Prostate Health Index (phi) Profile

Serum, frozen

1 mL

0.7 mL (Note: This volume does not allow for repeat testing.)

Red-top tube or gel-barrier tube

The Access Hybritech PSA assay is indicated for the measurement of serum PSA in conjunction with digital rectal examination (DRE) as an aid in the detection of prostate cancer in men aged 50 year or older.¹ This test is further indicated for the serial measurement of PSA to aid in the prognosis and management of patients with prostate cancer.

The Access Hybritech free PSA assay is intended to be used with Hybritech (total) PSA to calculate the ratio of free PSA to total PSA expressed as a percentage (percent free PSA).² Percent free PSA as measured by the Hybritech assays is indicated for use as an aid in distinguishing prostate cancer from benign prostatic conditions, when used in conjunction with Hybritech (total) PSA for prostate cancer detection in men aged 50 years and older with total PSA between 4 and 10 ng/mL (using Beckman Hybritech calibration) with digital rectal examination findings that are not suspicious for cancer.

The Prostate Health Index (phi) as calculated using the Beckman Coulter Access Hybritech assays is indicated for use as an aid in distinguishing prostate cancer from benign prostatic conditions, for prostate cancer detection in men aged 50 years and older with total PSA ≥4.0 to ≤10.0 ng/mL, and with digital rectal examination findings that are not suspicious for cancer.³

Prostatic biopsy is required for diagnosis of cancer.

The concentration of fPSA and PSA in a given specimen determined with assays from different manufacturers can vary due to differences in assay methods and reagent specificity.^1,2 PSA concentrations are dependent on the standard used to calibrate the assay. Values obtained with different manufacturers' assays cannot be used interchangeably. If, in the course of monitoring a patient, the assay method used for determining PSA levels serially is changed, additional sequential testing should be carried out to confirm baseline values.

PSA concentrations based on calibration to the WHO 96/670 Reference Preparation will differ significantly from PSA concentrations based on calibration to the original Hybritech Tandem-R assay.

Beckman Access Hybritech p2PSA should be used only with Beckman Access Hybritech PSA and Beckman Access Hybritech free PSA to calculate the Beckman Coulter phi. Use of another manufacturer's PSA and/or free PSA (fPSA) assays may result in:

• Selection of an inappropriate population of patients for follow-up testing.

• Significantly different cutoffs and cancer probabilities than those presented in the Expected Values section.

Expected values apply only to Beckman Coulter phi as measured by the Access Hybritech PSA free PSA, and [-2]proPSA (p2PSA) assays.

The Beckman Coulter phi results should be interpreted in light of the total clinical presentation of the patient, including symptoms, clinical history, data from additional tests and other appropriate information. Beckman Coulter phi should not be interpreted as absolute evidence for the presence or absence of prostate cancer. Elevated PSA concentrations, increased Beckman Coulter phi, or decreased %fPSA (ratio of fPSA to PSA) may be observed in the serum of patients with non-malignant disorders, as well as those with prostate cancer. Furthermore, low PSA concentrations, low Beckman Coulter phi, or elevated %fPSA (ratio of fPSA to PSA) are not necessarily indicative of the absence of cancer.

Serum PSA, fPSA, p2PSA and values should be used in conjunction with information available from the clinical evaluation of the patient and other diagnostic procedures as digital rectal examination (DRE). Some cases of early prostate cancer will not be detected by PSA testing; the same is true for DRE. Biopsy of the prostate is the standard method used to confirm the presence or absence of prostate cancer.

Routine use of 5 alpha-reductase inhibitor drugs typically lower PSA, fPSA and p2PSA levels in patients. Other drugs used to treat benign prostatic hyperplasia (BPH) may also affect PSA levels. Care should be taken in interpreting results from patients taking these drugs.

For assays employing antibodies, the possibility exists for interference by heterophile antibodies in the patient sample. Patients who have been regularly exposed to animals or have received immunotherapy or diagnostic procedures utilizing immunoglobulins or immunoglobulin fragments may produce antibodies, e.g., HAMA, that interfere with immunoassays. Additionally, other heterophile antibodies such as human anti-goat antibodies may be present in patient samples.^4,5 Such interfering antibodies may cause erroneous results. Carefully evaluate the results of patients suspected of having these antibodies.

