Prostate Cancer

Summary

Although mortality from prostate cancer has declined over the past few years, demographic trends, such as the general aging of the population, suggest that prostate cancer will remain one of the most common health threats for men in the developed world. Widespread implementation of prostate cancer screening, using the serum PSA, has resulted in a changing character of prostate cancer at its initial presentation, with younger men being diagnosed at earlier prostate cancer stages than ever before. The use of serum PSA testing for disease activity monitoring has changed the character of prostate cancer throughout the rest of its natural history, with healthier men having less prostate cancer at later stages of the disease than ever before. These changes have put new demands on improving prostate cancer treatment, whether offering active surveillance to selected men with indolently progressive disease, minimizing the morbidity of local prostate cancer treatment, or continuing to improve the efficacy of systemic prostate cancer treatment. The androgen signaling axis remains the major systemic treatment _target for advanced prostate cancer, with new agents introduced to restrain ongoing androgen receptor activation in castration-resistant disease.

Prevention and Early Detection

Prevention

Prostate cancer is an androgen-dependent tumor with a prolonged latency between initial malignant transformation and clinical expression, which are features well-suited to disease prevention efforts.⁷ Progression from tumor inception to invasive carcinoma often takes decades, allowing sufficient time for intervention.⁹ Chemoprevention strategies that use high-risk _target populations, particularly those with premalignant lesions (e.g., high-grade PIN), have the greatest potential to identify promising agents in a time-efficient manner.⁹⁸ The results of focused studies such as these can then be confirmed in large-scale trials applied to the general population. The ability to alter the hormonal environment of the host provides an excellent opportunity to interrupt the multistep process that results in clinical expression of the disease.⁷ Advances in our understanding of the process of carcinogenesis and the availability of promising new chemopreventive agents, including those producing reversible androgen deprivation, have the potential to favorably affect the morbidity and mortality of prostate cancer in the foreseeable future.

Luteinizing hormone-releasing hormone analogues (e.g., goserelin, leuprolide) reduce luteinizing hormone and (secondarily) testosterone levels. The long-term use of these agents may cause anemia, atrophy of reproductive organs, diminished muscle mass, loss of libido, and vasomotor instability, which limits the utility of these agents for chemoprevention in the general population. Nonsteroidal antiandrogens (e.g., flutamide, bicalutamide) competitively bind to androgen receptors in _target tissues. These agents are well tolerated in most patients, although adverse effects may include gastrointestinal disturbance, gynecomastia, and vasomotor instability.

Intracellular 5α-reductase converts testosterone to dihydrotestosterone (DHT), the hormone responsible for prostate epithelial proliferation. DHT has greater affinity for the androgen receptor and is the primary agonist leading to prostate maintenance and growth. Three isoforms of 5α-reductase have been identified with various levels in different tissues. Type 1 is expressed in benign prostate hyperplasia, and its expression is greatly increased in prostate cancer, especially high-grade tumors.⁹⁹ Type 2 5α-reductase expression is decreased in PIN and some early cancers but is increased in metastatic and recurrent prostate cancer.⁹⁹ The role of type 3 5α-reductase is less defined. Competitive inhibitors of 5α-reductase (e.g., finasteride and dutasteride) suppress intraprostatic dihydrotestosterone to castrate levels. The Prostate Cancer Prevention (PCP) trial was initiated to test the efficacy of finasteride as a chemoprevention agent in men at low risk of having prostate cancer.¹⁰⁰ This placebo-controlled phase III trial randomized 18,882 eligible men (age ≥55 years, normal digital rectal examination [DRE] and PSA levels <3 ng/mL) to finasteride (5 mg daily) or placebo for 7 years. There was a 25% reduction in the prevalence of prostate cancer over this 7-year period from 30.6% in the placebo group to 18.6% in the finasteride group.¹⁰⁰ Of note, however, is that more aggressive tumors, with Gleason score 7 to 10, were more common in patients who took finasteride: 37% of all tumors and 6.4% of all men on the finasteride arm versus 22% of all tumors and 5.1% of all men on the placebo arm. The increased incidence of high-grade cancers seen in the PCP trial has been a topic of great debate. The investigators have argued that the increase in high-grade cancers is due to a detection bias related to the reduced volume of prostate tissue and therefore a greater ratio of cancer to benign tissue. Furthermore, there was no dose effect from the finasteride with no significant increase in worse cancers with higher cumulative doses of the drug.¹⁰¹ The PCP trial was not designed or powered to detect differences in cancer-specific survival (CSS) or OS. Finasteride did reduce urinary symptoms compared with placebo, but there were also significantly more adverse sexual side effects.¹⁰⁰ A reduced volume of ejaculate, erectile dysfunction, loss of libido, and gynecomastia were more common in the finasteride group (p <.001), but urinary urgency, frequency, retention, urinary tract infection, and prostatitis were less common with finasteride (p <.001).¹⁰⁰

The Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, a phase III study testing inhibition of 5α-reductase with dutasteride, has completed its accrual of patients.¹⁰² Unlike finasteride, which blocks 5α-reductase type 2, dutasteride blocks both types 1 and 2, suggesting it may be more effective at preventing the development of prostate cancer.^99,103 Phase III trials evaluating dutasteride for the treatment of benign prostatic hyperplasia coincidentally showed a significant reduction in the incidence of prostate cancer. ^102,104 The REDUCE trial is a randomized trial of placebo versus dutasteride, 0.5 mg, administered daily to evaluate it as a chemopreventive agent for prostate cancer. This trial completed its accrual of 8000 subjects in 2004. Unlike the PCP trial, which enrolled men with a low risk of prostate cancer, the REDUCE trial sought patients with a higher risk of developing or being diagnosed with prostate cancer (e.g., PSA >2.5).¹⁰²

Etiology

Prostate cancer is the leading cause of cancer and the second leading cause of cancer-related death in men in the United States.¹ Nevertheless, only 3% of men ultimately die as a result of prostate cancer, even though the majority of men will harbor prostate cancer cells (usually undetected) if they live long enough. Among other things, this dichotomy reflects the marked variability in prostate cancer growth rates.

Tumor doubling times can vary from every 2 weeks to 5 years or longer. Faster growing tumors, especially those with dividing times of less than 12 months, are more likely to cause signs and symptoms and premature death if they are left untreated.

At the other end of the spectrum, slower growing tumors, particularly in men older than 65 years, usually remain indolent and are rarely life-threatening. Unfortunately, it is not possible to predict exactly when a prostate cancer becomes life-threatening. Nevertheless, it is possible to modify prostate cancer's behavior.

ETIOLOGY

Studies have not linked prostate cancer with sexually transmitted disease or sexual habits. However, studies are underway that implicate family history, dietary fats, low ultraviolet light exposure, and smoking. The role of benign prostatic hypertrophy (BPH) remains unclear but appears not to be a link.⁷ It is believed that benign hypertrophic prostatic cells do not directly transform into malignant cells. Vasectomy is not a definite risk factor for future development of the disease.⁸ Elevated serum testosterone concentrations probably have a link. Afro-American black men have serum testosterone levels 15% higher than American caucasians⁹ and this is one of many reasons given for higher rates in Afro-American men. Detectable prostate cancer in eunuchs, who have lower levels or neglible levels of testosterone, and vegetarians, is very low.¹⁰ Men with lower levels of sex-hormone-binding globulin (SHBG) seem to be at higher risk. Men with higher levels of estradiol seem to be at lower risk. The role of the hormone dihydrotestosterone (DHT), which was thought to increase prostate cancer risk, is undefined.

