Precision Molecular Pathology of Prostate Cancer

By Jae Y. Ro

This volume focuses on our current understanding of the molecular underpinnings of prostate cancer and their potential application for precision medicine approaches.  The emergence and applications of new technologies has allowed for a rapid expansion of our understanding of the molecular basis of prostate cancer and has revealed a remarkable genetic heterogeneity that may underlie the clinically variable behavior of the disease.  The book consists of five sections which provide insight about the following: (1) General principles; (2) Molecular signatures of primary prostate cancer; (3) Molecular signatures of advanced prostate cancer; (4) Key molecular pathways in prostate cancer development and progression; (5) and Precision medicine approach: Diagnosis, treatment, prognosis.  Precision Molecular Pathology of Prostate Cancer is an important resource for the practicing oncologist, urologist, and pathologist, and will also be useful for researchers in the prostate cancer community.

• Language: English
• Publisher: Springer
• Release date: Feb 13, 2018
• ISBN: 9783319640969

Book preview

Part IGeneral Principles

© Springer International Publishing AG 2018

Brian D. Robinson, Juan Miguel Mosquera, Jae Y. Ro and Mukul Divatia (eds.)Precision Molecular Pathology of Prostate CancerMolecular Pathology Libraryhttps://doi.org/10.1007/978-3-319-64096-9_1

1. Precision Medicine in Prostate Cancer: Approach to the Patient

Beerinder S. Karir¹, Bishoy M. Faltas¹ and Scott T. Tagawa¹  

(1)

Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA

Scott T. Tagawa

Email: [e-mail]

Introduction

Precision Medicine in Prostate Cancer

Initial Clinical Encounter

Tissue for Genomic Profiling and Need for Serial Biopsies

Understanding Precision Medicine Reports

Communicating Genomic Information to Clinicians and Patients

Unique Issues Related to Incidental Discovery of Germline Mutations

Future Direction

Resources for Patients and Clinicians

References

Keywords

Next-generation sequencingPrecision medicineGenomic profilingPatient preferencesData privacy

Introduction

The advent of genomic discoveries and decreasing cost of next-generation sequencing (NGS) technologies has ushered in a new era of precision medicine [1]. The early effects of this paradigm shift in oncology are beginning to impact patient care and thus increase the relevance of a discussion on the approach to patients with prostate cancer (PC). Bringing the application of precision medicine to the clinic raises new challenges related to informed consent prior to testing, effectively communicating the results of cancer genomic testing to the patient, understanding and managing the patient’s expectations, and working with the patient to select the best treatment options based on genomic tests (or not) [2, 3]. This introductory chapter will cover the approach to men with PC undergoing genomic testing of their tumors (see Table 1.1 for summary).

Table 1.1

Summary: approach to patient

Precision Medicine in Prostate Cancer

Prostate cancer (PC) is the most common non-skin cancer and the second leading cause of cancer death in men in the United States [4]. This disease is on the forefront of precision medicine with multiple opportunities for benefiting from translational genomics [5]. While any given man might benefit from individualized tumor testing, two very important clinical subsets within PC that might benefit most from additional molecular analysis are patients with clinically localized indolent disease that are probably best served without treatment and those with more aggressive, particularly advanced disease with no curative therapy.

Newly Diagnosed Prostate Cancer

Every year more than 1,000,000 men in the United States undergo prostatic biopsies based on elevated levels of prostate-specific antigen (PSA) . Among the newly diagnosed PC patients, many patients have clinically diagnosed (presumed) low-volume and low- to intermediate-risk Gleason scores (3 + 3 or 3 + 4 in a small percent of cores). This subset of PC patients presents a clinical dilemma for patients and their treating physicians. Various non-genomic biomarkers like Prostate Health Index (PHI) have been shown to better identify patients with aggressive disease, but there is still an unmet need for better biomarkers [6]. Genomic biomarkers including gene panels like the Decipher genomic classifier and Oncotype DX have demonstrated the ability to better stratify PC patients [7]. After various positive validating studies, Oncotype DX has recently been included under Medicare coverage thereby making such PC genomic-based diagnostics reimbursable [8]. In addition to gene panels, various other genomic biomarkers like urine TMPRSS2-ERG fusion transcripts and long noncoding RNAs(lncRNAs) may show promise in identifying PC patients who may need aggressive treatments [9, 10].