For patient samples containing elevated levels of total protein (>8 g/dL), the possibility exists for interference by total protein. Carefully evaluate the results of patients suspected of having elevated total protein levels.

Beckman Coulter phi values should not be interpreted as definitive evidence for the presence or absence of prostate cancer. Prostatic biopsy is required for diagnosis of cancer.

PSA and fPSA concentrations are dependent on the standard used to calibrate the assays. PSA and fPSA concentrations reported by Labcorp for this assay are based on the Beckman Coulter Hybritech calibration standards.⁶ It should be noted that a PSA range of 4 to 10 ng/mL using Hybritech calibration corresponds to a PSA range of 3.1 to 7.8 ng/mL using WHO calibration. The Beckman Coulter phi scores will also be different if the PSA and free PSA tests used to derive the Beckman Coulter phi score were WHO-calibrated. Beckman Access Hybritech PSA, fPSA and p2PSA are performed and used to calculate the Beckman Coulter phi.

Total PSA: 0.0–3.9 ng/mL

Total PSA is the first test performed for the Prostate Health Index score (P score). If the total PSA result is in the range of 4 to 10 ng/mL, then reflex testing of free PSA and p2PSA, along with calculation of the P score and percent free PSA, will be added. Additional charges will apply.

Testing was performed with Beckman Coulter unicel Dxl 800 assays using Hybritech calibration. Results obtained with different test methods or kits cannot be used interchangeably. PSA results calibrated to the WHO standard are approximately 20 percent lower than with the Hybritech calibration. Serum PSA in conjunction with digital rectal examination (DRE) is used as an aid in the detection of prostate cancer in men aged 50 years or older. Prostate biopsy is required for the diagnosis of cancer. Results cannot be interpreted as absolute evidence of the presence or absence of malignant disease.

Prostate Health Index Score

The Prostate Health Index (P score) is indicated for use as an aid in distinguishing prostate cancer from benign prostatic conditions, for prostate cancer detection in men aged 50 years and older with total PSA between 4 and 10 ng/mL, and with digital rectal examination findings that are not suspicious of cancer. Probability of prostate cancer on biopsy based on P score in patients with PSA between 4 and 10 ng/mL:

The P score may also be used to determine the probability of prostate cancer on biopsy for an individual patient. Higher P scores are associated with higher probability of prostate cancer. Prostatic biopsy is required for diagnosis of cancer.

Testing is performed with Beckman Coulter unicel DxI 800 Access PSA, Free PSA, and p2PSA assays using Hybritech calibration. Results obtained with different assay methods or kits cannot be used interchangeably. Results cannot be interpreted as absolute evidence of the presence or absence of malignant disease.

Free PSA Percent

Probability of prostate cancer for men with non-suspicious digital rectal exam (DRE) results and PSA between 4 and 10 ng/mL by patient age:

Testing was performed with Beckman Coulter unicel DxI 800 Access PSA and free PSA assays using Hybritech calibration. Results obtained with different assay methods or kits cannot be used interchangeably. Results cannot be interpreted as absolute evidence of the presence or absence of malignant disease.

PSA and free PSA (fPSA)

Prostate cancer is a leading cause of cancer mortality. The American Cancer Society estimates that approximately 288,300 new cases will be diagnosed and 34,700 will die from prostate cancer in 2023 in the United States.⁷ PSA, a serine protease, is produced by the epithelial cells of the prostate, and is produced by both benign and malignant cells. Abnormalities in the prostate gland architecture resulting from trauma or disease can lead to "leakage" of PSA into the bloodstream. Serum PSA exists primarily in either the free "non-complexed form" (fPSA) or in a "complex"(cPSA) primarily with the serum protease inhibitor, alpha 1-antichymotrypsin.^8,9 Typically, from 70 to 90 percent of the PSA in serum is cPSA, with the remainder being fPSA.¹⁰ The %fPSA (ratio of fPSA to PSA) in serum has been demonstrated to significantly improve the discrimination of prostate cancer from benign prostatic conditions, especially in patients with PSA levels in the ≥4 to ≤10 ng/mL range. A higher %fPSA in serum is correlated with a lower probability of prostate cancer, while %fPSA values below 10 percent are more highly associated with cancer.^10-12

