Sage Journals: Discover world-class research

Abstract

Aided by developments in diagnostics and therapeutics, healthcare is increasingly moving toward precision medicine, in which treatment is customized to each individual. We discuss the relevance of precision medicine in prostate cancer, including gene targets, therapeutics and resistance mechanisms. We foresee precision medicine becoming an integral component of prostate cancer management to increase response to therapy and prolong survival.

Keywords

androgen deprivation therapy resistance AR-V7 microsatellite instability organic anion transporting polypeptide 1B3 precision medicine sex determining region Y box2

Precision medicine in prostate cancer

Precision medicine is an emerging field that uses genetic and environmental markers to determine the diagnosis of disease subcategories, the prognosis of patients, the choice of therapeutic, and accurate dosing. Such practices have become increasingly sophisticated, involving information obtained from genomics, metabolomics, and proteomics. Moreover, precision medicine methodologies are now available throughout the space of medical oncology: drug design, drug development, use of currently approved medications, and salvage therapy.

Developments in the medical treatment of prostate cancer have historically depended on a more sophisticated understanding of how androgens influence the disease. In the 1940s, acting on observations from surgical castration,¹ Huggins and Hodges discovered that restricting testicular androgen production by means of oral estrogen analogues led to slower progression in many patients who developed metastatic disease.^2,3 In the 1960s, several groups discovered the androgen receptor (AR),^4–6 leading to the development of the first antiandrogens.⁷ Agents used to counteract adrenal hyperplasias, ketoconazole, and aminoglutethimide^8,9 were later repurposed to counteract prostate cancer in 1976 and 1983; these agents work by blocking the production of adrenal androgens. In the early 1980s, Andrew Schally developed the first luteinizing hormone releasing hormone (LHRH) agonists that were found to block testicular androgen production.¹⁰ However, such therapies are only temporarily effective in patients with disease outside of the prostate gland, and the majority of patients develop castration-resistant prostate cancer (CRPC). Effective CRPC treatments have only been discovered in the past 13 years, when docetaxel chemotherapy was found to prolong overall survival.^11,12 Nevertheless, treatment decisions were not typically based on the recognition of interindividual differences or a diversity of therapeutic options.

While a priori assessment of disease markers remains rare, recent advances in prostate cancer therapy have involved markers of prostate tumorigenesis, progression, and acquired therapeutic resistance (Table 1). Several of these markers are not involved in androgen pathways, reflecting a more nuanced understanding of the molecular drivers of prostate cancer. Such recognition of interindividual differences and a better understanding of the disease has led to several effective therapeutics that can be utilized in various disease subgroups harboring different genetic and mutational backgrounds. Prognostic tests have also recently emerged that can determine the likelihood of disease recurrence, metastases, and prostate cancer specific mortality (PCSM). The purpose of the present review is to discuss the recent progress of personalized approaches to the treatment of prostate cancer.

Table 1.

Genetic abnormalities in prostate cancer and potential therapies.

Gene	Type of aberration	Function and traits	Potential therapy
BRCA2	Somatic mutations	Repairs DNA strand breaks Tumor suppressor	Olaparib
CYP17A1	Differential expression in the tumor microenvironment	Involved in sterol synthesis	Ketoconazole, abiraterone, seviteronel
SOX2	Differential expression in tumor cells undergoing lineage plasticity	Transcription factor important for stem cells	EGFR inhibitors
OATP1B3	Differential expression in tumor cells, and inherited polymorphisms	Transporter of drugs, hormones and small molecules	–
AR-V7	Splice variants	Androgen receptor variant. Marker of resistance to abiraterone and enzalutamide	Miclosamide, onalespib, aurora A kinase inhibitors
TMPRSS2-ERG	Somatic mutations	Fusion of an enzyme and a transcription factor. Found in 40%–80% of prostate cancers¹³	–
MSI	Somatic mutations and hypermutability resulting from Lynch syndrome	Frequent mutational status	Pembrolizumab

CYP17A1, cytochrome P450 17A1; EGFR, epidermal growth factor receptor; MSI, microsatellite instability; OATP1B3, organic anion transporting polypeptide 1B3; SOX2, sex determining region Y box2.

Selective therapeutics

Antiandrogens

There are currently several classes of antiandrogens.¹⁴ Previously, antiandrogen therapy consisted of AR ligands that prevent AR transcription by blocking androgen binding (i.e. flutamide, nilutamide, and bicalutamide). In 603 treatment-naïve patients with disseminated prostate cancer, flutamide and leuprolide compared with placebo and leuprolide significantly prolonged duration of progression-free (16.5 versus 13.9 months) and overall (35.6 versus 28.3 months) survival.¹⁵ In 457 patients initially treated with orchiectomy, nilutamide compared with placebo had a significantly higher proportion of patients with normal prostate-specific antigen (PSA) at 3 months (59% versus 28%) and longer progression-free (21.2 versus 14.7 months) and cancer-specific survival (37.0 versus 29.8 months).¹⁶ In 205 patients with stage III or IV prostate cancer, bicalutamide with an LHRH agonist versus an LHRH agonist alone demonstrated a higher proportion of patients with normal PSA at 3 months (79.4% versus 38.6%) and a greater estimated 5-year overall survival rate (75.3% versus 63.4%).^17,18

Newer antiandrogens typically also block AR transcription via multiple mechanisms. For instance, enzalutamide, apalutamide, and darolutamide are AR ligands which inhibit androgen binding, AR nuclear translocation, and the DNA-binding capacity of the AR. Niclosamide prevents AR binding to promoter sites on DNA and promotes AR proteolysis. EPI-001 and niphatenones both prevent AR-DNA binding. Because they target multiple elements of the androgen biosynthesis and gene expression pathways at once, newer antiandrogens inhibit intratumoral AR transcription more strongly than older antiandrogens and are typically more effective. For instance, 396 men with CRPC were treated with enzalutamide or bicalutamide with androgen deprivation therapy (ADT) in the double-blind, phase II STRIVE trial.¹⁹ Patients treated with enzalutamide showed significantly better results than those with bicalutamide, including a proportion of patients with at least a 50% PSA decline (81% versus 31%), at least a 90% PSA decline (65% versus 9%), and progression-free survival (19.4 versus 5.7 months).

