Objec0ves. Next Genera0on Biomarkers in Prostate Cancer. UBC Department of Urologic Sciences. Jennifer Locke, R2 January 28, 2015

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1 UBC Department of Urologic Sciences Next Genera0on Biomarkers in Prostate Cancer Jennifer Locke, R2 January 28, 2015 Objec0ves 1. Highlight why biomarkers are important in prostate cancer management 2. Iden0fy key clinical scenarios where biomarkers offer the most relevance 3. Highlight some of the new 0ssue, blood, urine and image- based biomarkers 4. Describe the future of the next genera0on biomarkers 1

2 The role of PSA in prostate cancer management The Randomised Study of Screening for Prostate Cancer (ERSPC) The Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Schroder FH. Lancet Andriole GL. J Natl Cancer Inst Defini0ons Prognos0c biomarker provides informa0on on the likely course of the disease in an untreated individual Predic0ve biomarker can be used to iden0fy subpopula0ons of pa0ents who are most likely to respond to a given therapy Brunner N. Connec0ons

3 Key clinical scenarios for biomarkers in prostate cancer How do we dis0nguish aggressive disease from indolent disease in pa0ents on ac#ve surveillance (AS)? How do we iden0fy pa0ents with localized prostate cancer who will benefit from radia0on therapy post- radical prostatectomy? How do we select and sequence drugs for pa0ents with castra#on- resistant prostate cancer (CRPC) in the context of several recently approved new agents? Tissue- based gene signatures Myriad Gene0cs Prolaris Score TM Genome Health OncotypeDx TM Genomic Prostate Score (GPS) GenomeDx Biosciences Decipher TM NF- kb ac0vated recurrence predictor 21 (NARP21) 3

4 Myriad Gene0cs Prolaris Score TM 31 to 46- gene RNA expression signature in formalin- fixed paraffin- embedded (FFPE) biopsy specimens Clinical Evidence Predictor of biochemical relapse (BCR) acer radical prostatectomy (RP) in 3 cohorts of CaP pa0ents (n=582). Predictor of BCR acer external beam radia0on therapy (EBRT) in 141 CaP pa0ents. Predictor of overall survival (OS) especially when combined CAPRA- S* score in 413 CaP pa0ents. Bishoff JT. J Urol Cuzick J. Br J Cancer Cooperberg MR. J Clini Oncol Freedland SK. Int J Radiot Oncol Biol Phys Myriad Gene0cs Prolaris Score TM Kaplan- Meier plots of biochemical progression- free probability by cell- cycle progression (CCP) scores (Prolaris Score TM ) grouped the subset of pa0ents who were intermediate or high risk by clinical criteria defined by CAPRA- S score 3. With or without adjustment for clinical variables, increasing CCP score (Prolaris Score TM ), both as a con#nuous and categorized variable, was associated with markedly higher hazard ra#os for progression (con#nuous HR 2.1, 95% CI , P<0.001). CCP=cell- cycle progression score Cooperberg MR. J Clini Oncol

5 Genome Health OncotypeDx TM Genomic Prostate Score (GPS) 17- gene RNA expression signature in FFPE biopsy specimens Clinical Evidence Predictor of suitability for ac0ve surveillance in 441 RP and 562 biopsy specimens from men with low and intermediate risk. In the same popula0on the addi0on of GPS was shown to reclassify many men stra0fied to high risk based on CAPRA- S 6 alone. Pa0ents with both high GPS and high CAPRA- S risk scores were at markedly elevated post- RP risk for lethal CaP. Cooperberg MR. Eur Urol Klein EA. Eur Urol Knezevic D. BMC Genomics Genome Health OncotypeDx TM Genomic Prostate Score (GPS) Cumula0ve incidence of prostate cancer specific mortality (CSM) for the CAPRA- S high- risk stra0fied by genomic classifier (GPS). For pa#ents with both high CAPRA- S and high genomic classifier (GPS) scores, the cumula#ve incidence of CSM was 45% at 10 yrs. Cooperberg MR. Eur Urol

