Germline Genetics of Prostate Cancer

Abstract

A number of studies have identified an important fraction (>/~10%) of men with high risk localized prostate cancer and metastatic prostate cancer that carry germline (heritable) pathogenic and likely pathogenic variants (also known as mutations) in DNA repair genes. Moreover, growing evidence suggests that inactivation of specific genes, particularly key genes involved in homologous recombination and mismatch DNA repair, are important in prostate cancer initiation and/or development of metastases. This has led to substantial expansion of the national guidelines for which patients should be offered germline genetic testing. Here, we review key literature on individual genes, with BRCA2 best understood, and ATM, CHEK2, BRCA1, HOXB13, MSH2, MSH6, PALB2, TP53 and NBN discussed individually. Treatment implications in advanced disease include FDA-approval of rucaparib and olaparib, and pembrolizumab in the metastatic castration resistant setting, and newer clinical studies moving into early disease states and incorporating combination approaches. We review the current germline genetic testing national guidelines, and discuss the importance of cascade genetic testing of relatives, diverse populations and attention to inclusion, as well as prostate cancer screening updates and clinical trial opportunities for men who carry genetic risk factors for prostate cancer.

INTRODUCTION:

It has been well established that prostate cancer has a strong genetic association. The discovery of populations with higher prevalence of single high penetrance risk factors such as BRCA2 in specific subgroups such as men with metastatic disease, paired with the increased availability and decreased cost of next generation sequencing have led to the expanded recommendations for germline genetic testing in patients with prostate cancer. These new technologies have led to the discovery of more germline genetic factors implicated in prostate cancer and are now accompanied by new FDA-approved treatment options in the advanced disease setting. This review article will address the landscape of germline genetics of prostate cancer, review current guidelines for testing (including practical considerations), and describe the clinical practice implications of germline DNA repair mutations.

HERITABILITY OF PROSTATE CANCER:

The genetic heritability of prostate cancer has been notably highlighted by two key European studies. The Norwegian Twin Cancer study was published in 2016 and explored prostate cancer risk in 203,000 monozygotic and dizygotic twin pairs. This study suggested that up to 57% of prostate cancer can be attributed to genetic risk factors (1). The Prostate Cancer data Base Sweden (PCBaSE) study showed that the risk of developing prostate cancer was higher in men who had brothers with prostate cancer. In their study, by age 65, men who had brothers with prostate cancer had a risk of 14.9% of also developing prostate cancer, compared to a 4.8% risk of developing prostate cancer for men who did not have a brother with prostate cancer. At age 75, the risk of developing prostate cancer for those with a brother with the disease was 30.3%, compared to 12.9% for those without a brother with prostate cancer. The results were similar if exclusions were made for those with low-risk prostate cancer (2).

Genetic factors may influence not only risk of developing prostate cancer, but also the prognosis of disease that may develop. A separate study conducted in Sweden showed that sons with prostate cancer whose fathers had also had prostate cancer had an overall survival that correlated with their fathers’ (3).

DNA REPAIR GENES

Much of the early data exploring the genomic makeup of prostate cancer was obtained from diagnostic prostate biopsies; metastatic prostate cancer tissue was not studied until an international study to characterize the genomic makeup of metastatic biopsies was published in 2015. The review of 150 biopsies from patients with metastatic prostate cancer in this study identified a large number of actionable mutations, including 23% of men whose cancers had evidence of mutations in DNA repair genes including BRCA1, ATM, and BRCA2. Up to 8% of these DNA repair mutations were germline (4) ; much higher than previously recognized.

In 2016, Pritchard et al studied 692 patients with metastatic castrate resistant prostate cancer who underwent germline genetic testing reported rates of germline DNA repair mutations ranging from 4.6% in localized disease to up 11.8% in metastatic disease (5). Most common genetic germline alterations were in BRCA2 (5.3%), CHEK2 (1.9%), ATM (1.6%), and BRCA1 (0.9%). Other notable genes were RAD51D (0.4%) and PALB2 (0.4%). Of key importance, the men were not selected for family history of cancer or their age at diagnosis, and the presence of germline genetic mutations in DNA repair were not associated with family history of prostate cancer or age at presentation. In patients whose tumor tissue was also available for sequencing, 67% of tumors had second allele inactivation, suggesting that the germline alterations were contributing to the resulting prostate cancer.