Advanced Prostate Cancer

On the opposite end of the spectrum, advanced PC represents another disease state that could benefit from precision medicine approaches. Prostate tumors may remain responsive to androgen deprivation therapy for years (variable among patients) until it evolves into the castration-resistant state (CRPC) , which generally is still driven by the AR pathway. The median overall survival after diagnosis of CRPC is 18–32 months. Although newer-generation hormonal, cytotoxic, immunotherapeutic, and bone-targeted drugs have increased survival in CRPC patients leading to their FDA approval, the development of resistant PC disease remains inevitable. Using a combination of improved biopsy techniques and NGS technologies, molecular characterization of such advanced prostate tumors is increasingly being done. Recently, one such multi-institutional study found that 90% of advanced PC tumor harbor molecular alteration with potential targeting agent/drugs [11]. Another study that included mostly prostate cancer patients also demonstrated targetable alterations with an in-depth analysis of an exceptional responder based upon this mutation [12]. This highlights the importance of precision medicine for subclassification of prostate disease into molecularly defined subgroups with each subtype amenable to different targeted therapies [13].

Initial Clinical Encounter

The initial patient visit to a physician’s office generally includes comprehensive elicitation of disease history including diagnosis and initial treatments. Successful integration of precision medicine into oncology clinic will further emphasize clinical data recording and sharing. Without accurate linkage of genomic data to clinical data, even the latest genomic technologies will have a limited impact on patient outcomes [14].

Family History in Prostate Disease

Within PC patients’ histories, ethnicity is relevant as PC may sometimes harbor genetic determinants. Various single nucleotide polymorphism (SNPs) and copy number variants (CNVs) have been shown to be determinants of familial risk of prostate cancer [15]. Additionally, it is being increasingly realized that germline alterations like BRCA2, ATM, and BRCA1 mutations also play an important role in PC pathogenesis [11, 16]. So, any family history of such gene abnormalities can warrant increased level of diagnostic and therapeutic interventions.

Informed Consent

Precision medicine informed consents are important part of this new paradigm. Informed consents must delineate all the details including risks and also elaborate upon likelihood of finding somatic molecular alterations of unknown significance as well as incidental germline mutations. Pretest counseling should focus on addressing the key components of informed consent.

Patient Preferences and Data Privacy

One of the most important parts of the consent is the preferences of patients and families regarding level of detail and the scope of genetic information resulting from molecular testing, especially regarding incidental findings. This issue is discussed in detail in a separate section. Risks due to testing procedures (i.e., biopsy procedures) as well as data privacy should also be clearly detailed. Patients should also be made aware of existing legal protection against discrimination and the provisions of the Genetic Information Nondiscrimination Act (GINA). GINA protects US citizens from discrimination and restricts insurers from limiting coverage/altering premiums based on such genetic information. It prevents insurers from requiring policyholders to undergo genetic testing but could make testing a requirement for treatment [17].

Actionability of Precision Medicine Results

Due to enormous media attention generated by the precision medicine initiative started by President Obama [18], patients have high expectations from genomic profiling and its implications especially in terms of cancer cure [19]. These expectations, especially as they relate to the actionability of results, should be addressed up front within the framework of the consent process. The possibilities of nonactionable genomic results, biopsy failure (poor tissue quality/tumor content), analytical validity issues, and turnaround time should be discussed with the patient during this process [20]. Realistic expectations set through early patient education lead to better patient compliance and satisfaction. When managed appropriately, the potential for personal benefit from targeted therapy raises hopes and drives enhanced participation of patients in clinical trials [3].

It is important to understand that the definition of actionable molecular alterations is dependent on several molecular, patient-specific, and practical factors. A recent survey of practicing oncologists who had just received their patients’ cancer genome sequencing reports showed that 78% did not expect to implement any changes to the current treatment plan [21]. In this study, barriers to actionability included lack of local clinical trials (41%), absence of actionable mutation (33%), and good response to ongoing treatment (16%). In light of these findings, physicians need to explain to patients all the factors that could limit actionability of precision medicine test results.

Turnaround Time

Patient’s expectations about the turnaround time for genomic profile results also need to be recalibrated. Presently, waiting time ranging from weeks to months is needed starting with acquisition of tumor sample plus germline sample to generation of a precision medicine report. This is acceptable to stable patients and their treating physicians, but for patients with progressive advanced cancer, such long waiting time may not be clinically useful. Though the latest NGS methodologies have significantly shortened turnaround times, bottlenecks in the process still remain. These include sample acquisition and logistics and data analysis and interpretation [20].

