2/5/2014. BIOMARKERS AND PROSTATE CANCER Can new biomarkers improve clinical decision making? Samir Bidnur PGY Feb

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1 BIOMARKERS AND PROSTATE CANCER Can new biomarkers improve clinical decision making? Samir Bidnur PGY Feb Objec-ves Review the need for new biomarkers in prostate cancer management Discuss the current role of PSA in screening for prostate cancer and current tools to op-mize PSA Briefly review how an understanding of prostate cancer carcinogenesis can lead to clinically relevant biomarker discovery 1

2 Review the need for new biomarkers in prostate cancer management Biomarkers need to answer clinically relevant ques-ons Markers need to be validated and increase a mul-variate model s predic-ve accuracy Biomarkers need to be cost effec-ve and minimally invasive Biomarkers are characteris-cs that can be objec-vely measured and evaluated as indicators of normal processes, pathogenic processes, or pharmacological responses to a therapeu-c interven-on (Biomarkers Defini-ons Working Group) clinical parameters (age, performance status) laboratory measures (PSA) imaging- based measures (PET) gene-c and molecular determinants (Gene Expression Profiles) Biomarker development consists of two separate components: analymcal validamon and clinical validamon Analy-cal: Acquisi-on, assessment, processing and storage of a specimen Consistency and reproducibility of analysis Determina-on of specific measure that is associated with clinical outcome Clinical: How much addi-onal informa-on does the biomarker provide rela-ve to what is currently available Can biomarker reliably inform phase III study outcomes 2

3 Anderson et al., Mol Cell Prot 1:845 (2002) Although number of biomarkers described is increasing, fewer are reaching clinical significance and u-lity 3

4 Biomarkers as defined by Prostate Cancer Working Group 2 For most tumour types, disease burden and spread (TNM) have been considered the most reliable predictors of survival and determinants of the type and intensity of therapy to be used Molecular markers may help substra-fy within groups/stage of disease DNA markers: SNPs, promoter methyla-on, etc RNA markers: transcrip-on ac-vity, regulatory markers (micrornas) Protein markers: cell surface receptors, tumour an-gens, phosphoryla-on/ glycosylated states, secreted proteins First markers to be included in AJCC staging for tes-cular ca. 4

5 Biomarkers needed at key clinical -me points Assessed via Receiver Operator Characteris-c curve Pca Screening - Benign vs Malignant disease - Avoid overtreatment, including RP,TRUS Bx Par$n Nomogram Ac$ve Surveillance Protocols - Improving staging accuracy - Iden-fy micrometastases early - New markers for aggressiveness that are comparable to Gleason but not reliant on -ssue histology (Bx) Ac$ve Surveillance Protocols Epstein criteria - Determining insignificant vs significant Pca to improve pa-ent stra-fica-on - Possible avoidance of repeat TRUS Bx Ac$ve Surveillance Protocols Ka8an, Stephenson Nomograms - Differen-a-ng BCR from clinical metastases 5

6 Role of PSA in screening for prostate cancer and current tools to op-mize PSA Advocacy for popula-on level PSA screening declining Iden-fica-on of PSA variants may increase the specificity of PSA based models Most important if beneficial within diagnos-c grey zone of PSA range 4 10ng/mL Posi-ve Predic-ve Value of PSA only 25% 6

7 N Engl J Med. 2009;360:1320 Pca Dx increasing secondary to PSA screening with associated stage migra-on iden-fying much more indolent disease à Role for Ac-ve Surveillance Protocols Stra-fica-on needed in PSA range 4 10ng/mL (Cancer v Benign); (Indolent v Aggressive) - Can needed stramficamon come from refining PSA? 7

8 7 centres, 50 75yrs, no previous prostate hx, , with PSA 4 10ng/mL, N DRE Prospec-ve blinded study, sextant biopsies 25% fpsa cutoff detected 95%, avoiding 20% of bx fpsa independent predictor of Pca, stronger than PSA alone and age for dx of Pca 268 of 371 pts with Pca underwent RP fpsa >25%, 70% had Gleason <7, <10% gland involved, organ confined disease, vs 34% of pts with fpsa < 25% 8

9 Biology of PSA 17aa leader sequence - nicked PSA % of total PSA (primarily bound to α1- chymotrypsin) Free PSA = sum of propsa isoforms, benign PSA and intact inac-ve PSA PSA (hk3) is androgen- regulated serine protease and a member of the -ssue kallikrein family found in 300kb region on Ch19q13.4 Mikolajczyk and al. (Urology 50: 710, 1997) first iden-fied propsa as the major cons-tuent of fpsa BPSA expressed preferen-ally in the transi-onal zone of the prostate Iden-cal to intact PSA but inac-vated by two internal cleavage points ProPSA expressed within peripheral stone Mul-ple isoforms iden-fied, [- 2],[- 4], [- 7]proPSA Differences in exposure to proteases in the extracellular matrix / prosta-c ducts Free and BPSA have been associated with gland volume Intact PSA and hk2 have been associated with tumour volume Prostate 63:13 (2005) J Urol 170:2269 (2003) 9