Androgen synthesis inhibitors

In order for the AR to adopt its active conformation, bind DNA, and subsequently activate effector genes, it must first bind either testosterone or its more preferred ligand, dihydrotestosterone (DHT). To prevent transcription of AR-downstream genes, which lead to cellular growth, various therapeutics target the androgen synthesis pathway in an effort to deplete the cells of potential AR ligands. The cytochrome P450 17A1 (CYP17A1) enzyme converts pregnenolone to 17α-hydroxypregnenolone by its hydroxylase activity and 17α-hydroxypregnenolone to dehydroepiandrosterone by its lyase activity; 17α-hydroxypregnenolone and dehydroepiandrosterone are important precursors for testosterone and DHT.

Therapeutics, such as abiraterone and ketoconazole, inhibit both reactions catalyzed by the CYP17A1 enzyme, while seviteronel selectively inhibits its lyase activity. Once testosterone is synthesized, the 5α-reductase enzyme converts it into DHT, which has a stronger affinity for the AR. Thus, androgen synthesis inhibitors have a place in prostate cancer treatment, and abiraterone is a standard of care for patients with metastatic, CRPC regardless of previous treatment with docetaxel.^20,21 In 1195 patients with metastatic, CRPC previously treated with docetaxel, patients treated with abiraterone experienced a significantly longer overall survival than those treated with placebo (15.8 versus 11.2 months). In 1088 patients with metastatic, CRPC who had not received docetaxel, the abiraterone treatment group experienced a significantly longer radiographic progression-free survival than the placebo group (not reached versus 8.3 months) and a longer overall survival, even though not significant (35.3 versus 30.1 months). Abiraterone was also tested in 1199 patients with metastatic, castration-sensitive disease, and it showed significantly better results compared with placebo in radiographic progression-free (33.0 versus 14.8 months) and overall survival (not reached versus 34.7 months).²² Unfortunately, while androgen synthesis inhibitors effectively stem tumor growth for a brief period of time, resistance to these therapies eventually develops, and prostate cancer can progress without androgen signaling.

Cytotoxic chemotherapy

Cytotoxic chemotherapy, such as docetaxel and cabazitaxel, remains a mainstay of prostate cancer treatment based on several studies. The TAX327 trial showed that in 1006 patients with metastatic, castration-resistant disease treated with mitoxantrone, docetaxel weekly or docetaxel every 3 weeks, overall survival favored the last group (16.5, 17.4 versus 18.9 months), so docetaxel every 3 weeks has become the standard.¹¹ Indication for docetaxel was expanded to include metastatic, castration-sensitive disease based on two trials, STAMPEDE and CHAARTED.^23,24 In the STAMPEDE trial with 2962 patients, the group treated with docetaxel and ADT with or without radiotherapy exhibited a significantly longer overall survival compared with the group treated with ADT with or without radiotherapy (81 versus 71 months). This finding was duplicated in the CHAARTED trial with 790 patients, in which patients treated with docetaxel and ADT showed a significantly longer overall survival compared with those treated with ADT (57.6 versus 44 months). For patients with metastatic, castration-resistant disease already treated with docetaxel, cabazitaxel was shown to be efficacious.²⁵ In 755 patients treated with either cabazitaxel or mitoxantrone, the former group showed a significantly longer overall survival (15.1 versus 12.7 months). Thus, docetaxel and cabazitaxel are standards of care in metastatic prostate cancer.

Previous dogma stated that the taxanes acted by inducing G2/M cell cycle arrest.²⁶ Yet, several studies have now demonstrated that docetaxel and cabazitaxel also disrupt microtubules that are required for AR nuclear translocation, and that docetaxel is a substrate for dysregulated transporters that are expressed de novo in prostate cancer.¹⁴ Thus, even the application of docetaxel and cabazitaxel is warranted in some genetic contexts and not others.

Targeting AR cofactors

In addition to blocking androgen biosynthesis and AR gene signaling, drugs have recently been developed to target transcriptional coactivators and epigenetic regulators of AR. One such example is the bromodomain and extraterminal (BET) inhibitor, JQ1. JQ1 works by inhibiting the two bromodomains in BRD4 that are essential for its binding to the AR. Because BRD4 is the factor that helps the AR recruit RNA polymerase II to gene promoters, inhibition of BRD4 with JQ1 results in a loss of AR-driven gene transcription. In a VCaP xenograft model, enzalutamide demonstrated a prometastatic effect that was not seen with JQ1 treatment. JQ1 also inhibited tumor growth and AR target gene expression more than enzalutamide. However, JQ1 only altered gene expression in AR-positive cell lines, indicating that JQ1 treatment would be the most effective earlier in prostate cancer before patients’ tumors progressed to castration resistance.²⁷ While this treatment has yet to be tested in a clinical setting, these in vitro and in vivo results heavily suggest that AR cofactors and transcriptional regulators pose attractive targets for therapeutic development.

Therapeutic options for gene dysregulation in prostate cancer

ADT resistance

AR splice variants

While numerous AR splice variants have been identified, AR-V1 to AR-V7 are spliced in such a way that truncates the AR’s ligand binding domain and confers the potential for constitutive activation of the AR. However, AR-V2, AR-V3, and AR-V4 are not observed in clinical prostate cancer.^28,29 AR-V1 is expressed more frequently in CRPC, but it lacks several amino acids that decrease its ability to localize to the nucleus, and its expression is not correlated with treatment outcome in patients.^28,29 The AR-V7 splice variant excludes the ligand binding domain, making it the most relevant AR splice variant in prostate cancer. This deletion results in a constitutively active AR that can translocate to the nucleus and signal gene expression even in the absence of testosterone or DHT.^14,28,29 The upregulation of the AR-V7 splice variant likely occurs due to the increased expression of various splicing factors, such as splicing factor proline and glutamine-rich (SFPQ), that is observed in prostate cancer.^30–32 However, as of yet there are no clinically approved treatments targeting these factors.

