Personalized Approach to Prostate Cancer

In 2016, prostate cancer is projected to be the most common cancer among men (excluding skin cancers), occurring in 180,890 and causing death in 26,120.¹

The median age at time of diagnosis of prostate cancer is 66 years, with the median age at death being 80 years.² Simply considering both the low case fatality ratio and the potential for a significant time span from diagnosis to death suggests multiple opportunities for personalized considerations that balance the risks and benefits of disease assessment and treatment in an individual man at risk or in need of therapy for this disease. The rapid understanding of prostate cancer biology and oncogenesis provides a number of opportunities for making such decisions in a more refined and personalized manner. Here we will only briefly consider the opportunities for diagnosis and disease monitoring and then explore the opportunities for molecular characterization to personalize therapeutic decisions in more detail.

Diagnosis/Screening of Prostate Cancer

Much work has been done to determine the long-term effect on quality of life and survival of prostate-specific antigen (PSA)-diagnosed prostate cancers in the absence of clinical signs. Based on the natural history of many prostate cancers and the life expectancy at time of diagnosis, many of these cancers would ultimately not have exerted any significant clinical impact during the lifetime of some of these patients. For those patients who have undergone aggressive treatment for their prostate cancer, they may have the side effects of urinary, sexual, gastrointestinal, metabolic, or cardiovascular dysfunction in the absence of increased disease control or improved overall survival.

Current recommendations for prostate cancer screening have been established in an attempt to balance the benefits of early diagnosis and treatment with the risks associated with overdiagnosis. Multiple professional organizations such as the National Comprehensive Cancer Network (NCCN) and the American Urological Association (AUA) have established guidelines that include routine screening intervals of 2 years or greater to reduce the harm associated with screening.^3,4 Based on what we know regarding the general course of prostate cancer, standard PSA testing does not provide the greatest benefit to all patients. Shared and informed decision-making between physician and patient is encouraged based on individual risk and preferences.^3,4

African-American race, older age, and family history of prostate cancer, specifically having a first-degree relative with prostate cancer, continue to be the strongest contributors to the risk of developing prostate cancer.⁵ However, there are limited data to inform screening recommendations in African Americans or those with a family history of prostate cancer. Variables beyond age, race, and family history are being considered to help improve our ability to risk stratify and determine which men will benefit from prostate cancer screening. Efforts investigating the role of genetic variation are being made to determine how best to pursue prostate cancer screening in the population setting for high-risk populations. Lange et al⁶ have been able to show an association between high aggregate burden of both 23 new prostate cancer variants and 40 more established variants with early-onset prostate cancer. The association between the burden of common risk alleles and early-onset prostate cancer may serve as a tool to identify those men who could benefit from earlier screening.

Despite these challenges, a few highly penetrant germ­line mutations do play an important role in diagnosis. Germline BRCA mutations are well known to be associated with hereditary cancer syndromes, conferring increased risk of developing breast, ovarian, pancreatic, and prostate cancers.⁵ Men with BRCA mutations have been observed to have more aggressive variants of prostate cancer consisting of higher-grade disease with younger age at disease onset.⁵ The BRCA gene is involved in maintenance of chromosomal stability via the homologous recombination pathway for double-strand DNA repair.⁷ In men younger than 65 years, there is an 8.6-fold increased risk of prostate cancer in the setting of a germline BRCA2 mutation. That risk is somewhat reduced to a 3.4-fold increased risk in men with BRCA1 mutations. In those patients with germline BRCA mutations, prostate cancer displays a more aggressive phenotype associated with increased nodal involvement, distant metastases, and poorer survival.⁸

NCCN guidelines recommend men with BRCA2 mutations start screening for prostate cancer at age 40 years, with consideration of screening men with BRCA1 mutations at the same age.³ There are no specific recommendations for screening men with BRCA mutations from the AUA.⁴ Currently, IMPACT, an international consortium of 62 centers in 20 countries, is evaluating targeted prostate cancer screening in men with BRCA1/2 mutations. Results from the initial screening round found that of 59 newly diagnosed prostate cancers, 18 were diagnosed in men with BRCA1 mutations and 24 were diagnosed in BRCA2 mutation carriers. The positive predictive value of biopsy, using a PSA threshold of 3.0 ng/mL, was 48%, which is 2 times the positive predictive value of biopsy in population screening studies.⁸

