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AUA 2019

AUA 2019: Next Generation Biomarkers—As Reflex, Combination, or First Line?

Chicago, IL (UroToday.com) At the International Prostate Forum, Dr. David Crawford discussed the next generation of biomarkers specifically for prostate cancer screening. Dr. Crawford started by noting that in his opinion a PSA of 1.5 ng/mL is the new 4.0 ng/mL. But because of this, family practice physicians are confused by our message. Indeed, there are many factors for us and primary care physicians to take into consideration, including (i) cutoffs of 2.5 and 4, (ii) PSA velocity, (iii) PSA density, (iv) age specific PSA, (v) % free PSA, (vi) complex PSA, (vii) phi, (viii) PCA3, (ix) SelectMDx, and (x) 4KScore. 

The reason why Dr. Crawford feels that a PSA of 1.5 is the new 4 is because we need a simple message for those that order PSA – 90% of which are family practice/internal medicine physicians. In an assessment of prostate cancer mortality from the PLCO trial, an initial PSA <1 ng/mL meant that screening could safely be stretched out to every 5-10 year.1 In 2011, Dr. Crawford’s team used the Henry Ford health system to identify 21,502 eligible men from 1997-2008 to attempt to define an appropriate PSA level.2 These men all had an initial PSA from 1-5 ng/mL, a minimum of 5 years follow-up, and no 5-alpha reductase inhibitors. They found that prostate cancer rates were 15-fold higher in patients with PSA ≥1.5 ng/mL compared to patients with a PSA <1.5 ng/mL (7.85% vs 0.51%). Furthermore, African American patients with baseline PSA <1.5 ng/mL faced prostate cancer rates similar to the whole study population (0.54% vs 0.51%, respectively), while African American patients with PSA 1.5-4.0 ng/mL had a 19-fold increase in prostate cancer. Dr. Crawford calls a PSA of > 1.5 – 4 the “danger zone”.

In his opinion, a PSA > 1.5 ng/mL is the way forward and a surrogate for prostate health:

  • BPH-most common
  • Prostate cancer
  • Long term prostate cancer risk
  • It is important to evaluate the patient – don’t biopsy everyone with a PSA > 1.5 ng/mL
But, are we sure we are not missing significant cancers with the PSA 1.5 ng/mL cutoff? Data from the PLCO mortality analysis1 suggests we are not, as does recent data from the University of Toronto. Goldberg and colleagues3 assessed men younger than 50 years who underwent a first prostate biopsy between 2000 and 2016, who had a PSA 1 ng/ml or greater and those with a suspicious digital rectal examination, a positive family history or a suspicious lesion on transrectal ultrasound. Among 199 patients who met study inclusion criteria, 37 (19%) were diagnosed with prostate cancer and 8 (22%) had a Gleason score of 7 or greater. Of those diagnosed with prostate cancer, 25 (68%) had PSA 1.5 ng/ml or greater and all men with a Gleason score of 7 or greater had PSA 1.5 ng/ml or greater.

The following table suggests how molecular markers may perform with this PSA 1.5 ng/mL cutoff:
AUA2019_Next Generation Biomarkers_1 .png
According to Dr. Crawford, early detection is the way forward. Vital signs and many tests are routinely performed by primary care physicians before informed decision making. He notes that informed decisions should be made when tests are abnormal, so why not include this line of thinking regarding PSA testing as 73% of men will require no discussion? He feels this is important because men’s health is a broader issue and a PSA >1.5 ng/mL is a surrogate for BPH, prostatitis, and prostate cancer.

Dr. Crawford notes that prostate cancer has several clinical needs:

  • Screening: primary care physicians needs a simple message and that should be a PSA of 1.5 ng/mL
  • Informed Decision: it should happen like other tests that are “routinely performed” by the primary care physician
  • Identifying significant cancers/reducing unnecessary biopsies
SelectMDx is one such tool that can assist prostate biopsy decision making in routine clinical practice. In a US community setting, there was a 5-fold higher biopsy rate in men with SelectMDx positive vs negative results, and SelectMDx negative men who were biopsies had higher serum PSA levels compared to SelectMDx negative men who did not receive a biopsy. In men biopsied within 3 months of SelectMDx testing, the biopsy rate was 10-fold higher in SelectMDx positive compared to negative men.

Dr. Crawford provided his algorithm for PSA screening:
AUA2019 Next Generation Biomarkers 2
Several concluding remarks from Dr. Crawford:

  • PSA 1.5 ng/mL is a reasonable cut point, but nothing is perfect
  • PSA 1.5 ng/mL is simple for family physicians to remember
  • In general, informed decision making should happen when the PSA is abnormal
  • PSA 1.5-4.0 ng/mL is a grey zone, as this can be a surrogate for BPH, prostate cancer, and prostatitis
  • Clinical evaluation and genomic markers help determine whom to biopsy

Presented by: E. David Crawford, University of Colorado, Denver, Colorado

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University - Medical College of Georgia, Twitter: @zklaassen_md at the American Urological Association's 2019 Annual Meeting (AUA 2019), May 3 – 6, 2019 in Chicago, Illinois

References:
  1. Andriole GL, Crawford ED, Grubb RL 3rd, et al. Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 2009;360:1310-1319.
  2. Crawford ED, Moul JW, Rove KO, et al. Prostate-specific antigen 1.5-4.0 ng/mL: A diagnostic challenge and danger zone. BJU Int 2011 Dec;108(11):1743-1749.
  3. Goldberg H, Klaassen Z, Chandrasekar T, et al. Evaluation of an aggressive prostate biopsy strategy in men younger than 50 years. J Urol 2018 Nov;200(5):1056-1061.