Dr. Gomella explains the evolution of precision medicine in prostate cancer

Precision medicine is now an integral part of the entire spectrum of prostate cancer care, and recommendations for optimal testing and how best to leverage the results to inform clinical decisions continue to rapidly evolve, according to Leonard G. Gomella, MD, FACS.

Leonard G. Gomella, MD, FACS

As such, it is important to continually check for new guideline updates, understand the role of germline and somatic testing in the paradigm, be aware of biomarkers that can inform treatment, and stay informed of new therapies that are under investigation.¹

“What is precision medicine? This is not just a vague term; [it] really looks at individual characteristics of a patient to decide treatment,” Gomella explained in his presentation delivered during the 16th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies.1 “Instead of throwing spaghetti against the wall and seeing what sticks, we’re getting better and better at identifying specific characteristics. In prostate cancer, we have a lot of opportunities. We have biomarkers, pharmacogenomic markers, polygenic risk scores, and the like that are rapidly evolving.”

In his talk, Gomella, who is the chairman of the Department of Urology, senior director of Clinical Affairs at Sidney Kimmel Cancer Center, and enterprise vice president for Urology at Jefferson Health System, of Thomas Jefferson University, in Philadelphia, Pennsylvania, provided a comprehensive background on the evolution of precision medicine in the realm of prostate cancer.¹

Taking it Back to the Basics

A lot of what is known about precision medicine was driven by discoveries made through the Human Genome Project, according to Gomella. The project was initiated in 1990 and was determined to be complete in 2003.²

“Although the Human Genome Project, on paper, was finished in 2003, in reality, it took about another 15 to 20 years to [fill] the last little gaps [in what was known about] the human genome,” he said. “Really, the genome was not fully sequenced until 2022. It’s really the iceberg concept. There is just so much we do not know about the human genome, and we’ll be learning more and more about that as the years go on.”

When it comes to modern tumor evaluation, imaging is utilized to look at gross pathology and then histology to further examine cell, nuclear, and chromosome abnormalities. Looking at molecular tumor markers is essential to understand the unique characteristics of the disease, Gomella said. He added that it is important to understand the difference between germline and somatic mutations.¹

“Germline mutations are inherited from your parents; they are present in every cell except for red [blood] cells and the like,” he said. “Somatic mutations [are] what I like to call ‘the wild west of the tumor.’ You don’t necessary inherit somatic mutations; they can arise de novo in a tumor, and they are not in every cell in the body. They tend to usually just be localized in the tumor.” He added that both mutations can be utilized to inform treatment—especially in those with advanced prostate cancer.

With inherited cancer risk testing, it is possible to identify mutations inherited from parents and grandparents via buccal/blood testing that can increase cancer risk. Gomella noted that this test can be leveraged for screening and prevention, as well as to inform treatment. With genomic profiling, tissue-based biopsies and proprietary molecular signatures are used to manage the disease. Lastly, genomic tumor sequencing is a “very, very hot area,” according to Gomella; this is somatic testing done by tissue or liquid biopsy that has the potential to detect over 300 mutations and can guide therapeutic interventions.

Genetic Testing Guidance

Before 2016, the association between BRCA mutations and prostate cancer screening was only noted in Hereditary Breast and Ovarian Cancer Guidelines issued by the National Comprehensive Cancer Network (NCCN). In 2017, the first hereditary genetic considerations and screening for prostate cancer emerged. A year later, prostate cancer guidelines suggested consideration of germline testing for risk; in 2020, it became a recommendation.³

Prostate cancer is primarily a sporadic disease, according to Gomella; 70% to 80% of all cases are sporadic, with an unknown exact cause. However, 10% to 15% of all prostate cancer cases are hereditary and are usually due to a single inherited genetic mutation, such as BRCA1 or BRCA2.⁴

“These [inherited] mutated genes do not cause prostate cancer [but increase risk]. We still do not know what causes prostate cancer,” Gomella noted. “However, we know if the patients have these mutated genes, and they develop prostate cancer, something goes usually very wrong. It becomes much more aggressive and more likely to be a metastatic cancer.”