The HOXB13 G84E variant has also been identified as a germline mutation associated with early-onset hereditary prostate cancer. The HOX genes are characterized by a highly conserved DNA-binding domain and are a subfamily of the homeobox superfamily of transcription factors.⁹ Although it is a rare variant, noted to occur at a 5% germline carrier frequency in families of European descent with prostate cancer, it is strongly penetrant, increasing the risk of early-onset prostate cancer 5- to 7-fold in carriers.¹⁰ In addition to identification of the G84E variant, Ewing et al also identified other rare missense HOXB13 variants that further support a role for HOXB13 in the development of prostate cancer. Although the role of HOXB13 has not been elucidated, and there has been work showing HOXB13 functioning as both a tumor suppressor and oncogene, there is evidence of interaction between HOXB13 and the androgen receptor (AR), potentially supporting its role in prostate cancer pathogenesis.⁹ There are no specific recommendations regarding screening for men harboring HOXB13 G84E mutations. There has been a suggestion for targeted allele testing for BRCA2 and HOXB13 mutations in families with unfavorable cancer profiles in addition to PSA testing due to their strong association and implications for an aggressive disease course.⁵

Disease Monitoring

In contrast to the limitations associated with the use of PSA as a diagnostic tool, the use of PSA for monitoring disease recurrence, disease burden, or response to treatment is a much better accepted component of the clinical management of prostate cancer. Rises in PSA are usually the first indication of prostate cancer progression. PSA monitoring after definitive treatment of localized prostate cancer serves as an indicator of disease recurrence and is recommended by several professional organizations to be performed on a routine basis.¹¹ PSA monitoring in this setting has significant clinical impact as a measure to identify which patients may have rapidly progressing disease and warrant rapid intervention.

The use of PSA kinetics, such as PSA doubling time (PSADT) or PSA velocity (PSAV), have been suggested as tools for clinical decision-making when monitoring for prostate cancer recurrence and disease progression. Although shorter PSADT and increased PSAV tend to be associated with higher risk of developing radiologically evident metastatic disease, these values have limited predictive value as independent variables and should be considered in the context of clinical symptoms and absolute PSA value.¹² Although PSADT is a singular measure, the Prostate Cancer Working Group 3 recommends following it to focus novel interventions and therapy on patients with shorter times who tend to be at the greatest risk for developing symptomatic metastases and dying of their disease.¹³

The use of patient-reported outcome (PRO) tools has become widely incorporated in the evaluation of multiple cancer types in clinical practice and in the evaluation of patients on clinical trials. For patients with prostate cancer, pain is the most clinically relevant PRO and is associated with inferior outcomes and reduced quality of life when rated high.¹³ However, PROs that measure fatigue, pain, and functional status can also be useful in assessing response to treatment and overall well-being of patients.

The use of CT scans of the chest, abdomen, and pelvis; MRI of the pelvis; and bone scintigraphy with technetium-99m are common methods of evaluating disease burden in prostate cancer.¹³ As metastatic disease can involve lymph nodes, viscera, and bone, most patients will be evaluated by each of these modalities multiple times in the course of their disease, with each one providing different information.¹³ Whereas the evaluation for disease progression is a straightforward process using CT scan and MRI, bone scans do not directly visualize osseous metastases and are not quantifiable. The abnormalities seen on a bone scan persist after the completion of treatment, making it difficult to gauge response.¹⁴

Alternative methods of bone imaging are being studied to allow a more sensitive and quantitative approach to evaluating bone disease. Positron imaging can be quantitative and provide an informative multidimensional representation of a patient’s disease. The tracer F-18 sodium fluoride has been demonstrated to be a more sensitive bone-seeking agent attracted to areas of new bone formation.¹⁴ F-18 sodium fluoride fell out of favor once technetium-99m started to be used and had better resolution. However, with improved techniques, these limitations are no longer a barrier to incorporation into clinical practice. Although F-18 sodium fluoride is used on a limited basis in clinical practice, a Centers for Medicare & Medicaid Services National Oncologic PET Registry study is being performed to evaluate the role for coverage of NaF in evaluating osseous metastases.¹⁵