p2PSA

ProPSA and BPSA represent distinct forms of fPSA that demonstrate greater disease-association than PSA, fPSA, or cPSA alone.⁹ Truncated forms of proPSA were found to be elevated in peripheral zone cancer tissue compared with BPH tissues.¹³ The proPSA was elevated in prostate tumor tissue compared with BPH tissues.¹³ The proPSA was elevated in prostate tumor tissue, while BPSA was elevated in nodular BPH transition zone tissue, compared to its concentration in peripheral zone tissue. ProPSA has been found as the native proPSA form containing a 7 amino acid pro leader peptide ([-7]proPSA),¹⁴ as well as forms with truncated pro leader peptides. Truncated proPSA forms consist primarily of proPSA with a 5 amino acid pro leader peptide ([-5]proPSA), 4 amino acids ([-4]proPSA) and 2 amino acids (p2PSA).^15,16 The p2PSA has received the most attention since it was the primary form found in tumor extracts and shows higher immunostaining in prostate tumor than benign tissue.^10,17 Additionally, in vitro the most stable of the five identified proPSA forms is p2PSA.^18,19

Access Hybritech p2PSA was developed by Beckman Coulter, Inc. to measure p2PSA in serum. In studies of men with biopsy confirmed prostate cancer, p2PSA in the ≥4.0 to ≤10.0 ng/mL PSA range was shown to improve the specificity for cancer detection relative to %fPSA alone.¹⁰ Reports from the literature are consistent with the intended use for the Access Hybritech p2PSA assay, used in conjunction with Access Hybritech PSA and fPSA assays to calculate the prostate health index (phi) in the further evaluation of patients with PSA levels in the ≥4.0 to ≤10.0 ng/mL range. Literature reports support the conclusion that precursor forms of PSA are emerging as potentially important diagnostic serum markers to augment PSA and improve prostate cancer detection.^10,20-22

Results of the Beckman Coulter, Inc. multi-center pivotal clinical trial found that Beckman Coulter phi values significantly enhanced the clinical specificity relative to PSA and %fPSA for prostate cancer detection in the ≥4.0 ng/mL to ≤10.0 ng/mL PSA range.³ At 95 percent clinical sensitivity, the clinical specificity for Beckman Coulter phi was 14.1 percent compared to 9.9 percent for %fPSA. At 90 percent clinical sensitivity, the clinical specificity for Beckman Coulter phi was 31.1 percent. At 80 percent clinical sensitivity, the clinical specificity for Beckman Coulter phi was 46.1 percent. The improvement in clinical specificity for Beckman Coulter phi relative to %fPSA represents a substantial improvement in testing intended as an aid in distinguishing prostate cancer from benign prostatic conditions in men aged 50 years and older with total PSA ≥4.0 to ≤10.0 ng/mL, with digital rectal examination findings that are not suspicious for cancer.

Beckman Coulter phi is an in vitro Diagnostic Multivariate Index Assay (IVDMIA), a combination of the results from the Access Hybritech PSA, free PSA and p2PSA assays designed to optimize clinical sensitivity and specificity as an aid in distinguishing prostate cancer from benign prostatic conditions. Beckman Coulter phi is used as an aid in distinguishing prostate cancer from benign prostatic conditions. A multi-center (seven clinical sites) clinical trial with a combination of prospective (97 percent) and retrospective (3 percent) subjects was conducted to test the effectiveness of Beckman Coulter phi. Subjects included men who were being evaluated to determine their prostate status.

All subjects were between 50 and 84 years of age, with serum PSA values between 4 and 10 ng/mL (Hybritech calibration) and digital rectal examination (DRE) findings that were not suspicious for cancer. These men represent the "diagnostic gray zone," in which PSA has identified the men as high risk (25 percent cancer rate in men above 50 years of age), but where clinical specificity could be improved.^23-25 The study was blinded; clinicians did not have access to Beckman Coulter phi values, and laboratory technicians did not have access to diagnoses. Inclusion criteria included subjects who signed informed consent, men ≥ 50 years of age, subjects who were untreated for prostate disease at the time of their blood draw, Hybritech PSA ≥4.0 and ≤10.0 ng/mL and ≤6 core biopsy. TRUS guided needle biopsy and diagnosis was histologically confirmed.