Studies still underway show a more definitive link with diet, especially a diet high in animal fat. In fact, there is a great deal of evidence that the diet responsible for cardiovascular disease is also responsible for prostate cancer. Asians tend to eat less fat and larger quantities of fish (a good source of vitamin D). Vitamin D allows better absorption of vitamin A and vitamin A may play a role in decreased incidence because African, Dravidian and Aryan blacks living in southern climates with higher ultraviolet light exposure (vitamin A) do not have a high incidence of prostate cancer. This may link diet, ultraviolet light exposure, and lower testosterone levels to prevention. No studies have assessed the role of societal stress and race in combination with higher testosterone levels and prostate cancer.

Beta-carotene has not been shown to reduce risk but lycopene, found in tomato pigment, has been found to lower the risk of many cancers, including prostate cancer. The risk of getting prostate cancer rises with the amount of alcohol consumed. Hyperinsulinemia and prediabetic conditions may contribute to the cancer environment and promoting factors in many cancers, including prostate cancer.

People who work in industries such as water treatment, aircraft manufacturing, power, gas, and water utilities, farming, fishing and forestry have a higher risk of prostate cancer. It is thought that chemical exposures are at fault but these exposures, unfortunately, have not been specifically studied. Environmental exposures are often the last area of pathogenesis to be researched.

Every decade of ageing nearly doubles the incidence of microscopic prostate cancer from 10% for men in their 50s to 70% for men in their 80s.^11,12

There appears to be significant clustering of prostate cancer within families, along with breast and central nervous system tumors.¹³ This suggests a role for genetic factors. Men in families in which two or more first-degree relatives have prostate cancer may have as high as eight times greater risk for prostate cancer than the average male. This inherited susceptability may lead to much earlier onset, and earlier onset usually means a more aggressive form of prostate cancer.

Some occupational exposures include metallic dust, liquid fuel combustion products, lubricating oils, polyaromatic hydrocarbons from coal, rare elements like tritium, ⁵¹Cr, ⁵⁹Fe, ⁶⁰Co, ⁶⁵Zn, or large amounts of herbicides and pesticides.

Box 5.1 lists risk factors for prostate cancer; Box 5.2 lists factors that decrease risk for prostate cancer.

Foods that are beneficial with regards to prostate cancer include soy, green tea, seafood, and especially deep water fish with high omega-3 fatty acid content, olive oil, tomato, vegetables, especially broccoli sprouts and pumpkin seeds, legumes and whole grains. Soy contains high levels of genistein, which inhibits the growth of prostate cancer. A survey of 42 countries found that soy provided more protection against prostate cancer than any other food.

INTERNATIONAL EPIDEMIOLOGICAL OBSERVATIONS

Although latent or clinically insignificant prostate cancer occurs at equal rates in autopsy studies among men in Asia and the United States (∼30% of men older than 50 years), the incidence of clinically significant prostate cancer is 15 fold higher in the United States than in Asian countries (Muir et al., 1991).

Chinese and Japanese men who immigrate to the United States have a higher incidence of and mortality from prostate cancer than Chinese and Japanese men in their native country (Shimizu et al., 1991; Whittemore et al., 1995). The incidence of prostate cancer in Japan has also been increasing at a time when Western diets and lifestyles are being adopted into that country (Wynder et al., 1991). These data suggest that a significant proportion of prostate cancers may be caused by and, conversely, prevented by changes in the environment. Substantial data suggest that obesity, secondary to dietary patterns and the sedentary lifestyle in Western developed countries, may play an important role in the development, progression, and mortality from prostate cancer.