He added that it is important to perform genomic or genetic germline testing because results can potentially inform therapeutic options and offers the opportunity to screen and prevent other at-risk cancers in the patient and in their family unit.

Most of the gene mutations that have been associated with prostate cancer appear to be related to defects in DNA repair mechanisms, according to Gomella. “In prostate cancer, [we] mostly [see] BRCA2 and [then] BRCA1. These are DNA damage response genes and when they’re mutated, they increase the lifetime risk of developing prostate cancer significantly; it’s more likely to be aggressive,” Gomella explained. “You also have to remember that it not only increases the risk of other cancers in the individual, but if an inherited gene mutation is in other family members, they can also be at risk for other cancers like pancreatic cancer, breast cancer, and others.”

Some of the available genetic testing panels for prostate cancer include the Ambry Genetics ProstateNext test, which tests 14 genes; the GeneDx Prostate Panel, which tests 12 genes; the Invitae Prostate Cancer Panel, which tests up to 15 genes; and the NeoGenomics Hereditary DNA Repair Panel for Prostate Cancer, which tests 20 genes. General genetic cancer panels, such as the MyRisk 28-gene screen from Myriad and the Hereditary Cancer Panel 30-gene screen from Color Genomics, have also emerged.

“In urology, we tend to not use the [general genetic panels] because they might open up a can of worms for diseases that we’re not necessarily interested in at the time, that may not impact the patients,” Gomella said. “We tend to stick with the prostate cancer gene panels.”

He underscored that urologic cancer questionnaires need to focus more on acquiring a detailed family history beyond just prostate cancer. These questionnaires can inform whether genetic testing or counseling is needed. “I am a big believer in genetic counseling,” Gomella noted. “I like to send patients for genetic counseling to understand, do they need germline testing? Do other members of their family need germline testing? When and where should it be done?”

As a part of genetic counseling for inherited cancer risk, key discussion points will include genetic testing options, types of results, cancer risks, insurance implications, and reproductive implications.⁵ Patients are then able to make informed decisions with regard to genetic testing. Gomella added that germline testing is recommend for patients with a personal history of prostate cancer and those with metastatic/node-positive/high-risk localized disease, family history, and prostate cancer intermediate risk or cribriform, among other factors.

Biomarkers to Guide Biopsy

“Prostate-specific antigen [PSA] is still the best test for following patients who have been treated for prostate cancer,” Gomella said. “However, where PSA kind of falls apart is, for screening we get a lot of false positives, false negatives, and the like. At the end of the day, a single PSA is not as good as PSA tracked over time. Study after study has shown that a single PSA level when a man is young and then followed over time is one of the best predictors of either clinically advanced or clinically localized prostate cancer. We’re trying to do better [though.]”

Certain biomarkers can be leveraged to determine whether to biopsy. For men with a PSA between 2 ng/mL and 10 ng/mL, the prostate health index (PHI) can be leveraged. “It’s an algorithm that looks at the combination of these different families of PSA in the blood and comes up with a risk of prostate cancer,” Gomella said. Biopsy should be avoided in those with elevated PSA and low PHI.

According to Gomella, the non-invasive 4 kallikrein blood test examines 4 kallikrein genes— total PSA, free PSA, intact PSA, and hK2—to determine whether someone is at low or high risk for having prostate cancer.

“In the late 1990s, we finally discovered that you could shed prostate cancer into the urine, and this led the charge for all the urine tests with the discovering of the PCA3-mutated gene in prostate cells in the urine,” Gomella said. “That led to a whole other series.” The MyProstate Score, out of the University of Michigan, “combines a blood test with a urine test to identify a variety of recognized molecular genes.” The test calculates the quantitative risk of having prostate cancer detected on a biopsy.

Additionally, the Select MDx test “is an RNA test that looks at several families in the urine and it’s good for the detection of higher-grade cancer,” Gomella noted. The test provides a relative risk of having low-grade or high-grade disease by looking at HOXC6 and DLX1 mRNA.⁶ Those determined to have high risk can benefit from biopsy and those low risk may avoid unnecessary invasive procedures with routine follow-up and screening. The ExoDx Prostate (IntelliScore) or EPI test looks at exosomes in the urine and computes a low- or high-risk score.