The ability to image both bone and soft tissue disease at the same time is an attractive prospect offered by molecular imaging. There are a number of tracers under evaluation, but none have proved to have clinical relevance other than fluorodeoxyglucose (FDG) at this time.¹⁴ Studies have shown that FDG PET is more sensitive than a bone scan, making it a viable option for disease monitoring in more advanced disease.¹⁵

Fluorodihydrotestosterone (FDHT) is an androgen analog that allows for the direct visualization of ARs in prostate cancer. It has been used successfully in both recurrent and metastatic disease. Its activity is decreased with use of antiandrogen drugs, showing its value as a proof of principle imaging modality for the evaluation and development of AR-targeted agents.¹⁵

Circulating Biomarkers

Circulating Tumor Cells

The use of circulating tumor cells (CTCs) in monitoring disease progression is an active area of research. There is only 1 FDA-approved platform for the evaluation of CTCs, called CellSearch. This assay detects the number of CTCs obtained from whole blood using an EpCAM-positive immunomagnetic ferrofluid.¹³ Studies have shown an association between CTC number and responses to treatment, progression-free survival, and overall survival.¹⁶ It is suggested that CTCs can be used for predicting and monitoring responses to treatment. In the CellSearch platform, CTC counts are classified as “favorable” or “unfavorable,” with cell number cutoffs of <5 versus ≥5 CTCs/7.5 mL of blood, and this classification system is an independent prognostic indicator of survival in metastatic castration-resistant prostate cancer (mCRPC).¹³ CTCs are also being used for their easy access to tumor tissue for molecular profiling. This can allow for multiple “liquid biopsies” throughout the course of disease and monitoring of changes in the molecular landscape in a patient’s prostate cancer over time. Crespo et al¹⁷ identified persistent nuclear AR expression in CTCs from patients who had progressed on abir­aterone or enzalutamide therapy, suggesting that tumor biology in these patients may involve the presence of activating AR mutations or AR splice variants (AR-Vs) responsible for persistent AR expression. Antonarakis et al, in a 2014 study, were able to correlate the expression of AR-V7 in CTCs with lack of response to enzalutamide and abiraterone (see also next section).

Cell-Free DNA

Cell-free DNA (cfDNA) has also been investigated as a potential biomarker in both the diagnosis and monitoring of prostate cancer. In regard to disease monitoring, cfDNA has been shown to be a predictor of PSA recurrence after radical prostatectomy. Higher levels of cfDNA have been seen in metastatic disease and are associated with prostate cancer–specific mortality in the metastatic patient population.¹⁸ Investigations of cfDNA have already shown the presence of AR-Vs, copy number variants, and AR point mutations to be associated with abiraterone resistance. In addition, genomic profiling using comparative genomic hybridization and next-generation sequencing in patients with mCRPC taking enzalutamide identified clinically actionable genetic variations in subjects at the time of progression.¹⁹

Biomarkers to Guide Systemic Therapy

Prostate cancer is a clinically and biologically heterogeneous disease. Our inability to predict response to treatment or risk of progression to mCRPC is the basis of the uncertainty in the management of early-stage or localized disease. The heterogeneity of prostate cancer is likely related to its genomic diversity.⁷ Next-generation sequencing and evaluation for germline mutations have provided a wealth of knowledge regarding mutations that may drive therapeutic targeting in prostate cancer. This information in conjunction with clinical and laboratory-based disease monitoring may be the advent of a new approach to managing prostate cancer.

AR

The AR is part of the steroid hormone group of nuclear receptors. It functions as a ligand-dependent transcription factor, stimulated by binding of androgen to the C-terminal ligand-binding domain. The AR plays a vital role in the transition to castrate-resistant prostate cancer (CRPC). Metastases in patients with CRPC have been found to frequently express AR variants, with high levels being associated with poorer disease outcomes.²⁰ Despite the lack of response to testicular androgen-depriving therapies in CRPC, the AR appears to remain an active driver of disease progression in these men.²¹ Kumar et al looked at resected prostate cancer tissue from 63 men and noted 63% of the men with CRPC had amplification or mutation in the AR gene. This was rare in the men with untreated prostate cancers. Whereas upregulation and amplification of the AR is the basis for the efficacy of current second-line AR-targeting agents such as enzalutamide and abiraterone, the role of AR variants is becoming increasingly evident.