Patients with AR-V7 experienced lower response rates and survival after treatment with enzalutamide and abiraterone compared with those without the variant.^33,34 Patients with AR-V7 had better response to and survival with taxanes than with abiraterone and enzalutamide. These phenomena are attributable to an absence of the ligand-binding domain. Such differences in response and survival by treatment type did not occur for patients lacking AR-V7. Therefore, AR-V7 may be a useful biomarker for prostate cancer treatment selection.

Candidate agents, which may target AR-V7, include niclosamide, onalespib, and aurora A kinase inhibitors. Niclosamide is an antihelminthic drug, which reduces AR-V7 protein levels and inhibits growth of AR-V7-expressing cancer cells in vitro and in vivo.³⁵ It also shows synergistic effects with enzalutamide or abiraterone in vitro and in vivo.^35,36 Onalespib, a heat shock protein inhibitor, reduces the generation of AR-V7 by introducing alternative splicing events.³⁷ Aurora A kinase inhibition reduces AR-V7 mRNA and protein levels.³⁸ In summary, specific agents may soon become available for patients for whom abiraterone and enzalutamide are ineffective.

ADT evasion via CYP17A1 androgen synthesis

In normal prostate cells, AR-mediated gene signaling is activated by gonadally derived testosterone, which is subsequently converted into the more potent androgen, DHT. However, in prostate cancer, tumors utilize the CYP17A1 enzyme to convert androgen precursors from the adrenal glands, such as dehydroepiandrostenedione (DHEA), into testosterone, thereby evading the low androgen environment caused by chemical or surgical castration. The CYP17A1 enzyme specifically catalyzes the synthesis of androgen and glucocorticoid precursors (17α-hydroxypregnenolone and 17α-hydroxyprogesterone) through hydroxylase activity and weak androgens (DHEA and androstenedione) via lyase activity.³⁹ Once these precursors are converted to testosterone, the steroid-5α-reductase isoenzyme-2 (SRD5A2) reduces testosterone to DHT, which has an even higher affinity for the AR than testosterone and, subsequently, plays a larger role in upregulating androgen-dependent gene transcription.⁴⁰ While SRD5A2 is the dominant isozyme in normal prostate tissue, prostate tumors upregulate the SRD5A1 enzyme.

As a result of its role in developing resistance to ADT, CYP17A1 is an established target for prostate cancer therapy. Ketoconazole, an antifungal, weakly and nonspecifically inhibits CYP17A1 and has been noted to be active in prostate cancer at high doses.⁹ A newer agent, abiraterone, more selectively inhibits CYP17A1 resulting in decreases in circulating androgens (DHEA, testosterone, and dihydrotestosterone). Thus, abiraterone inhibits AR signaling, prolongs survival, and is a standard therapy for metastatic, castration-resistant cancer.^41,42 Since abiraterone inhibits CYP17A1 hydroxylase sixfold more selectively than CYP17A1 lyase, it causes glucocorticoid deficiency and must be administered with prednisone. Another CYP17A1 inhibitor, seviteronel, more selectively inhibits the lyase function of CYP17A1 and thereby reduces androgen biosynthesis, AR signaling, and tumor growth without causing glucocorticoid deficiency. Therefore, should seviteronel demonstrate similar or superior efficacy to abiraterone, it may also become a standard option.^43,44

OATP1B3

The organic anion transporting polypeptide (OATP) family of transporters is implicated in prostate tumorigenesis, with relevant potential therapy to be developed. As indicated by their name, the OATP family of transporters carries drugs, hormones including testosterone, and small molecules, and thus is essential for a functional liver, which processes and detoxifies numerous substances.⁴⁵ OATP family expression has also been noted in other organs, such as breast, lung, and prostate, and specifically OATP1B3, a member of this family, has been implicated in prostate tumorigenesis.⁴⁶ Testosterone uptake differed among the cells exhibiting different polymorphisms, and the patients who harbored the haplotypes with reduced testosterone uptake exhibited longer progression-free and overall survival than those who did not. Furthermore, OATP1B3 mRNA and protein expression directly correlated with Gleason scores, implicating it as a biomarker of aggressive disease.⁴⁷ Therefore, OATP1B3 inhibition leading to testosterone reduction may have a role in prostate cancer therapy.

It was also recently determined that in addition to testosterone, OATP1B3 has the ability to transport docetaxel and abiraterone into the cell.^48,49 The knowledge that OATP1B3 is upregulated in resistance can allow physicians to make more informed decisions regarding the sequence of taxane and androgen biosynthesis targeting drugs.

Therapeutic options for somatic mutations in prostate cancer

AR mutations

As tumors grow and progress, they accumulate somatic mutations that benefit the tumor. Because the AR plays a large role in the development of prostate cancer, mutations that allow the AR to bind alternative ligands, such as estrogen and progesterone, and continue to signal gene expression in the absence of androgens are selected for. Among the more than 70 different missense mutations identified in prostate cancer, H874Y, F876L, T877A, and W741L/C are particularly interesting because they are linked to drug resistance and disease progression.^14,50,51

Each of these mutations changes the conformation of the AR by replacing amino acids in the ligand binding pocket, so that it can bind ligands other than testosterone and DHT. The H874Y and T877A somatic mutations similarly affect the AR and create more space in the ligand binding pocket, allowing the AR to bind estradiol, progestins, and cyproterone acetate, among other ligands.^14,52,53

The F876L and W741L/C mutations relate more directly to drug resistance. The F876L mutation alters the ligand binding pocket so that enzalutamide binds the AR and promotes its activation rather than inhibition.⁵⁴ Similarly, the W741L/C mutation promotes bicalutamide binding in a way which moves the AR into its active conformation.^55,56 Such mutations create obstacles for designing effective treatment of CRPC.