“A new player is the IsoPSA [test] that came out of Cleveland Clinic,” Gomella said. “It’s a blood test” that measures PSA structure and all isoforms present in serum, and it is agnostic as to which isoforms are present.

Leveraging Precision Medicine in Advanced Disease

Significance of AR-V7

It is known that AR-V7–negative patients have a completely intact androgen receptor and those who are positive have a mutated or truncated androgen receptor, Gomella said. He explained that if this is detected on circulating tumor cells, and a patient is found to be positive for AR-V7, they are unlikely to respond to androgen receptor pathway inhibitors. Conversely, if they are AR-V7 negative, they may respond better to androgen receptor–targeted agents.

Germline Mutations in Metastatic Disease

The most common germline mutations found in those with metastatic disease include BRCA2 (44%), ATM (13.5%), CHEK2 (11%), and BRCA1 (7%). “There are many, many germline mutations but we tend to focus on the more common ones that help us direct cancer treatments,” Gomella said. These kinds of mutations can be detected in up to 25% of cases of metastatic castration-resistant prostate cancer (mCRPC).

Somatic tumor DNA testing has allowed for the detection of actionable mutations for clinical trials and for treatment. The presence of mutations in homologous recombination repair (HRR) deficiency genes can make a patient eligible to receive PARP inhibitors like rucaparib (Rubraca) and olaparib (Lynparza). Those found to have microsatellite instability–high or mismatch repair–deficient disease, or to have a high tumor mutational burden of more than 10 Mb, may be able to receive pembrolizumab (Keytruda).

The AUA/ASTRO/SUO Guidelines issued in 2020 state that PARP inhibitors should be offered to patients with deleterious or suspected deleterious germline or somatic HRR gene–mutated mCRPC after previous treatment with enzalutamide (Erleada) or abiraterone acetate (Zytiga), and/or taxane-based chemotherapy.⁷ For those who cannot receive or obtain a PARP inhibitor, platinum-based chemotherapy may serve as an alternative approach.

Recommendations for Germline and Somatic Testing

Germline testing is recommended for all men with high-risk, very high–risk, regional, or metastatic prostate cancer, irrespective of family history. This testing is also recommended for men with prostate cancer who have a suspicious family history or intraductal/cribriform histology. Somatic testing is recommended for men with metastatic prostate cancer and should be considered for men with regional prostate cancer. This kind of testing may need to be repeated upon disease progression and following treatment.

“Both germline and somatic testing are helpful. They are complementary of each other,” Gomella concluded. “Just because someone has a somatic mutation does not mean they shouldn’t get germline [testing] and vice versa.”

References

1. Gomella L. The evolution of precision medicine in the management of prostate cancer. Presented at: 16th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies; March 10-11, 2023; New York, NY. Accessed March 10, 2023.
2. Timeline of the Human Genome Project, 1990-2003. Accessed March 10, 2023. https://www.mun.ca/biology/scarr/Human_Genome_Project_timeline.html
3. Hereditary Breast and Ovarian Cancer Guidelines and Prostate Cancer Guidelines. National Comprehensive Cancer Network website. https://www.nccn.org/. Accessed March 10, 2023.
4. Klein EA, Kupelian PA, Witte JS. Does a family history of prostate cancer result in more aggressive disease? Prostate Cancer Prostatic Dis. 1998;1(6):297-300. doi:10.1038/sj.pcan.4500257
5. Giri VN, Hegarty SE, Hyatt C, et al. Germline genetic testing for inherited prostate cancer in practice: implications for genetic testing, precision therapy, and cascade testing. Prostate. 2019;79(4):333-339. doi:10.1002/pros.23739
6. Van Neste L, Hendriks RJ, Dijkstra S, et al. Detection of high-grade prostate cancer using a urinary molecular biomarker-based risk score. Eur Urol. 2016;70(5):740-748. doi:10.1016/j.eururo.2016.04.012
7. Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline (2020). American Urological Association website. Accessed March 10, 2023. https://www.auanet.org/guidelines-and-quality/guidelines/advanced-prostate-cancer