6 GenomeDx Biosciences Decipher TM 22- gene RNA expression signature in FFPE RP specimens Clinical Evidence Predictor of early metastasis in 545 high- risk RP pa0ents. Predictor of metastasis in 1010 high- risk RP pa0ents. Erho N. PLoS Ross AE. Prostate Cancer Prosta0c Dis Karnes RJ J Urol Den RB. Radiat Oncol Bio Phys Badani KK. BJU Int GenomeDx Biosciences Decipher TM Metastasis Risk at 5 yrs ~1 in 4 Popula#on Prevalence 19% 20% 10% ~1 in 17 21% 0% ~1 in 42 60% # at Risk Karnes RJ. J Urol

7 GenomeDx Biosciences Decipher TM Clinical Evidence Predictor of BCR and metastasis in 139 high- risk RP pa0ents post- adjuvant radia0on. Predictor of early metastasis in 219 high- risk RP pa0ents, especially when combined with CAPRA- S score. Predictor of early metastasis in 85 men with BCR acer RP. Erho N. PLoS Ross AE. Prostate Cancer Prosta0c Dis Karnes RJ J Urol Den RB. Radiat Oncol Bio Phys Badani KK. BJU Int GenomeDx Biosciences Decipher TM Clinical Evidence Decipher TM results affect decision making with respect to post- RP adjuvant radia0on clinical u0lity tes0ng. Badani KK. BJU Int

8 NF- kb ac0vated recurrence predictor gene signature in RP specimens Clinical Evidence Predictor of metastasis- free and disease specific survival in previously publically archived dataset of 596 RP samples. Jin R. Cancer Res NF- kb ac0vated recurrence predictor 21 Kaplan Meier plot for the systemic metastasis- free survival of pa0ents with prostate cancer who had lymph node metastasis at the 0me of RRP surgery. Survival analyses showed that the NF- kb signature predicts significant differences in the distant metastasis- free survival of the pa#ents that had lymph node metastasis at the #me of surgery (HR = 2.1; 95% CI, ; P = ). Jin R. Cancer Res

9 Tissue- based gene signatures The Prolaris Score TM and the OncotypeDx TM can be used in prostate biopsy 0ssue to iden0fy adverse pathologic features that predict those pa0ents who may benefit from ac0ve interven0on rather than ac0ve surveillance. Prognos0c. Decipher TM, the Prolaris Score TM and the NF- kb signature have been designed to predict clinical outcome acer radical prostatectomy. Prognos0c. Decipher TM has been validated in mul0ple cohorts and has demonstrated poten0al to influence the clinical decision to recommend radia0on post- radical prostatectomy. Tissue- based gene signatures A cri0cal considera0on for 0ssue markers in prostate cancer is under sampling of the prostate with the risk of missing a more threatening tumour. All of these markers have been developed in retrospec0ve studies. Op0mal clinical valida0on to prove clinical u0lity will require prospec0ve clinical trials. Cost may be a factor in decision making. 9

10 Tissue- based gene signatures Tissue- based gene Signature Cost per pa0ent (US) Prolaris Score TM Oncotype Dx TM GPS GenomeDx Decipher TM NF- kb gene signature $3400 $3800 $4250* - hlp://prostate- cancer.org/wp- content/uploads/insights/august2013/insights_august2013_%20new_biomarker_test.pdf Blood- based biomarkers microrna cell- free DNA Circula0ng tumour cells 10

