Prostate cancer is a significant cause of male cancer deaths [1]. Approximately one in eight men who are diagnosed with prostate cancer will die of it ^[2][3][2,3]. It is well established that certain germline pathogenic variants confer an increased risk of both being diagnosed and dying of prostate cancer ^[4][5][4,5]. Contemporary data demonstrate that variants that disrupt the function of genes involved in DNA damage repair (e.g., BRCA 1 and BRCA 2) are associated with aggressive prostate cancer ^[6][7][8][6,7,8]. The risk of metastatic disease is particularly striking among BRCA 2 carriers. Furthermore, the identification of germline mutations in hereditary prostate cancer genes can help identify family members at high risk of cancer, providing the opportunity to pursue targeted genetic testing, tailored screening, and risk-reducing approaches along with the opportunity for personalized treatment recommendations.

While germline mutations are relatively rare, it is likely that they account for a significant proportion of population level risk burden beyond traditional factors (e.g., age and African heritage). Various testing panels assess many germline mutations, but we will consider the main elevation in prostate cancer risk will be considered to occur among individuals with germline mutations in (1)  BRCA 1, (2) BRCA 2, (3) ATM, (4) CHECK 2, and (5) HOX B13. Estimates of the prevalence for each of these genes vary between 0.3 to 1.2% within the general population ^{[9][10][11][12]}[9,10,11,12] but are much higher among individuals with prostate cancer [4]. Pritchard et al. identified that among men with metastatic prostate cancer, 11.8% had at least one presumed pathogenic germline mutation. Furthermore, they found that having a germline mutation was associated with a significantly increased risk of prostate cancer metastases (varying from a nonsignificant relative risk (RR) for ATM mutation (RR: 1.6 (95% CI: 0.8–2.8) to highly significant for individuals with BRCA 2 mutations (RR: 26.7 (95% CI: 18.9–36.4)). Among those with germline mutations, 71% had a first-degree relative with prostate cancer. Clearly while these mutations are relatively rare in the general population, these individuals are at significantly increased risk to develop prostate cancer and disproportionately contribute to the burden of prostate cancer deaths.

2. The Possibillity for the Prevention of Prostate Cancer among Individuals with an Identified High-Risk Germline Mutation

There is no approved medical agent for the prevention of prostate cancer. Numerous randomized control trials were performed on potential agents including the 5-alpha reductase inhibitors (which act at the prostate gland to block the action of androgens in the prostate, e.g., Dutasteride and Finasteride), medications which manipulate the hormonal axis (e.g., Toremifene), nonsteroidal anti-inflammatory drugs (e.g., Refocoxib), and a number of nutritional supplements (e.g., Selenium, Vitamin E, and Soy). Results of these trials were mixed, with some being stopped because of cardiovascular toxicity (e.g., Refocixib ^[13][19]), some trials showing increased prostate cancer risk (e.g., Vitamin E ^[14][20]), and, most famously, two trials that showed a decreased risk of prostate cancer overall but an increased high grade disease in the treatment arm (PCPT and REDUCE trials ^[15][16][21,22]). This last association resulted in a US Federal Drug Agency black box warning for these medications ^[17][23]. There are several theories regarding the cause for this association ^[18][24], but these medications are not routinely used for prostate cancer prevention. Recently, there has been renewed interest in exploring the role of statins and metformin in the prevention of prostate cancer development, progression, and death ^[19][20][25,26], and while these agents have considerable promise for the general population, their specific effectiveness in individuals with high-risk germline mutations has not been evaluated.

3. Types of Prostate Cancer Screening Protocols for Men with Identified High-Risk Germline Mutations

Prostate cancer screening in the general population has been controversial. The discovery of the serum prostate specific antigen (PSA) in the early 1990s resulted in a sudden increase in population screening for prostate cancer with associated aggressive treatment that resulted in overtreatment among certain populations ^[21][29]. Three large-scale randomized control trials were performed with mixed results. The European ERSPC and Gotenberg studies found a 20–30% and 42% relative reduction in prostate cancer mortality ^[22][23][30,31], while the US PLCO trial showed no difference between the treatment and control arm (largely attributed to the presence of contamination of the control arm ^[24][32]). The results of these three trials resulted in the US preventative task force’s recommendation against PSA screening ^[25][33]. This has been subsequently updated to a recommendation for a discussion of the risks and benefits of screening in men aged between 55 and 69 and against screening for men over 70. It is important to recognize that these recommendations do not apply to men at increased risk for the development of prostate cancer. Several organizations provide specific recommendations regarding screening for men at increased risk including the American Urological Association (AUA) and National Comprehensive Cancer Network (NCCN) and the American Cancer Society (ACS). The AUA recommended that men at increased risk discuss their individual cases with their doctors and states that their recommendations do not apply to men at increased risk. NCCN recommends that men with a germline mutation in BRCA 1 and BRCA 2 consider beginning shared decision making about PSA screening at the age of 40 and to consider annual screening ^[26][14]. ACS recommends starting a discussion about screening at the age of 40 for men at higher risk (e.g., those with more than one first degree relative who had prostate cancer at an early age) ^[27][34].

