Biomarkers in Prostate Cancer

Transcription

1 Biomarkers in Prostate Cancer Current clinical implications and future perspectives Rui Henrique Serviço de Anatomia Patológica e Centro de Investigação Instituto Português de Oncologia do Porto Francisco Gentil, E.P.E. & Departamento de Patologia e Imunologia Molecular Instituto de Ciências Biomédicas Abel Salazar Universidade do Porto

2 Conflicts of interest statement For the purposes of this presentation and its content, I declare that I have no conflicts of interest

3 Biomarkers in prostate cancer Why? Clinically silent disease at early, curable stages Considerable heterogeneity Limitation of currently available clinical and pathological parameters What for? Early detection / Diagnosis Prognosis Prediction of response to therapy 3

4 Prostate carcinogenesis: the source for biomarkers? 4 Mitchell & Neal, 2015 Li & Dahiya, 2007

5 Molecular taxonomy of prostate cancer 5 Barbieri & Tomlins, 2014

6 Clinically tested biomarkers Biomarcador Prostate Health Index (phi) Progensa PCA3 Mi-Prostatic Score Oncotype DX Prolaris Decipher Prostarix PAM50 / Prosigna ConfirmMDx ProCaM Indicações / desempenho Distinção entre PCa e condições benignas da próstata em pacientes com PSA entre 4 e 10ng/ml com toque rectal negativo Previsão do resultado de re-biópsia após biópsia negativa; potencial associação com a agressividade da doença Deteção de PCa em pacientes com níveis de PSA ligeiramente aumentados. Preditor independente de doença mais agressiva Estratificação de acordo com risco de progressão da doença quando da realização de biópsia Preditor do risco de metástases a 5 anos ou de recorrência bioquímica, após prostatectomia radical Auxilio na estratificação pacientes com PSA ligeiramente aumentado com toque rectal negativo Classificação molecular do PCa (luminal A, luminal B e tipo basal), com implicações prognósticas e terapêuticas Estimativa de risco de diagnóstico de PCa em re-biopsia após biopsia prostática negativa Estratificação de risco de diagnóstico de PCa significativo, em pacientes com valores de PSA entre 2-10ng/ml 6 Torres-Ferreira, Henrique & Jerónimo, 2016

7 Detection / Diagnosis Prostate Health Index (FDA approved) Its an algorithm based on serum levels of Pro-PSA, free PSA and total PSA: (p2psa/fpsa) PSA½ Indicated for men with serum PSA of 4-10ng/mL to determine the risk of finding PCa in biopsy Using the reference value 27.0, PHI provides 90% clinical sensitivity and 31.1% clinical specificity, avoiding 1 in 3 prostate biopsies and detecting 90% of prostate neoplasms Higher values associate with high risk pathological features and biochemical recurrence following prostatectomy In the context of active surveillance, it is predictive of PCa reclassification in subsequent biopsy 7

8 PRoGensa / PCA3 score (FDA approved) Non-coding RNA, overexpressed specifically in PCa, comparatively with normal prostate tissue and other urological cancers 8 Detection / Diagnosis Measured in urine (quantitative RT-PCR, using PSA mrna PSA as normalizer for input), requiring previous prostatic massage Using reference value 25, it displays 77.5% sensitivity and 57.1% specificity for PCa diagnosed in biopsy, reducing up to 50% the number of unnecessary repeat prostate biopsies In the context of active surveillance, it might identify PCa patients with increased risk of progression It increases the identification of clinically insignificant and small volume PCa

9 Detection / Diagnosis Mi-Prostate Score MiPS (CLIA certified) This test combines serum PSA levels and urine levels of PCA3 and TMPRSS2-ERG fusion transcript It quantitatively predicts the risk of detecting PCa in biopsy, being used as continuous variable without a cutoff value for reference, and the performance estimates are 80% sensitivity and 90% specificity It is estimated that its use might reduce by 50% the number of prostate biopsies MiPS HG (high-grade, i.e., GS > 6) associates with detection of high-risk PCa in biopsy There is no evidence of usefullness in the context of active surveillance 9