Tissue for Genomic Profiling and Need for Serial Biopsies

Successful application of precision medicine requires availability of tissue of origin and/or metastatic site [22]. In many cases with a distant history of prostatectomy, tissue acquisition is not feasible thus leaving only the option of metastatic site biopsy. As most common site for PC metastasis is the bone which is a difficult organ to biopsy, metastatic site biopsies in PC have been very daunting process until lately. However, advancements in biopsy technology have increased the chances of successful tissue procurement from a PC patient [11, 23].

Over time, the true success of precision medicine may hinge on our ability to get serial biopsies to see real-time genomic evolution of the prostate disease. Liquid biopsy technologies such as circulating tumor cells (CTCs) or cell-free DNA (cfDNA) are a good surrogate for tissue biopsies [24]. Though true utility of liquid biopsies needs further validation [25], application of liquid biopsies seems immense extending to CTC-derived xenografts [26]. Another useful application of CTCs for prostate cancer patients may be in generation of patient-derived organoid cultures. Such cultures have shown to recapitulate the entire molecular diversity of prostate disease and hold promise for use in genetic and pharmacologic studies [27].

Understanding Precision Medicine Reports

All procedures for precision medicine outside of a research setting should be performed in CLIA-certified labs. After running the tissue sample through sequencing pipelines, genomic data is streamed through analytical/bioinformatic pipeline. The entire process needs to be standardized throughout for validity. Eventually a precision medicine report on patient’s tumor-specific somatic alterations is generated and usually contains the following elements:

Somatic alterations in clinically relevant genes—these alterations occur in genes that are potentially actionable as drug targets or confer resistance or susceptibility to treatment.

Somatic alterations of unknown significance in known cancer genes—these alterations occur in genes that are cancer associated, but their impact on the disease is not fully understood.

Somatic alterations of unknown significance—these alterations are not known to have any effect on the disease but are profiled in the event that, in future, progress in scientific knowledge could determine their role.

In addition to these, details on quality control metrics like depth and coverage of sequencing are often provided [12].

Communicating Genomic Information to Clinicians and Patients

A recent study done at Duke Medical Centre has found a number of challenges faced by institution when implementing genomic testing into patient care [28]. This necessitates a policy and education program to improve clinician support, enabling them to effectively deliver precision medicine care. One such problem is that precision medicine reports may or may not yield actionable somatic alterations in cancer-related genes. If such molecular alterations are found, these can either be targeted by FDA-approved drug for PC or other cancer types (i.e., off-label use), or there may be approved or investigational drug available as a clinical trial. Such drugs/trials are often enlisted in precision medicine reports made available to treating physician. But procuring the drugs targeting actionable genomic alteration can be a big hurdle. This can be especially problematic if PC is an off-label use of the drug [29].

For effectively communicating genomic results to patients, the treating physician needs to ensure proper patient education (starting with pretest counseling) and decision support systems are in place. This may require strong collaboration among genetic counselors, physicians, and nurses. Realistic expectations set during informed consent education can be especially helpful if sequencing results yield no obvious actionable alterations. In the case of incidental germline finding , the role of genetic counselors is very important to facilitate family communication [30] (see next section). To conclude, the proper utilization of cancer genomic medicine needs to be accompanied by careful thought about how the genetic test results will be communicated to patients in order to maximize their benefit.

Unique Issues Related to Incidental Discovery of Germline Mutations

Genome sequencing provides unprecedented opportunities to study the genomic landscapes and identify the actionable driver mutations for targeted therapy in precision medicine clinics. Because some NGS approaches rely on comparison between germline and somatic variants, germline alterations may be incidentally discovered. These alterations may be associated with inherited health risk or familial susceptibility to cancer. In the setting of cancer, some patients may find it burdensome to bear the knowledge of such inherited health risk in family [31]. This may have psychological consequences associated with the guilt of passing the inherited risk or increased cost of health care. This knowledge is perceived as an obligation to family and is difficult to refuse. Providing patients with simple summaries to share with their families and making local genetic counseling resources available at point of contact for the family can be helpful during the process [32]. Implications of reporting such incidental discoveries of germline mutations are very complex. Discussing these issues during the informed consent for sequencing highly penetrant disease genes and genetic counseling is essential to address the challenges faced in this situation [33]. Overall, the likelihood of finding incidental genetic variants does not appear to significantly discourage patients from adopting genomic profiling though the extent of incidental findings patients wish to be disclosed varies significantly [34].