II Screening for Prostate Cancer

There are several issues concerning screening for prostate cancer. Two fundamental components of a successful screening strategy are the ability to identify significant cases and the ability to administer effective therapy. Despite multiple studies, current diagnosis and therapy of prostate cancer remain controversial in these two aspects. The measurement of the serum content of prostate-specific antigen (PSA) provides an early indicator of the presence of prostatic disease, but not necessarily prostate cancer. PSA levels reflect abnormalities in the prostate—benign hypertrophy, infection, infarction, or cancer. Until recently it was unclear whether men who are diagnosed with prostatic malignancy using a PSA-based strategy have clinically significant disease that will result in morbidity and mortality. Data from the Physician's Health Study in 1999 indicate that an elevated PSA level on a single blood draw is predictive of clinically significant prostate cancer with a low false-positive rate. This argues strongly that PSA-based screening will be unlikely to overdetect indolent cancers. A more difficult problem to address is the fact that the definitive therapies for prostate cancer have not been shown to improve unequivocally quality of life or overall survival. Identifying a patient with prostate cancer may lead to significant diagnostic and therapeutic morbidity and cost for the patient and family. Treatment decisions are difficult to avoid once the diagnosis is made. Thus, prior to obtaining a screening serum PSA level, a frank and open discussion about the use of the information and the consequences of the various options is needed. The specific clinical parameters of each individual must be considered. For a man with a life expectancy of less than ten years, even the most ardent therapist is hard pressed to suggest an advantage to diagnosing and subsequently treating prostate cancer.

Case 1: FDG PET/CT—Staging

Family History and Genetic Factors

Having a first-degree relative with prostate cancer incurs a twofold to threefold risk which increases with the number of relatives affected and earlier age at diagnosis. These observations are consistent with an inherited genetic predisposition. Analyses of families with multiple cases of prostate cancer have inferred dominant patterns of inheritance, as well as recessive and X-linked patterns. It has therefore long been considered that mutations in more than one gene might increase susceptibility to prostate cancer. A handful of prostate cancer susceptibility genes have been identified, for example, ELAC2, RNASEL, and MSR1, and male carriers of mutations on the BRCA2 gene (a gene associated with increased risk of breast cancer for women) are at increased risk of early-onset prostate cancer, as are carriers of rare mutations in the HOXB13 gene (chromosome 17q21-2) but, taken all together, rare mutations in these genes only account for a very small number of cases.

Association studies have also been carried out for variants in candidate genes known to be in pathways important to prostate development and function, such as steroid hormone metabolism, DNA repair, insulin, and insulin-like growth factors (IGFs) and response to infection and inflammation. For example, much has been published concerning genetic variants in the androgen receptor, 5 alpha reductase type 2, the vitamin D receptor, IGF-1, interleukins, toll-like receptors, and a number of cytochrome P450 enzymes. Using this approach, seldom have initial reports generated from small, poorly designed studies been replicated by studies with greater statistical power. It is now recognized that genetic association studies need to be substantially larger than previously thought.

Large multi center genome wide association studies (GWAS) that have measured hundreds of thousands of common single nucleotide polymorphisms (SNPs – where one DNA nucleotide pair is replaced by another) have now identified a large number of SNPs associated with prostate cancer risk and have replicated these findings in tens of thousands of cases and controls (Eeles et al., 2014). The number of SNPs associated with risk is likely to increase over the next few years as it is thought there may be an additional 1000 SNPs of similar risk profile. Whereas mutations are rare (<1% of the population carry them) and are associated with high risks, the more common SNPs are carried by much larger proportions of the population but are associated individually with very small risks. Taken all together, however, the current list of identified SNPs explains about a third of the heritable component of prostate cancer. The question now is the extent to which the SNP information combined with routine histopathology, PSA, and other molecular markers in tissue might be useful in generating accurate risk prediction models – i.e., to better identify who might benefit from treatment and who might be better off without any intervention (Helfand and Catalona, 2014).

It is considered that the search for prostate cancer genes might have been thwarted by tumor heterogeneity, since different genes may be involved in susceptibility to aggressive or to nonaggressive tumors. Interestingly, most germ line genetic variants identified to date have failed to differentiate risks for indolent and aggressive disease. Should this remain the case, it might be that inherited genetic risk is related more to cancer initiation and that cancer progression is related more to environmental and lifestyle exposures that promote further genetic alterations in tumor cells possibly via epigenetic pathways. Epigenetics refers to mechanisms by which the DNA sequence is not altered but the expression of genes is. One common epigenetic mechanism is methylation, whereby methyl groups become aberrantly attached to DNA and silence its function and vice versa. Importantly, DNA methylation can be influenced by lifestyle exposures such as diet, alcohol, smoking, and obesity; thus providing a plausible basis for interactions between environmental and genetic risks.