10 Detection / Diagnosis Prostarix (CLIA certified) It is based on the analysis of urinary levels of 4 metabolites (sarcosine, alanine, glycine and glutamate) by means of mass spectometry and liquid chromatography, requiring previous prostatic massage It aims to aid in the decision of selecting candidates for prostate biopsy that have negative DRE and slightly elevated serum PSA levels This metabolic profile might augment the ability to predict organconfined PCa as well as the risk of recurrence at 5 years. 10

11 Detection / Diagnosis ProCaM It is based on the quantification of GSTP1, APC and RARB-2 gene promoter methylation levels, in urine samples Indicated for individuals with serum PSA levels between 2.0 and 10.0 ng/ml, displaying 80% sensitivity and 60% specificity for predicting the histopathological diagnosis of PCa in biopsy It outperforms DRE and serum PSA-based tests for predicting PCa in biopsy and it identifies a larger proportion of cases with higher Gleason score ( 7) GS 7 No PCa 11 Baden et al., 2011

12 ConfirmMDx (CLIA certified) This test evaluates GSTP1, APC and RASSF1A gene promoter methylation levels in prostate biopsy tissues (FFPE) Detection / Diagnosis Owing to the presence of molecular alterations in morphologically normal cells adjacent to tumor foci ( halo effect ), allows for the identification of PCa in tissue samples with normal/benign morphology Indicated for cases with negative prostate biopsy, discriminating individuals without PCa from those with occult PCa, providing a negative predictive value of 88-90% In a study that evaluated the potencial clinical impact of this test, from 138 PCa suspects with negative biopsy, only 6 (4%) were re-biopsed. However, there are no long-term follow-up data to assess the real clinical impact. 12

13 Prognosis Circulating Tumor Cells Test (FDA approved) It is based on the identification and enumeration of circulating tumor cells (CTCs) using epithelial markers(epcam, CK8/18, CK19) Enumeration of CTCs correlates with disease progression, as well as overall and progression-free survival In castration-resistant PCa patients, high CTC count (> 5CTCs/7.5ml) is an independent predictive factor of poor prognosis and of higher risk of metastatic spread The FDA approved test (CellSearch ) is indicated for monitoring of patients with metastasized PCa 13

14 Prognosis Oncotype DX Genomic Prostate Score (CLIA certified) Based on the expression levels of 12 target genes (involved in androgen signalling, cell organization, proliferation and stromal response) and 5 reference genes, in prostate biopsy tissue samples (FFPE) It estimates the risk of high-grade (GS 4+3) and/or stage ( pt3) PCa in the prostatectomy specimen, with a predictive value that is independent of clinicopathological parameters and CAPRA score It improves the discrimination among very low, low and intermediate risk Pca, aiding in the selection of candidates for active surveillance It is an independent prognostic factor (adjusted for risk) of time to biochemical recurrence and metastatic progression after radical prostatectomy 14

15 Prognosis Prolaris (CLIA certified) Evaluates the expression levels of 31 genes involved in cell cycle progression and 15 reference genes, in tissue samples from prostate biopsy or radical prostatectomy (FFPE) The CCP (cell cycle progression) score correlates with tumor agressiveness and it is an independent prognostic factor for biochemical recurrence and metastatic progression It predicts for the mortality risk due to PCa at 10 years (< 0.0: 7%; : 15%; : 36%; > 2.0: 59%) In a study that evaluated the potential clinical impact of this test (n=305), in 65% of cases the therapeutic strategy was changed (in 40% of cases it was altered from interventional to non-interventional). However, there are no long-term follow-up data to assess the real clinical impact. 15

