Clinical translation of prostate cancer genomics, Department of Biosciences and Nutrition, Karolinska Institutet, Henrik Grönberg Copenhagenomics 2012

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Clinical translation of prostate cancer genomics

Clinical translation of prostate cancer genomics

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  • OriginReason so good -> qPCR sensitivity -> investigate breakpoints rather than SNPsCaveats -> Have to have access to the tumor Cancer heterogeneity 50 ng/ml and <30% of that <300 bp

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  • 1. Clinical translation of prostate cancer genomicsHenrik GrönbergProfessor Cancer Epidemiology,ChairmanDepartment of Medical Epidemiology and Biostatistics (MEB)Karolinska Institutet, Stockholm, Sweden
  • 2. Do I have prostate canceralternative how big is my risk to I have been diagnosedget prostate cancer? with prostate cancer, but do I really need treatment?I was diagnosed with prostatecancer and was treated, but am I I will be treated for mycured from the cancer? prostate cancer, which treatment is best for me?
  • 3. ProstateProduceseminal fluidCreates problems- Prostate cancer- Hyperplasia- Prostatitis
  • 4. Prostate cancer is common and a large challenge to clinical care  Prostate cancer is the most common cancer in the western world  Lifetime risk 10-15% and over 70.000 men in Sweden are living with prostate cancer today  Mortality is still substantial as 25% dies due to prostate cancer  Highest heritability of all cancers  PSA screening is very controversial
  • 5. Do I have prostate canceralternative how big is my risk to I have been diagnosedget prostate cancer? with prostate cancer, but do I really need treatment?I was diagnosed with prostatecancer and was treated, but did I I will be treated against myreally get rid of my cancer? prostate cancer, which treatment is best for me?
  • 6. Through GWAS there are 75 loci identified associatedwith prostate cancer• 8q24 (8 separate loci) Each SNP:• 17q12 (2)• 17q24.3 Odds Ratio 1,05-1,7• 3p12• 6q25 Common( 5-50%) in the population• 7p15• 10q11• 11q13 (2)• 19q13• Xp11• 18 NEW in September 2009 Aly et al 2011 (Euro Urology)• 35 NEW in 2011-2012 Using 35 SNPs 20-25% of prostate biopsies could be savedHenrik Grönberg 29 juni 2012 5
  • 7. Today Insensitive • 2 of 3 positive tests are diagnostics incorrect based on one single • 15-20% of all high risk marker, PSA cancers are missed
  • 8. Tomorrow • Enables screening to reduce prostate cancer mortality Improved diagnostics • Excludes 50% from further based on testing combination of 100+ markers • Significant reduction in un- necessary biopsies
  • 9. The road to tomorrow : Randomized clinical trial• All men in Stockholm and on Gotland between 50-69• Conducted 2013-2014 Control arm• 260.000 men Clinical practice=PSA Prostate biopsyBest possible panel• PSA• 75+ SNPs Experimental arm• 8-10 protein biomarkers Best possible panel• Family history• Prediction Model
  • 10. All participants in STHLM3 will receive an answer • Low risk of prostate cancer PSA < 1 50% • Testing is recommended in 10 years • Normal risk of prostate cancer Answer 35% PSA 1-3 • Testing is recommended in 2 years • Increased risk of prostate cancer 15% PSA < 3 • Biopsy is recommended
  • 11. The expected patient and health economic value of STHLM3 isbig Significant reduction of biopsies Reduced number of non- aggressive cancers treated Identification of aggressive cancers earlier Significant reduction of health care cycle time Reduce anxiety – improved quality of life
  • 12. Do I have prostate canceralternative how big is my I have been diagnosedpersonal risk to get prostate with prostate cancer, butcancer? do I really need treatment?I was diagnosed with prostatecancer and was treated, but did I I will be treated against myreally get rid of my cancer? prostate cancer, which treatment is best for me?
  • 13. Today We want to be able to identify the 30% that benefit from treatment 70% survive without any treatmentSmall 10% dies despite treatmenttumors 20% survive thanks to treatment 12
  • 14. • Using gene expression score of 31 cell cycle genes • From FFPE samples • Validated in 2 independent cohortsHenrik Grönberg 2012-06-29 13
  • 15. The road to tomorrow 1(2) + Panel of DNA and RNA markers differentiating the tumors benefitting treatment from those not benefitting
  • 16. BUT, this is difficult !!!!! STUDY DESIGN and PROSPECTIVE VALIDATION TUMOUR HETEROGENEITY TECHNICAL ISSUES and TUMOUR SAMPLING 15
  • 17. Do I have prostate canceralternative how big is my I have been diagnosedpersonal risk to get prostate with prostate cancer, butcancer? do I really need treatment?I was diagnosed with prostatecancer and was treated, but did I I will be treated against myreally get rid of my cancer? prostate cancer, which treatment is best for me?
  • 18. Today Situation after treatment Not cured Everybody receives same Cured treatment No adjuvant treatments 17
  • 19. Tomorrow • Non-cured identified directly and given adjuvant treatment • 75% receives feedback ”you are completely healthy” 18
  • 20. The road to tomorrow:Circulating tumor DNA – a promising personal biomarker 1 2 Analyze tumor’s Identify patient specific DNA post operation cromosome changes 3 4 Sample blood Measure circulating tumor- post treatment DNA in patients blood Behandling
  • 21. Three examples of possible use of genomic markers in the clinic • Q1:Do I have prostate cancer alternative how big is my risk to get prostate cancer? SNPs + protein biomarkers Low-risk project and TTC (time to clinic) 2-3 years • Q2: I have been diagnosed with prostate cancer, but do I really need treatment? DNA and RNA based markers in FFPE tissue High-risk project and TTC 3+ ? years • Q3:I was diagnosed with prostate cancer and was treated, but did I really get rid of my cancer? Circulating tumor DNA in plasma High risk and TTC 6-24 months 20
  • 22. AcknowledegementsKarolinska Institutet CRISP-Center at Karolinska• Hans-Olov Adami • Per Hall • Kamila Czene• Fredrik Wiklund • Sven Cnattingius• Katarina Bälter • Juni Palmgren• Carin Cavalli-Björkman • Juha Kere• Mikael Broms • Peter Wiklund• Johan Lindberg • Gunilla Svane• Markus Aly • Jan Adolfsson• Tobias Nordström • Yvonne Brandberg • Lars Egevad • Jan FrisellWake Forest Univ, NC• Jianfeng Xu• Lilly Cheng Human Protein Atlas , KTH • Jochen Schwenk • Mattias UhlenJohns Hopkins Hospital • Ulrika Igel• Bill IsaccsNamn Efternamn 2012-06-29 21
  • 23. Improved diagnostics and treatment of prostate cancer