The molecular characterization of prostate cancer tissue reveals significant mutational heterogeneity with many of the established pathways to carcinogenesis being dysregulated, such as those for cell cycle control and more particularly for prostate cancer, androgen signaling. Epigenetic processes are also commonly described in tumor tissue where they usually precipitate genomic instability and exacerbate the loss of regulatory pathways. It is considered that the molecular genetic/epigenetic profiling of tumor DNA might be useful in the future to identify more homogeneous sub groups of tumors that would be suitable for specific management strategies and _targeted therapies.

Clinical Validity of Inherited Genetic Variants

The clinical validity of high-penetrance mutations for risk prediction in PCa has been well established. Specifically, loss-of-function mutations in high-penetrance genes such as BRCA2 and ATM have been shown to be strongly associated with PCa [12,17–21]. To establish the clinical validity of mutations of high-penetrance genes for their abilities to predict PCa diagnosis or prognosis, it is necessary to consider impact of mutations on gene function, associations of the particular gene with PCa in multiple populations, and biallelic alterations in germline and/or somatic DNA.

For most studies of PCa risk-associated SNPs, cumulative SNP effect is assessed using a quantitative measure commonly known as a “Genetic Risk Score” or “GRS.” The clinical validity of PCa risk-associated SNPs, specifically in the form of GRSs, has been well established among large samples of independent populations [14,15,22]. There are three commonly used methods for calculating a GRS: (1) a simple count of risk alleles; (2) a weighted count of risk alleles, which incorporates the effect size of each SNP based on OR; and (3) population-standardization by incorporating risk allele frequency, which provides a value one’s genetic risk relative to their same demographic population. Using the population-standardized method, GRS values center around a value of 1.0, no matter how many SNPs are included, with values greater and less than 1.0 conferring risk above or below the average population risk of developing PCa, respectively.

Various studies of these three GRS methods, particularly the weighted risk allele count and population-standardized methods, have demonstrated the superior ability of GRS to assess risk of developing PCa compared to the currently used methods in biopsy cohorts, clinical trial populations, and large case–control studies [14,22,23]. At present, FH of PCa is the most commonly used variable by clinicians, in addition to age and race, for assessing a man’s risk of developing PCa. However, only ~7–17% of men in the general population are estimated to have a FH of PCa [2], and many of those men are unaware of their comprehensive PCa FH information. A recent study analyzing data from the Prostate Cancer Prevention Trial demonstrated the ability of GRS to identify twice as many men at higher risk of developing PCa when GRS was combined with FH compared to when FH is used to identify high-risk men alone [24].

Though GRSs show great promise as a tool for allowing clinicians to more accurately assess one’s risk of developing PCa, some studies have shown that GRS may not yet be ready for clinical use as a PCa risk stratification tool [25]. However, utilizing the data from Reduction by Dutasteride of Prostate Cancer Events where four sets of sequentially discovered SNP were analyzed, we found GRS values calculated from each of the four sequential sets of PCa risk-associated SNPs were significantly associated with PCa risk and had a better performance in discriminating PCa from non-PCa than FH. Although there was variability in GRS values for individual patients when using these four sequential sets of risk-associated SNPs, they were highly correlated. More importantly, multiple GRS values from evolving SNP sets actually provide a valuable tool for refining risk for all subjects. Risk reclassification effectively captures men with GRS values in a gray zone that are at intermediate risk, and men who have consistently lower or higher GRS values from multiple SNP sets are further assured of their low or high genetic risk, respectively ([24], submitted).