Other studies have identified similar rates of DNA repair mutations in metastatic prostate cancer patients (6-9). DNA repair mutations have also been seen in metastatic hormone sensitive prostate cancer (9), as well as high-risk localized disease. A recent study conducted by Berchuck et. al found that 9.5% of 201 patients with high-risk localized disease had evidence of DNA repair mutations, most commonly BRCA2 (3%) and ATM (2%) (10). These studies provide justification for expanding the criteria for offering men with high risk localized and those with metastatic prostate cancer opportunities for germline genetic testing.

AGGRESSIVE NATURE OF PROSTATE CANCER WITH DNA REPAIR MUTATIONS

While there have been important advances made in the treatment of metastatic prostate cancers with DNA repair mutations, discussed in further detail later in this issue, it is also important to recognize that prostate cancers with DNA repair mutations (both localized and metastatic) may be associated with a more aggressive phenotype. Several recent studies have highlighted this link between DNA repair mutations and more aggressive disease.

A retrospective study of almost 800 patients with localized prostate cancer analyzed the association of lethal prostate cancer with DNA repair mutations (11). This study included 313 patients with lethal prostate cancer (died of their disease), and 486 patients with low risk localized prostate cancer. Mutations in DNA repair genes including BRCA1, ATM, and BRCA2 were higher in those with lethal prostate cancer, with an incidence of 6.1%, compared with localized disease only, with incidence of 1.4%. In the population with lethal prostate cancer, the incidence of a DNA repair mutation decreased with age; from 10% for those 60 and younger, to 3% for those 75 and over, suggesting that DNA repair mutations lead to an earlier age at death due to prostate cancer.

There has been significant evidence that germline carriers of DNA repair mutations that develop prostate cancer have a higher risk of metastatic progression and subsequent death. Castro et al studied the association of patients with prostate cancer that had germline BRCA1 and BRCA2 mutations, and found that patients with these DNA repair alterations were likely to have more aggressive disease. Specifically, this included a Gleason score 8 or above, nodal involvement, and higher T stage. Patients with germline BRCA1 and BRCA2 mutations were also more likely to have metastatic disease at diagnosis. Survival related to prostate cancer was longer in patients who were not carriers , at 15.7 years, compared to 8.6 years in patients who were carriers of germline BRCA1 and BRCA2 mutations. (12).

Castro et al conducted another study in 2015 that compared rates of metastases in patients with prostate cancer who carried BRCA1 and BRCA2 mutations, compared with patients with prostate cancer that did not carry BRCA1 and BRCA2 mutations. This study showed that there were lower rates of metastases at 3, 5, and 10 years of treatment in those who were not BRCA carriers (90%, 72%, and 50% in carriers respectively) compared with men who were carriers of BRCA1 or BRCA2 mutations (97%, 94%, and 84% respectively), suggesting that germline carriers of BRCA1 and BRCA2 mutations have a higher rate of metastatic disease (13). They also found that 3 year, 5 year, and 10 year prostate cancer specific survival was significantly worse in carriers of BRCA mutations (96%, 76%, and 61% respectively), when compared to non-carriers (99%, 97%, and 85%).

A prospective cohort study called the PROREPAIR-B study investigated the treatment outcomes of patients with metastatic prostate cancer, and the relationship to germline DNA repair mutations. Sixty-eight out of 419 study participants (16%) had germline DNA repair mutations (14 with BRCA2, 8 with ATM, 4 with BRCA1). There was no statistically significant difference in cause-specific survival between carriers of all combined DNA repair mutations (BRCA2, ATM, and BRCA1) and non-carriers, however the cause-specific survival was significantly less in BRCA2 carriers (17 months vs. 33 months) (6).