11 microrna Small noncoding RNAs found in 0ssue and serum samples that are involved in post- transcrip0onal regula0on of a large number of biological processes. Sample microrna mrna microrna induce gene silencing by binding to target sites found within the 3 UTR of the targeted mrna micrornas are involved in a wide range of biological processes such as cell cycle control, apoptosis and several developmental and physiological processes hlp:// are- micrornas. Diagnosis Ac#ve Surveillance Serum mir- 141 is associated with higher GS in 170 pa0ents undergoing prostate biopsy. Serum mir- 16 levels is useful in discrimina#ng CaP from BPH in 47 pa0ents undergoing biopsy. In serum higher mir levels are correlated with CaP diagnosis in a series of pa0ents (78 with CaP and 28 without CaP). microrna Disease progression Localized Prostate Cancer A serum signature of 2-3 differen0ally expressed mirs had a high posi0ve predic0ve value for biochemical failure in 105 CaP pa0ents at 0me of RP. Serum mir- 182 expression is associated with biochemical and clinical progression free survival in various samples (60 RP, 273 biopsies, and 92 urine) from CaP pa0ents. CRPC Serum mir- 375, mir- 141 are significantly overexpressed in 30 high risk localized CaP pa0ents and 26 metasta#c CRPC pa0ents. Higher serum mirna signature is associated with worse outcome on docetaxel chemotherapy in 97 CRPC pa0ents. Bryant RJ. Br J Cancer Westermann AM. An0cancer Res Nguyen HC. Prostate Lichner Z. Clin Chem Lin HM. Br J Cancer De Malos- Arruda L. Nat Rev Clin Oncol Den RB. Radiat Oncol Biol Phys

12 Cell- free DNA Small amounts of cell- free DNA in plasma, which likely originates from cancer cells and, therefore, might cons0tute source of gene0c material for the iden0fica0on of tumour- associated molecular altera0ons. Sample dying tumour cells release small pieces of their DNA into the bloodstream known as cell- free DNA screening cell- free DNA for soma0c muta0ons can be used to detect and follow the progression of a pa0ent's tumour hlp:// hlp:// Diagnosis Ac#ve Surveillance There was a significant differences in cell- free DNA levels in CaP versus BPH pa0ents. Higher cell- free DNA levels are significantly correlated with tumour stage and category in 81 CaP pa0ents. Cell- free DNA Disease progression Localized Prostate Cancer A significantly shorter biochemical recurrence free survival is associated with at least one value above 140ng/ ml of cell- free DNA in 133 pa0ents with CaP as compared to 33 controls. CRPC The presence of the androgen receptor (AR) gene aberra0on in cell- free DNA is correlated with radiographic and clinical disease progression on enzalutamide (AR directed therapy). The detec0on of AR gain and AR L702H muta0on in cell- free DNA is associated with resistance to abiraterone. A muta0on in F876L detected in cell- free DNA was associated with resistance to novel drug ARN Schwarzenbach H. Clin Cancer Res Dawson SJ. N Eng J Med hlp://mee0nglibrary.asco.org/ content Carreira S. Sci Transl Med Joseph JD. Cancer Discov

13 Circula0ng tumour cells (CTCs) Rare circula0ng cancer cells in the peripheral blood that may have an important role in tumour dissemina0on and progression. Sample pooled CTCs Metastasis Primary Single cell CTC- capture technologies* genomic, transcriptomic, proteomic, and metabolomic profiles of individual CTCs reveal mechanisms of disease progression Barradas AM. Nat Biotechnol De Malos- Arruda L. Nat Rev Clin Oncol Circula0ng tumour cells Diagnosis Ac#ve Localized Surveillance Prostate Cancer CTC detec0on is rare in 12 pa0ents with localized CaP. Disease progression CTC CD117 levels decrease acer radical prostatectomy and increase again in pa0ents who have biochemical recurrence. CRPC Unfavorable pretreatment CTC counts are predic#ve of shorter overall survival in 231 pa0ents with progressive CRPC pa0ents. Baseline CTC counts are well correlated with overall survival in 100 pa0ents with CRPC. Higher CTC counts are associated with overall survival in 57 pa0ents treated with docetaxel. High CTC counts are associated with high risk of death in 276 pa0ents with metasta0c CaP (IMMC38 trial). Higher CTC counts were observed in pa0ents with bone metastasis rela0ve to those with soc 0ssue disease (n=120 pa0ents with CRPC). CTC with AR- V7 posi0vity are associated with lower PSA response rates, shorter PSA progression free survival and shorter overall survival in 31 CRPC enzalutamide- treated pa0ents and 31 CRPC abiraterone- treated pa0ents. Kling J. Nat Biotechnol Lin BK. Biomicrofluidics Kerr BA. Oncotarget Khrana KK. Cur Urol de Bono JS. Clin Cancer Res Scher HI. Lancel Oncol Miyamoto DT. Nat Rev Clin Oncol Okegawa T. An0cancer Res