16 Prognosis Decipher (CLIA certified) It is based on the expression levels of 22 mrnas involved in several signalling pathways that are relevant PCa, which are evaluated in tissue samples from prostate biopsy or radical prostatectomy (FFPE) It allows for risk stratification after surgery, predicting the likelihood of metastization and of disease-specific mortality, and determine the need for salvage vs. adjuvant therapy In patients with biochemical recurrence, it might be useful for aiding in the decision of early salvage/multimodal therapy vs. salvage therapy only In a study that evaluated the potential clinical impact (12 patients candidate for adjuvant therapy and 12 patients candidate for salvage therapy and external beam RT) there was a change in treatment recommendation in 43% and 53% of cases, respectively 16

17 PAM50 / Prosigna (CLIA certified) It makes use of the classifier developed for breast cancer, categorizing PCa into 3 subtypes: luminal A, luminal B and basal type The preliminar results (recently published) indicate na association between PCa subtype and biology, validating this aproach Luminal B subtype displays the worse prognosis: Prognosis 10-year brfs DMFS PCSS OS Luminal A 41% 73% 89% 82% Luminal B 29% 53% 78% 69% Basal 39% 73% 86% 80% 10-year biochemical recurrence-free survival [brfs]; distant metastasis-free survival [DMFS]; prostate cancer-specific survival [PCSS]; overall survival [OS] However, response to androgen-deprivation therapy seems to be significantly better in luminal B PCa 17

18 Prognosis Cell proliferation (Ki67) index Assessed by immunohistochemistry in tissue samples from prostate biopsy or radical prostatectomy (FFPE) Low cost and easy to implement as immunohistochemistry is a widely available technique in most Pathology Departments/Laboratories Several studies have demonstrated independent prognostic value for high Ki67 levels, which have been associated with worse overall, disease-specific and disease-free survival, as well as biochemical recurrence-free survival and rate of distant metastases after curative intent treatment There is, however, a wide variability in the results from the several studies published to date and a lack of agreement about the most significant cutoff value (5-10%) 18

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21 Lobo et al., 2017

22 Lobo et al., 2017

23 High Ki67, EZH2 and SMYD3 immunoexpression independently predicted PCa patient outcome, adjusted for standard clinicopathological parameters This assessment might assist in discriminating indolent from aggressive PCa, improving treatment selection 23 Lobo et al., 2017

24 Clinical usefulness of biomarkers in prostate cancer Prostate Health Index PRoGensa PCA3 Mi-Prostate Score Prostarix Oncotype Dx Prolaris Decipher PAM50 Prostate Health Index ProCaM ConfirmMDx Ki67 index CTCs Early detection Diagnosis Therapeutic decision Prognosis Monitoring 24

25 Biomarkers in prostate cancer Most of them (if not all!) are complementary of routine clinical and pathological parameters They might increment the accuracy of detection, diagnosis, prognostication and prediction of response to therapy They are usually expensive and there are no costeffectiveness studies that may anticipate the real clinical impact in the long term As a rule, test results convey a relative risk information, that has to be interpreted based on the clinical and pathological context 25

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27 Future perspectives The use of so-called liquid biopsies as source of nucleic acids, exosomes or CTCs for molecular analyses will probably expand in the near future These samples might provide a better assessment of tumor heterogeneity, as well as less invasive and, potentially, more specific disease monitoring 27 Larger confirmatory and validation studies are required to fully support its use in clinical practice, but the sooner we start, the sooner we will know the answer to our doubts!

28 My proposal for the clinical cases Clinical case #1: raising serum PSA but negative biopsies Prostate Health Index: ** PCA3: ** MiPS: ** ConfirmMDx: *** (high negative predictive value) Prostarix: * 28 Clinical case #2: low-risk PCa: intervention vs. active surveillance Prostate Health Index: ** PCA3: * Prolaris: *** (in combination with CAPRA risk of mortality)

29 Biomarkers in Prostate Cancer Current clinical implications and future perspectives Rui Henrique Serviço de Anatomia Patológica e Centro de Investigação Instituto Português de Oncologia do Porto Francisco Gentil, E.P.E. & Departamento de Patologia e Imunologia Molecular Instituto de Ciências Biomédicas Abel Salazar Universidade do Porto