An end to the decline in prostate cancer mortality

Dr. Gaylis is chief scientific officer of Genesis Healthcare Partners and voluntary professor of urology, University of California, San Diego. Dr. Kader is professor of urology at Moores Cancer Center, University of California, San Diego. Disclosures: Dr. Gaylis is a scientific board advisor at, and Dr. Kader is the founder of, Stratify Genomics.

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Prostate cancer (PCa) is the most common solid organ malignancy affecting American men and the second leading cause of death from cancer. Since the introduction of the PSA blood test in the early 1990s, there has been a progressive decrease in the stage and grade of PCa at diagnosis as well as a dramatic decline in PCa death rates. However, due to the variable natural history of PCa and the PSA test’s poor specificity, universal PSA-based screening has also led to increased cost and suffering in many men who will never be affected by PCa.

This controversy has led to confusion and varying recommendations, ultimately resulting in a decrease in PSA-based screening. Coinciding with this decrease in screening, a recent report from the American Cancer Society indicates, for the first time in 30 years, a halt in the decline in presentation of metastatic disease and PCa mortality.¹

Citing two controversial papers in 2012 suggesting that there is minimal survival benefit to PSA-based screening average risk men, the U.S. Preventive Services Task Force (USPSTF) considered that PSA-based screening harmsmany (side effects include anxiety from screening, infection and bleeding from prostate biopsy, and urinary incontinence and sexual dysfunction from treatment) and benefits few (men saved through early detection). The USPSTF recommended that no man should be screened for PCa.

This stance was adopted by the American Academy of Family Physicians, among others, and what followed was an indiscriminate cessation of screening in most men, and with that, the dramatic decline in new PCa diagnoses by almost 60,000 cases.

Subsequent to the Task Force’s recommendation in 2012, several research groups including ours published disturbing trends of more men presenting with more aggressive and advanced PCa.^2,3 We now see for the first time a changing course in the death rate from the disease. We are entering a dangerous era. Should we go back to the days before PSA-based screening, the increase in death and suffering will not be felt for another decade-at which point it might be too late for a generation of men.

Due to a backlash stemming from these reports and an acknowledgement of the flaws in the original screening studies, the USPSTF in 2018 amended its recommendation slightly to  suggest that a conversation be held between physician and patient (between the ages of 55 and 69 years) about the risks and benefits of PSA-based screening with no allowance for risk factors (family history or race).

Rather than forgoing screening in everyone, we suggest a risk-stratified approach whereby our screening efforts are focused on those men who stand to gain the most and be harmed the least. Men expected to live beyond 10 years who have a family history of PCa, are of African-American race, and/or have a genetic predisposition to the disease should be offered screening at an earlier age (mid-40s) and more aggressive screening (yearly). Average- and low- risk men (based on genetic testing) should be counseled regarding the risks and benefits of screening (called shared decision-making) and allowed to make an informed decision regarding screening at longer intervals (possibly every 3-7 years).

Furthermore, to avoid overtreatment of indolent PCa, men diagnosed with low-risk disease should consider active surveillance (close monitoring with intent to treat and cure if the disease worsens).

Genetic predisposition to PCa is based on newly discovered germline genetic (inherited DNA) abnormalities, which have been associated with the development of PCa and sometimes aggressive disease. The latter may develop as a result of mutations of the breast cancer DNA damage repair genes (BRCA1 and BRCA2). In addition, abnormalities in other components of the DNA called single nucleotide polymorphisms (SNPs) are associated with the development of PCa.

Tests for specific SNPs have recently become commercially available to predict a man’s lifetime risk of developing PCa. A San Diego startup, Stratify Genomics, recently launched Prompt - prostate genetic score (PGS), one of the first germline SNP tests based on a cheek swab. Studies of Prompt-PGS have shown promising results, with data showing it being two times more predictive than PSA and three times more predictive than a positive family history in determining the risk of a man developing PCa.^4,5 Additional new tests either currently available or in testing include urinary exosomes (which contain DNA), liquid biopsies (blood and urine tests designed to detect the presence of PCa), and other biomarkers looking at cancer-associated cell changes in urine.

The recently reported change in PCa death rates should prompt men to undergo genetic testing and have a discussion with their doctor regarding the benefits and potential harms of PSA-based screening based on their individualized risk of developing the disease. Together with race and family history, this new genetic information can help men and their physicians make an informed decision regarding screening and hopefully reverse this disturbing trend in PCa death rates.

References

• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020; 70:7-30.

• Gaylis FD, Choi JE, Hamilton Z, et al. Change in prostate cancer presentation coinciding with USPSTF screening recommendations at a community-based urology practice.Urol Oncol 2017; 35:663.e1-663.e7.

• Gaylis FD, Choi J, Kader AK. Trends in Metastatic Breast and Prostate Cancer.N Engl J Med 2016; 374:594-5.

• Chen H, Liu X, Brendler CB. Adding genetic risk score to family history identifies twice as many high-risk men for prostate cancer: Results from the prostate cancer prevention trial.Prostate 2016; 76:1120-9.

• Kader AK, Liss MA, Trottier G. Impact of prostate-specific antigen on a baseline prostate cancer risk assessment including genetic risk.Urology 2015; 85:165-70.