Future Direction

Successful application of precision medicine approaches in the routine clinical care of patients requires not only a wider availability of next-generation sequencing technologies but also resourceful databases possessing consolidated clinical information [14]. As we proceed ahead, the missing metrics of clinical data will need to be filled in and clinical information annotated with genomic data. Another issue will be to improve our ability to complete the entire process of genomic sequencing, generating reports, and matching/administering drugs targeting driver alterations within a rapid turnaround time . This may further require sophisticated rapid machine learning methods [35]. In addition to therapeutic benefits, the promise of precision medicine in prostate cancer will also lie in discovering and validating molecular biomarkers that distinguish aggressive from indolent disease and those that predict treatment resistance [36, 37]. Finally regarding our heightened expectations, we will need to be cautious in terms of seeking quick results through this new paradigm of precision medicine. As Amara’s law correctly states We tend to overestimate the effect of a technology in the short run and underestimate the effect in the long run. We may have outclassed Moore’s law for NGS method cost efficacy, but regarding patient outcomes, it may take few years before we realize the full potential of precision medicine for prostate cancer patients.

Resources for Patients and Clinicians

My Cancer Genome—http://​www.​mycancergenome.​org/​: This is a personalized cancer medicine knowledge resource for physicians, patients, caregivers, and researchers. It provides latest information on what mutations make cancers grow and related therapeutic implications, including available clinical trials.

cBioPortal—http://​www.​cbioportal.​org/​: This portal maintained by Memorial Sloan Kettering Cancer Center stores genomic data from large-scale, integrated cancer genomic data sets. It allows explorative genomic data analysis

COSMIC database—http://​cancer.​sanger.​ac.​uk/​cosmic: COSMIC is a freely available online database of somatically acquired mutations found in human cancer. It is maintained by Sanger Institute, UK.

National Cancer Institute Cancer Genetics Services Directory—http://​www.​cancer.​gov/​about-cancer/​causes-prevention/​genetics/​directory: This NCI directory lists professionals who provide services related to cancer genetics (cancer risk assessment, genetic counseling, genetic susceptibility testing, and others).

National Society of Genetic Counselors (NSGC)—http://​nsgc.​org/​p/​cm/​ld/​fid=​164: For finding genetic counselors in a local area, United States.

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© Springer International Publishing AG 2018

Brian D. Robinson, Juan Miguel Mosquera, Jae Y. Ro and Mukul Divatia (eds.)Precision Molecular Pathology of Prostate CancerMolecular Pathology Libraryhttps://doi.org/10.1007/978-3-319-64096-9_2

2. Epidemiology and Etiology

Padraic O’Malley¹  

(1)

Department of Urology, Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, Nova Scotia, Canada

Padraic O’Malley

Email: [e-mail]

Introduction: Incidence and Mortality

Etiology and Risk Factors

Conclusions

References

Keywords

AgeFamily historyRace and ethnicityMetabolicSmoking

Introduction: Incidence and Mortality

In 2016, in the USA, approximately 180,890 men are expected to be diagnosed with prostate cancer, and almost 26,120 men are expected to lose their life to prostate cancer [1]. It is the number one non-cutaneous, solid tumor in men and the second most common cause of cancer death in the USA among men [2]. The estimated number of new cases worldwide in 2012 was 1,112,000, making it the second most common cancer diagnosed in men [3]. 759,000 of these cases are estimated to be seen in developed countries and only 353,000 in developing countries [3]. The estimated cases of prostate cancer deaths were 307,500 worldwide, with 142,000 in developed countries and 165,500 in developing countries [3]. Cumulative lifetime risk for prostate cancer incidence varied markedly between developed countries at 8.8% versus only 1.7% in developing countries. However, lifetime mortality risks were less disparate at 0.8% and 0.6%, respectively [3]. The incidence of prostate cancer underwent a dramatic increase in the USA in the early 1990s (Fig. 2.1) [2] with the widespread introduction of transurethral prostatectomy and then the prostate-specific antigen (PSA) test , leading to an almost threefold increase in incidence in 1975 to its peak in 1993 [2, 4, 5].

../images/324579_1_En_2_Chapter/324579_1_En_2_Fig1_HTML.gif

Fig. 2.1

Trends in incidence rates for selected cancers in men, USA, 1975–2011. Rates are age adjusted to the 2000 US standard population and adjusted for delays in reporting. Asterisk includes intrahepatic bile duct

This dramatic rise was not seen in other high-income countries with less widespread adoption of PSA testing, such as those in Western Europe, and these countries demonstrated a gradual increase in incidence instead [6]. As such, due to screening and PSA utilization, as well as no doubt due to the variable risk of disease in certain population, there are marked variations, as much as 25-fold, in incidence and mortality globally (Fig. 2.2) [3, 6].

