1. Prostate Cancer Genetics and Diagnosis
Luke Frederick
SUNA 2015

2. Outline Prostate cancer genetics Prostate cancer diagnosis
Hereditary risk
Genetics
Prostate cancer diagnosis
PSA and prostate cancer screening
Pre-biopsy tools for diagnosing prostate cancer
Recent advances in prostate cancer diagnosis
Biopsy techniques
Prostate MRI
The future of prostate cancer diagnosis

3. Prostate cancer inheritance
Familial studies
Ethnicity
Single nucleotide polymorphisms
BRCA1/BRCA2

4. Familial studies Prostate cancer risk Twin study
2x increased risk with first degree relative
5-11x increased risk with 2-3 affected relatives
Relative dx at age <55 increases risk
Twin study
Much higher risk if identical twin had prostate cancer
Sons prognosis correlates with fathers prognosis
Sons of fathers who survived 5 years vs. Sons of fathers who survived 2 years

5. Ethnicity African-American men 1.6x increased risk of diagnosis
Earlier age of onset
8.3% of AA men <50
3.3% white men <50

6. Genome studies Single nucleotide polymorphisms Swedish study
Alleles that are associated with an increased susceptibility to prostate cancer
Swedish study
Panel of five SNPs from three loci in 8q24, as well as single sites in 17q12 and 17q24.3
If 4/5 SNPs were present then 4x increased risk
4/5 SNPs with family hx of prostate cancer then 9x risk

7. BRCA1/BRCA2
BRCA1
Breast, ovarian, fallopian, and prostate cancer
1.8x increased risk of prostate cancer
BRCA2
Breast, ovarian, Fallopian tube, prostate, and pancreatic cancer
4.7x increased risk of prostate cancer

8. HOXB13 Homeobox B13 (HOXB13) gene
codes for a transcription factor that is important in prostate development.
The G84E variant of the HOXB13 gene
20-fold increase in the frequency of this variant in men with prostate cancer compared with those without prostate cancer

9. Prostate cancer diagnosis
Prostate cancer screening
What is PSA
Guidelines on PSA screening
What’s new? Pre-biopsy tools

10. Cancer screening test Goals of a screening test
Find cancer before symptoms appear
Screens for a cancer that is easier to treat and cure when found early
Has few false-negative test results and false-positive test results
Decreases the chance of dying from cancer
Screening tests do NOT diagnose cancer

11. PSA Prostate specific antigen PSA elevation
Enzyme secreted by the prostate gland
Produced for the ejaculate  it liquefies semen and allows sperm to swim freely
PSA elevation
Cancer
Benign prostatic hyperplasia (BPH)
Infection

12. PSA as a screening test Find cancer before symptoms appear
Yes
Screens for a cancer that is easier to treat and cure when found early
Yes, metastatic prostate cancer is not curable
Has few false-negative test results and false-positive test results
Needs some work
Decreases the chance of dying from cancer

13. AUA guidelines on prostate cancer screening
< 40: No screening
40-54: May screen men with family history or African Americans
55-69: Shared decision making process
>70: No screening, or if the person's life expectancy is less than 10 years
Screen every 2-4 years

14. PSA is high (>3), What’s next?
Has few false-negative and false-positive test results
Pre-biopsy tools
First recheck PSA
Available tools
Individualized Risk Assessment of Prostate Cancer
Free and total PSA
Prostate health index
PCA3
We need these because of the morbidity of prostate bx, infection, pain, and to reduce the number of negative biopsies we do.

