Prostate Cancer Update

• The presentation gives an update on prostate cancer, including risk factors, testing methods, and treatments
• It mentions the work of Pamela W. Smith, M.D., MPH, MS
• The material is copyrighted 2024

Continuing Education Credit

• CE credit for the activity is being provided by AKH Inc., Advancing Knowledge in Healthcare
• AKH Inc. is jointly accredited by ACCME, ACPE, and ANCC to provide continuing education for healthcare teams
• The live activity offers a maximum of 24.0 AMA PRA Category 1 Credits for physicians
• Physicians should only claim credit commensurate with their participation extent
• Hours of participation are equivalent to the AMA PRA Category 1 Credits awarded
• There is no commercial support for this activity
• The fee to participate is $2,700.00
• A certificate of completion will be awarded based on attendance and after completion of an online evaluation
• Contact AKH Inc at [email protected] for questions about CE activity
• Credit claim deadline is December 17, 2024

Objectives

• Review risk factors for prostate cancer
• Learn new testing methods
• Understand that cancer can be localized and potentially curable when limited to the prostate
• Know differential diagnoses
• Evaluate traditional treatments
• Examine personalized medicine therapies

Disclosure Statement

• AKH Inc. has a policy to ensure integrity in its continuing education activities
• Authors must disclose significant relationships with ineligible companies whose products/devices are mentioned
• Conflicts of interest are mitigated before accreditation
• AKH planners and reviewers have no relevant financial relationships to disclose
• Pamela Smith is a speaker and owner of Center For Precision Medicine and has speaker arrangements / ownership with Biotics Research, Doctors Data, Genova Diagnostics, MDLifespan PCCA and ZRT Laboratory
• Dorothy Caputo, MA, BSN, RN, Michele Bielarski, RN, AKH Staff and Planners, and Precision Medicine Consultants Staff and Planners have nothing to disclose
• All relevant financial relationships are mitigated

References

• Mentions references published between 2010 to 2023

Prostate Cancer Statistics

• Prostate cancer is the most commonly diagnosed malignancy and the fourth leading cause of cancer death in men worldwide
• In 2018, there were 1,280,000 new cases and 359,000 deaths worldwide
• Most prostate cancers grow slowly and tend to be low-grade with relatively low risk and limited aggressiveness
• The overall 5-year survival rate for prostate cancer patients in the US is 99%
• An estimated 3 million prostate cancer survivors were in the US as of 2015, projected to reach 4 million by 2025
• Prostate cancer is more common in Blacks, with a rate more than double that of the general US population
• Prostate cancer is less common in men of Asian and Hispanic descent than in Whites
• Overall incidence increases with age, but cancer aggressiveness decreases with age
• Ninety-nine percent of all prostate cancers occur in those over age 50, but if prostate cancer occurs in younger men it can be very aggressive

Newer Diagnostic Modalities

• Diagnostic modalities include free and total PSA levels, PCA3 urine testing, Prostate Health Index scoring (PHI), the "4K" test, exosome testing, genomic analysis, MRI imaging, PIRADS scoring, and MRI-TRUS fusion guided biopsies
• Diagnosis is primarily based on Prostate-Specific Antigen (PSA) testing and Transrectal Ultrasound-guided prostate tissue biopsies, but PSA testing remains controversial

Prostate Cancer Risk Factors

• Risk factors include male gender, older age, positive family history, increased height, obesity, hypertension, lack of exercise, persistently elevated testosterone levels, Agent Orange exposure, and ethnicity

5-Alpha-Reductase Inhibitors

• 5-alpha-reductase inhibitors like finasteride and dutasteride may decrease low-grade cancer incidence
• They do not appear to affect high-grade risk and do not significantly improve survival
• These medications reduce PSA levels by about 50%, which must be accounted for when comparing sequential PSA readings

Genetics

• The exact cause of prostate cancer is unknown, but genetics is certainly involved
• Genetic background, ethnicity, and family history all contribute to prostate cancer risk
• Men with a first-degree relative (father or brother) diagnosed with prostate cancer have twice the risk of the general population, and risk increases more with an affected brother than an affected father
• Patients with a strong family history of prostate cancer tend to present at a younger age (2.9 years) and with more locally advanced disease
• Men with two affected first-degree relatives have a five-fold greater risk and a higher risk of biochemical recurrence after radical prostatectomy surgery
• In the United States, prostate cancer is more deadly in blacks
• The incidence and mortality are one-third lower for Hispanic men than for non-Hispanic whites
• No single gene is responsible, but mutations in BRCA1 and BRCA2 have been associated with prostate cancer and breast cancer
• P53 mutations are relatively rare in primary prostate cancer but frequently seen in metastatic disease and are considered a late and ominous finding
• Over 100 Single Nucleotide Polymorphisms (SNPs) and other genes have been linked to an increased risk of prostate cancer
• A Genetic Risk Score (GRS) has been proposed to help with risk stratification, but this testing is not yet ready for individual patient diagnostics

Cigarette Smoking

• Smoking increases the risk of the development of prostate cancer and patients should be counseled to stop smoking