../images/324579_1_En_2_Chapter/324579_1_En_2_Fig2_HTML.gif

Fig. 2.2

Prostate cancer incidence and mortality rates by world area. (Reproduced from Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015 Feb 4;65(2):87–108)

Fortunately, we have also seen a decline in mortality rates, particularly in developed countries. Beginning in 1996, the mortality rates were seen to decline after the introduction of PSA testing and continued to fall, perhaps due to this testing and/or due to improved treatment strategies, most likely in the metastatic setting [7, 8]. The effect of radical treatment on localized disease is less clear as to its overall benefit given the conflicting results of the Prostate Cancer Intervention Versus Observation Trial (PIVOT) and the Scandinavian Prostate Cancer Group 4 randomized trial [9, 10]. In the metastatic setting, however, we have seen the advent of many new therapeutics in the last 25 years including docetaxel and most recently abiraterone and enzalutamide, as well as combination therapy as seen in the recent CHAARTED and STAMPEDE studies and the benefits in overall survival these treatments have offered [11–13].

Etiology and Risk Factors

Over the last few decades, we have gained an increasing understanding of prostate cancer. Although we do not know the exact etiology of prostate cancer, we have identified a number of risk factors through epidemiological studies that may provide insight into possible mechanisms that would account for it. These factors can be divided into two distinct groups as seen in Table 2.1.

Table 2.1

Risk factors for prostate cancer by category

To begin let us examine each category’s individual risk factors and the epidemiological evidence behind their possible role in prostate cancer:

Modifiable

Age

Although several guidelines suggest screening men as young as 40 if they have high-risk features, prostate cancer is a disease of older men. Prostate cancer does have the steepest age-incidence curve of all malignancies, predominantly in the seventh decade [14–17]. The incidence of prostate cancer in men 45–54 years of age has remained fairly stable at approximately 35.7 per 100,000 in 2009–2011 [18]. There is a moderate increase in the following decade to 236 per 100,000. However, the subsequent two decades, 65–74 and 75–84, are both significantly higher at 609 and 769 per 100,000, respectively, in the modern era (Fig. 2.3). In North America, SEER data suggests approximately 0.6% of prostate cancer diagnosis are made before age 45, a further 9.7% before age 55, and 86% between the age of 55–84 years [19]. So while there has been an increase in younger men being diagnosed with prostate cancer, the lion’s share of new cases is still in the seventh and eight decades of life. The role of aging in causing prostate cancer is most likely through similar mechanisms common to many malignancies. We know that the process of aging itself leads to a myriad of changes in the genome including telomere shortening, epigenetic changes including methylation and demethylation, senescence, and alterations in gene expression. Why prostate cancer is so sensitive to these influences has not yet been elucidated.

../images/324579_1_En_2_Chapter/324579_1_En_2_Fig3_HTML.jpg

Fig. 2.3

Prostate cancer incidence rates per 100,000 men by age in the UK, 2009–2011. Data from the Cancer Research UK—UK National Statistics Office [18]. http://​www.​cancerresearchuk​.​org/​health-professional/​cancer-statistics/​statistics-by-cancer-type/​prostate-cancer/​incidence#heading-One

Twin studies in monozygotic twins have demonstrated epigenetic changes occur with aging and that these are a result of both environmental changes and stochastic processes as well [20]. In addition, the multifocal nature of prostate cancer demonstrates the field effect that arises from accumulation of these changes [21]. This field effect has been termed by Damaschke et al. as Age-Related Epigenetic Alterations inducing Susceptibility (AREAS) as it is related more to the field effect generated by alterations associated with age rather than alterations associated with the presence of a neoplastic nidus [22]. Specific epigenetic changes will be discussed in subsequent chapters.

Family History and Genetic Alterations (Inherited and Acquired)

Suffice it to say that there is an abundance of epidemiological evidence to support both familial and genetic components to the development of prostate cancer. As early as the mid-twentieth century, familial clustering was noted and demonstrated an increased risk for the development of prostate cancer for relatives of men with prostate cancer [23]. In more contemporary studies, this risk increases with a greater number of relatives affected, the closer the degree of relation, and younger age of the relatives at diagnosis [24]. Early age of development of aggressive prostate cancer belies a genetically driven phenotype [25]. A number of prostate cancer susceptibility genes have been identified by looking at familial prostate cancers specifically. These and other genetic alterations both inherited and acquired will be discussed in much greater detail in this book.