10 pts, years par-cipated in the first screening round of ERSPC Roserdam (94% par-cipa-on) during 1993 to 2000 (Original study from Goteborg) pts excluded (biopsied for reasons other than an elevated PSA (DRE,TRUS) pts with an elevated PSA, pts biopsied with serum available Sextant biopsies as per protocol Full model would save 513 pts per from biopsy, 307 less compared to clinical model, but 66 pts advised against biopsy, 12 with Gleason score >7 10

11 Mul-kalikrein panel consists of total PSA, fpsa, intact PSA and kalikrein- related pep-dase 2 (hk2) Two independent popula-ons from ERSPC: First round screening in Roserdam, Goteborg between Included men with PSA >3 ng/ml (3 260) Four models compared overall: gold standard model (PSA, DRE and TRUS); kalikrein panel; DRE and kalikrein panel; DRE, TRUS, kalikrein model Correla-on between kalikrein panel and TRUS- es-mated volume 0.60 (Spearman s coefficient) Authors conclude that kalikrein panel could replace TRUS as it has similar discriminatory ability for any and high grade Pca 11

12 Prospec-ve study of consecu-ve men with tpsa ng/ml and nega-ve digital rectal examina-on who were scheduled for prostate biopsy at a ter-ary academic center between Mar Aug 2010, n = 268 TRUS Bx performed according ins-tu-onal satura-on scheme (18 22 cores) Prostate Health Index (PHI) %[- 2]PSA and phi had highest accuracy of diagnosing Pca at biopsy in group where tpsa was not different between those with and without Pca 12

13 Role of PSA in screening for prostate cancer and current tools to op-mize PSA Advocacy for popula-on level PSA screening declining Trend towards individual level shared decision making Iden-fica-on of PSA variants may increase the specificity of PSA based models Further clinical valida-on required Most important if beneficial within diagnos-c grey zone of PSA range 4 10ng/mL Iden-fy pa-ents at risk of clinically significant Pca Minimize harms related to overtreatment 13

14 Understanding of prostate cancer carcinogenesis can lead to clinically relevant biomarker discovery Markers of carcinogenesis may provide increased specificity to Pca diagnosis in both early and late stage disease Tissue specimens readily available once Pca diagnosed and treated Can biomarkers help predict who will recur post RP 24mo training period for Belgian Malinois shepherd to discriminate Pca vs control urine Correct selec-on in 30 of 33 cases 14

15 Authors hypothesize that dis-nct vola-le organic compounds (VOCs) are produced by altered physiology and metabolism of malignant cell Similar ar-cles for breast, melanoma and lung cancer exist Changes in gene expression and metabolism fall into several broad categories: Genes related to cell cycle prolifera-on Genes related to cell adhesion and mo-lity Genes related to control of differen-a-on Genes related to immune response Epithelial to mesenchymal transi-on in Pca can poten-ally promote metastasis 15

16 mrna expression profiles can help in iden-fica-on of puta-ve biomarkers differen-ate benign/malignant, low risk/high risk 16

17 Mul-ple gene domains iden-fied Several standard housekeeper genes included along Genome Classifier panel Gene classifier developed via modeling RNA expression arrays of 545 pa-ent samples with median follow up 16 yrs. (213 with BCR + clinical metastasis) PLoS ONE 8(6): e66855 high- risk Pca treated with radical prostatectomy, BCR defined as PSA >0.4 ng/ml Metastasis defined as posi-ve bone scan or visceral or extra- pelvic nodal disease Primary outcome: clinical metastasis following BCR 17

18 GC was only significant variable on mul-variable analysis PSAdT was also predictor of metastasis Molecular markers of the primary tumour might help beser predict metasta-c progression Example of biomarker development producing a clinically relevant marker that may help dictate treatment in a specific clinical sevng Molecular markers of the primary tumour might help beser predict metasta-c progression Early iden-fica-on of pts at high risk of clinical metastasis awer RP can poten-ally change management 18

19 Understanding of prostate cancer carcinogenesis can lead to clinically relevant biomarker discovery Markers of carcinogenesis may provide increased specificity to Pca diagnosis in both early and late stage disease Thousands of poten-al markers available Tissue specimens readily available once Pca diagnosed and treated May reflect an individual s tumour recurrence characteris-cs early Conclusions Biomarkers in prostate cancer should be developed to guide specific clinical scenarios early disease best assessed from blood, urine Late disease may have -ssue readily available Constant biomarker development requires rigorous analy-cal and clinical valida-on prior to widespread adop-on Avoidance of overdiagnosis and overtreatment will prompt new pa-ent centred management strategies 19

20 Ques-ons? Thanks to Dr. Black Goal to determine whether urinary PCA3 and TMPRSS2:ERG mrna levels are associated with higher volume or grade prostate cancer in a mul-- ins-tu-onal ac-ve surveillance cohort Post- DRE urine collected as per protocol 387 pts, with core biopsies followed on ac-ve surveillance 20