Diet and Prostate Cancer

• Prostate cancer is generally linked to the consumption of the typical Western diet
• Increased sugar consumption is associated with an increase in developing prostate and breast cancer
• Vitamin supplements do not lower the risk, and high calcium intake is associated with advanced prostate cancer
• There is little evidence that demonstrates an association between trans fat, saturated fat, or carbohydrate intake and prostate cancer
• Research suggests diets high in saturated fat and milk products seem to increase the risk
• Whole milk consumption after a diagnosis of prostate cancer has been linked to an increased risk of recurrence, especially in overweight men
• Red and processed meats overall have little effect but some studies suggest increased meat consumption is linked to higher risk
• Fish consumption may lower prostate cancer deaths but does not affect the occurrence rate
• Some evidence supports a belief that a vegetarian diet lowers the rate of prostate cancer, but this has not been considered to be conclusive or a significant influence

Chemical Exposure

• Prostate cancer is linked to some medications, medical procedures, and medical conditions
• Statins and metformin, as well as NSAIDs with anti-COX 2 activity, may decrease the prostate cancer risk
• Regular aspirin use may reduce prostate cancer risk
• NSAIDs' beneficial effect is more significant in aggressive prostate cancer and those with prostatitis
• Agent Orange exposure may increase the risk of prostate cancer recurrence, particularly following surgery

Sexual Activity

• Multiple lifetime sexual partners or starting sexual activity early increases the risk of prostate cancer
• Frequent ejaculation may decrease prostate cancer risk, but reduced ejaculatory frequency is not associated with increased risk of advanced prostate cancer

Infections

• Infections are associated with the incidence and development of prostate cancer
• Infections with chlamydia, gonorrhea, or syphilis increase the risk of developing prostate cancer
• Human Papilloma Virus (HPV) may play a role in prostate cancer incidence, but the evidence is inconclusive

Chronic Inflammation and Obesity

• A link has been discovered between prostate cancer and inflammation
• Obesity has a positive relationship with prostate cancer and it promotes more aggressive and severe carcinomas due to changes in the amounts of metabolic and sexual steroid hormones, which enhance prostate cancer

Vasectomy

• There was once thought to be an association between vasectomy and prostate cancer; but larger, follow-up studies have failed to confirm any such relationship

Prostate-Specific Antigen (PSA)

• Elevated PSA levels (greater than 4 ng/ml) in the blood is how 80% of prostate cancers initially present even though elevated PSA levels alone correctly identify prostate cancer only about 25% to 30% of the time
• Current research recommends at least two abnormal PSA levels or the presence of a palpable nodule on DRE to justify a biopsy and further investigation
• The value of PSA screenings remains controversial due to concerns about possible overtreatment of low-risk cancers, overdiagnosis, complications from unnecessary biopsies, presumed limited actual survival benefit from early diagnosis and treatment and the true value of definitive therapy intended to cure

Tests for Detecting Prostate Cancer

• There is an attempt to improve on PSA testing alone, many alternative pre-biopsy screening tests are now available.
• Free and total PSA: The percentage of free PSA in the blood can be a useful indicator of malignancy
  • If the total PSA is between 4 and 10 ng/ml, a free PSA percentage is considered valid
  • The percentage is calculated by multiplying the free PSA level by 100 and dividing by the total PSA value
  • If the free PSA percentage is more than 25%, the cancer risk is less than 10%
  • If the free PSA percentage is less than 10%, the cancer risk is about 50%

Additional PSA Tests

• PSA Density is the total PSA divided by the prostatic volume determined by MRI or ultrasound
  • The formula for the volume of the prostate is prostate volume = width x height x length x pi/6 or width x height x length x 0.52
  • If the PSA density is greater than 0.15, it is considered suggestive of malignancy
• PSA Velocity compares serial, annual PSA serum levels
  • An annual PSA increase of greater than 0.75 ng/ml or greater than 25% suggests a potential cancer of the prostate (total PSA 4 to 10 ng/ml).
  • If the total PSA is 2.6 to 4 ng/ml, then an annual increase of 0.35 ng/ml would be considered suspicious
• Prostate Cancer Antigen 3 (PCA3) is an RNA based genetic test performed from a urine sample obtained immediately after a prostatic massage
  • It is a non-coding RNA molecule that is overexpressed exclusively in prostatic malignancies and is upregulated 66-fold in prostate cancers
  • and is more reliable than PSA as it is independent of prostate volume
  • Serial samples can help monitor patients with active surveillance of low-grade concerns