The technological advancements in the last decade have also allowed us to begin performing genome-wide association studies (GWAS) to identify correlation between disease and common variants in the genome [26]. Most genetic variants discovered have been modest in their effect size, most likely because GWAS have been performed in sporadic cases. The utility of GWAS may have greater implications and utilizations in family cases or specific racial groups [27]. Replications of previously identified genetic variants were highest in African American men followed by among men with a family history. The large majority of these variants are found in chromosome 8q24 [28]. Family linkage studies have further identified variants such as HOXB13 that are associated with hereditary prostate cancer [29]. Furthermore, BRCA mutations have been clearly seen to increase the risk for developing prostate cancer and more aggressive disease [30, 31]. BRCA1 mutation carriers have roughly a 3.5-fold increased risk, while men with BRCA2 have an 8.6-fold increased risk in men younger than 65 years of age [32, 33]. Moving forward we will hope to be able to identify further genetic variants that are common to the pathway that leads to progression to cancer from a preneoplastic, benign state. Furthermore, we would like to be able to do so on a more individualized level utilizing the knowledge previously gained from the study of specific high-risk groups.

Race and Ethnicity

Along with family history, we also inherit our forbearer ethnic and racial identity . Clearly, certain populations have a much higher risk not only of developing but also a risk of dying from prostate cancer [6]. At particular risk are men of African American and Caribbean descent. These men have been shown to present with more aggressive disease [34] and suffer the highest prostate cancer-related death rates among all ethnic groups [35]. Clearly there are other key factors besides racial and ethnic biological variability which contribute to these outcomes including factors such as disparities in access to appropriate health care [36] and greater prevalence in this population of anterior tumors that are prone to under-sampling [37]. Important to note is that there is limited evidence to suggest black men in the USA of either African or Caribbean have any significant variability from one another in terms of prevalence of significant disease (see Table 2.2) [38–40]. In comparison to previously published studies from West Africa, the rates were similar in US-born men of West African background [38, 41–43]. This raises two important points. First, black men inherently have more biologically aggressive disease regardless of their specific ancestry. Second, the demonstration that rates of advanced disease at presentation are being essentially equivalent between a screened and an unscreened population suggests a shorter lead time in black men [38, 44].

Table 2.2

Rates of advanceda prostate cancer among Black racial groups of varying geography and ancestry

aDefined as Gleason >7

Conversely men of Asian background have a relatively lower risk of developing prostate cancer as well as improved prostate cancer-specific and overall survival in several clinical settings [45, 46]. However, this has yet to be consolidated with several studies that have shown worse clinical outcomes in US Asian men [47] and the higher prevalence of higher-grade disease on autopsy in Asian men [48]. Nonetheless, consideration of a patient’s race and its implications on their biology are important and may become of greater importance as studies are beginning to now look at novel biomarkers within racial subgroups in the current age of personalized medicine.

Modifiable

We move on now to the modifiable drivers of prostate cancer biology, those which we can potentially manipulate and perhaps improve prognosis with. Let us begin first by examining those that center around our body’s metabolism, primarily: obesity, exercise, diet, and metabolic syndrome.

Obesity, Exercise, Diet, and Diabetes (Metabolic)

Body mass index (BMI), the old standard for gauging obesity, has been correlated with colon and breast cancer risk in middle- and older-age men [49]. It was suggested as a putative risk factor for prostate cancer. Wynder proposed a role for overnutrition in the development of prostate cancer in 1976 [50]. In 1984, the prospectively conducted Seventh-day Adventist study by Snowdon et al. identified a higher rate of fatal prostate cancer in men with body weights greater than 130% of ideal body weight [51]. Several important studies in the last few decades have demonstrated the clear association between obesity and increased risk and death from prostate cancer [52–54]. Furthermore, there is clear evidence demonstrating that obesity is also associated with progression of low-risk cancer in men on active surveillance [55]. Although the risk of obesity may be modest, it has been shown to be consistent [54, 56, 57]. Further confounding the issue is the lower PSA as a result of obesity may lead to a detection bias when PSA is the main driving force behind biopsy utilization [58–60]. Unlike inheritable or acquired genetic alterations, obesity more than likely drives prostate cancer risk and development via a hormonal mechanism. However, the end result on a molecular level results in a perturbation of genomic expression which leads to events such as increase tumor proliferation, reduced apoptosis, and a transition to a castrate resistant state [61]. So, if obesity promotes disease development and impacts prognosis, what can we do to alter this?