Approximately 5% of patients with high-risk localized prostate cancer have germline DNA repair mutations. There is emerging data to suggest that germline DNA repair mutations may be associated with specific histologic features in the localized disease setting, which may offer a potential clinical correlate (10, 14-15). Specifically, patients with germline BRCA2 mutations are more likely to have intraductal histology, which has been associated with an aggressive clinical course ; higher risk of biochemical recurrence, metastatic disease, and even mortality (16). Aside from intraductal histology, there have been associations with other high-risk pathologic features in patients with localized prostate cancer, such as cribriform pattern 4, lymphovascular invasion, ductal histology, and the presence of Gleason group 5 histology (17-19).

INDIVIDUAL GENES:

DNA repair genes refer to a group of genes that collectively aid in repairing errors in DNA during the replication process. There are variable data for individual genes and an emerging understanding of how they may impact prostate cancer risk and cancer behavior. The data known about individual genes is reviewed below.

BRCA2

The strongest data about the inherited risk of prostate cancer relates to BRCA2 mutations, largely obtained from cohorts assembled from female relatives with breast and ovarian cancer. The relative risk of developing prostate cancer for germline BRCA2 mutation carriers by the age of 65 is estimated to be between 2.5 to 8.6 fold when compared with non-carriers (20-22). In another study, the cumulative incidence of being diagnosed with prostate cancer by the age of 65 ranged from 7% to 33% (23).

It has been shown that BRCA2 mutation carriers have a more aggressive prostate cancer phenotype. Genomic profiles of localized prostate cancer from 14 patients with germline BRCA2 mutations show a more aggressive phenotype (15). Tumors displayed more genomic instability, with profiles that more closely resemble metastatic prostate cancer than localized prostate cancer. These researchers also discovered genomic and epigenomic dysregulation of the MED12L/MED12 axis, a pathway often dysregulated in metastatic prostate cancer. The molecular observation that germline BRCA2 mutations lead to more aggressive disease is also highlighted in several observational studies.

In an Icelandic study, patients with the founder mutation BRCA2 999del5 and prostate cancer were more likely to have a higher-risk disease at a younger age (24). Those patients were also observed to have a shorter median survival time, and an increased risk of prostate-cancer related mortality, when adjusted for age, year of diagnosis, and stage. Yet another study done showed that the risk for developing prostate cancer was three times higher among BRCA2 carriers, and was also associated with a higher Gleason score (25). This study also showed a higher risk of prostate cancer recurrence and prostate cancer-related death, when compared to non-carriers.

There is also data from the Consortium of Investigators of Modifiers of BRCA1/2 to suggest that carriers of BRCA2 mutations have an increased risk of developing prostate cancer when compared to BRCA1 carriers (26).

BRCA1

Germline mutations in BRCA1 are also associated with higher risks of development of prostate cancer and aggressive nature of disease (12, 25) though the strength of evidence and apparent risk appears to be less than BRCA2 mutations. In one study, the risk of prostate cancer in carriers of BRCA1 mutations was estimated to be about 3.75 fold, though not as high as BRCA2 mutation carriers (27).

ATM

While ATM is also a gene involved in DNA repair and is the second most common DNA repair alteration in metastatic prostate cancer after BRCA2 (5), studies show that it works somewhat differently to BRCA2, especially in its response to PARP inhibitors. It is also unclear whether a loss of ATM functions to promote initiation of cancer, and/or enhance metastatic potential.

Many of the studies describing germline ATM mutations and their pathogenic potential in prostate cancer have been done with other genes of DNA repair, such as BRCA2. Much of that data has been presented elsewhere in this article. An Icelandic study published in 2015 studied genetic variants associated with gastric cancer, and identified two loss-of-function variants of ATM that were associated with prostate cancer with an OR of 2.18, along with an association with gastric cancer (28).