Additional Tests

• The Prostate Health Index (PHI) is a blood test with free PSA, total PSA, and the [-2] proPSA isoform of free PHA where a formula is used to combine test results which gives the PHI score
  • The PHI score appears to be superior to PSA as well as free and total PSA in predicting the likelihood of prostate cancer
• Prostate Score is a predictive algorithm developed at the University of Michigan that includes PSA, PCA3 and urine TMPRSS2:ERG (found in about 50% of all prostate cancers)
  • This is better than PSA alone, but if this algorithm significantly outperforms PCA3 alone is currently uncertain
• The "4K" Test measures serum total PSA, free PSA, intact PSA and human kallikrein antigen 2, and includes clinical DRE results as well as information from any prior biopsies
  • Clinically significant prostate cancer is usually defined as Gleason 3 + 4 = 7 or higher disease and a risk analysis of 10% or more would typically suggest proceeding with a biopsy
• It has not been shown to be any better than PSA testing alone when used for tracking active surveillance patients
• "ExoDx Prostate Intelliscore (EPI)" uses PCA3 and urinary TMPRSS2:ERG to detect clinically significant prostate cancer
  • It analyzes exosomal RNA for three biomarkers known to be expressed in the urine of men with high-grade prostate cancer
  • It uses a proprietary algorithm is then used to assign a risk score based on Gleason score, unlike with other tests does not require any digital rectal examination or prostatic massage
  • Negative predictive value is 91.3% with a sensitivity rating of 91.9%
• A urine-based test measures the urinary mRNA levels of the HOXC6 and DLX1 biomarkers following a prostatic digital rectal exam
  • Measurements are done utilizing reverse transcriptase quantitative PCR Technology, together with other clinical information such as age, density and family history
• Predictive testing that includes clinical variables (Select MDx and "4K") is more reliable than those tests which do not (PHI, ExoDx, and PCA3)

Prostate Imaging and Biopsy

• Ultrasound and MRI are the main imaging modalities used for prostate cancer detection and diagnosis
• Various MRI tissue characteristics determine the relative cancer risk which is documented in the final report as a PIRADS score
  • PIRADS 1-2 is unlikely to be cancer, PIRADS 4-5 is highly suspicious of clinical disease per Gleason score and histologic confirmation/biopsy is recommended for those levels
• PIRADS 3 lesions usually demonstrate benign histology on biopsy, but low-grade prostate cancer is possible and about 20% (17%-25%) of all patients will show intermediate-grade pathology
• Even in experienced centers, the negative predictive value for MRI has been to 72%-76%, meaning negative reports can miss high-grade cancers
• It is suggested that a bioassay marker be used for additional confirmatory testing for elevated PSA and that MRI not proceed to a biopsy
• A confirmatory genomic test helps to identify those at higher risk before the clinical disease progresses on a long term
• It is standard to perform a prostate biopsy to confirm that all areas of the prostate have been adequately sampled via transrectal ultrasounds
• A 12 Core sextant biopsy is the most common practice and it tests 2 specimens from the base, mid-gland and apex on both sides
• Biopsies are the only test that can dependably and conclusively a cancer diagnosis

Diffential Diagnosis

• Diagnoses can include acute/chronic bacterial prostatitis
• Prostatic Abscess
• Benign Prostatic Hyperplasia
• Nonbacterial Prostatitis
• Tuberculosis of the Genitourinary system

Treatments

• When the cancer is limited to the prostate, it is considered localized and potentially curable
• The serial monitoring of disease can be safe and is the preferred approach for aggressive, particularly those with Prostate-Specific level of less than 10 NG/mL and Gleason Score 3+3 tumor
• Surgery and Radiation are used in localized disease but can have effects that diminish the quality of life

Metastatic Treatment

• If the disease has spread to the bones or elsewhere; pain medications, Bisphosphonates, rank Ligand inhibitors, Hormone treatment, chemotherapy, radiopharmaceuticals, Immunotherapy, focused radiation and other types of Therapy can be used
• Outcomes depend On Age, associated Health problems, Tumour Histology, and the Size and extant

Personalized Medicine Therapies and Diet

• Consider dietary intervention to prevent cancer
• Consuming fish and tomato sauce has been found to have a protective association
• That tomatoes when cooked are more readily absorbed by they are raw
• Omega-3 fatty acid intake May be protective with Vegetable consumption overall
• Where Dairy products with higher in calcium levels that made it more likely to cause aggressive cancer
• Coffee can play and protective role against prostate cancer of 1-2 cups a day while maintaining moderation of health

Diet, Sugar and Other Therapies

• Alcoholic beverages tends to be associated risk for the development of a variety of cancers including prostate cancer
• Increased Consumption of sugar where increase the risk
• Increased intake of high sugar beverages increased risk with higher with prostate Cancer
• Total dietary intake of sugar was independently associated with high serum PSA Concentrates
• Those with fruit juice we're found to increase with developing Prostate Cancer

Weight Loss and Stress

• Obesity is linked to cancer and the more over weight it would be be told to have that intake
• The reverse effects obesity helps promote cancer
• Stress increase transcripts of cancer

Medicine Therapies

• It has been found Estrogen may have some effects with it
• To help measure estradiol to lower
• Some have identified has as causing to tumors/cancer

Low Dose Naltrexone

• a drug that helps with those diagnosed with prostatic intraepithelial neoplasia

Metformin

• Metformin has beneficial activity against cancer
• Lowers amount with high sugar problems

Conclusion

• Prostate cancer is a common cancer
• This has been the seminar review with risk and therapies
• There also have been modern that can help test