14 CTCs - limita0ons The major limita0on impac0ng the clinical u0lity of CTCs is not having sufficient DNA capture due to low CTC numbers in biological samples. Current plavorms can also be limited by their selec0vity and ability to extract the separated cells. New technologies are being validated to overcome this shortcoming. Placorms for the capture of CTCs EpCAM- affinity based CellSearch system AdnaTest BreastCancerDetect CTC- Chip Dynal MACS MagSweeper On- Q- Ity CTC- ETI Physical proper0es- based ISET ScreenCell ApoStream Density Gradient Centrifuga0on Other methods FAST EPISPOT Flow cytometry (FACS) PRO Onc Assay Barradas AM. Nat Biotechnol De Malos- Arruda L. Nat Rev Clin Oncol Blood- based biomarkers microrna can be used to predict outcome in pa0ents on docetaxel chemotherapy. Prognos0c and Predic0ve. cell- free DNA can be used to predict resistance to enzalutamide, abiraterone and ARN Predic0ve. CTCs can be used to prognos0cate disease and predict response to enzalutamide and abiraterone. Prognos0c and Predic0ve. 14

15 Blood- based biomarkers Blood- based biomarkers have the poten0al to overcome the inherent heterogeneity of CaP and capture the tumour characteris0cs in their en0rety. Blood- based biomarkers fulfill the goal of a liquid biopsy, enabling non- invasive, real- 0me monitoring of disease status and response to therapy, especially in the context of metasta0c CRPC. Using blood- based biomarkers we are able to monitor molecular changes in response to therapy. Thus we are able to monitor drug targets and guide corresponding altera0ons in therapy; the essence of precision oncology. Urine- based biomarkers PCA3 TMPRSS2- ERG Metabolin Prostarix TM 15

16 PCA3 CaP- specific gene located on chromosome 9q21-22 that can be detected in urine samples. Clinical Evidence The urine PCA3 assay demonstrated a sensi0vity of 69% and specificity of 79% for predic0ng CaP diagnosis in 143 men undergoing biopsy. Marks LS. Urology Badani KK. BJU Int Antonoarakis ES. N Engl J Med Deras IL. J Urol PCA3 Clinical Evidence Urine PCA3 levels were predic0ve of those pa0ents who need a repeat biopsy in men who have elevated PSA and a prior nega0ve biopsy. For biopsy- naïve pa0ents, a high PCA3 level increases the probability that an ini0al prostate biopsy will iden0fy cancer. Higher urine PCA3 levels are associated with higher volume CaP and high- grade disease in 387 men on an ac0ve surveillance protocol. Badani KK. BJU Int Antonoarakis ES. N Engl J Med Deras IL. J Urol Wei JT. J Clin Oncol

17 TMPRSS2- ERG Gene fusion involving the 5 untranslated region of the androgen- regulated gene TMPRSS2 with ERG or ETV1 that can be detected in urine samples. Clinical Evidence TMPRSS2- ERG detec0on has yielded a specificity of 93% and a posi0ve predic0ve value of 94% for the diagnosis of CaP in 78 men with PSA >3ng/mL and/or abnormal DRE. Casanova- Salas I. J Urol Tomlins SA. Neoplasia Lin DW. Clin Cancer Res TMPRSS2- ERG Clinical Evidence TMPRSS2- ERG detec0on independently predicted Gleason score and clinical tumour stage in 497 men undergoing biopsy. TMPRSS2- ERG score is associated with higher volume CaP and high- grade disease in 387 men on an ac0ve surveillance protocol. Casanova- Salas I. J Urol Tomlins SA. Neoplasia Lin DW. Clin Cancer Res

