Clinical translation of prostate cancer genomics

1. Clinical translation of
prostate cancer genomics
Henrik Grönberg
Professor Cancer Epidemiology,
Chairman
Department of Medical Epidemiology and Biostatistics (MEB)
Karolinska Institutet, Stockholm, Sweden

2. Do I have prostate cancer
alternative how big is my risk to I have been diagnosed
get prostate cancer? with prostate cancer, but
do I really need treatment?
I was diagnosed with prostate
cancer and was treated, but am I I will be treated for my
cured from the cancer? prostate cancer, which
treatment is best for me?

3. Prostate
Produce
seminal fluid
Creates 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 cancer
alternative how big is my risk to I have been diagnosed
get prostate cancer? with prostate cancer, but
do I really need treatment?
I was diagnosed with prostate
cancer and was treated, but did I I will be treated against my
really get rid of my cancer? prostate cancer, which
treatment is best for me?

6. Through GWAS there are 75 loci identified associated
with 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 saved
Henrik 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
biopsy
Best 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 is
big
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 cancer
alternative how big is my I have been diagnosed
personal risk to get prostate with prostate cancer, but
cancer? do I really need treatment?
I was diagnosed with prostate
cancer and was treated, but did I I will be treated against my
really 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 treatment
Small
10% dies despite treatment
tumors
20% survive thanks to treatment
12

14. • Using gene expression score of 31
cell cycle genes
• From FFPE samples
• Validated in 2 independent cohorts
Henrik 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 cancer
alternative how big is my I have been diagnosed
personal risk to get prostate with prostate cancer, but
cancer? do I really need treatment?
I was diagnosed with prostate
cancer and was treated, but did I I will be treated against my
really 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. Acknowledegements
Karolinska 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 Frisell
Wake Forest Univ, NC
• Jianfeng Xu
• Lilly Cheng Human Protein Atlas , KTH
• Jochen Schwenk
• Mattias Uhlen
Johns Hopkins Hospital • Ulrika Igel
• Bill Isaccs
Namn Efternamn 2012-06-29
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23. Improved diagnostics and treatment of prostate cancer