4. Focal or Whole Gland Minimally Invasive Treatments for Prostate Cancer

Numerous alternatives to “traditional” treatments (e.g., surgery or radiotherapy/brachytherapy) for localized prostate cancer exist and include cryotherapy, high-intensity frequency ultrasound, and focal therapy options (e.g., partial prostate ablation with laser). These treatments are advantageous as they can be offered in patients who desire to avoid the side effect profile of traditional treatments. Currently, these treatments only have a conditional recommendation for the treatment of low or intermediate favorable prostate cancer as per the AUA/ASTRO/SUO risk stratification ^[28][41], with many being considered experimental in the standard patient population. When considering minimally invasive treatments for prostate cancer, it is essential to differentiate between focal versus whole gland ablative therapies. A review of the broad range of potential treatment options is outside of the scope of herthis article, but it iswe do not believed that individuals with high-risk germline mutations are candidates for focal treatments as the entirety of this prostate should be considered “at risk” for subsequent disease development and potential for metastatic spread. There is a need for more research in this area. At this time, given that these treatments are experimental for individuals without germline mutations, whole gland ablative treatments should not be offered to individuals with a high-risk germline mutation outside the context of a clinical trial.

56. The Preferred Treatment for Clinically Localized Prostate Cancer among Men with High-Risk Germline Mutations

Traditional treatments for localized prostate cancer broadly include surgery or radiotherapy. The efficacy and side effect profile has been well established for both surgery and radiotherapy ^[29][43]. Studies of the effectiveness of surgery or radiotherapy for individuals with high-risk germline mutations are all retrospective. Castro et al. [6] examined the tumor features and outcomes of 2019 patients with prostate cancer, which included 18 BRCA 1 and 61 BRCA 2 carriers. They found that BRCA mutation carriers were more likely to be diagnosed with high-risk disease (Gleason Grade group ≤ 4), advanced clinical stage disease (T3/4), involvement of local lymph nodes, or with metastatic disease at diagnosis. Five-year Cancer specific survival (CSS) and metastases-free survival (MFS) were significant improved in noncarriers compared to carriers (CSS: 96% vs. 82% MFS: 93% vs. 77%) [6].

Special discussion should be made for ATM mutation carriers and the risks of radiotherapy. Early work on the relationship between ATM mutations and prostate cancer found that there was a strong association between late complications of external beam radiotherapy and mutations of this gene ^[30][31][45,46]. Subsequent work has demonstrated that there is potential for increased therapeutic efficacy of radiotherapy, but, for known ATM, carriers care must be taken to minimize radiation dose to prevent toxicity or the potential for secondary malignancies ^[32][47]. The evidence around late toxicity and second malignancy is scant for the other germline mutations, but the best evidence in BRCA 1/2 carriers does not suggest any increased risk ^[33][48].

67. The Preferred Treatment for Disease Recurrence Post-Definitive Prostate Cancer Treatments in Men with High-Risk Germline Mutations

All definitions of disease recurrence post-surgery or radiotherapy rely on PSA definitions. After surgery, the most adopted definition is a PSA rise to 0.2 ng/mL or greater with a second confirmatory value ^[34][49]. After radiotherapy, the most accepted definition for recurrence is PSA nadir (baseline PSA level after stabilization post radiotherapy) plus 2 ng/mL ^[35][50]. Approximately 30–50% of patients will develop biochemical recurrence after surgery or radiotherapy ^[36][37][38][51,52,53]. While the natural history of progression to metastatic disease is dependent on multiple risk factors, many men have an indolent disease course. Commonly utilized treatments for biochemical recurrence include salvage radiotherapy with androgen deprivation after surgery and typically androgen deprivation therapy after radiotherapy. Individuals with these germline high risk mutations are at increased risk to have poor prognostic disease at presentation, node positive disease, and to have metastatic disease [6]; thus, these individuals are at increased risk for biochemical recurrence after PSA nadirs or even to have PSAs remain detectable after surgical management. Given that these individuals have different responses to therapy than noncarriers, they may be candidates for early cisplatin-based chemotherapy, early use of Poly (ADP-ribose) polymerase (PARP) inhibitors, or early androgen deprivation therapy. While there is recent evidence that adjuvant radiotherapy is no better than early salvage radiotherapy among a non-selected population with adverse pathologic features post-surgical management ^[39][54], these results should be interpreted with caution in high-risk germline carriers who may benefit from earlier and more aggressive treatment.

