Context.—

Low-risk (Gleason score 3 + 3 = 6) and intermediate-risk (Gleason score 3 + 4 = 7) prostate carcinoma cases diagnosed on needle biopsies are frequently referred for gene expression studies such as Oncotype DX to help validate the risk. Risk assessment helps in determining prognosis and therapeutic decision making.

Objective.—

To determine if addition of molecular testing is necessary, by evaluating its correlation with risk stratification provided by pathology report (Gleason score, Grade Group, proportion of positive cores) and serum prostate-specific antigen (PSA) level.

Design.—

Our institutional database was searched for cases that had Oncotype DX testing after prostate biopsy. The final risk category determined by molecular testing was compared to the risk stratification predicted by the pathology report and serum PSA levels. Cases were classified as concordant if they fell under the same National Comprehensive Cancer Network risk and recommended initial therapy group. Follow-up information on discordant cases was obtained and used to determine if risk stratification by molecular testing was superior to that obtained from the clinicopathologic data.

Results.—

A total of 4967 prostate biopsies (2015–2020) were screened. Of these, 131 prostate carcinoma cases (2.6%) had Oncotype DX testing and 111 of 131 cases (85%) had follow-up information. There was risk stratification concordance in 93 of 111 cases (84%). All 18 of 111 cases (16%) that were discordant had a follow-up course that matched the risk predicted by pathology data and serum PSA.

Conclusions.—

Risk stratification provided by information in the pathology report on routine biopsy assessment coupled with the serum PSA level is equivalent to that obtained by Oncotype DX testing.

Clinical risk assessment for prostatic adenocarcinoma helps in determining prognosis and therapeutic decisions such as watchful waiting or active surveillance versus intervention. National Comprehensive Cancer Network (NCCN)–recommended traditional risk assessment tools include serum prostate-specific antigen (PSA), histologic Gleason score on needle biopsies, and clinical stage (NCCN Prostate Cancer Guidelines, Versions 2.2019, 3.2022).1,2  Prior studies have demonstrated that patients may have more advanced disease than demonstrated by the biopsy characteristics, potentially due to sampling bias. Conversely, not all patients with higher Gleason grade have aggressive disease at surgery.3,4  Prostate cancer aggressiveness is influenced by a complex genomic biology. The heterogeneous nature of the disease generates challenges to predict the outcome and choose the right treatment. Molecular diagnostic assays were developed to provide measures of tumor aggressiveness with increased confidence.5 

Recent clinical practice stresses the identification of indolent disease with low risk of progression that can be managed with active surveillance. Thus, prostate carcinoma cases diagnosed as Gleason score 3 + 3 = 6 (low risk/grade) or 3 + 4 = 7 (intermediate risk/grade) on needle biopsy are frequently referred for gene expression studies such as Oncotype DX (Genomic Health, Redwood City, California) to help confirm or validate the risk.6  It consists of a clinically validated multi-gene real-time polymerase chain reaction (RT-PCR) assay utilizing formalin-fixed, paraffin-embedded biopsy tissue to measure the expression of 12 cancer-related genes and 5 reference genes to calculate the Genomic Prostate Score. The genes are involved in the regulation of the androgen pathway (AZGP1, KLK2, SRD5A2, and FAM13C), cellular organization (FLNC, GSN, TPM2, and GSTM2), proliferation (TPX2), and stromal response pathway (BGN, COL1A1, and SFRP4). The Genomic Prostate Score result is indexed to NCCN risk category to produce an estimated likelihood for favorable pathology (Gleason score 3 + 4 = 7 or less and pT2 disease) as well as a prediction of aggressiveness (adverse pathology and biochemical recurrence after radical prostatectomy).68  The limitations of this diagnostic assay, which include the heterogeneous, multifocal nature of the cancer and the low volume of tumor available from a newly diagnosed biopsy, have partly been addressed by analytical validation studies. Addition of the Oncotype DX assay has been shown to improve healthcare savings in men with low-risk cancer by increasing the percentage of patients managed by active surveillance. However, an increase in healthcare costs was noted for patients with intermediate-favorable-risk disease, as additional data from the test led to underutilization of active surveillance. Definitive interventions increased the unrealized cost of managing the chronic side effects of treatment like erectile dysfunction and urinary incontinence.9 

Thus, considering the physical and economic impact of therapeutic interventions in patients with low- and intermediate-risk disease, the goal of this study was to determine if addition of molecular testing is necessary by evaluating its correlation with risk stratification provided by clinicopathologic information, which includes Gleason score, Grade Group, number of positive cores in routine biopsies, and serum PSA level. To our knowledge, such a study in which the biopsy pathology data in most cases were assessed by one pathologist prior to molecular testing and subsequent outcome was followed up has not been previously published.