15. Individualized Risk Assessment of Prostate Cancer

16. Individualized Risk Assessment of Prostate Cancer

17. Individualized Risk Assessment of Prostate Cancer

18. Free PSA PSA is both free and bound to proteins in the blood
Free PSA to PSA ratio

19. Prostate Health Index Blood test Men >50, PSA 4-10, and normal DRE
Free PSA
Total PSA
p2PSA
Men >50, PSA 4-10, and normal DRE
3x more specific for prostate cancer
Option in 2014 NCCN guidelines
p2PSA is an isoform of free PSA

20. PCA3 Urine test Procedure
Nucleic acid amplification test
Measures the concentration of prostate cancer gene 3 (PCA3) and PSA
Uses that to provide a score
Procedure
DRE, first catch urine specimen, sent to outside lab
FDA approved for men 50 years of age or older who have had one or more previous negative prostate biopsies

21. PCA3 How is it used? Considering repeat bx
>35 provided the greatest diagnostic accuracy
≥ 35 had a 2.5-fold increased risk of a positive biopsy
≥ 35 had a 43% probability of a positive biopsy
*FDA approved cutoff is 25

22. PCA3 What about initial biopsy? Not FDA approved
≥ 35 had a 2-fold increased risk of a positive biopsy
≥ 35 had a 62% probability of a positive biopsy
PCA3 cutoff of 35: 21% false negative
PCA3 cutoff of 25: 15% false negative
PCA3 cutoff of 10: 5% false negative

23. What’s next?
Elevated PSA  rechecked PSA  pre biopsy tool of choice confirms risk  prostate biopsy
In order to dx cancer you must have tissue

24. Prostate biopsy Transrectal ultrasound guided prostate biopsy
Prostate MRI
MRI fusion prostate needle biopsies

25. Prostate biopsy

26. TRUS bx Results Up to 20% will miss cancer
75% of those biopsied will be negative
50% will have hematuria/hematospermia
4% will have fever/hospitalization after bx
Up to 20% will miss cancer
Up to 40% will be under sampled
i.e. actually have intermediate risk cancer when only low risk cancer was found

27. Prostate MRI Multiparametric MRI, no endorectal coil Three elements
T2 weighted images
Diffusion weighted images
Perfusion images

28. Prostate MRI T2 weighted images Tissue water content
Clearly define the zonal anatomy of the prostate
Prostate cancer can appear as an area of low signal intensity.
The degree of intensity decrease differs with Gleason score as higher Gleason score components show lower signal intensities

29. Prostate MRI

30. Prostate MRI Diffusion weighted images
Diffusion weighted MRI measures the random motion of water molecules.
Prostate cancer shows a low apparent diffusion coefficient

31. Prostate MRI Perfusion images Contrast enhanced MRI
Sequences covering the prostate before and after gadolinium
Prostate cancer typically enhances faster and to a greater extent than the surrounding prostate, and will also show more rapid washout of contrast

32. Prostate MRI

33. How can we use this? Targeted biopsies
Take MRI and fuse to real time ultrasound images to perform targeted biopsies

34. MRI fusion biopsy Potential benefits Reduce false negative biopsies
Improve accuracy in risk classification through better tumor sampling
Reduction in false-negative biopsies could reduce the necessity of repeat biopsies

35. MRI fusion biopsy
223 men
TRUS bx detected PCa in 56.5% and 37.3% were low risk.
MRI bx detected 69.7% with equivocal or suspicious MRI, of which 6.1% were low risk.
MRI pathway
Reduced the need for biopsy by 51%,
Decreased the diagnosis of low-risk PCa by 89.4%, and
Increased the detection of intermediate/high-risk PCa by 17.7%.
European Urology 2014
PMID:

36. SIU Urology SIU/SJH - prostate MRI imaging using MSK protocols
SIU has one of the most extensive experiences in Illinois
Dr. Kevin McVary and Dr. Shaheen Alanee
SIU/SJH – One of only 2 MRI targeted biopsy centers in Illinois

37. What’s next?
Will Multi-Parametric Magnetic Resonance Imaging be the Future Tool to Detect Clinically Significant Prostate Cancer?

38. Review Prostate cancer genetics Prostate cancer diagnosis
Hereditary risk
Genetics
Prostate cancer diagnosis
PSA and prostate cancer screening
Pre-biopsy tools for diagnosing prostate cancer
Recent advances in prostate cancer diagnosis
Biopsy techniques
Prostate MRI