PALB2

The PALB2 gene is part of the DNA repair pathway and is commonly associated with DNA repair mutations in breast and ovarian cancer cohorts. In fact, much of the early data linking PALB2 mutations with prostate cancer comes from data from female relatives with breast and ovarian cancer. However, the exact nature of PALB2 in the pathogenesis of prostate cancer is unclear. This historic, early data is viewed with caution, as prostate cancer in these studies was often underreported, and there was not a clear distinction between low risk, early-stage prostate cancer, and more advanced, metastatic prostate cancer. Additionally, earlier studies did not show a clear association between germline PALB2 mutations and hereditary prostate cancer in families with a high rate of prostate cancers before age 55 or multiple affected family members (29-31). However, other, more recent studies have suggested the association of germline PALB2 mutations with aggressive prostate cancer, and some studies have reported resistance of PALB2-mutated cancers to PARP inhibitors (32-33)

There is a need to identify more patients with germline PALB2 mutations, to understand the conferred risk of disease and the biological significance and therapeutic consequences in prostate cancer.

CHEK2

Most of the data that associates germline CHEK2 mutations with increased prostate cancer risk comes from Poland. Cybulksi and colleagues have led much of this work and have found that there are founder mutations in CHEK2 including CHEK2 1100delC and CHEK2 IVS2 1 1G>A which are associated with a moderate risk of prostate cancer. These two driver mutations were found in 0.5% of controls, compared with 1.6% of unselected patients with prostate cancer, with an OR of 3.4 (34). Additionally, there is a missense CHEK2 variant I157T that has been reported in association with prostate cancer (35) and there have been several studies evaluating CHEK2 c.1100delC separately. A meta-analysis published in 2014 reviewed 12 studies that discussed the specific CHEK2 c.1100delC variant and its association with prostate cancer risk. Five out of the 12 studies had independent data, which when pooled, showed that CHEK2 c.1100delC is associated with increased risk of prostate cancer (36). Further, Wu and colleagues showed that CHEK2 c.1100delC has a higher carrier rate in those with lethal prostate cancer, when compared with lower-risk prostate cancer patients, with an estimated OR of 7.86 in lethal prostate cancer (37).

HOXB13

HOXB13 has been identified as a gene that codes for a transcription factor that is important in prostate development, however the mechanism and pathways that lead to its role in prostate cancer development are not yet identified. There have been several studies that have shown the association of the HOXB13 G84E variant with prostate cancer, including a European study which showed an increased frequency of the HOXB13 G84E variant in patients with prostate cancer at 1.4% compared to those without prostate cancer at 0.1% (38). In a separate cohort of 3607 patients with prostate cancer, the HOXB13 G84E variant was found at a rate of 1.1% (39). The HOXB13 G84E gene variant does not appear to be independently associated with more aggressive features of prostate cancer (40).

NBN (also called NBS1)

A Polish study showed that the NBS1 657del5 founder mutation is associated with increased risk of prostate cancer. They studied the prevalence of this mutation in 56 familial cases of prostate cancer, and compared this to 305 nonfamilial cases of prostate cancer, along with 1500 control cases. They found that the NSB1 657del5 founder mutation was present in 9% of patients with familial prostate cancer, 2.2% of patients with nonfamilial prostate cancer, and 0.6% in non-cancer controls. This study also analyzed somatic alterations of NBS1 to assess for loss of heterozygosity, with 8 samples from carriers of the founder NBS1 germline mutation. 7/8 samples from founder mutation carriers were found to have second allele inactivation, compared with 1/9 tumors from non-carriers, suggesting that heterozygous carriers of the NBS1 founder mutation have an increased risk of prostate cancer (41).

