Learning Objectives

At the conclusion of the activity, participants will be able to:

• Counsel men with BRCA1/2 mutations, Lynch syndrome and other key inherited syndromes regarding their prostate cancer risk and appropriate strategies for cancer screening.
• Identify the criteria for genetic testing of prostate cancer patients, the gene panels available and options for testing these men.
• Interpret results of genetic testing and relay this information to patients in order to facilitate shared decision making based on the test results.
• Utilize the results of genetic testing to improve outcomes among patients with metastatic prostate cancer, including recommendations regarding PARP-inhibition, chemotherapy and immunotherapy.

Introduction

Over the past several years, our understanding of germline mutations as an important cause of aggressive prostate cancer has dramatically increased. Urologists treating men with prostate cancer are incorporating germline genetics into routine prostate cancer care, from early detection to management of men with localized or metastatic prostate cancer. Multiple organizations now provide guidance to aid in the appropriate use of genetic testing, but significant work remains to optimize and refine the field of germline genetics in prostate cancer.

Hereditary and Familial Prostate Cancer

Family history is a critical consideration for prostate cancer risk. Men with a family history of prostate cancer have a higher incidence of prostate cancer and higher prostate cancer specific mortality (compared to men without a family history of prostate cancer).¹ For men who have first-degree relatives diagnosed with prostate cancer, the risk of developing the disease increases by roughly twofold compared to the general population. It is important to distinguish between hereditary prostate cancer (HPC) and familial prostate cancer. HPC is estimated to account for 5%-10% of prostate cancer cases. These are generally considered to be due to higher penetrance inherited genetic variants, such as mutations in BRCA1 or BRCA2, and these variants can greatly increase lifetime risk. Familial prostate cancer is a broader term that encompasses 15%-20% of cases and can include those patients with a strong family history of prostate cancer but no detectable genetic mutations. More common polygenic variants with smaller effect sizes likely factor into many of these familial cases. These are often recognized as single nucleotide polymorphisms (SNPs), which may or may not themselves have a functional role in increasing the risk of developing prostate cancer.²

Germline Alterations

A number of genes have been implicated in heritable prostate cancer, most of which have important roles in the DNA damage repair machinery. These include BRCA1, BRCA2, CHEK2, ATM and PALB2, along with mismatch repair mutations responsible for Lynch syndrome (MLH1, MSH2, MSH6 and PMS2). BRCA1 and BRCA2 are critical proteins in the process of homologous recombination, and pathogenic mutations in these genes have long been known to increase the risk of breast and ovarian cancers in women. Germline BRCA1 and BRCA2 mutations in men are associated with a significant increase in the risk of prostate cancer, and men with pathogenic BRCA2 mutations are typically diagnosed at a younger age, have higher Gleason grade tumors, and have a shorter median survival time than men with sporadic prostate cancers.^3,4

Several options for germline genetic testing are now available for those men with prostate cancer who are at high risk of harboring a genetic alteration. While single gene testing, such as for BRCA1 or BRCA2, can be performed, multigene panel testing has become more commonplace in the absence of a known familial mutation. These tests include a panel of genes associated with the disease of interest. For prostate cancer, these panels typically include BRCA1, BRCA2, ATM, CHEK2, MLH1, MSH2, MSH6, PMS2, EPCAM and TP53 among others specific to the individual commercial platform. Importantly, while many of the genes included in these panels have a clear association with prostate cancer risk, others carry a still unknown clinical significance with poorly defined cancer risk. Particular caution should be taken before performing a test that includes >20–30 genes, as these often include genes without confirmed relevance to prostate cancer risk. Importantly, while insurance coverage continues to improve, not all carriers will cover germline testing even in those who meet guidelines-based criteria.

Importantly, many variants identified on multi gene panel testing may not be clinically relevant. Some are known to be non-pathogenic, while others are indeterminate and classified as variants of uncertain significance (VUS). This occurs when a genetic change is present that differs from a normal control but there is insufficient information to classify it as deleterious or benign with respect to cancer risk. The possibility of a VUS, or “gray area,” result should be discussed with patients before any testing is performed.

Guideline Statements on Testing and Early Detection

In recognizing the importance of germline mutations, the National Comprehensive Cancer Network^® (NCCN) Genetic/Familial High-Risk Assessment Guideline now distinguishes indications according to tumor characteristics vs. family/ancestry indications. Tumor-specific indications include: metastatic prostate cancer, high/very high risk prostate cancer, or intraductal/cribiform histology. Family history characteristics include 1 or more close blood relatives with: breast cancer diagnosed at ≤50 years of age; ovarian cancer; pancreatic cancer; or metastatic, intraductal/cribiform, or high/very high risk prostate cancer. Additional indications include 2 or more relatives with breast or prostate cancer (any grade), or individuals with Ashkenazi Jewish ancestry.