TMPRSS/ERG

An important discovery was noted in 2005, in which TMPRSS2-ETS gene fusions were noted in 23 of 29 prostate cancer tissues, identifying it as an important somatic mutation.⁵⁷ This discovery was notable because such gene translocations and consequent fusions had been well described for other malignancies, which include BCR-ABL in chronic myeloid leukemia, MYC-IGH in Burkitt’s lymphoma, and EWS-FLI1 in Ewing’s sarcoma but not for prostate cancer.^58–60 As a result of the gene fusions, TMPRSS2 may mediate the overexpression of ETS family members, ERG or ETV1. This is significant because ERG is a frequently expressed oncogene in prostate cancer, and TMPRSS2-ERG fusions mediate invasion in both in vitro and in vivo models of prostate cancer.^61,62 When coupled to serum PSA, urine detection of TMPRSS2-ERG has been shown to enhance the ability to predict prostate cancer in tissue biopsy.⁶³ However, TMPRSS2-ERG has been an elusive therapeutic target, with mixed results from clinical trials of agents including inhibitors of poly ADP ribose polymerase 1 (PARP1), DNA protein kinase, and histone deacetylase 1.⁶⁴ Nevertheless, the potential of a successful, targeted therapy for a majority of prostate cancers has sustained research efforts into TMPRSS2-ERG.

BRCA1/2

BRCA1 and BRCA2 mutations have emerged as potential therapeutic targets in certain patients with prostate cancer because cells expressing such mutations have a significantly diminished capacity to repair double-stranded DNA (dsDNA) breaks. Studies have reported on the frequencies and relative importance of BRCA1/2 mutations. In 692 men with metastatic disease, 0.9% had germline mutations in BRCA1 and 5.3% in BRCA2.⁶⁵ In 251 Ashkenazis with prostate cancer, 2% had BRCA1 mutations compared with 3.2% with BRCA2.⁶⁶ BRCA1 mutation carriers had no increased risk of prostate cancer, in contrast to a 4.8-fold increased risk among BRCA2 mutation carriers.

Since normal (BRCA1/2-positive) cells efficiently repair dsDNA breaks, tumor cells that have acquired BRCA1/2 mutations can be specifically targeted.^67,68 Olaparib, a PARP inhibitor, prevents repair of single-stranded DNA (ssDNA) breaks, leading to rapid accumulation of dsDNA breaks in BRCA1/2 mutated cells. A phase I study showed that not only did olaparib have a favorable side-effect profile, it also showed antitumor activity only in those with BRCA1 or BRCA2 mutation.⁶⁹ The TOPARP-A trial assessed olaparib as a therapy among 50 patients with metastatic, CRPC, most of whom were pretreated with abiraterone (96%), androgen deprivation, and docetaxel (100% each).⁷⁰ In TOPARP-A, the 16 responders included all seven patients with a BRCA2 mutation. Thus, olaparib may become part of the prostate cancer therapeutic regimen for a subset of patients with DNA repair defects. Of interest, circulating cell-free DNA (cfDNA) samples collected during the TOPARP-A trial showed great promise for precision medicine as a prognostic, predictive, and resistance biomarker.⁷¹ Reduction in their levels correlated with overall survival. Not only were DNA repair mutations detectable in cfDNA, their allelic frequencies decreased in responders, and cfDNA could be utilized to detect emergence of resistance to therapy.

Microsatellite instability

The US Food and Drug Administration approved the use of pembrolizumab in patients harboring tumors with microsatellite instability (MSI) regardless of the tumor site.⁷² A minority of prostate tumors (~4–25%) demonstrate MSI,⁷³ which is defined by hypermutability of repeated sequences of DNA resulting from mismatch repair deficiencies and leads to heritable risk of prostate cancer.^74,75 Such mutational burden results in sensitivity to blockade of the programmed cell death protein 1 (PD-1), a negative feedback pathway that represses T helper 1 (Th1) cytotoxic immune response.⁷⁶

Therapeutic resistance mechanisms

ARv7

Since Antonarakis and colleagues linked the presence of AR-V7 mRNA in circulating tumor cells with resistance to both enzalutamide and abiraterone, AR-V7 has been at the forefront of prostate cancer resistance research.⁷⁷ As mentioned previously, the AR-V7 splice variant excludes the AR’s ligand binding domain, which is the target of both enzalutamide and (indirectly) abiraterone. Without the ligand binding domain, there is no place for enzalutamide to bind and, as a result, AR-V7 continues to translocate to the nucleus and activate AR-dependent gene transcription. Abiraterone works by inhibiting the synthesis of both testosterone and DHT, however the AR-V7 isoform no longer depends on ligand binding for activation, and therefore the therapeutic activity of abiraterone no longer has an effect.

Additionally, a growing body of evidence suggests that AR-V7 may play a role in an overlapping resistance mechanism to both abiraterone and docetaxel. In a clinical study, patients who received docetaxel treatment following abiraterone did not respond as well to docetaxel as those who had not received prior abiraterone treatment.⁷⁸ Furthermore, patients who were abiraterone resistant also demonstrated resistance to subsequent docetaxel treatment.

Sex determining region Y box2

Sex determining region Y box2 (SOX2) is an essential stem cell transcription factor that promotes enzalutimide resistance by promoting lineage plasticity, a process by which prostate tumor cells undergo dedifferentiation to neuroendocrine cells that simultaneously display luminal, basal, and epithelial characteristics.⁷⁹ SOX2 expression also promotes growth and inhibits apoptosis in untreated CRPC cells,^80,81 and its expression is clinically associated with biochemical recurrence, lymph node metastasis, migration, and invasion of prostate cancer cells.⁸² Although no SOX2 inhibitor for prostate cancer therapy has been developed, an epidermal growth factor receptor (EGFR) inhibitor reduces SOX2 expression in prostate cancer cells, implicating a possible therapeutic option.⁸³