The same authors also conducted a separate study to explore lethality of NSB1 founder mutation status among patients with prostate cancer. They found that overall mortality as well as 5-year survival was worse for patients with prostate cancer with the NBS1 657del5 founder mutation, with a HR for overall mortality at 1.85 and 5 year survival of 49% in those with the founder mutation, compared with 72% for mutation negative cases (42)

Lynch Syndrome Genes

Historically, Lynch syndrome has primarily been associated with increased risk for colorectal and endometrial cancer, however there is mounting evidence that prostate cancer risk may also be increased in associations with mutations in germline Lynch Syndrome genes. These genes are primarily DNA mismatch repair genes including MSH2, MSH6, MLH1, and PMS2. The Prospective Lynch Syndrome Database reported data on 6350 men with Lynch Syndrome mutations, and found that 1808 of these men prospectively developed prostate cancer. In this population, MSH2 carriers were noted to have the highest rate of prostate cancer. By the age of 75, men with MSH2 mutations had a cumulative incidence of 23.8%, compared to 13.8% for MLH1, 8.9% for MSH6, and 4.6% for PMS2 (43).

The IMPACT study is an ongoing prospective study that assessed PSA screening in patients aged 40 to 69 with known mutations in MLH1, MSH2, or MSH6, and matched them with age-matched controls without mutations in Lynch syndrome genes. They found that in their total population, 1.9% of patients developed prostate cancer. The incidence of prostate cancer was higher among carriers of pathogenic variants of MSH2 and MSH6, but there was no prostate cancer detected in carriers of MLH1. The incidence of clinically significant prostate cancer was higher in carriers of MSH2 and MSH6, when compared to noncarrier controls. This finding has important screening implications, and suggests that germline carriers of MHS2 and MSH6 mutations should undergo targeted PSA screening (44).

TP53

Germline TP53 mutations are well known for their association with Li Fraumeni Syndrome, an autosomal dominant condition that predisposes affected individuals to multiple cancers early in life, most commonly breast cancers and sarcomas. A recent study conducted by Maxwell et al describes the relevant association of germline TP53 mutations and prostate cancer (45). In the cohort of 163 men with Li Fraumeni Syndrome (with a germline TP53 mutation) studied in this group, 31 were identified to have prostate cancer. Among 117 men with Li Fraumeni Syndrome who did not have prostate cancer at the time of testing, 6 were diagnosed with prostate cancer at a median timeframe of 3 years. In the cohort of prostate cancer patients without known Li Fraumeni Syndrome, 38 of 6850 patients were found to have a germline TP53 mutation at the time of genetic testing—a relative risk 9 times higher when compared to population controls. The data also indicate that germline TP53 mutations conferred a more aggressive phenotype of prostate cancer, with 44% of patients having a Gleason score of 8 or above, and 29% with aggressive disease at diagnosis. These findings support inclusion of TP53 testing for patients with prostate cancer who meet criteria for germline genetic testing, and also support prostate cancer screening of patients with known Li Fraumeni Syndrome.

POLYGENIC RISK SCORES:

Due to the well-documented increased risks and aggressive nature of prostate cancer with germline DNA repair mutations, there have been attempts to quantify that risk using polygenic risk scoring. There have been several studies that have used susceptibility variants derived from prior studies of BRCA1 and BRCA2 mutated breast cancers. A study by Lecarpentier et al demonstrated that by age 80, prostate cancer risk at the 5^th and 95^th percentile of the polygenic risk score does very greatly—from 7% to 26% for BRCA1 mutation carriers and from 19% to 61% for BRCA2 mutation carriers (46). A recent study by Barnes et al used a population based polygenic risk score based approach to determine risk, and found that polygenic risk score for prostate cancer based on a population was associated with higher rates of prostate cancer for BRCA1 carriers and BRCA2 carriers. For BRCA2 carriers by age 85, the 5^th and 95^th percentile prostate cancer risks were reported as 34.1% to 87.6%, respectively (47).

