Prostate Cancer: The Unwanted Family Heirloom

Early detection and regular screening is critical to improve outcomes for people with a family history

Prostate cancer seems to be the family heirloom no one asks for. My grandfather succumbed to the disease in India during the 1970s, likely diagnosed only after it had metastasized. Fortunately, my father and his younger brother (my uncle) were luckier; their cancers were detected early and treated effectively. As for me, it's probably not a matter of "if" I will get prostate cancer, but more like, "when will I get my unwelcome family souvenir?" Research indicates that men with a family history of prostate cancer have a significantly increased risk compared to those without such a history. Specifically, men with one affected first-degree relative (father, son, or brother) are twice as likely to develop prostate cancer, and the risk increases with the number of affected relatives. About 1 in 8 men will be diagnosed with prostate cancer during their lifetime, and other than skin cancer, is the most common cancer in men in the United States.  Specific genes, such as BRCA1 and BRCA2, which are also associated with breast and ovarian cancer in women, increases the risk of prostate cancer in men. These mutations can be inherited from either parent and are involved in the repair of cellular DNA.

Fortunately, the 10-year survival rate for prostate cancer is extremely high with close to 95% survival rates for stages I, II and III. Only stage 4, when the cancer has spread into nearby body organs such as the bladder, nearby lymph nodes, or spread to other parts of the body outside the pelvis, has a unfavorable survival range in the vicinity of 25 to 50%. Early detection is crucial for surviving prostate cancer, and thankfully, a blood test can screen for it. PSA (Prostate Specific Antigen) is a protein produced by the prostate gland, present in both normal and cancerous prostates. Elevated PSA levels (above 4 ng/dL) in the blood typically lead to further diagnosis. Unfortunately, the PSA test has been found to have high sensitivity¹ but low specificity. A systematic review has reported a sensitivity of a PSA greater than or equal to 4 ng/mL of 0.93 and a specificity of 0.20. This indicates that while the PSA test is highly sensitive in detecting prostate cancer, its low specificity means that it has a high rate of false positives, leading to many men without prostate cancer being identified as having elevated PSA levels. In fact, around 3 in 4 men with a raised PSA level will not have cancer.

Given that PSA is produced by both normal and cancerous prostate cells, elevated PSA levels can also be caused by benign prostate conditions. As a result, the PSA test does not distinguish between these benign conditions or the aggressiveness of cancer. Moreover, the test does not provide specific information about the nature of the prostate cells producing the elevated PSA levels. As a result, the test cannot differentiate between slow-growing (indolent) tumors and those that are more likely to grow quickly and spread aggressively. This typically leads to over-diagnosis of prostate cancer, and over-treatment, including surgery and radiation, which can have significant side effects without providing a clear benefit in terms of survival for men with slow-growing tumors. In fact, of the 1 million prostate biopsies performed annually in the U.S. triggered by elevations in PSA levels, only about 240,000 new cases of prostate cancer are discovered each year. Thus, about 75 percent of biopsies are negative for cancer, and ~40% of men receive multiple biopsies for fear of cancer being missed.

4Kscore Test Prevents Unnecessary Biopsies

Fortunately, there are multiple tests for prostate cancer offering higher specificity than the standard PSA test. Amongst them, the 4Kscore test demonstrates the highest sensitivity and specificity. The 4Kscore Test combines four prostate-specific biomarkers: Total PSA, Free PSA, Intact PSA, and human kallikrein 2² (hK2) along with clinical factors such as age, prior biopsy status, and digital rectal exam (DRE) results to determine an estimate of the Gleason score. A Gleason score helps in determining (after a biopsy is performed) how much the cancer cells differ from normal prostate cells, and predicts how quickly the cancer is likely to grow and spread aggressively. The Gleason score ranges from 6 to 10, with a score greater than 7 indicating high-grade aggressive prostrate cancer. Total PSA and Free PSA are important markers for prostate cancer but have low specificity for risk of aggressive prostate cancer. Intact PSA and human kallikrein 2 are present in much lower concentrations than total PSA and Free PSA, and changes in these biomarkers are associated with aggressive types of prostate cancer.

As shown in the chart, the 4Kscore test avoids unnecessary biopsies by stratifying patients with the aggressive form of the disease from those who need only active monitoring. It is particularly useful after an abnormal PSA or DRE screening test to assist in the biopsy decision, improving specificity for detecting aggressive prostate cancer. The 4Kscore® test is FDA approved and included in current U.S., Canadian, and European prostate cancer early-detection guidelines, and over a dozen studies in more than 20,000 men attest to its clinical effectiveness. In addition, its accuracy has been demonstrated in two multi-center prospective validation studies, that reported a combined sensitivity of 94% and Negative Predictive Value (NPV)³ of 95% for the detection of aggressive prostate cancer when a 7.5% 4Kscore cutoff value was used.

The 4Kscore test is also covered by Medicare for patients meeting certain criteria. It is offered by BioReference Laboratories, Inc., which is a wholly owned subsidiary of OPKO Health, Inc.. The test is performed at BioReference Laboratories, a CLIA-certified and CAP-accredited laboratory, and is available through its specialty oncology and urology division, GenPath.

Several natural and lifestyle approaches can potentially help to lower or manage increasing PSA. Consuming tomatoes, which are rich in lycopene, may help lower PSA levels. Lycopene is an antioxidant that has been linked to a reduced risk of prostate cancer and lower PSA levels. Including cruciferous vegetables like broccoli, cauliflower, and cabbage which are high in antioxidants may also help reduce inflammation associated with prostate cancer risk. Finally, drinking green tea has been associated with providing protection against prostate cancer. Interestingly, medications such as statins and metformin have been associated with lowering PSA levels in prostate cancer patients. So if you are already taking statins or metformin, you may be in luck.  

Meanwhile, my PSA level in August '23 was 0.33 ng/dL, just a smidge lower than in 2021. Fingers crossed I can keep dodging that family heirloom for a bit longer!

Takeaway: People with a family history of prostate cancer should monitor their PSA levels annually. If PSA levels exceed 4 ng/dL, a 4Kscore test is recommended to assess whether the cancer might be aggressive and if an invasive biopsy is necessary.

1. Sensitivity: the ability of a test to correctly identify patients with a disease. Specificity: the ability of a test to correctly identify people without the disease.

2. hK2 is a protein that is highly expressed in poorly differentiated cancer cells, and also serves as a therapeutic target.

3. The likelihood that an individual with a negative test result is truly unaffected and/or does not have the disease in question.