Prognostic genetic testing

Integration of genomics and pharmacogenomics into patient care is closely connected with improvement of diagnostics, and RNA profiling tests, such as Decipher(GenomeDx, San Diego, CA), Oncotype DX (Genomic Health, Inc., Redwood City, CA), and Prolaris (Myriad Genetic Laboratories, Inc., Salt Lake City, UT), can offer additional information for providers and patients with prostate cancer (Table 2). Decipher predicts metastasis and prostate-cancer-specific mortality after radical prostatectomy.^84,85 Oncotype DX predicts biochemical recurrence after radical prostatectomy and prostate-cancer-specific mortality in patients under active surveillance.^86,87 Prolaris predicts biochemical recurrence, metastasis, and prostate-cancer-specific mortality after radical prostatectomy, as well as mortality in those under active surveillance.^88–90 How these tests will fare compared with one another remains to be determined. Although they are currently not part of treatment planning for prostate cancer, they may become so in the future. Unfortunately, Decipher, Oncotype DX, and Prolaris provide prognostic, but not predictive information, and they are costly (greater than $3000 per test).⁹¹ The lack of predictive information deters widespread adoption, and a 24-gene signature, reported to predict which patients with prostate cancer would benefit the most from postoperative radiation, may address the deficiency.⁹² A retrospective study noted that patients with high Post-Operative Radiation Therapy Outcomes Score (PORTOS (Genome Dx, San Diego, CA)) who had postoperative radiotherapy were less likely to have metastasis at 10 years compared with those with high PORTOS who did not. After PORTOS is validated in additional trials and patients, and becomes commercially available, it may become a useful tool in prostate cancer management.

Table 2.

Genomic diagnostic tests for prostate cancer.

Test	Test material	Methodology	Sample type	Distinguishing features
Decipher	Tumor RNA expression	Whole transcriptome microarray of 22 coding and noncoding RNAs	Tissue	Predicts metastasis
Oncotype DX	Tumor RNA expression	RT-PCR of 12 cancer-related and 5 reference genes	Tissue	Predicts BCR
Prolaris	Tumor RNA expression	RT-PCR of 31 cell cycle and 15 reference genes	Tissue	Predicts BCR and metastasis
PORTOS	Tumor RNA expression	RT-PCR of 24 DNA damage, immune and radiation response genes	Tissue	Predicts response to postoperative radiation therapy
FoundationACT	Somatic mutations in cell-free DNA	ctDNA of 62 genes and 6 gene fusions	Peripheral whole blood	Advantageous if tissue is not available

Modified and adapted from Falzarano et al.⁹³

BCR, biochemical recurrence; ctDNA, circulating tumor DNA; RT-PCR, reverse transcriptase polymerase chain reaction.

Another issue facing pharmacogenomics is utilization of information from diagnostic tests. Several companies, including Foundation Medicine (Cambridge, MA), employ high-throughput sequencing to detect germline or somatically acquired genomic perturbations in patients with solid and hematological malignancies.^94–96 Personalized, targeted treatments based on the genomic information thus acquired have led to mixed results, ranging from no difference in outcome to improved response rates in metastatic breast cancer. This spectrum of responses affirms that genomic aberrations and a multitude of other factors influence treatment response, and furthermore, survival. In addition, understanding of disease mechanism and treatment resistance needs to improve to take advantage of genomic diagnostic information. Foundation Medicine offers several tests, including FoundationACT, which is designed to detect mutations in cancers of breast, colon, lung, and prostate. Hopefully, FoundationACT and other genomic diagnostic tests will yield discoveries, which will ultimately lead to improved responses in prostate cancer.

Future of precision medicine in prostate cancer

As outlined so far, successful establishment of precision medicine in prostate cancer hinges on numerous factors, including accurate diagnostic tests, specific gene targets, and effective treatments. In order to put precision medicine into practice, clinicians and scientists need to be able to readily access clinical and genomic data of patients, and some search tools include Oncology Data Retrieval Systems (OncDRS (Dana Farber Cancer Institute, Cambridge, MA)) and GeneMed (National Cancer Institute, Bethesda, MD).^97,98 Physicians can utilize OncDRS to quickly search and obtain clinical and genomic data of patients with cancer, and such information can be used to tailor treatment and design clinical trials. Within a year of release, OncDRS aided data retrieval for more than 50 publications. GeneMed has facilitated a molecular profiling-based assignment of cancer therapy (MPACT) clinical trial [ClinicalTrials.gov identifier: NCT01827384] by operating as a hub to integrate information from biostatisticians, clinicians, and sequencing laboratory. This trial uses next-generation sequencing to identify actionable mutations in patients with advanced solid tumors and randomize eligible patients to two arms, one with a targeted drug for mutation, and the other with a nontargeted drug. The list of targeted drugs includes inhibitors of MEK, mTOR, PARP, and Wee1. Upon disease progression, patients on the arm with the nontargeted drug can cross over to the arm with the targeted drug, and outcome measures include response rate and progression-free survival. At the time of writing the trial is ongoing and recruiting participants [ClinicalTrials.gov identifier: NCT01827384].

Overall, precision medicine is not yet standard practice in prostate cancer, so more work is needed. Unlike BRCA2 and CYP17A1, SOX2, OATP1B3, AR-V7, and TMPRSS2-ERG currently do not have approved targeted agents. It also appears that therapeutics such as pembrolizumab are effective in certain tumors with high microsatellite instability or mismatch repair deficiencies.^99,100 Thus, detection of genomic abnormalities with appropriate treatments may help establish precision medicine in prostate cancer. In addition, results from genomic diagnostic tests, such as Decipher, Oncotype DX, Prolaris, PORTOS, and FoundationACT need to be interpreted with caution because no large randomized clinical trial has supported their routine use in patient care. Another reason to apply caution is that a considerable variation of gene expression levels exists among tissue cores from the same patients, so multiple biopsies from the same patients may need to be subjected to genomic diagnostic tests, and their results averaged before application.¹⁰¹ Although FoundationACT reduces sampling bias by using peripheral blood, it, too, has not been validated in a large prospective study. Also, scores from Decipher, Oncotype DX, and Prolaris varied both within and among tissue cores from the same patients, which indicates a need for a uniform, standardized genomic diagnostic test in prostate cancer. Despite these concerns, the field is moving toward precision medicine aided by advances in diagnostics, therapeutics, understanding of disease mechanism, and integration of clinical and genomic data (Figure 1). Therefore, clinicians and scientists are well positioned to take advantage of the new resources to establish precision medicine in prostate cancer.