We screened prostate biopsies from our institutional pathology database from 2015 to 2020 to identify cases that had molecular Oncotype DX testing performed at the time of the primary prostate biopsy. The search criteria were age- and provider-independent. The retrospective biopsy data from all the selected cases were reviewed. The final risk category determined by Oncotype DX studies was recorded and compared to the risk stratification predicted by the surgical pathology report (Gleason score, Grade Group, number of positive cores) and clinical information (stage and serum PSA levels). Concordance percentage was calculated by the number of cases classified into the same NCCN risk and recommended initial therapy group by both methods. Cases that were up-staged or down-staged from their risk category by Oncotype DX, leading to a change in the recommended initial therapy from active surveillance to definitive intervention, were calculated as the discordant percentage. Prospective outcomes on discordant patients who underwent active surveillance, radiation, androgen-deprivation therapy (ADT), or radical prostatectomy were studied and used to determine if risk stratification by Oncotype DX was superior to that obtained from the clinicopathologic data (Supplemental Figure 1 in the supplemental digital content, at https://meridian.allenpress.com/aplm in the October 2023 table of contents). The follow-up parameters for active surveillance included repeat biopsy findings, serum PSA, and/or magnetic resonance imaging (MRI), whereas the radical prostatectomy cases were studied for adverse outcome (higher grade or stage at prostatectomy). Time to biochemical recurrence was monitored for patients who underwent radical prostatectomy or radiation. ADT response was assessed for development of therapy resistance. The mean follow-up to latest PSA level or repeat biopsy was calculated. The study was approved by the University of Nebraska Medical Center Institutional Review Board (Omaha, Nebraska).

High Concordance Between Clinicopathologic Criteria Versus Oncotype DX–Derived Risk Assessment

A total of 4967 prostate biopsies from 2015 to 2020 were screened. More than 95% of the carcinomas had been diagnosed and graded by one of the authors (S.M.L.). One hundred thirty-one prostate carcinoma cases had Oncotype DX testing (2.6%), and 111 of these 131 cases (85%) had follow-up information. Following the NCCN guidelines, we observed concordance between clinicopathologic versus Oncotype DX–derived risk groups in 93 of 111 cases (84%). The concordant cases were distributed as 49 of 111 low risk (44%), 29 of 111 intermediate-favorable risk (26%), and 15 of 111 intermediate-unfavorable risk (14%). In this study, we focused on the evaluation of the 18 of 111 discordant cases (16%).

Most Discordance in the NCCN Intermediate-Favorable Risk Group

Among the 18 of 111 discordant cases (16%), 17 of 111 cases (15%) were diagnosed as Gleason score 3 + 4 = 7 (Grade Group 2) prostatic adenocarcinoma with less than 50% of the biopsy cores involved. The mean serum PSA value for the 17 of 111 cases (15%) was 6.7 ng/mL. Within this group, 15 of 111 cases were clinical stage T1c (13%), whereas 2 of 111 cases (2%) were clinical stage T2a. Thus, all the 17 of 111 cases (15%) were classified as intermediate-favorable risk by the surgical pathology report, serum PSA levels, and clinical stage. Further, 1 of 111 cases (1%) showed Gleason score 3 + 4 = 7 adenocarcinoma with more than 50% of the biopsy cores involved, serum PSA of 12.7 ng/mL, and clinical stage T2b, thus qualifying for a classification into intermediate-unfavorable risk disease. The median age of the discordant patients was 67 years. Subsequent Oncotype DX testing on the intermediate-favorable cases up-staged 16 of 111 cases (14%) to intermediate-unfavorable risk and 1 of 111 cases (1%) to high risk (Figure 1), whereas it down-staged the intermediate-unfavorable case (1 of 111, 1%) to intermediate-favorable risk.

Figure 1.

Distribution of discordant cases into risk groups. Sixteen percent of discordant cases (18 of 111) were distributed according to clinical and pathology data–based risk groups, followed by Oncotype DX–determined reclassification into higher- or lower-risk groups. Percentage values are calculated from total cases (111) as the denominator. Abbreviation: PSA, prostate-specific antigen.

Figure 1.

Distribution of discordant cases into risk groups. Sixteen percent of discordant cases (18 of 111) were distributed according to clinical and pathology data–based risk groups, followed by Oncotype DX–determined reclassification into higher- or lower-risk groups. Percentage values are calculated from total cases (111) as the denominator. Abbreviation: PSA, prostate-specific antigen.

