Lynch syndrome.

After such information has been gathered, a genetic counselor can be brought in to discuss testing options, result types, cancer risks, insurance complications, and reproductive implications.

Current guidelines recommend genetic testing/counseling in the event of:

• At least 2 cases of prostate cancer in close relatives 55 years of age or younger regardless of risk category
• At least 3 first-degree relatives with prostate cancer regardless of risk
• Aggressive prostate cancer with a Gleason score above 7
• At least 2 cases of breast, ovarian, and/or pancreatic cancer in a close relative
• Metastatic prostate cancer or metastatic castration-resistant prostate cancer (mCRPC)
• Intraductal/cribriform prostate cancer
• Active surveillance
• Somatic tumor sequencing with mutations in hereditary cancer genes
• Ashkenazi Jewish ancestry
• Family history of cancer at an early age of diagnosis
  • Breast (<45 years)
  • Uterine or colon (<50 years)
  • Ovarian (<60 years)

“Looking for genetic risk has become baked into our management of prostate cancer today,” Gomella said. “Germline and somatic testing are complementary. One does not replace the other. They should both be considered in the management of many patients with prostate cancer.”

When it comes to determining whether to biopsy patients for prostate cancer, several things can be used, including prostate-specific antigen (PSA) kinetics, the Prostate Health Index score, OPKO 4K, Prostarix, Select MDx, ExoDx, MyProstate Score, PCA3, as well as MRI and ultrasound, the Prompt Prostate Genetic Score, germline testing, and online calculators.

In terms of whether to perform a repeat biopsy, Gomella cited the ConfirmMDx, Prostate Score Mitomic Test, MyProstate Score, OPKO 4K, and PCA3 as helpful options.

“Whatever test you’re comfortable with is the most important,” Gomella said. “[At Jefferson Health,] we rotate different tests to give our residents exposure to the different potential assays that are available.”

Following biopsy, several tissue tests can be used to determine disease aggressiveness, including ConfirmMDx, Decipher, Prolaris, and the Oncotype DX genomic prostate score test.

“[These tests] are used after the biopsy. This is taking the biopsy of someone with known prostate cancer and deciding whether this a cancer, based on the characteristics beyond Gleason score, PSA, and digital rectal exam, that can be watched or [one] that requires further testing,” Gomella said.

Turning to treatment implications, Gomella explained that in the setting of heavily pretreated metastatic castration-resistant prostate cancer, in the presence of a germline or somatic BRCA1/2 mutation or homologous recombination repair gene mutation, patients may be eligible to receive rucaparib (Rubraca) or olaparib (Lynparza),^2,3 respectively, and in the presence of high microsatellite instability/mismatch repair deficiency or tumor mutational burden greater than 10 mut/Mb, pembrolizumab (Keytruda).⁴

“Many of the new treatments under study today are associated with precision medicine with the identification of a precise marker that can be used to guide treatment,” Gomella concluded.

References

1. Gomella L. The evolution of biomarkers and genetics in the management of prostate cancer. Presented at: New York GU 15th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies; March 11-12, 2022; virtual. Accessed March 12, 2022.
2. Rubraca highlights of prescribing information. FDA. Updated December 2016. Accessed March 15, 2022. https://bit.ly/3Ibfx9b
3. Lynparza highlights of prescribing information. FDA. Updated May 2020. Accessed March 15, 2022. https://bit.ly/2WLJt7u
4. Keytruda highlights of prescribing information. FDA. Updated March 2021. Accessed March 15, 2022. https://bit.ly/37zl8tu