Figure 1.

Components of precision medicine cooperating towards a better outcome (dx: diagnostic).

Footnotes

Acknowledgements

Edel M. McCrea and Daniel K. Lee are joint first authors.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

References

White

II . The present position of the surgery of the hypertrophied prostate. Ann Surg 1893; 18: 152–188.

Huggins

Stevens

Jr Hodges

. Studies on prostatic cancer: II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg 1941; 43: 209–223.

Huggins

Hodges

. Studies on prostatic cancer. I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941; 1: 293–297.

Anderson

Liao

Selective retention of dihydrotestosterone by prostatic nuclei. Nature 1968; 219: 277–279.

Bruchovsky

Wilson

JD.

The intranuclear binding of testosterone and 5-alpha-androstan-17-beta-ol-3-one by rat prostate. J Biol Chem 1968; 243: 5953–5960.

Mainwaring

WI.

A soluble androgen receptor in the cytoplasm of rat prostate. J Endocrinol 1969; 45: 531–541.

Denmeade

Isaacs

JT.

A history of prostate cancer treatment. Nat Rev Cancer 2002; 2: 389–396.

Sanford

Drago

Rohner

Jr et al . Aminoglutethimide medical adrenalectomy for advanced prostatic carcinoma. J Urol 1976; 115: 170–174.

Trachtenberg

Halpern

Pont

Ketoconazole: a novel and rapid treatment for advanced prostatic cancer. J Urol 1983; 130: 152–153.

10.

Tolis

Ackman

Stellos

et al . Tumor growth inhibition in patients with prostatic carcinoma treated with luteinizing hormone-releasing hormone agonists. Proc Natl Acad Sci U S A 1982; 79: 1658–1662.

11.

Tannock

de Wit

Berry

et al . Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502–1512.

12.

Petrylak

Tangen

Hussain

et al . Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513–1520.

13.

Clark

Merson

Jhavar

et al . Diversity of TMPRSS2-ERG fusion transcripts in the human prostate. Oncogene 2007; 26: 2667–2673.

14.

McCrea

Sissung

Price

et al . Androgen receptor variation affects prostate cancer progression and drug resistance. Pharmacol Res 2016; 114: 152–162.

15.

Crawford

Eisenberger

McLeod

et al . A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989; 321: 419–424.

16.

Dijkman

Janknegt

De Reijke

et al . Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer, and the significance of early prostate specific antigen normalization. International Anandron Study Group. J Urol 1997; 158: 160–163.

17.

Akaza

Yamaguchi

Matsuda

et al . Superior anti-tumor efficacy of bicalutamide 80 mg in combination with a luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist monotherapy as first-line treatment for advanced prostate cancer: interim results of a randomized study in Japanese patients. Jpn J Clin Oncol 2004; 34: 20–28.

18.

Akaza

Hinotsu

Usami

et al . Combined androgen blockade with bicalutamide for advanced prostate cancer: long-term follow-up of a phase 3, double-blind, randomized study for survival. Cancer 2009; 115: 3437–3445.

19.

Penson

Armstrong

Concepcion

et al . Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE trial. J Clin Oncol 2016; 34: 2098–2106.

20.

Fizazi

Scher

Molina

et al . Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012; 13: 983–992.

21.

Ryan

Smith

de Bono

et al . Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013; 368: 138-148. DOI: 10.1056/NEJMoa1209096.

22.

Fizazi

Tran

Fein

et al . Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 2017; 377: 352–360.

23.

James

Sydes

Clarke

et al . Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016; 387: 1163–1177.

24.

Sweeney

Chen

Carducci

et al . Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015; 373: 737–746.

25.

de Bono

Oudard

Ozguroglu

et al . Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010; 376: 1147–1154.

26.

Nehme

Varadarajan

Sellakumar

et al . Modulation of docetaxel-induced apoptosis and cell cycle arrest by all- trans retinoic acid in prostate cancer cells. Br J Cancer 2001; 84: 1571–1576.

27.

Asangani

Dommeti

Wang

et al . Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 2014; 510: 278–282.

28.

Dunn

Wei

et al . Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res 2009; 69: 16–22.

29.

Hornberg

Ylitalo

Crnalic

et al . Expression of androgen receptor splice variants in prostate cancer bone metastases is associated with castration-resistance and short survival. PLoS One 2011; 6: e19059.

30.

Fei

Chen

Xiao

et al . Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proc Natl Acad Sci U S A 2017; 114: E5207–E5215.

31.

Takayama

Suzuki

Fujimura

et al . Dysregulation of spliceosome gene expression in advanced prostate cancer by RNA-binding protein PSF. Proc Natl Acad Sci U S A 2017; 114: 10461–10466.

32.

Wang

Ceniccola

Hwang

et al . Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer. Nat Commun 2017; 8: 15921.

33.

Antonarakis

Luber

et al . Androgen receptor splice variant 7 and efficacy of taxane chemotherapy in patients with metastatic castration-resistant prostate cancer. JAMA Oncol 2015; 1: 582–591.

34.

Scher

Schreiber

et al . Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol 2016; 2: 1441–1449.

35.

Liu

Lou

Zhu

et al . Niclosamide inhibits androgen receptor variants expression and overcomes enzalutamide resistance in castration-resistant prostate cancer. Clin Cancer Res 2014; 20: 3198–3210.

36.

Liu

Armstrong

Zhu

et al . Niclosamide enhances abiraterone treatment via inhibition of androgen receptor variants in castration resistant prostate cancer. Oncotarget 2016; 7: 32210–32220.

37.