18 Metabolin Prostarix TM Four metabolite signature detected in urine by liquid chromatography mass spectrometry. Diagnosis Ac#ve Surveillance Biopsy Prostarix TM score was associated with increased risk of CaP in 1122 pa0ents. Disease progression Localized Prostate Cancer RP Prostarix TM score was associated with disease free survival rates in 148 CaP pa0ents. CRPC Urine Prostarix TM score was associated with metastases in pa0ents with CaP (bone metastases n=20, normal bone n=14, malignant prostate 0ssue n=13, benign prostate 0ssue n=17 and plasma samples n=15). McDunn JE. Prostate Koutros S. Carcinogenesis Goodman OB. Cancer Epidemiol Biomarkers Prev Danila DC. Clin Cancer Res Urine- based biomarkers The PCA3 assay can be used to predict need for repeat biopsy in men who have elevated PSA and a prior nega0ve biopsy. Prognos0c. The Prostarix TM score can be used to stra0fy the risk of a pa0ent with previous nega0ve biopsy for occult cancer. Prognos0c. The Prostarix TM score can be used to predict for disease free survival and metastasis. Prognos0c. 18

19 Urine- based biomarkers Urine- based biomarkers are available in large quan00es and can be collected non- invasively. Urine- based biomarkers are par0cularly alrac0ve when the prostate is intact, especially in the seng of screening and early stage disease. MRI PET/CT Image- based biomarkers 19

20 MRI Disease progression Diagnosis MRI can help guide repeat biopsy in pa0ents with previously nega0ve biopsy and elevated PSA. Ac#ve Surveillance Localized Prostate MRI is important in Cancer staging with reduc0on in the risk of missing occult higher- risk disease. MRI is used to assess for extraprosta#c extension prior to radical prostatectomy. CRPC MRI predicted biochemical relapse acer radical prostatectomy and metastas0c disease progression. Sciarra A. BJU Int Hoeks CM. Eur Urol Hambrock T. J Urol Hoeks CM. Invest Radiol Baco E. Eur Urol Rud E. World J Urol Somford DM. J Urol Agner SC. Radiology MRI MRI images of a 76M with four nega0ve biopsies and a PSA of 329. Picchio M. Eur J Nucl Med Mol Imaging

21 Diagnosis PET has not proven useful in differen0a0ng biopsy- proven CaP from BPH. PET/CT Disease progression Ac#ve Surveillance Localized Prostate Cancer CRPC (11)C- choline PET/CT before salvage radia0on therapy during the early phase of biochemical relapse helps select pa0ents who may benefit from this aggressive treatment. 18F- fluorocholine PET/CT may be u0lized in biochemical relapse of prostate cancer acer radical treatment, with an overall disease detec0on rate close to 50%. Reske SN. J Nucl Med Scher B. Eur J Mucl Med Castellucci P. J Nucl Med Rodado- Marina S. BJU Int Image- based biomarkers MRI provides clinical u0lity in diagnosis, ac0ve surveillance, localized prostate cancer and CRPC sengs in conjunc0on with other biomarkers. PET may provide clinical u0lity in the CRPC seng. 21

22 Image- based biomarkers U0liza0on of MRI for quan0ta0ve image analysis is a novel concept that is in the early stages of development: Comparison of enhanced appearance and textural features of triple- nega0ve cancer and fibroadenoma Comparison of dynamic enhanced appearance and textural discrimina0on between triple- nega0ve cancer (TN) in 52- year- old woman and ER- posi0ve cancer in 55- year- old woman Quan0ta0ve image analysis can also be used to measure tumour response to therapy, which in turn can guide clinical decision- making. Agner SC. Radiology Key clinical scenarios for biomarkers in prostate cancer How do we dis0nguish aggressive disease from indolent disease in pa0ents on ac#ve surveillance (AS)? How do we iden0fy pa0ents with localized prostate cancer who will benefit from radia0on therapy post- radical prostatectomy? How do we select and sequence drugs for pa0ents with CRPC in the context of several recently approved new agents? 22

23 Diagnosis Blood- based microrna and cell- free DNA can be used to discriminate CaP from BPH. Prognos0c. Urine PCA3 can prognos0cate need for repeat biopsy in men who have elevated PSA and a prior nega0ve biopsy. Prognos0c. Urine Prostarix TM can stra0fy risk of occult cancer in men with previous nega0ve biopsy. Prognos0c. Ac0ve Surveillance Tissue- based gene signatures (e.g. Prolaris Score, OncotypeDx ) can iden0fy pa0ents on ac0ve surveillance who may harbor occult higher- risk disease warran0ng defini0ve interven0on. Prognos0c. Image- based MRI can help focus repeat biopsy on specific prosta0c lesions. Prognos0c. 23