Several studies have looked at the role of exercise and diet in reducing prostate cancer incidence and prognosis [62]. Three large prospective population studies have demonstrated a decreased risk of aggressive prostate cancer [63–65]. The underlying mechanistic effects of exercise have not been examined in great detail. Of course, it is difficult to tease out the effects of exercise from those independent of its role in reducing obesity. There is some suggestion that there may be a role of altered vascular permeability and at least temporal resolution of hypoxia in the tumor microenvironment as seen in orthotopic animal models [66]. Other effects may be more endocrine related such as affecting adipokines and the insulin-like growth factor axis [67].

Many studies have examined the role of dietary components on prostate cancer susceptibility. Intake of red meat [68–71], green tea [72, 73], dairy products [74, 75], eggs [70, 76], selenium [77, 78], etc. has all been examined. However, results have invariably been inconsistent among the majority of studies. Debate has existed, for instance, whether it is the high levels of dietary branched fatty acids and the upregulation of α[alpha]-methyl-CoA racemase (AMACR) or whether the heterocyclic amines produced from cooking at high temperatures is the driving factor behind the association of red meat with prostate cancer [79, 80]. Meanwhile, soy products have been associated with a decreased risk owing to their phytoestrogens, either due to altering the level of circulating androgens, effects on the estrogen receptor directly, or apoptotic effects [81–83]. Micronutrients have also been examined extensively, in particular selenium and vitamin E. However, the largest randomized trial demonstrated initially no significant difference in prostate cancer development with the use of selenium, vitamin E, both, or placebo [84]. Furthermore, it was subsequently found that vitamin E was associated with an increased risk [85]. The idea of nutritional and metabolic effects and prevention strategies are not dead; however, as researchers have turned to metabolomics and the role of diet affecting these, in particular, much attention has been given to diabetic medications , especially metformin. There are currently a number of trials assessing the role of metformin in both prostate cancer prevention and prostate cancer progression in the active surveillance setting. Perhaps a better understanding of the role of the human body’s metabolism in prostate cancer will allow us to return to dietary and lifestyle modifications which may impact significantly on the disease.

Smoking

Smoking is a well-described risk factor for a number of malignancies including primary lung and urothelial carcinoma. Its association with prostate cancer has been under increasing scrutiny in the last decade [86]. A meta-analysis by Huncharek et al., published in 2010, examined the risk of prostate cancer from studies performed up to and including 2007 [87]. This meta-analysis demonstrated a 14% increased risk of prostate cancer death associated with current smoking and as high as 24–30% in those who were heavier smokers [87]. A more recent meta-analysis by Islami, Moreira, Boffetta, and Freedland examined prostate cancer mortality, incidence, and population attributable risk (PAR) [86]. Meta-regression analysis showed no association between smoking and prostate cancer risk (p = 0.09) and if anything perhaps a trend toward an inverse relationship. However, current (RR 1.24, 95% CI 1.18–1.31) and ever having smoked (RR 1.18, 95% CI 1.11–1.24) both showed a significant correlation with prostate cancer mortality. Furthermore, the total number of prostate cancer deaths attributable to cigarette smoking in the USA and Europe was approximately 10,400 deaths per year. In addition to higher prostate cancer mortality, smoking has been seen to be associated with more advanced disease at the time of surgery and subsequently higher risk of recurrence, metastasis, and death [88–92].

The possible pathways by which smoking may lead to worse outcomes in prostate cancer may be due to CpG hypermethylation of several genes which in turn leads to tumor angiogenesis [93, 94]. Other putative mechanisms include increased heme oxygenase expression (HO-1), altered adhesion molecules and extracellular matrix, and smoking-induced inflammation [95–98]. Indeed smokers have a greater degree of inflammatory changes in the prostate than non-smokers [98], and inflammation may well have a role in prostate cancer progression and/or initiation [99].