There is, for example, significant evidence to support the role of AR-Vs as a mechanism of AR-targeted therapy resistance. AR-Vs delete the ligand-binding domain while retaining the C-terminal transactivating domain.²² This alternative splicing leads to a constitutively active AR. Over 20 AR-Vs have been identified; however, AR-V7 has become strongly associated with resistance to abiraterone and enzalutamide.²²

Other proposed mechanisms of resistance include missense mutations in the ligand-binding domain of AR, leading to decreased specificity of binding between AR and its ligand and activation from other hormones. The F876L mutation has been observed in cells treated with enzalutamide. This mutation causes enzalutamide to act as a partial agonist.²³ Similarly, the T877A mutation confers a gain of function leading to activation of AR by first-generation antiandrogens (ie, flutamide) and steroid hormones such as progesterone.^22,23 In prior work, activity of AR target genes was induced by progesterone activity on T877A-mutant AR in cells treated with abiraterone.²³ Both H874Y and T877A AR point mutations were seen in cfDNA from patients resistant to abiraterone.²⁴ Other proposed mechanisms for resistance to AR-directed agents include increased expression of CYP17 leading to increased extragonadal and intratumor production of androgens, leading to resistance to abiraterone.²⁰

The glucocorticoid receptor (GR) shares DNA-binding sites with AR and can regulate genes downstream in the AR pathway. In doing so, GR has also been shown to contribute to PSA expression in more advanced prostate cancer.¹⁷ Kach et al have investigated the role of selective GR antagonist modulators (SGRMs) in models of CRPC. Their previous work showed upregulation of GR following AR antagonism and decreased effectiveness of AR-directed therapy. Their current model used SGRMs in AR-antagonized cell models and demonstrated the inhibition of CRPC tumor progression with this combination treatment approach.²⁵

The question remains of the best management strategy for the CRPC population who does not respond to enzalutamide or abiraterone due to AR resistance. Prior work has shown that taxane therapy may inhibit activity of the AR by disrupting cytoplasmic to nuclear transport along microtubules. In addition, a recent study showed that taxane efficacy was not affected by AR-V7 positivity, with further investigation in this study showing conversion of AR-V7–positive status to AR-V7–negative status in patients treated with taxanes.²⁶ Further investigation is warranted to determine how effective AR-V7 expression is in predicting response to treatment and whether AR-V7 conversion in response to taxanes can also be used to guide clinical management. These findings inspire one to consider novel combinations of therapy such as chemotherapy in conjunction with enzalutamide or abiraterone, AR-V7–targeted therapies in conjunction with enzalutamide and abiraterone, or even agents targeted to nonligand-binding domain portions of the AR.

Along these lines, several newer agents are under development to overcome secondary AR-targeted resistance. Galeterone is a potent CYP17A1 inhibitor with a putative trimodal mechanism of action. This agent inhibits CYP17A1 irreversibly and prevents intratumoral androgen synthesis. Like abiraterone, it does so by selectively inhibiting C17, 20-lyase, blocking androgen production, but may do so more specifically and thus without causing mineralocorticoid excess and a need for prednisone therapy.²³ Galeterone is also an AR antagonist, preventing androgen from binding to AR. Finally, it has shown an ability to decrease AR levels through degradation of the AR.²³

EPI-001 is another novel AR-directed compound under study. It has shown its efficacy is through blocking AR N-terminal domain leading to inhibition of AR axis signaling.²³ This agent shows potential promise because of its ability to bypass the known AR resistance mechanism of splice variant formation.