Ferraldeschi

Welti

Powers

et al . Second-generation HSP90 inhibitor onalespib blocks MRNA splicing of androgen receptor variant 7 in prostate cancer cells. Cancer Res 2016; 76: 2731–2742.

38.

Jones

Noble

Wedge

et al . Aurora A regulates expression of AR-V7 in models of castrate resistant prostate cancer. Sci Rep 2017; 7: 40957.

39.

Culig

Targeting the androgen receptor in prostate cancer. Expert Opin Pharmacother 2014; 15: 1427–1437.

40.

Chang

Papari-Zareei

et al . Dihydrotestosterone synthesis bypasses testosterone to drive castration-resistant prostate cancer. Proc Natl Acad Sci U S A 2011; 108: 13728–13733.

41.

Attard

Reid

A’Hern

et al . Selective inhibition of CYP17 with abiraterone acetate is highly active in the treatment of castration-resistant prostate cancer. J Clin Oncol 2009; 27: 3742–3748.

42.

de Bono

Logothetis

Molina

et al . Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 364: 1995–2005.

43.

Maity

Titus

Gyftaki

et al . Targeting of CYP17A1 lyase by VT-464 inhibits adrenal and intratumoral androgen biosynthesis and tumor growth of castration resistant prostate cancer. Sci Rep 2016; 6: 35354.

44.

Norris

Ellison

Baker

et al . Androgen receptor antagonism drives cytochrome P450 17A1 inhibitor efficacy in prostate cancer. J Clin Invest 2017.

45.

Obaidat

Roth

Hagenbuch

The expression and function of organic anion transporting polypeptides in normal tissues and in cancer. Annu Rev Pharmacol Toxicol 2012; 52: 135–151.

46.

Hamada

Sissung

Price

et al . Effect of SLCO1B3 haplotype on testosterone transport and clinical outcome in Caucasian patients with androgen-independent prostatic cancer. Clin Cancer Res 2008; 14: 3312–3318.

47.

Pressler

Sissung

Venzon

et al . Expression of OATP family members in hormone-related cancers: potential markers of progression. PLoS One 2011; 6: e20372.

48.

Iusuf

Hendrikx

van Esch

et al . Human OATP1B1, OATP1B3 and OATP1A2 can mediate the in vivo uptake and clearance of docetaxel. Int J Cancer 2015; 136: 225–233.

49.

Mostaghel

Cho

Zhang

et al . Association of tissue abiraterone levels and SLCO genotype with intraprostatic steroids and pathologic response in men with high-risk localized prostate cancer. Clin Cancer Res 2017; 23: 4592–4601.

50.

Brooke

Bevan

CL.

The role of androgen receptor mutations in prostate cancer progression. Curr Genomics 2009; 10: 18–25.

51.

Gottlieb

Beitel

et al . The androgen receptor gene mutations database (ARDB): 2004 update. Hum Mutat 2004; 23: 527–533.

52.

Duff

McEwan

IJ.

Mutation of histidine 874 in the androgen receptor ligand-binding domain leads to promiscuous ligand activation and altered p160 coactivator interactions. Mol Endocrinol 2005; 19: 2943–2954.

53.

Steketee

Timmerman

Ziel-van der Made

et al . Broadened ligand responsiveness of androgen receptor mutants obtained by random amino acid substitution of H874 and mutation hot spot T877 in prostate cancer. Int J Cancer 2002; 100: 309–317.

54.

Korpal

Korn

Gao

et al . An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov 2013; 3: 1030–1043.

55.

Liu

et al . Interaction mechanism exploration of R-bicalutamide/S-1 with WT/W741L AR using molecular dynamics simulations. Mol Biosyst 2015; 11: 3347–3354.

56.

Bohl

Gao

Miller

et al . Structural basis for antagonism and resistance of bicalutamide in prostate cancer. Proc Natl Acad Sci U S A 2005; 102: 6201–6206.

57.

Tomlins

Rhodes

Perner

et al . Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310: 644–648.

58.

Aplan

PD.

Causes of oncogenic chromosomal translocation. Trends Genet 2006; 22: 46–55.

59.

Cai

Medeiros

et al . MYC-driven aggressive B-cell lymphomas: biology, entity, differential diagnosis and clinical management. Oncotarget 2015; 6: 38591–38616.

60.

Downing

Head

Parham

et al . Detection of the (11;22)(q24;q12) translocation of Ewing’s sarcoma and peripheral neuroectodermal tumor by reverse transcription polymerase chain reaction. Am J Pathol 1993; 143: 1294–1300.

61.

Tomlins

Laxman

Varambally

et al . Role of the TMPRSS2-ERG gene fusion in prostate cancer. Neoplasia 2008; 10: 177–188.

62.

Petrovics

Liu

Shaheduzzaman

et al . Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome. Oncogene 2005; 24: 3847–3852.

63.

Tomlins

Day

Lonigro

et al . Urine TMPRSS2:ERG plus PCA3 for individualized prostate cancer risk assessment. Eur Urol 2016; 70: 45–53.

64.

Feng

Brenner

Hussain

et al . Molecular pathways: targeting ETS gene fusions in cancer. Clin Cancer Res 2014; 20: 4442–4448.

65.

Pritchard

Mateo

Walsh

et al . Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 2016; 375: 443–453.

66.

Kirchhoff

Kauff

Mitra

et al . BRCA mutations and risk of prostate cancer in Ashkenazi Jews. Clin Cancer Res 2004; 10: 2918–2921.

67.

Rottenberg

Jaspers

Kersbergen

et al . High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. Proc Natl Acad Sci U S A 2008; 105: 17079–17084.

68.

Balmana

Tung

Isakoff

et al . Phase I trial of olaparib in combination with cisplatin for the treatment of patients with advanced breast, ovarian and other solid tumors. Ann Oncol 2014; 25: 1656–1663.

69.

Fong

Boss

Yap

et al . Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361: 123–134.

70.

Mateo

Carreira

Sandhu

et al . DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med 2015; 373: 1697–1708.

71.