There has also been recent evidence to suggest that more rare variants of DNA repair mutations such as HOXB13 also contribute to polygenic risk score assessment, and should be considered in further studies. In a recent study conducted by Darst et al, polygenic risk score assessment for carriers of HOXB13, BRCA2, ATM, and CHEK2 showed that by the age of 85y, the absolute risk of prostate cancer among carriers of the above genes in combination ranged from 9% in the lower polygenic risk score percentile, to 56% in the highest risk score percentile (48).

STANDARD OF CARE CLINICAL GENETIC TESTING GUIDELINES:

Based on the above data, the National Comprehensive Cancer Network (NCCN) guidelines for prostate cancer recommend germline genetic testing for the following groups of patients with prostate cancer (version 1.2022):

NCCN guidelines recommend offering germling testing to these subsets of patients (NCCN guidelines):

1. Patients with node-positive, high-risk, or very high-risk localized prostate cancer

2. Patients with metastatic prostate cancer

3. Patients that meet family history criteria

   1. Family history of high-risk germline genetic mutations, such as BRCA1/2 and Lynch Syndrome
   2. Ashkenazi Jewish ancestry
   3. Personal history of breast cancer
   4. At least one or more first degree, second degree, or third degree relative with breast cancer at age of 50 or less, male breast cancer, ovarian cancer, exocrine pancreatic cancer, or metastatic/regional high-risk, or very high-risk prostate cancer at any age.
   5. One or more first degree relative with prostate cancer at age 60 or less (except for localized, grade group 1).
   6. Two or more first, second, or third degree relatives with breast or prostate cancer (except for localized, grade group 1) at any age
   7. Three or more first or second degree relatives with Lynch Syndrome related cancers especially diagnosed at age 50 or less; cancers of the biliary tract, endometrium, stomach, ovary, exocrine pancreas, upper tract urothelial, small bowel, colorectal, or glioblastoma.

NCCN guidelines recommend considering germline testing to these subsets of patients:

1. Intermediate risk prostate cancer and intraductal/cribriform histology

2. Personal history of exocrine pancreatic, colorectal, gastric, melanoma, pancreatic, upper tract urothelial, glioblastoma, biliary tract, or small intestinal cancers

The NCCN guidelines recommend that if done, testing includes genes associated with Lynch Syndrome (MSH1, MSH6, MLH1, and PMS2), and homologous recombination repair genes (BRCA 1 and 2, ATM, PALB2, and CHEK2). The NCCN does state that other genes can be tested based on family history or clinical suspicion. Most commercially available genetic testing vendors including Color and Invitae offer much larger panel sizes, that could be more appropriate for metastatic prostate cancer and those considering clinical trial participation.

The optimal delivery method of germline testing is currently unclear. Traditionally, patients have been referred to a genetic counselor to receive education and undergo a pre-test risk assessment prior to undergoing testing. The counselor usually meets with the patient a second time after germline genetic testing results return, to discuss the implications of the results, possibly including cascade genetic testing. Nuances of this testing and proposed new methods to advance testing are presented below.

NOVEL GENETIC TESTING IMPLEMENTATION APPROACHES:

The traditional model has worked well for some time, however given the expanded recommendations for germline testing for prostate cancer and for other malignancies, workforce and resource limitations are being called into question. There have been several recent attempts to standardize provider-led germline testing initiatives. A recent prospective study conducted at multiple cancer centers provided training in germline testing and in patient counseling for cancer providers. Patients who accepted germline testing received pre-test counseling by their oncologist, then underwent testing. If a germline mutation was discovered on their testing, they were then referred to a genetic counselor to discuss further recommendations. The majority of patients (95%) in this study accepted germline testing when offered by their oncologist (49). Another study at the VA evaluated provider-led initiation of germline testing; in this study, 80% of participants accepted germline testing, and were provided with a phone-based counseling visit with a genetic counselor if the test was positive for a germline genetic mutation (50). These results suggest that provider-led germline genetic testing could work to improve access to genetic testing, while being mindful of resource limitations. Several ongoing studies are exploring innovative ways to incorporate germline genetic tsting in the face of these limitations, including the GENTLEMEN study (NCT03503097), TARGET study (NCT04447703), and PROMISE study (NCT04995198).

