Prostate Cancer Diagnosis and Risk Assessment Peter R. Carroll, MD, MPH Department of Urology University of California, San Francisco
Disclosure Guidelines and practice patterns are and are changing based on a better understanding of tumor biology/natural history and use of novel molecular markers and imaging
Prostate Cancer • 1 in 6 US men diagnosed over their lifetime • 1 in 6 of these men may die of prostate cancer (2 – 3% of US men) • Most common non – cutaneous cancer in US men • Is a very common “incidental” cancer
Serum PSA • Serum protease • Total PSA = free PSA + bound (complex) PSA – Lower free PSA associated with increased risk of cancer
• T ½ = 2 – 3 days • PSA levels higher with advancing age, BPH, African American ethnicity, infection, trauma (instrumentation) and prostate cancer
Recommendations Important Note – Recommendations based on trials performed generally on Caucasian men. They may or may not apply to African American men Who AUA USPTF ACS NCCN
When to biopsy
55 to 69
“high risk”, 40 10 life expect
45 ‐ 75
2.5 ng/ml 3.0 ng/ml
No Economic Analyses http://www.cancer.org/cancer/prostatecancer/moreinformation/prostatecancerearlydetection/prostate‐cancer‐early‐detection‐acs‐recommendations http://www.cancer.org/cancer/prostatecancer/moreinformation/prostatecancerearlydetection/prostate‐cancer‐early‐detection‐acs‐recommendations
USPTF Recommends Against Testing More Advanced Disease Will Increase
Barocas et al. J Urol epub 2015
ARS‐Q1 A 55 – year – old man is found to have a serum PSA of 3.6. The next step in assessment is: A. B. C. D. E.
Repeat PSA 14 days of oral antibiotic, then re – test Prostate Health Index or 4K score Multiparametric MRI Prostate biopsy
Answer: A Repeat PSA : Serial PSA testing shows variability. A second PSA test could inform biopsy decisions and spare men from the morbidity associated with a prostate biopsy. Biopsy can primarily be postponed for men with a low second PSA value (eg, ≤3 ng/mL). J Natl Cancer Inst. 2016 Jul 14;108(12). pii: djw165. doi: 10.1093/jnci/djw165. Print 2016 Dec
Serum PSA is Elevated (2.5 to 3 ng/ml) • • • •
Repeat PSA Perform DRE If DRE positive, strongly consider biopsy If DRE – and PSA elevated, discuss biopsy and ancillary testing
Prostate Cancer Screening RCTs: Two important studies—two different results?
• • • • •
21% reduction in death due to prostate cancer
One performed in US and one in Europe One protocol vs. several One shows no benefit, one shows substantial mortality reduction One most often quoted USPTF gave equal weight to both Andriole et al. NEJM 2009; 360:1310 Schröder et al. NEJM 360:1320
Prostate‐Specific Antigen (PSA) Testing in Participants without Baseline Screening Contamination in the Control Group of PCLOTrial.
Shoag JE et al. N Engl J Med 2016;374:1795‐1796.
Prostate Cancer Mortality at 13 years P=0.001 RR 0.79, 95% CI 0.69-0.91, p=0.001 Adjustment for non-participation: 0.71 (95% CI 0.58-0.88, p=0.001)
NNI 1410 NND 48 NNI 979 NND 35 NNI 781 NND 27
Schroder et al., Lancet. 2014 Dec 6;384(9959):2027-35.
PSA only screening in US 1000 men Benefits
5 fewer Pca deaths
Harms 130 negative biopsies 120 positive biopsies
35 develop bladder, bowel or sexual side effects 8 complications of biopsy or treatment (i.e. sepsis, wound infection, DVT, MI, etc.) ¾ – Identify those most likely to benefit
Refine Prostate Cancer Screening Best Impact on QALYs Saved • • • •
Target population 50 – 70 Stop screening at low PSA/later age Increase screening interval More stringent indications for biopsy – Increase cut – point – Increase specificity • High use of active surveillance in low risk patients • Use of higher volume centers/expertise for care
Presentation Title JAMA Oncol. Published online March 24, 2016. doi:10.1001/jamaoncol.2015.6275and/or Sub Brand Name Here 9/19/2016
Beginning and Ending Testing • All emphasize shared decision making and not testing those who do not have at least a 10 – 15 ‐ year life expectancy • AUA – Begin at age 55, earlier in “high risk” populations – End at age 70
• NCCN – Begin at age 45 – End at age 75
High Risk 1. African American men 2. Family history 3. BRCA 1 and 2
The strongest predictor of the future risk of prostate cancer is:
• • • • •
Family history of prostate cancer. African American ethnicity. von Hippel‐Lindau syndrome. Baseline serum PSA. Digital rectal examination.
