Elsevier

Cancer Treatment Reviews

Volume 81, December 2019, 101927
Cancer Treatment Reviews

Hot Topic
Hereditary prostate cancer – Primetime for genetic testing?

https://doi.org/10.1016/j.ctrv.2019.101927Get rights and content

Highlights

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    The proportion of all PCa attributable to high-risk hereditary factors is 5–15%

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    Germline mutations/alterations, single nucleotide polymorphisms or copy number variations are associated with PCa incidence and progression.

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    New technologies led to the evolvement of different commercially available tests for genetic testing.

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    Genetic profiling helps to treat PCa patients in a personalized manner.

Abstract

Prostate cancer (PCa) remains the most common cancer in men. The proportion of all PCa attributable to high-risk hereditary factors has been estimated to 5–15%.

Recent landmark discoveries in PCa genetics led to the identification of germline mutations/alterations (eg. BRCA1, BRCA2, ATM or HOXB13), single nucleotide polymorphisms or copy number variations associated with PCa incidence and progression. However, offering germline testing to men with an assumed hereditary component is currently controversial.

In the present review article, we provide an overview about the epidemiology and the genetic basis of PCa predisposition and critically discuss the significance and consequence in the clinical routine. In addition, we give an overview about genetic tests and report latest findings from ongoing clinical studies.

Lastly, we discuss the impact of genetic testing in personalized therapy in advanced stages of the disease.

Introduction

Prostate cancer (PCa) is the most prevalent cancer in men and one of the predominant causes of death among men in European countries [1]. While most PCa remain localized, a subset will be aggressive, leading to metastasis formation associated with significant morbidity and mortality. Thus, one major issue in PCa research is to early detect those patients who are likely to harbor an aggressive variant of PCa at young age importantly needing an active anti-cancer treatment.

Large epidemiological studies described that family history is an important risk factor for PCa incidence hence suggesting a genetic component. Genome wide association studies identified around 100 susceptibility loci that contribute to the risk of PCa development and it has been postulated that these loci account for up to 38.9% of the familial risk for PCa [2], [3]. According to current guidelines, positive family history is defined as three or more relatives with PCa, or at least two relatives who have developed early-onset PCa defined as diagnosis at age of 55 or less [4], [5].

Besides the hereditary PCa incidence component, genetic alterations in deoxyribonucleic acid (DNA) repair systems are found in 20% of metastatic castration resistant PCa (mCRPC) patients and emerging data suggest that they may predict therapeutic responses to developing therapies like Poly-ADP-Ribose-Polymerase (PARP) inhibition or immunotherapy leading to improved treatment strategies [6].

In the present review article, we provide an overview about the epidemiology and the genetic basis of PCa predisposition and critically discuss the significance and consequence in the clinical routine. In addition, we give an overview about genetic tests and report latest findings from ongoing clinical studies. Lastly we discuss the impact of genetic testing in personalized medicine in mCRPC.

Section snippets

Epidemiology

Familial history is a well-established risk factor for the development of PCa. Approximately 10–15% of men with PCa have at least one relative who is also affected by PCa. Large epidemiologic studies have demonstrated that men who have a their first-degree relative (father and/or brother) with PCa are at increased risk of developing the disease [7], [8], [9], [10]. Data from more than heterozygous and homozygous twins showed a PCa heritability index of varying from 42 to 58% depending on the

Association of prostate cancer with hereditary cancers

Several epidemiological studies have demonstrated that an association of prostate and breast cancer can be present in certain families. The Breast Cancer Linkage Consortium evaluated 173 breast/ovarian families with a BReast CAncer Gene (BRCA2) mutation and showed a significantly increased risk for PCa (RR = 4.65). This risk was considered even higher before age of 65 (RR = 7.33) with an estimated cumulative incidence of 7.5%–33%, depending on the population used as reference. Statistically

Germline mutation/alterations

Generally, the prevalence of inherited alterations in DNA-repair genes in healthy men and in localized PCa unselected for genetic background is relatively low with a percentage of 2.7% and 4.6% respectively. A recent milestone study by Pritchard and collaborators including 692 males with metastasized disease demonstrated that 11.8% of them harbored germline mutations in 16 genes [33], [34]. Related to the whole number of mutations, those involving BRCA2 (44%), ataxia teleangiectasia mutated

Genetic screening for hereditary prostate cancer

In general, screening for hereditary PCa can have major clinical implications considering the fact that PCa has a certain degree of heritability even mimicking autosomal dominant pathways [13]. Nevertheless, most PCa occur in a sporadic manner, thus screening for hereditary PCa should be focused on specific clinical scenarios leading to the fact that compared to other tumor entities like breast or colorectal cancer genetic counseling in PCa is still in its infancy [5]. However, is it well

Surveillance strategies for high risk patients after local therapy

A special focus should be set on patients with a confirmed hereditary component in the surveillance after primary local therapy. More than 20 years ago, Kupelian and colleagues reported 3-year rates of freedom from biochemical PSA recurrence (BCR) of 52% and 72% in men with and without a family history of PCa, respectively. The 5-year BCR was 52% for men without a family history of PCa and 29% for men with such a history [78]. Also a recent German study evaluated the difference in clinical

Genetic testing for precision oncology in mCRPC patients

In the past years the treatment landscape of mCRPC expanded leading to the fact that several different drugs like chemotherapeutic agents, or hormonal therapies are approved in the same therapy line claiming for appropriate biomarkers for therapy response [85], [86]. In this context, genetic testing can harbor a major impact on therapy decisions. Some years ago, a multi-institutional integrated sequencing analysis of 150 PCa patients demonstrated that 23% of mCRPC harbor DNA repair pathway

Genetic alterations across ethnicities

Generally, most genetic studies have been performed in European and Asian populations, while studies of genetic susceptibility in African descent populations are limited. However, there are strong hints that genetic etiology differs among population diversity. For example, it has been shown that SNPs that had been previously reported in white or Asian populations were not replicated in Afro-American men [93]. In line with this trial also other GWAS studies did not replicate most of the

Ongoing clinical trials

To identify relevant ongoing trials related to this topic, we searched recruiting and not yet recruiting trials in ClinicalTrials.gov (https://clinicaltrials.gov/ct2/home). The terms “germline”, “hereditary”, or “genetic mutations” were used in association with “prostate cancer”. The following information was abstracted from ClinicalTrials.gov and analyzed: title, sponsor, status, objective, primary and secondary outcomes, and eligibility criteria.

A trial (NCT00959023) led by Institute of

Conclusion

It is well recognized that genetic predisposition represents an important risk factor for PCa development and progression. Various recent studies suggest a hereditary component in 8 to 12% of PCa cases mostly associated with germline mutations or alterations in genes like BRCA1, BRCA2, HOXB13 or DNA MMR genes. Moreover, SNPs and copy number variations are discussed as drivers for PCa development and progression. Early onset of aggressive PCa combined with family members also suffering from PCa

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of Competing Interest

None regarding the topic of this article.

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