IDC-P is associated with adverse findings in radical prostatectomies, including high GS, large tumor volume, high pathologic stage, and is also an independent predictor of clinical outcomes.25–27 In addition, studies have shown that cribriform architecture/IDC-P are associated with lymph node metastasis.28 Taken together, both cribriform architecture/IDC-P are associated with aggressive disease and poor clinical outcomes.15,29,30 Furthermore, the presence of IDC-P on needle biopsy is a significant prognostic factor in patients with metastatic castration-resistant prostate cancer (mCRPC) at initial presentation.31 Kato and colleagues demonstrated that the presence of IDC-P on needle biopsy was the strongest prognostic parameter for cancer-specific survival and overall survival. Additional studies have shown that the presence of IDC-P is an independent prognosticator for clinical outcomes and could be a potential marker in predicting poor response to initial androgen deprivation therapy (ADT) and sequential docetaxel-based chemotherapy.20,21,32
Tumor stromal response has been shown to be discriminatory in patients with higher risk of recurrence.34 By definition, stromogenic prostate cancer requires at least 50% reactive stroma (stroma/epithelium ratio ≥1). Typically, the reactive stroma is disorganized, pale, loose and rich in extracellular matrix with infiltrating angulated and distorted glands.35 McKenney and colleagues determined that “stromogenic carcinoma” is independently predictive of lower recurrence-free survival in GS 3+3=6 and GS 3+4=7 tumors after adjusting for preoperative serum PSA, patient age, extraprostatic extension, seminal vesicle invasion, and margin status.14 Furthermore, detailed histomorphologic analysis of “stromogenic carcinoma” has made evident that GS 6 and 7 tumors have the greatest benefit from the predictive information provided by tumor stromal response in the prognostication of BCR and overall survival.35,36 Various studies have shown that “stromogenic carcinoma” is an independent marker for BCR-free survival and should be considered in the armamentarium for the prediction of unfavorable disease.35,37
IDC-P is associated with a number of genetic derangements that can predict disease aggressiveness, some of which remains to be elucidated. Prensner et al44 identified SChLAP1 as the highest-ranked overexpressed gene in prostate cancer with metastatic progression by gene expression assay.45 Furthermore, SChLAP1 expression increased with cancer progression and independently predicted BCR after radical prostatectomy.46,47 In one of the largest and most rigorously analyzed multi-institutional cohorts to assess the clinical and biological impact of IDC-P in men with localized prostate cancer, Chua and colleagues found that cribriform architecture/IDC-P was associated with a 2 to 3-fold higher rate of biochemical failure, and a 4-fold higher rate of metastasis. In an effort to identify a molecular fingerprint for the cribriform architecture/IDC-P phenotype, the authors discovered that SChLAP1 was expressed at over threefold higher levels in cribriform architecture/IDC-P positive tumors compared with cribriform architecture/IDC-P negative ones. The authors proposed a model of prostate cancer pathogenesis, termed “nimbosus,” consisting of a constellation of genomic instability, SChLAP1 overexpression, and hypoxia which manifests as increased metastatic capacity and lethality.39 This work sets the stage for further understanding of the pathogenesis of clinically aggressive disease by characterizing the chronology of molecular “hits” in the evolution of cribriform architecture/IDC-P tumors.
PTEN loss and chromosome 8p/8q alterations have been associated with aggressive disease. As such, Trock and colleagues evaluated whether measurement of PTEN gene or protein, chromosome 8q (MYC) gain, and 8p (LPL) loss could identify a more aggressive form of Gleason pattern 3 tumors. They concluded that PTEN protein loss, MYC/8q gain or LPL/8p loss in a Gleason pattern 3 tumor core is a strong indicator that the core comes from a Gleason 7 tumor, and more frequently occurs in GS 4+3=7 (Grade Group 3) than 3+4=7 (Grade Group 2) tumors. These results further support the idea of tumor clonality and suggest that Gleason pattern 3 in a GS 7 tumor is biologically distinct from Gleason pattern 3 from a GS 6 tumor. PTEN protein loss was more common in GS 6 tumors that were upgraded at radical prostatectomy.41
Recently, the presence of IDC-P was shown to be independently associated with overall survival in BRCA2 carriers and BRCAX patients, resulting in poorer outcome.43 This finding highlights the importance of recognition of IDC-P in BRCA2 carriers, who are already known to have poor overall survival, and suggests that IDC-P may be a useful new clinical marker in these patients.
There is an increased need for reliable biomarkers to complement and improve upon conventional risk assessment tools to aid in decision-making, particularly in challenging clinical settings. Several diagnostic and prognostic innovative biomarker panel tests have been introduced in the last decade. Diagnostic tests to guide biopsy decisions include PHI, 4K score, SelectMDx, ConfirmMDx, PCA3, MiPS, and ExoDX. Of those, ConfirmMDx is the only tissue-based assay. Prognostic tests that have been used to aid in treatment selection (ie, definitive treatment vs. active surveillance) include OncotypeDX GPS, Prolaris, ProMark, DNA-ploidy, and Decipher.68,69 The tests supported by the highest level of evidence and in widespread clinical use are herein reviewed (Table 4); although the ordering of these tests currently varies based on treating clinician or institution.
Recent technological advances have raised the possibility of extending the use of molecular biomarkers in advanced prostate cancer disease by monitoring metastatic tumor burden, response, and resistance to therapy.114 Novel liquid biopsy approaches, such as circulating tumor cells (CTCs) in blood and circulating cell-free tumor DNA (cfDNA) in plasma, have been utilized as predictive biomarkers in metastatic CRPC and might support the advent of an individualized oncological approach in the nearer future. CTC may serve as a surrogate marker for treatment efficacy in CRPC patients. Studies have demonstrated the potential use of molecular analysis of CTCs in monitoring and predicting response to therapy. cfDNA testing can serve as an early indicator of recurrence, resistance, or metastasis.115 Exosomal RNAs is also another potential source for tumor genetic material. These molecular tests could impact clinical utility by reducing drugs toxicity, improving treatment selection and patients survival, and enhancing cost-effectiveness by reducing the use of ineffective drugs.116
cfDNA represents a noninvasive biomarker that can be isolated from human plasma, serum and other body fluids. Circulating tumor DNA shed from primary and metastatic tumors, primarily through apoptosis and/or necrosis of tumor cells, may allow real-time noninvasive serial monitoring of tumor genomes during treatment and disease progression through “liquid biopsies.” “Liquid biopsy” may unravel genetic and epigenetic alterations involved in the metastatic process and allow tracking of emerging subclones of tumor cells resistant to therapy.114,117
Recently, AR-V7 expression by immunohistochemistry has been evaluated in prostate biopsy tissue from men newly diagnosed with locally advanced or metastatic prostate cancer.127 Patients with AR-V7 positive tumors had significantly lower PSA response rates to ADT and shorter time to CRPC progression after ADT compared with men with AR-V7 negative tumors. Additional prospective, large-scale trials are warranted before AR-V7 detection on tissue can be considered for prognostic assessment in newly diagnosed prostate cancer patients who are planning to receive ADT.
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