Goodall

Mateo

Yuan

et al . Circulating cell-free DNA to guide prostate cancer treatment with PARP inhibition. Cancer Discov 2017; 7: 1006–1017.

72.

Goldberg

Blumenthal

McKee

et al . The FDA oncology center of excellence and precision medicine. Exp Biol Med (Maywood) 2018; 243: 308–312.

73.

Watson

Berg

Soreide

Prevalence and implications of elevated microsatellite alterations at selected tetranucleotides in cancer. Br J Cancer 2014; 111: 823–827.

74.

Raymond

Mukherjee

Wang

et al . Elevated risk of prostate cancer among men with Lynch syndrome. J Clin Oncol 2013; 31: 1713–1718.

75.

Rosty

Walsh

Lindor

et al . High prevalence of mismatch repair deficiency in prostate cancers diagnosed in mismatch repair gene mutation carriers from the colon cancer family registry. Fam Cancer 2014; 13: 573–582.

76.

Uram

Wang

et al . PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372: 2509–2520.

77.

Antonarakis

Wang

et al . AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med 2014; 371: 1028–1038.

78.

Mezynski

Pezaro

Bianchini

et al . Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance? Ann Oncol 2012; 23: 2943–2947.

79.

Zhang

Benelli

et al . SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 2017; 355: 84–88.

80.

Kregel

Kiriluk

Rosen

et al . Sox2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer. PLoS One 2013; 8: e53701.

81.

Jia

et al . SOX2 promotes tumorigenesis and increases the anti-apoptotic property of human prostate cancer cell. J Mol Cell Biol 2011; 3: 230–238.

82.

Russo

Esposito

Tupone

et al . SOX2 boosts major tumor progression genes in prostate cancer and is a functional biomarker of lymph node metastasis. Oncotarget 2016; 7: 12372–12385.

83.

Rybak

Tang

SOX2 plays a critical role in EGFR-mediated self-renewal of human prostate cancer stem-like cells. Cell Signal 2013; 25: 2734–2742.

84.

Karnes

Bergstralh

Davicioni

et al . Validation of a genomic classifier that predicts metastasis following radical prostatectomy in an at risk patient population. J Urol 2013; 190: 2047–2053.

85.

Cooperberg

Davicioni

Crisan

et al . Combined value of validated clinical and genomic risk stratification tools for predicting prostate cancer mortality in a high-risk prostatectomy cohort. Eur Urol 2015; 67: 326–333.

86.

Klein

Cooperberg

Magi-Galluzzi

et al . A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur Urol 2014; 66: 550–560.

87.

Cullen

Rosner

Brand

et al . A biopsy-based 17-gene genomic prostate score predicts recurrence after radical prostatectomy and adverse surgical pathology in a racially diverse population of men with clinically low- and intermediate-risk prostate cancer. Eur Urol 2015; 68: 123–131.

88.

Cuzick

Berney

Fisher

et al . Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort. Br J Cancer 2012; 106: 1095–1099.

89.

Cooperberg

Simko

Cowan

et al . Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort. J Clin Oncol 2013; 31: 1428-1434.

90.

Bishoff

Freedland

Gerber

et al . Prognostic utility of the cell cycle progression score generated from biopsy in men treated with prostatectomy. J Urol 2014; 192: 409–414.

91.

Davis

JW.

Novel commercially available genomic tests for prostate cancer: a roadmap to understanding their clinical impact. BJU Int 2014; 114: 320–322.

92.

Zhao

Chang

Spratt

et al . Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis. Lancet Oncol 2016; 17: 1612–1620.

93.

Falzarano

Ferro

Bollito

et al . Novel biomarkers and genomic tests in prostate cancer: a critical analysis. Minerva Urol Nefrol 2015; 67: 211–231.

94.

Wheler

Atkins

Janku

et al . Presence of both alterations in FGFR/FGF and PI3K/AKT/mTOR confer improved outcomes for patients with metastatic breast cancer treated with PI3K/AKT/mTOR inhibitors. Oncoscience 2016; 3: 164–172.

95.

Blumenthal

Dvir

Lossos

et al . Clinical utility and treatment outcome of comprehensive genomic profiling in high grade glioma patients. J Neurooncol 2016; 130: 211–219.

96.

Heuck

Jethava

Khan

et al . Inhibiting MEK in MAPK pathway-activated myeloma. Leukemia 2016; 30: 976–980.

97.

Orechia

Pathak

Shi

et al . OncDRS: An integrative clinical and genomic data platform for enabling translational research and precision medicine. Appl Transl Genom 2015; 6: 18–25.

98.

Zhao

Polley

et al . GeneMed: an informatics hub for the coordination of next-generation sequencing studies that support precision oncology clinical trials. Cancer Inform 2015; 14: 45–55.

99.

Graff

Alumkal

Drake

et al . Early evidence of anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget 2016; 7: 52810–52817.

100.

Vaishampayan

UN.

Changing face of metastatic prostate cancer: the law of diminishing returns holds true. Curr Opin Oncol. Epub ahead of print 18 March 2017. DOI: 10.1097/CCO.0000000000000370.

101.

Wei

Wang

Lampert

et al . Intratumoral and intertumoral genomic heterogeneity of multifocal localized prostate cancer impacts molecular classifications and genomic prognosticators. Eur Urol 2017; 71: 183–192.

Precision medicine applications in prostate cancer

Abstract

Keywords

Precision medicine in prostate cancer

Selective therapeutics

Antiandrogens

Androgen synthesis inhibitors

Cytotoxic chemotherapy

Targeting AR cofactors

Therapeutic options for gene dysregulation in prostate cancer

ADT resistance

AR splice variants

ADT evasion via CYP17A1 androgen synthesis

OATP1B3

Therapeutic options for somatic mutations in prostate cancer

AR mutations

TMPRSS/ERG

BRCA1/2

Microsatellite instability

Therapeutic resistance mechanisms

ARv7

Sex determining region Y box2

Prognostic genetic testing

Future of precision medicine in prostate cancer

Footnotes

Acknowledgements

Funding

Conflict of interest statement

References