In terms of early detection for men without a diagnosis of prostate cancer, current guidelines suggest that men with germline mutations that increase the risk of prostate cancer undergo prostate cancer screening starting at age 40 after a risk and benefit discussion. These guidelines recommend biopsy for PSA>3 ng/ml or for suspicious exam in these high risk men. Furthermore, the guidelines suggest follow-up based upon initial PSA level for those whose initial screening does not trigger a biopsy. However, there is a need to better define the early detection approach for these high risk men.

The role for dedicated and early screening in men with known or potential germline mutations predisposing to prostate cancer is being evaluated in a number of settings, including the IMPACT and PROFILE trials in the UK.^5,6 At the University of Michigan Prostate Cancer Risk Clinic, men who are known carriers of germline pathogenic mutations related to prostate cancer (e.g. BRCA1/2) are offered PSA screening and digital rectal exam starting at age 35, with a low PSA threshold for biopsy. PSA thresholds are set at 2 ng/ml for men under 50 years old and 2.5 ng/ml for men 50 years and over.⁷ This is combined with additional urine biomarker testing (SelectMDx) with the objective of better defining the role for intensified risk-based prostate cancer screening in the United States. Another open study out of the National Cancer Institute (NCI) utilizes a similar algorithm but also adds multiparametric MRI (NCT03805919)

Treatment Implications

Men with BRCA1/2 mutations have been shown in multiple studies to potentially have more aggressive prostate cancer and decreased survival compared to patients with sporadic prostate cancer. Key questions regarding eligibility of active surveillance in low risk disease or treatment intensification in men with high risk localized disease remain to be answered. In the metastatic setting, there is emerging evidence of the efficacy of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors and platinum-based chemotherapy in patients with germline and/or somatic biallelic defects in DNA repair genes. In the TOPARP-A trial, which led to U.S. Food and Drug Administration (FDA) breakthrough designation for olaparib in metastatic castration resistant prostate cancer (mCRPC), having a DNA damage repair alteration appeared to predict response to olaparib.⁸ This is particularly relevant in the context of the work by Pritchard and colleagues, finding germline DNA damage repair mutations in 11.8% of men with metastatic prostate cancer.⁹ Further evidence for the phase 3 PROFOUND trial demonstrated the efficacy of olaparib in mCRPC patients with a mutation in BRCA1, BRCA2, or ATM, leading to FDA approval in this setting.¹⁰ Additionally, in the single arm TRITON2 trial, the large proportion of men with germline or somatic alterations in BRCA1 or BRCA2 who responded to rucaparib led to its approval in BRCA1 and BRCA2 mutated mCRPC as well.¹¹

There is also evidence of increased sensitivity to platinum-based chemotherapy in metastatic prostate cancer patients with germline DNA repair mutations, likely related to platinum’s mechanism of action through DNA damage.¹² Due to the treatment implications, potential relevance for family members along with inconsistent insurance coverage and access to services, studies are ongoing to explore novel methods of delivering cancer genetic testing and counseling to men with metastatic prostate cancer. One of these is the University of Washington/Fred Hutch Cancer Center web-based GENTleMEN study (www.clinicaltrials.gov, NCT03503097). There are also a number of ongoing therapeutic trials in this space (see table).

Finally, there is also evidence across multiple different cancers that patients with increased tumor mutational burden, such as those with DNA mismatch repair (MMR) deficient tumors, are particularly sensitive to immune checkpoint inhibition. This is most commonly seen in colorectal cancer, which is the most common malignancy associated with Lynch syndrome. However, as mentioned above, mutations in MMR genes are also associated with prostate cancer and are likely present in approximately 5% of advanced prostate cancers.¹³ The emerging data regarding MMR deficiency and checkpoint inhibition sensitivity have led to an FDA approval for pembrolizumab, a PD-1 inhibitor, in solid tumors with mismatch repair deficiency such as in Lynch syndrome.¹⁴ While there are still only limited data surrounding PD-1 sensitivity in MMR-deficient prostate cancer, there are reports of extreme responses to pembrolizumab in this setting.

Conclusion

Germline mutations predisposing to prostate cancer have an increasing impact on the clinical management of prostate cancer–from pre-diagnosis genetic counseling, to screening and early detection, to newly diagnosed localized prostate cancer, and to metastatic disease. Utilizing platinum-based therapies, immunotherapy, or PARP inhibitors in men with metastatic prostate cancer who have known germline mutations may lead to improved long-term outcomes, though additional research in these areas is needed. Given emerging evidence and guidelines, clinical pathways are now needed to facilitate germline testing in appropriately selected patients in order to inform treatment plans. Further work to improve access to genetic counseling, cancer screening, and treatment options for men with relevant germline mutations is likely to yield significant long-term benefits for these patients.