Conclusions

Clearly there are a number of risk factors, both non-modifiable and modifiable, which have significant impact on a man’s risk of developing prostate cancer and risk of dying from prostate cancer. However, we have yet to derive a single genomic pathway which drives prostate cancer similar to the VHL gene in renal cell carcinoma. Furthermore, the exact mechanisms through which these risk factors impose an increased risk are relatively unknown, and most proposals of mechanisms of action are somewhat speculative. Perhaps this explains then to some degree the amazing degree of clinical heterogeneity we see in patients. Examination of genetic and genomic events in the modern era, however, may allow us to reverse engineer/discover what those mechanisms may be. The high-throughput processing and immense degree of information gained from molecular studies are rapidly opening up new areas of discovery and thought into prostate cancer biology. By understanding this biology better, we may hopefully treat these patients more efficiently and one day prevent these cancers from having the significant impact they have now on men’s health and lives. Once we can understand the biology, we can truly influence the modifiable risk factor component of the equation.

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© Springer International Publishing AG 2018

Brian D. Robinson, Juan Miguel Mosquera, Jae Y. Ro and Mukul Divatia (eds.)Precision Molecular Pathology of Prostate CancerMolecular Pathology Libraryhttps://doi.org/10.1007/978-3-319-64096-9_3

3. High-Grade Prostatic Intraepithelial Neoplasia

Fadi Brimo¹  

(1)

Department of Pathology, McGill University Health Center, Montreal, QC, Canada

Fadi Brimo

Email: [e-mail]

Definition, Incidence and Evidence of Preneoplastic Process

Molecular Features of HGPIN

Clinical Significance of HGPIN

References

Keywords

Prostatic intraepithelial neoplasiaTelomere shorteningCytogenetic alterationsDysregulation of annexinMammalian target of rapamycin (mTOR) pathwayMicroRNA expression profilesTMPRSS2-ERG fusion

Definition, Incidence and Evidence of Preneoplastic Process

Prostatic intraepithelial neoplasia [1] is defined as a noninvasive neoplastic transformation of the lining epithelium of prostatic ducts and acini [2–6]. It is the only well-established preinvasive lesion of prostatic adenocarcinoma Prostate cancer (Pca). Although PIN was originally divided into three grades (I, II and III), the poor reproducibility and lack of clinical significance of a diagnosis of PIN I have resulted in the virtual disappearance of this diagnosis from contemporary pathology reporting [7, 8]. Currently, the term PIN is used as a synonym for high-grade PIN (HGPIN) which includes PIN II and III.

HGPIN is characterized by glands of medium to large size with an intact or fragmented basal cell layer in which a neoplastic cellular proliferation replaces the secretory epithelium. The neoplastic cells have basophilic cytoplasm, enlarged nuclei and prominent nucleoli at 200× magnification. Four main architectural patterns have been described: flat, tufting, micropapillary and cribriform. Other unusual patterns include the signet ring, small cell, mucinous, foamy and inverted patterns [4].

The incidence of a diagnosis of HGPIN varies significantly in the literature and ranges from 0.7 to 20% in needle biopsies and 3 to 33% in transurethral resection specimens [5, 9]. Isolated HGPIN is reported in 5–10% of needle biopsies with a mean incidence of 5.2%. Such variations are due to difference in the studied population and the inconsistent application of diagnostic criteria [4].

There is spatial, epidemiological , morphological and molecular evidence suggesting HGPIN to be the precursor of Pca. As an example, autopsy series report the incidence and extent of HGPIN to increase with age and to predate the onset of carcinoma by more than 5 years [10, 11]. The severity, multicentricity and frequency of HGPIN in prostates with cancer are also greatly increased compared with that of prostates without cancer [4, 11]. Also, similar to Pca, HGPIN preferentially involves the peripheral rather than the transition zone and occurs at a higher prevalence in African Americans compared to other races, with the lowest incidence in Asian population [10–13]. The finding of foci of HGPIN from which budding-off of rare invasive carcinoma glands occurs is further histological evidence that HGPIN is a true precursor of cancer. Such foci, referred to in the literature as HGPIN with microinvasive carcinoma, are present in 2% of high-power microscopic field of PIN and are seen in equal frequency in all architectural patterns [4, 5]. Further evidence suggesting a strong relation between HGPIN and adenocarcinoma is the fact that both lesions share similar molecular anomalies. Those molecular features are highlighted below.

Molecular Features of HGPIN

Telomere Shortening

It has been shown that telomere shortening is an early event in prostatic neoplasia that occurs frequently in HGPIN and Pca [14]. Using FISH technique applied to 6 prostatectomies with 11 HGPIN lesions and 20 needle biopsies with HGPIN without cancer, Meeker et al. [15] confirmed the presence of a significant telomere shortening