24 Localized Prostate Cancer Tissue- based gene signatures (e.g. Decipher ) can predict recurrence and progression acer RP and help determine if the pa0ent may benefit from adjuvant radia0on therapy. Prognos0c. Blood- based microrna can predict biochemical and clinical progression. Prognos0c. Blood- based cell- free DNA can predict biochemical recurrence. Prognos0c. CRPC Blood- based microrna can predict outcome on docetaxel chemotherapy. Prognos0c and Predic0ve. Blood- based cell- free DNA can predict resistance to enzalutamide, abiraterone and ARN Predic0ve. Blood- based circula0ng tumour cells can prognos0cate disease progression and predict response to enzalutamide and abiraterone. Prognos0c and Predic0ve. Urine Prostarix TM score can prognos0cate for metastases. Prognos0c. Image- based MRI, PET/CT can predict for biochemical relapse. Prognos0c. 24

25 The Future of Biomarkers in Prostate Cancer Future technology must focus on improving biomarker assay robustness. Paterlini- Bréchot. Cancer Microenvironment, The Future of Biomarkers in Prostate Cancer With the novel agents arising in the management of CRPC disease the use of easily accessible urine and blood- based biomarkers will bloom. The development of microrna, cell- free DNA and CTCs technologies for urine and blood samples will be instrumental to predic0ng specific therapy outcome and op0mizing sequen0al use of these novel agents in the treatment of pa0ents with CRPC. 25

26 The Future of Biomarkers in Prostate Cancer Two significant barriers: the need for careful clinical valida0on, the associated costs to the system. Incorpora0ng of these biomarkers into ongoing and future clinical trials will be essen0al in developing and implemen0ng them in clinic. Clinical Valida0on Vasan RS. Circula0on

27 Tissue Tissue- based gene Signature Cost per pa0ent (US) Associated Costs Prolaris Score TM OncotypeDx TM GPS GenomeDx Decipher TM NF- kb gene signature $3400 $3800 $4250* - Blood CTCs $ assay + $35.11 interpreta0on fee (Medicare Fee; covered in roughly half of the US) Urine PCA3 $385 Image? The Future of Biomarkers in Prostate Cancer Two significant barriers: the need for careful clinical valida0on, the associated costs to the system. Incorpora0ng of these biomarkers into ongoing and future clinical trials will be essen0al in developing and implemen0ng them in clinic. 27

28 Acknowledgements Dr. Peter Black Dr. Richard Wassersug Defini0ons Accuracy - The degree of agreement between the results of a measurement and the true value of the measurement. Precision - The degree of agreement between independent test results obtained under s0pulated condi0ons. Clinical (diagnos#c) sensi#vity - The propor0on of pa0ents with a well- defined clinical disorder whose test values are posi0ve or exceed a defined decision limit. Clinical (diagnos#c) specificity - The propor0on of pa0ents who do not have a specified clinical disorder whose test results are nega0ve or within the defined decision limit. Gutman S. Nature Review Cancer

29 Defini0ons Effec#veness - The use of the device for its intended uses and condi0ons of use, when accompanied by adequate direc0ons for use and warnings against unsafe use, will provide clinically significant results in a significant por0on of the target popula0on. Safety - The probable benefit to health from use of the device for its intended uses and condi0ons of use, when accompanied by adequate direc0ons and warnings against unsafe use, will outweigh any probable risk. Gutman S. Nature Review Cancer

30 Rela0onship between biomarker publica0ons and patents Drucker E. Genome Medicine Drucker E. Genome Medicine

31 A prognos0c DNA signature for prostate cancer Mul0variate Cox propor0onal hazard model adjus0ng for clinical covariates (Gleason score and pretreatment PSA) in the low- risk and intermediate- risk groups (A) and when applied to the full pooled radical prostatectomy cohort (n=271) the signature for copy number altera0on iden0fies pa0ents who will fail rapidly (B). Lalonde E. Lancet Oncology