78. The Optimal Treatment and Sequencing for Men with High-Risk Germline Mutations Who Develop Metastatic Prostate Cancer

Approximately 5% of men present with (de novo) metastatic prostate cancer at diagnosis. Sixty-five percent % of men with biochemical recurrence after surgery will also develop metastatic prostate cancer in 10 years ^[40][55]. The current 5-year prostate-specific survival with metastatic prostate cancer is 29% ^[41][56]. The conventional treatment for metastatic prostate cancer is androgen deprivation therapy, which has resulted in the distinction between castrate sensitive (responds to androgen blockage) and castrate resistant (PSA risk or radiographic evidence of progression of disease) metastatic prostate cancer. Historically, 10–20% of patients with metastatic prostate cancer develop castrate resistance within 5-years ^[42][57] at a median time between 13 and 19 months ^[43][58]. For high-risk germline carriers, it is known that they are at risk of progressing from castrate sensitive to resistant metastatic disease earlier than noncarriers ^[44][45][46][59,60,61]. Once carriers progress to castrate resistance, there are mixed data about how they perform compared to noncarriers. Several retrospective studies showed that patients with castrate resistance either have worse overall survival ^[44][59], have better progression free survival ^[47][62], or that there is no difference compared to non-carriers [4]. This could be a consequence of differences in disease burden or their treatment with either cisplatin-based chemotherapy or PARP inhibitors. PROREPAIR-B ^[45][60] is an ongoing prospective study for evaluating the outcomes of patients with metastatic castrate resistant prostate cancer. They have demonstrated that mutations in BCRA 2 have worse outcomes, but the association is not clear in other germline mutations.

89. Conclusions

The recommendations for clinical considerations based on the low-level of evidence are summarized in Table 13. The identification and paradigm for managing patients with genetic mutations and prostate cancer prevention and therapy will evolve in the coming decade. Aside from the role of PARP inhibition in CRPC, novel data are required to provide level 1 guidance. 

Clinical Question	Clinical Consideration	Level of Evidence/Justification
Which prostate cancer patient should be tested for a germline genetic mutation?	As per standing prostate cancer germline testing guidelines, all men who meet NCCN guidelines should undergo germline genetic testing using an accepted laboratory method (Table 1).	Clinical guidelines on appropriate populations for testing are well established and consistent across guidelines from several organizations.
Are there any methods for the prevention of prostate cancer among individuals with an identified high-risk germline mutation?	Currently, no agents are accepted for the prevention of prostate cancer among individuals at average or high risk.	Extensive research has been performed on medication prevention of prostate cancer but has not been performed in high-risk genetic populations.
What types of prostate cancer screening protocols should men with identified high-risk germline mutations undergo?	These men should consider earlier screening including regular PSA and MR follow-up with a low threshold for prostate biopsy.	Level 1 evidence is accumulating regarding this question and indicates that more intensive screening among these individuals is justified.
Are men with high-risk germline mutations candidates for active surveillance treatment protocols?	Men with high-risk germline mutations should not be eligible for active surveillance treatments using traditional selection criteria.	There is very little research in this area and, thus, active surveillance should be considered only in clinical trials for these populations.
Are men with high-risk germline mutations good candidates for either focal or whole gland minimally invasive treatments for their prostate cancer?	Focal or whole gland ablative therapies are considered experimental and so should not be routinely offered to men with high-risk germline mutations outside the context of a clinical trial.	Should be considered only in clinical trials for these populations.
What is the preferred treatment for clinically localized prostate cancer among men with high-risk germline mutations?	High-risk germline mutation carriers should be offered escalated treatment for their prostate cancer above what is typically recommended for noncarriers by clinical parameters (e.g., biopsy result, PSA).	Only retrospective evidence exists regarding this issue and thus these men should be considered to be at high-risk for disease recurrence and progression.
What is the preferred treatment for disease recurrence (e.g., biochemical recurrence) post-definitive prostate cancer treatments in men with high-risk germline mutations?	Men identified with a high-risk germline mutations with recurrent prostate cancer should be treated using an escalated approach compared to men at average risk of prostate cancer.	Only retrospective evidence exists regarding this issue and, thus, these men should be considered to be at high-risk for disease progression and death from prostate cancer.
What is the optimal treatment and sequencing for men with high-risk germline mutations who develop metastatic prostate cancer?	Individuals with a high-risk germline mutation should consider enrolling in a clinical trial to establish the optimal sequencing of agents in this population.	Level 1 evidence is accumulating for the use of these agents in high-risk populations but ideal sequencing is still under investigation.