TMPRSS2-ETS Fusion Gene

Approximately 50% to 70% of prostate cancers have somatic mutations resulting from the fusion between the transmembrane protease serine 2 (TMPRSS2) and the ETS transcription family. This TMPRSS2-ETS gene fusion is an early event in prostate cancer and has been associated with worse outcomes in earlier-stage prostate cancers.⁷

The TMPRSS2-ERG fusion has been associated with inhibition of nonhomologous end joining DNA repair and enhanced DNA damage. Other studies have shown an enhanced sensitivity to ionizing radiation in prostate cancers with TMPRSS2-ERG gene fusions due to the synthetic lethality effect of poly(ADP-ribose) polym­erase inhibitors (PARPis) in this setting.²⁷ The role of PARPis in treating prostate cancers with TMPRSS2-ERG gene fusions is under active investigation. One such study is a randomized combination therapy trial of veliparib and abiraterone in patients with metastatic hormone-resistant prostate cancer (NCT01576172).⁷

BRCA2 Mutations

In addition to its impact on prostate cancer development, the presence of a germline BRCA2 mutation has been associated with poor prognosis in all stages of prostate cancer, including men with localized disease.⁷

PARPis have been established as an effective treatment strategy in cancers with germline BRCA mutations. Studies have shown significant and durable responses from PARP inhibition in mCRPC patients with deleterious germline BRCA mutations.^28,29 In addition, we have seen evidence of efficacy of PARPis in BRCA-like tumors, tumors that share molecular characteristics of germline BRCA-mutated cancers. The synthetic lethality that PARPis are known for in the treatment of germline BRCA mutations is also relevant in solid malignancies with somatic mutations in DNA repair genes.²⁸ In prostate cancer, Mateo et al observed PARPis sensitivity in individuals with somatic mutations in BRCA2 in addition to other DNA repair mutations (ATM, BRCA1, PALB2, CHEK2, FANC1, and HDAC2) that are associated with defective DNA repair.²⁹

PTEN/PI3K/AKT/mTOR Pathway

The PTEN/PI3K/AKT/mTOR pathway is integral in the regulation of cell growth and apoptosis and has been shown to be central to metastatic activity in prostate cancer. PTEN mutations are seen in approximately 2% to 14% of prostate cancers, with copy number loss in 12% to 41%.⁷ Loss of a single allele is most commonly noted in primary prostate cancer. Metastatic prostate cancer is more often associated with mutations in PTEN.¹⁰ PIK3CA mutations occur in approximately 3% to 4% of prostate cancer, and amplifications of PIK3CA occur in approximately 4% to 10% of patients.⁷ Several studies have shown an association between loss of PTEN tumor suppressor activity, activation of the mTOR pathway, and poor prognosis in prostate cancer.¹⁰ Alterations in PTEN function were also associated with decreased disease-free interval and time to metastatic spread in a cohort with high-risk prostate cancer.¹⁰ This suggests a role for management with PI3K inhibitors, AKT inhibitors, or inhibitors of the mTOR pathway. Everolimus has demonstrated an effect on PSA with an 11% decrease in a nonbiomarker-selected cohort of CRPC patients,⁷ but mTOR inhibitors have generally had little clinical efficacy, likely due to feedback activation of the pathway.

Therapies directed toward the PTEN/PI3K/AKT/mTOR pathway have shown modest antitumor activity. Their effectiveness is limited by the presence of other mutations and lack of complete feedback inhibition in tumors treated with these pathway inhibitors. In addition, broadly targeted inhibition of mTOR and PI3K has been associated with significant on-target and off-target toxicities that limit use in the clinic.³⁰ Schwartz et al have shown in vivo inhibition of PTEN-mutant prostate tumors with combined PI3Kα, PI3Kβ, and AR inhibition, which led to sustained inhibition of PI3K.

TP53 Mutations

The tumor suppressor gene p53 functions to maintain genomic stability and prevent tumorigenesis. It is present in a mutated form in approximately 3% to 47% of prostate cancers and in 2% to 15% of prostate cancers as a homozygous deletion.⁷ Mutations are more commonly noted in later disease and are found in approximately 50% of advanced or CRPC.¹⁰ Cancers with TP53 mutations or deletions were associated with an increased risk of recurrence. Studies have shown a potential role for both Wee1 inhibitors and antiangiogenic agents in TP53-mutated prostate cancer. More work is needed to determine if this will direct clinical practice, as a study of docetaxel with or without prednisone showed no benefit in an unselected population.⁷

RB Gene

The RB gene is a tumor suppressor shown to be associated with castration resistance through the upregulation of AR output. It is mutated in up to approximately 14% of prostate cancers, with loss of gene in 5% to 23% of prostate cancers.⁷ Some studies have also shown methylation of RB in CRPC, making the use of hypomethylating agents a potentially interesting option for treatment.⁷

The CDK-RB-E2F pathway has been identified as a successful target of therapy in multiple cancers. One such example is the CDK4/6 inhibitor palbociclib in combination with an aromatase inhibitor, which has proved to be a successful treatment regimen for estrogen receptor–positive breast cancer.³¹ Similar approaches are under investigation in CRPC.