With the increased acceptance of and expanded guidelines for germline genetic testing, there are important unanswered questions that remain. One of these questions is regarding optimal prostate cancer screening for men at risk for prostate cancer by virtue of being a germline carrier of a known prostate cancer risk gene; detailed screening guidelines for individuals carrying germline mutations (pathogenic variants) in prostate cancer risk genes are beginning to emerge. The ongoing IMPACT study preliminarily supports screening men aged 40-69 with BRCA1 and BRCA2 mutations using yearly PSA testing (44, 51-52). As discussed earlier in this review, the IMPACT study’s cohort of MLH1, MSH2, and MSH6 carriers show an increased risk of prostate cancer in the MSH2 and MSH6 mutation carriers, supporting early screening for this group as well.

The NCCN currently supports referral to a cancer genetics professional for those who carry a germline high-risk pathogenic variant, to engage in shared decision making regarding their individual screening recommendations. They suggest that PSA screening begin at the age of 40, with an annual PSA and DRE, with possible prostate biopsy if PSA is above the median age-matched range (53). The Philadelphia Prostate Cancer Consensus Conference, last convened in 2019, recommends starting screening for prostate cancer at the age of 40, or 10 years prior to the first affected relative’s development of prostate cancer, for known carriers of BRCA2 mutations, with consideration of a similar screening pattern for carriers of ATM, BRCA1, HOXB13, and mismatch repair genes (54). However, further research will be important to further refine cancer risk estimates and develop more comprehensive early detection strategies, ideally developing and validating new diagnostic methods. There is ongoing research in this field, to hopefully further refine screening practices for high-risk groups. The NCI is currently conducting a study of men who do not have prostate cancer but are known to have high risk genetic changes including germline DNA repair mutations, to assess their risk for developing prostate cancer. This study incudes close follow up with screening modalities such as PSA testing, physical exam, and prostate MRI (NCT03805919). The PATROL study is ongoing at the University of Washington, and is collecting blood and urine samples every 6-12 months for patients with germline DNA repair mutations for early detection of prostate cancer (NCT04472338). The results of these studies will further inform screening guidelines for these high-risk populations.

As the recommendations for germline testing in prostate cancer incorporate more groups, it is important to ensure that equitable access to genetic testing exists for all patients. There is significant data in the breast cancer population to suggest that disparities in genetic testing for women of color do exist (55-56), raising the possibility of disparities in genetic testing in men with prostate cancer given the shared genetic factors that may contribute to cancer development and pathogenesis. Several studies have highlighted the racial and ethnic disparities that exist in germline genetic testing, specifically in the prostate cancer population.

A study of 867 patients with metastatic prostate cancer evaluated the rates of pathogenic variants, likely pathogenic variants, and VUS in cancer genes among patients that identified as Caucasian and African American. They showed that the pathogenic and likely pathogenic variants of known cancer genes did not vary by race, however the rates of VUS were higher in the African American group (57).

This effect has also been shown in studies involving larger databases from a commercial provider of germline testing, Color Genomics™. One study using genetic testing from Color analyzed 1351 men with prostate cancer at any stage who underwent germline testing; 78% of these men identified as Caucasian, 11% as Ashkenazi Jewish, 3% as African American/Canadian, 2% as Hispanic, 2% as Asian/Pacific Islander, and 4% as other. The rates of pathogenic variants, likely pathogenic variants, and VUS were compared by race. There were higher rates of VUS in the African American/Canadian, Hispanic, and Asian/Pacific Islander population (58). Another analysis using data from Color Genomics, this time using publicly available, de-idenfied data from 50,000 individuals within the Color Genomics database, was conducted in 2019. This analysis revealed that among individuals who had no personal history of cancer, most identified as European. The pathogenic variant, likely pathogenic variant, and VUS rate was also compared in this study, and found that among the hereditary breast and ovarian cancer syndrome, Lynch syndrome genes, and the “other cancer gene” groups, the rate of VUS was higher in the non-European groups (which included African American, Hispanic, and Asian & Pacific Islander populations) (59).