Baseline serum PSA A baseline PSA between ages 45 to 50 is a very strong predictor of the future risk of prostate cancer, more so than family history or ethnicity. Those who carry BRCA1 or 2 mutations are at an increased risk as those with Lynch syndrome (mismatch repair gene mutations). DRE actually adds little to early detection compared to serum PSA testing alone. VHL syndrome is associated with clear cell renal cancer and pheochromocytoma.
ARS‐Q2 A 45 – year – old man is found to have a serum PSA of 1.3 ng/ml (confirmed). DRE is normal. The next step in assessment is: A. B. C. D. E.
Serum PSA at age 50. Serum PSA in 1 to 2 years. Free/total PSA. Multiparametic (mp) MRI. Prostate biopsy.
Answer: B A baseline PSA between ages 45 to 50 is a very strong predictor of the future risk of prostate cancer. The median PSA in this age group is 0.7 ng/ml. This patient’s PSA is above the median and he should be re – tested in 1 to 2 years. There is no evidence to support a biopsy at this PSA level (as opposed to a cut – point of 2.5 to 3 ng/ml). Similarly, mpMRI has not been validated to improve outcomes at such levels.
Modifications • A single PSA at age 45 is a very strong predictor of future risk, including risk of advanced disease – At age 45, median PSA @ 0.7 ng/ml
• May stop testing men whose PSA is below a cut point at later ages – Stop testing at age 60 if PSA PCA3
PCA3 PHI 4K MRI
New Tests of Specificity Test
ExoDx Prostate Urine IntelliScore Michigan Prostate Urine Score
PSA, fPSA,, ‐2proPSA PSA, fPSA, intact PSA, kallikrein – related peptidase 2 ETS transcription factor, ERG, PCA3 PCA3, PSA, TMPSS2:ERG
When to Re – biopsy? • Atypical small acinar proliferation (ASAP) – 2% ‐ 6% of biopsies – Predictive of cancer on repeat biopsy (17% ‐ 60%)
• HGPIN if > 2 cores • Consider ancillary tests
Commercial application: ConfirmMDx • Employs multiplex methylation‐specific PCR to measure epigenetic status of GSTP1, APC, and RASSF1 (ACTB reference gene) in residual cancer‐negative biopsy core samples
Clinical validation studies: MATLOC • Methylation Analysis to Locate Occult Cancer • 498 subjects from UK and Belgium with pathologically negative prostate biopsies followed by repeat biopsy within 30 months • Similar validation of GSTP1, APC, RASSF1 • NPV 90% (95% CI 87‐93%) • Multivariate model correcting for age, PSA, DRE, first biopsy histology, epigenetic assay was a significant independent predictor of outcome (OR 3.17, 95% CI 1.81‐5.53)
Stewart GD et al. . J Urol. 2013 Apr 18 [Epub ahead of print]
Multi‐parametric prostate MRI T2
DCE – Dynacad image shows early enhancement and washout (red) Image Courtesy Antonio Westphalen, MD PhD
• Prospective cohort study of 1,003 men undergoing concurrent targeted and systematic biopsy at the NCI 2007-2014 • Objective: detection of high risk PCa (Gleason ≥4+3) • Nearly equivalent detection of PCa (461 targeted vs. 469 standard) • Targeted diagnosed 30% more high risk cases (173 vs. 122, p 10 ng/ml. The patient has already had an MRI and CT would be duplicative. C11 acetate and PSMA PET are not widely available and require validation. Gene expression profiling would add limited value in treatment selection/indication. Confirm Dx is used to assess tissue in those who have a negative initial biopsy who are being considered for repeat biopsy
Radiographic Imaging Test
Indications T1C and PSA > 20 T2 and PSA > 10 GS > 8 T3, T4 Symptomatic T3, T4 T1, T2 and nomogram probability of LN metastases > 10%
CT or MRI
NCCN Treatment Guidelines
D’Amico or AUA Risk Groups Variable PSA Gleason Score
Low 8 > T2c (T3a)
Very Low Risk: GS 3, PSA