Of the 658 total evaluable subjects, 652 (99.1 percent) had ≥8 core biopsies; 644 (97.9 percent) of the subjects had ≥10 core biopsies. Exclusion criteria included: prior history of prostate cancer, use of Avodart or Proscar at any time prior to blood draw, use of other drugs or therapies or recent prostatic manipulation that might have affected PSA values in the three months preceding the blood draw (including Propecia and androgen therapy including testosterone or Androgel), acute prostatitis, urinary tract infection, prior transurethral resection of the prostate (TURP), equivocal biopsy results, DRE with discrete nodules suspicious for cancer or PSA <4.0 or >10.0 ng/mL.

A total of 658 men participated in the study (324 with prostate cancer and 334 without prostate cancer). Median age for both cancer and benign disease subjects was 63 years.

Individual Patient Probability of Prostate Cancer on Biopsy

Beckman Coulter phi may be used to determine the probability of prostate cancer on biopsy in individual men. Family and patient history can be used in combination with Beckman Coulter phi results to determine the best individualized patient management decisions.

In addition to the sensitivity and specificity analyses of the multi-site study data, we estimated an individual's probability of having detectable cancer based on the Beckman Coulter phi values. In a population of men with PSA in the 4.0 to 10.0 ng/mL range and a non-suspicious DRE, a 25 percent positive biopsy rate has been previously reported.^6,25 The multi-site study population consisted of approximately 49.2 percent (324/658) cancer subjects and 50.8 percent (334/658) non-cancer subjects.

Cancer probabilities based on the 49.2 percent proportion of cancer subjects would inflate the probability estimates for detecting cancer. Therefore, the proportion of cancer subjects was adjusted to 25 percent prior to calculating cancer probabilities for various Beckman Coulter phi scores. This adjustment provides accurate probabilities for the group of men in whom this test will be used. The bootstrap method was used to repetitively sample the multi-site study population.²⁶ Each sampling consisted of 334 (75 percent) benign subjects and 111 (25 percent) cancer subjects, for a total of 445 subjects. This random sampling process was repeated 1,000 times. We calculated mean cancer probabilities on biopsy and nonparametric 95 percent confidence intervals (2.5th and 97.5th percentiles). This repetitive sampling method increases the reliability of the probability of prostate cancer on biopsy estimates.

Higher Beckman Coulter phi values are associated with higher probability of prostate cancer.³

Interpretation of Beckman Coulter phi

Beckman Coulter phi is an in vitro Diagnostic Multivariate Index Assay (IVDMIA) used in combination with the Access Hybritech PSA, free PSA, and p2PSA assays designed to optimize specificity relative to %fPSA and PSA to determine the probability of prostate cancer on biopsy.³ Beckman Coulter phi has been shown to significantly improve clinical specificity across the range of clinical sensitivity and cancer detection relative to PSA (p-value <0.001) and %fPSA (p-value = 0.009) in the PSA range of 4 to 10 ng/mL, in men ≥50 years of age with non-suspicious DRE.

The selection of an appropriate Beckman Coulter phi score that guides patient management considers the percentage of cancers detected (clinical sensitivity), and the percentage of men without cancer, in whom biopsy may be avoided (clinical specificity). For example, using the Hybritech calibration for PSA and free PSA, a Beckman Coulter phi value of 22.1 corresponds to 95 percent sensitivity and 14.1 percent clinical specificity. Therefore, approximately one in seven men may avoid prostate biopsy while detecting 95 percent of cancers if their Beckman Coulter phi value is less than 22.1.

A Beckman Coulter phi value of 27.0 corresponds to 90 percent clinical sensitivity and 31.1 percent clinical specificity. Therefore, nearly one in three men may avoid prostate biopsy while detecting 90 percent of cancers if their Beckman Coulter phi value is less than 27.0.

A Beckman Coulter phi value of 31.3 corresponds to 80 percent clinical sensitivity and 46.1 percent clinical specificity. Therefore, approximately one in two men may avoid prostate biopsy while detecting 80 percent of cancers if their Beckman Coulter phi value is less than 31.3. For men with a Beckman Coulter phi value above the cutoff, the probability of prostate cancer on biopsy of cancer increases and may affect the clinical management of each patient.

Low Beckman Coulter phi scores are associated with a lower probability of prostate cancer on biopsy, and higher scores are associated with an increased probability of prostate cancer on biopsy. The choice of an appropriate Beckman Coulter phi score to be used in guiding clinical decision-making may vary for each patient and may depend in part on other clinically important factors or on family history of disease.