These studies highlight the disparities in genetic testing that already exist in prostate cancer; in particular with the demonstrated higher rates of VUS, raising the question of inadequate representation among these groups in these larger databases. In order to identify more pathogenic variants among these groups and provide better-informed screening recommendations, improved representation in these larger databases will be imperative. The reasons for these disparities in genetic testing are multifactorial and involve systematic, educational, and workforce issues, well-highlighted in this recent review (60).

IMPORTANCE OF CASCADE GENETIC TESTING:

An important concept within the field of genetic testing is cascade testing, or testing family members of an individual who has tested positive for a pathogenic germline variant that may be an inherited cancer risk for family members. With the widespread use of germline genetic testing in prostate cancer, it is becoming more common for an individual with prostate cancer to be the proband in that family. It is important to identify all possibly affected family members and refer them for genetic counseling and testing, to inform their own cancer risks and screening initiation. For example, this could include opportunities for early detection and risk reduction for women found to have germline mutations (pathogenic variants) in cancer predisposition genes such as BRCA1 and BRCA2 through cascade testing, and may prove to be life-saving.

CLINICAL PRACTICE IMPLICATIONS:

Germline genetic testing may lead to the identification of a germline mutation that may have treatment implications. There has been mounting evidence suggesting the sensitivity of homologous recombination-deficient prostate cancers to platinum chemotherapy (60-62).

The results of the TOPARP-A trial (63) introduced evidence of the efficacy of PARP inhibitors in patients with metastatic prostate cancer who harbored mutations in DNA repair genes in a limited sample of patients. Since then, the FDA has approved two PARP inhibitors for use in patients with metastatic prostate cancer with DNA repair mutations. Rucaparib was studied in the phase II TRITON study (64), and showed a 51% radiographic response rate in patients with metastatic castrate resistant prostate cancer (mCRPC) and BRCA1 and BRCA2 alterations. Notably, the response rate for patients with DNA repair alterations aside from BRCA1 and BRCA2 had a much lower response rate at only 13%, and thus are not included in rucaparib’s label (64-65). Olaparib was evaluated by the phase III ProFOUND study, and enrolled patients with DNA repair alterations and prostate cancer who had progressed on at least one line of AR-targeted therapy, and treated them with another AR-targeted agent or Olaparib. Olaparib was shown to have a higher progression free survival at 5.8 months vs. 3.5 months, and is approved for patients with metastatic castrate resistant prostate cancer and a mutation in BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L (66).

Immunotherapy may also be considered in patients with mCRPC. A phase II KEYNOTE-199 prospectively evaluated pembrolizumab in mCRPC (not selected for biomarkers), and showed a 5% radiographic response rate with a 16.8 month median duration of response, suggesting a durable response (67). Another retrospective study showed that 53% of patients with mCRPC and mismatch repair deficiency or microsatellite instability had a 50% decrease in their PSA (68).

Notably, there is not consistent evidence to suggest that patients with DNA repair alterations do not also have a good response to conventional therapies that are not biomarker-selected (6-8,69-70). Treatments such as abiraterone, enzalutamide, and taxanes are similarly effective in carriers of BRCA2 mutations and non-carriers, as shown by the PROREPAIR-B study (6), however, more research is needed for this. Registry studies such as the ongoing PROMISE study (NCT04995198) are vital to continue expanding this knowledge.

CONCLUSIONS:

Germline genetic testing has become more widespread in prostate cancer, due to studies reporting the clinically significant prevalence of germline DNA repair alterations. These studies have led to the incorporation of germline genetic testing into prostate cancer guidelines. Information about germline genetics can have impacts on treatments available for patients with prostate cancer, and inform screening and testing for their family members. Ongoing research in this field will lead to continued advancement in how we treat patients with prostate cancer and their families.