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Hereditary Prostate Cancer: History
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Subjects: Oncology
Contributor: Maria Teresa Vietri

Hereditary prostate cancer (HPCa) has the highest heritability of any major cancer in men. The proportion of PCa attributable to hereditary factors has been estimated in the range of 5–15%. To date, the genes more consistently associated to HPCa susceptibility include mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) and homologous recombination genes (BRCA1/2, ATM, PALB2, CHEK2). Additional genes are also recommended to be integrated into specific research, including HOXB13, BRP1 and NSB1. Importantly, BRCA1/BRCA2 and ATM mutated patients potentially benefit from Poly (ADP-ribose) polymerase PARP inhibitors, through a mechanism of synthetic lethality, causing selective tumor cell cytotoxicity in cell lines. Moreover, the detection of germline alterations in MMR genes has therapeutic implications, as it may help to predict immunotherapy benefits.

  • hereditary prostate cancer
  • genetic testing
  • genotype–phenotype correlation
  • surveillance

1. Introduction

Prostate cancer (PCa) is globally the second most diagnosed cancer type in men [1] and the most common cause of cancer-related deaths, with an estimated 1,600,000 cases and 366,000 deaths annually [2]. Established risk factors include older age, African American race, and a positive family history of PCa [3].

PCa is clinically a very heterogeneous disease; indeed, many patients show an aggressive disease with progression and metastasis while other patients show a slow disease with low propensity to progression [2]. Histologically, these tumors are measured in terms of the Gleason score that evaluates how much the biotic prostatic specimen is similar to the normal prostate gland [2].

Compared to sporadic cases, HPCa is characterized by an early age onset, an aggressive disease progress and locally advanced stage. Furthermore, men with HPCa have a higher risk of recurrence after surgery, while there is not much difference between HPCa and sporadic PCa regarding overall survival [4].

Family history of PCa, hereditary breast and ovarian cancer (HBOC) syndrome and Lynch syndrome (LS) are among the most important risk factors compared to age, race, ethnicity and environmental factors for the development of PCa [5][6][7][8][9] and this risk is estimated at 40%−50 % [3]. Men with a brother or father diagnosed with prostate cancer have a two- to four-fold greater risk of developing PCa [10].

Hereditary prostate cancer (HPCa) has the highest heritability of any major cancer in men [11]. Since PCa is asymptomatic in the early stage of the disease, it is critical to develop an individualized approach for early detection [12]. Patients with early onset of PCa associated to family members affected with PCa or other heritable cancers are suitable candidates to undergo a genetic testing [6]. Over time, about 170 susceptibility loci for HPCa, accounting for ~33% of familial prostate cancer risks, have been identified with genome wide association studies (GWAS) [13][14]. Further insights have suggested that mutations in the different DNA damage repair (DDR) genes (BRCA1, BRCA2, CHEK2, ATM and PALB2) and in the DNA mismatch repair genes (MMR) (MLH1, MSH2, MSH6 and PMS2), are biomarkers of HPCa [6][15][16]. Importantly, while many genes have a clear association with HPCa risk, others carry a still unknown clinical significance with a poorly defined cancer risk [16]. Besides, there is strong emerging evidence that mutation in some genes may predict the response to poly-ADO ribose polymerase (PARP) inhibitors and platinum-based chemotherapy in prostate cancer [17].

2. Therapeutic Target

The therapeutic landscape of PCa is constantly evolving thanks to clinical trial benefits, new therapeutics, use of NGS, advanced functional imaging and the better use of existing therapies in the early-stage disease. PCa initiation and disease progression are driven by AR signaling [18]. It is known that the PCa is unique in its dependence on androgen for growth and progression, and androgen deprivation therapy (ADT) is an effective treatment for patients with advanced disease over 75 years [19]. However, when a castration-resistant state occurs, the patient is more likely to die of PCa than other causes [20]. Alterations in AR signaling in metastatic castration resistant PCa (mCRPC) cause persistent AR activation, which in turn leads to AR amplification, AR splice variants and intra-tumoral androgen biosynthesis [19]. Therapeutic strategies involve the use of enzalutamide, an AR antagonist that blocks AR translocation function, and abiraterone which inhibits androgen biosynthesis [21].

Recently, mCRPC patients with germline defects in DNA damage repair showed a decreased response to AR targeted therapy [6]. In contrast, other authors reported an improved response to second generation ADT with administration of drugs, including abiraterone or enzalutamide, in men with BRCA or ATM mutations compared to those without deleterious germline mutations [21].

Thus, the mutation status of genes involved in HPCa may have an impact on therapeutic strategies [16][22]. For instance, mutated patients potentially benefit from PARP inhibitors such as Olaparib, rucaparib, niraparib and telazoparib [1][23], through a mechanism of synthetic lethality, causing selective tumor cell cytotoxicity in cell lines.

The Food and Drug Administration (FDA) approved the drug Olaparib for the treatment of patients with mCRPC, mutated in BRCA1/BRCA2 and ATM genes. In line with previously described results, in patients with germinal BRCA2 or ATM mutations, treatment with the PARP inhibitor Olaparib has a durable antitumor activity [24]. Moreover, based on further studies, PARP inhibitor rucaparib was also added for mCRPC patients with deleterious BRCA alterations previously treated with ADT, but not for patients with ATM mutations [25]. Besides, other studies have shown that the presence of DDR defects may also be predictive of a higher likelihood of a response to carboplatin-based chemotherapy in patients with mCRPC [26].