APC Gene

The APC gene is a tumor suppressor gene that is involved in cell migration and adhesion, transcriptional activation, and apoptosis. It has been shown to affect the Wnt signaling pathway. It is present in 3% to 10% of prostate cancers.⁷ The serine/threonine protein kinase CK2 has been linked to the Wnt pathway and identified as a regulator of multiple components of the pathway. Inhibition of CK2 has been shown to decrease transcription of Wnt target genes and lead to apoptosis in a number of colorectal cancer cell lines and in xenograft models.³²

CHD1 Gene

The CHD1 gene is thought to alter gene expression via modification of chromatin structure. Mutations are seen in 2% to 8% of prostate cancers, with deletions in 5% to 20%. The role CHD1 will play in the management of prostate cancer is unknown, as there are no current targetable agents for CHD1 dysfunction.⁷

MYC Gene

Amplification of MYC is present in 2% to 20% of prostate cancers. The protein encoded by this gene has a functional role in cell cycle progression, senescence, apoptosis, and cellular transformation.^1,8 Low-level MYC amplification is common in advanced prostate cancer.¹⁰ Use of the small-molecule bromodomain inhibitor JQ1 has led to the identification of BET bromodomain proteins as regulatory factors for c-Myc. These small-molecule inhibitors lead to downregulation of transcription of Myc and Myc-dependent target genes at a genome-wide level.³³ The highly specific bromodomain inhibitor I-BET762 has the ability to reduce Myc expression, inhibit cell growth in prostate cancer cell lines, and reduce tumor burden in vivo,³⁴ and a number of BET inhibitors are undergoing clinical evaluation.

ATM Gene

ATM is a DNA repair gene that acts as a moderator of cell cycle checkpoint signaling, which ultimately plays a role in genomic stability. It is present in both somatic and germline form and is seen in 5% of prostate cancers as a somatic mutation and in 1% of pathologic germline mutations. ATM has been observed in prostate cancers that have shown clinical responses to PARPis, demonstrating a possible role for PARP inhibition in the management of these cancers, as noted above.⁷

Neuroendocrine Prostate Cancer

The above discussion has focused on individual molecular abnormalities and their potential for driving personalized and specific therapies. More recently, it has been recognized that highly therapy-resistant prostate cancer develops a phenotype that has been variably described as “neuroendocrine” or “intermediate atypical carcinoma” (http://meetinglibrary.asco.org/content/109789?media=sl) (www.ncbi.nlm.nih.gov/pubmed/26855148). The molecular drivers of this phenotype are still being defined, and it remains to be seen whether therapeutic targets and approaches for this highly lethal version of prostate cancer can be identified.

Conclusion

The current debate over the limitations of PSA-based screening and use of PSA for long-term monitoring of prostate cancer demonstrate the need for additional biomarkers that can be used in the clinical setting for risk stratification and guidance in the selection and sequencing of therapies. There has been significant advancement in the development of prostate cancer therapies in recent years, with an associated benefit in quality of life and overall survival for patients. Nevertheless, these newer agents target either normal (albeit upregulated) AR (enzalutamide/abiraterone) or are rather nonspecific cytotoxins (cabazitaxel, Ra 223). Furthermore, the prognosis for patients whose tumors are resistant to these agents is very poor. Finally, the mechanisms of resistance to highly potent AR-directed and tubule-targeted agents is likely heterogeneous, as are the molecular alterations responsible for this phenotype. A few specific targets, such as PARP in patients with DNA repair alterations, have already been identified. Further molecular characterization of individual patient cancers and further investigation of therapies targeted to specific pathways promise to improve treatment for prostate cancer patients in the coming years.

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