The detection of germline alterations in MMR genes also has therapeutic implications, as it may help to predict immunotherapy benefits. Recent studies have suggested that metastatic PCa patients with germline MMR pathogenic variants may have a particular sensitivity to hormonal therapies, as well as a possible response to PD−1 inhibitors [27]. Additional clinical studies reported either a complete or a partial response to PD−1 inhibitors in mCRPC patients [28]. Based on these findings, the FDA has recently approved the PD−1 inhibitor pembrolizumab (KEYTRUDA) for the treatment of patients with microsatellite instability-high (MSI-H)/MMR-deficient [29]. The use of genetically based therapies sustains the importance of applying genetic testing in the clinical management of these PCa patients.

The PD−1 pathway includes the programmed death protein−1 (PD−1) and its ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC). This pathway has emerged as a mechanism for immune tolerance whereby tumor cells can suppress an antitumor immune response. Taking into account the high aggressivity of PCa, particularly mCRPC, and the success of PD−1/PD-L1 blockade in other cancers, patients with mCRPC could benefit from correct modulation of the immune system and, hence, from the use of checkpoint inhibitors [23]. The activity of the checkpoint inhibitors is limited to a certain percentage of patients, depending on the tumor type. This is especially important in tumors with low objective response rates to immunotherapy, such as PCa. Tumor cell PD-L1 expression is a predictive biomarker for PD−1 inhibitor sensitivity. Examples of subgroups of PCa patients with enriched PD-L1 expression are patients with aggressive tumors and with tumors harboring somatic or germline DDR mutations, including patients with HPCa. The presence of DDR or MMR mutations may favor the activity of checkpoint immunotherapy. Therefore, the use of PD−1/PD-L1 inhibitors for advanced prostate cancer should be encouraged in the setting of clinical trials and to identify the patient subgroups that can benefit from these therapies. Furthermore, it would be interesting and useful to develop a biomarker panel to predict benefit and response of these and other checkpoint inhibitors [29].

Current National Comprehensive Cancer Network (NCCN) guidelines recommend three gene expression-based tests for PCa prognosis in men with low or favorable intermediate risk disease: Decipher, Oncotype DX Prostate, and Prolaris [30]. Particularly, the current recommendations evaluate the role of each of the panels in both prostate biopsy and post-surgery settings. Overall, these tests provide more precise estimates of disease aggressiveness, beyond clinical factors, and they could help to guide on appropriate disease management and therapy. Thus, they could also be used for active surveillance in HPCa. Among the current commercially available tests are ExoDx and Liquid CDx. The test ExoDxTM Prostate (IntelliScore) detects RNA from three genes (ERG, PCA3, and SPDEF) that have been linked to the development and progression of prostate cancer. The RNA is encapsulated in lipid membrane-coated structures called exosomes that are excreted by cancer cells into urine. FoundationOne Liquid CDx is an FDA-approved next generation sequencing-based in vitro diagnostic device that targets 324 genes utilizing circulating cell-free DNA (cfDNA) isolated from plasma derived from the anti-coagulated peripheral whole blood of cancer patients [31]. The latter test includes HPCa related genes. The detection of a mutation and, hence, of a positivity to the somatic test in the genes related to HPCa, must be confirmed in the germline. In this way, identifying the mutation in the HPCa susceptibility gene, the test allows an early diagnosis of HPCa.

3. Conclusions

HPCa remains an important clinical entity, with a spectrum of epidemiologic and genetic risk factors. Advances in NGS sequencing will allow new discoveries of PCa genetic predisposition. A more accurate knowledge of the mechanisms of HPCa predisposition could be brought by individualized PCa screening and treatment. As for the main cancer predisposition syndromes, including Lynch and HBOC, commercial NGS panels contain a large number of cancer susceptibility genes to detect mutations in patients with inherited cancer predisposing syndromes [32][33]. This useful approach has the advantage of being cost effective and to have a relatively feasible handling of raw data through validated bioinformatics pipelines; moreover, the detection of VUS, which are difficult to interpret in the clinical management, is quite limited [32][33]. Noteworthy, targeted sequencing of 94 cancer genes has also been recently used in probands with early onset/familial prostate cancer and has allowed successful identification of novel putative PCa predisposing germline mutations [34]. However, by multigene panels genetic testing, between 70–92% of patients (depending on the cancer syndrome), still remain mutation-negative or undiagnosed [33][35]. Thus, the use of Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) strategies will be the preferred method in the near future when decreased costs and improved pipeline analyses will also make these strategies more suitable in the clinical setting. In this context, NGS methods will be useful even in searching for novel common variants conferring small to modest effect sizes by GWAS in patients with PCa predisposition [36]. Furthermore, approaches like RNA sequencing may allow the identification of genetic causes that are not recognizable by genomic DNA screening [33].

The liquid biopsy approach could allow not only an early diagnosis but also an analysis of the genetic tumor characteristics that are already present and that are relevant to providing the best therapy. For instance, molecular testing is able to identify patients who could benefit from PARPi treatment or platinum chemotherapy and to determine the cancer risk in family members. Current ongoing clinical trials may provide new indications on combinations of PARPi and immune checkpoint inhibitors with alterations in MMR and HR genes. To date, guidelines give no uniformed recommendations on which patients should undergo genetic testing and, at the same time, on the tests to be performed. Therefore, a clear policy regarding genetic testing could point to a more accurate active surveillance as a management strategy for patients with low-risk PCa.

This entry is adapted from the peer-reviewed paper 10.3390/ijms22073753

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