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No Adverse Follow-up Outcome of Discordant Cases

On follow-up of the discordant 16 of 111 cases (14%) predicted intermediate-unfavorable by Oncotype DX, 10 of 111 cases (9%) were actively surveilled with repeat biopsy, serum PSA levels, and/or MRI. We focused on the assessment of risk group outcome on repeat biopsies. The median surveillance follow-up interval from Oncotype DX testing to latest repeat biopsy was 24 months (minimum of 12 months to a maximum of 55 months). Failure of active surveillance is typically defined as increased Gleason score, increased number or proportion of cores involved on repeat biopsy (pathologic criteria), or increased PSA kinetics such as serum PSA levels, PSA doubling time <3 years, etc (clinical criteria).10  Repeat biopsies showed no worsening in Gleason score, and the proportion of positive cores remained <50%. Serum PSA values remained <20 ng/mL for all the cases, with no evidence of doubling from the previous value. Clinical stage was maintained at the original established baseline. Therefore, within these 10 of 111 cases (9%), 8 of 111 cases (7%) showed no change in the risk group category from previous biopsy-determined intermediate-favorable risk, whereas 2 of 111 cases (2%) interestingly qualified for a low-risk categorization. Thus, no adverse outcomes were encountered on follow-up of the above 10 of 111 actively surveilled cases (9%) (Figure 2, A).

Figure 2.

Surveillance and therapy outcome on discordant cases. (A) Discordant cases that were classified as intermediate-favorable risk by clinical and pathology data, but subsequently reclassified to intermediate-unfavorable or higher risk by Oncotype DX testing were followed. (B) Follow-up for the intermediate-unfavorable risk case that was down-staged by Oncotype DX. Figure shows the different management options chosen and their corresponding outcomes. Percentage values are calculated from total cases (111) as the denominator.

Figure 2.

Surveillance and therapy outcome on discordant cases. (A) Discordant cases that were classified as intermediate-favorable risk by clinical and pathology data, but subsequently reclassified to intermediate-unfavorable or higher risk by Oncotype DX testing were followed. (B) Follow-up for the intermediate-unfavorable risk case that was down-staged by Oncotype DX. Figure shows the different management options chosen and their corresponding outcomes. Percentage values are calculated from total cases (111) as the denominator.

Close modal

Further, 4 of 111 cases (3%) underwent radical prostatectomy. Gleason score at prostatectomy was consistent with prior biopsy-determined score (3 + 4 = 7), the tumors were organ confined (stage pT2 pN0), and the margins were negative. The mean follow-up interval from prostatectomy to latest serum PSA level was 36 months. All cases showed PSA levels <0.05 ng/mL at latest follow-up. Additionally, 2 of 111 cases (2%) underwent radiation therapy with a mean prospective follow-up of 15 months. Biochemical recurrence was defined as PSA >0.2 ng/mL 6–12 weeks after prostatectomy and a confirmatory value showing persistent >0.2 ng/mL or increase of 2 ng/mL or more above the nadir PSA after radiation therapy.1113  There was no evidence of biochemical recurrence in any of the above 6 of 111 cases (5%). Next, the discordant case (1 of 111, 1%), which was predicted high-risk by Oncotype DX testing, received a combination of radiation and ADT. Follow-up interval to latest serum PSA (0.55 ng/mL) was 33 months. Thus, no biochemical recurrence or ADT-resistance was seen (Figure 2, A). Lastly, the discordant case (1 of 111, 1%) that was down-staged as intermediate-favorable risk by Oncotype DX showed an increase in the percentage of involved cores (60% in the initial biopsy to 75% in the repeat biopsy at 24-month follow-up) (Figure 2, B). No evidence of definitive therapy was noted in this case, likely indicating patient preference.

To summarize, all the actively surveilled discordant cases (11 of 111, 10%) had a follow-up course that matched the risk determined by the pathology biopsy data and serum PSA level, and not by the risk predicted by Oncotype DX analysis. None of the discordant cases that received intervention (7 of 111, 6%) showed evidence of biochemical recurrence, thus aligning to the intermediate-favorable risk determined by the clinicopathologic data. The patient characteristics and respective treatments are summarized in Tables 1 through 3.

Table 1.

Clinical and Pathologic Parameters for Individual Discordant Cases With Repeat Biopsy

Clinical and Pathologic Parameters for Individual Discordant Cases With Repeat Biopsy
Clinical and Pathologic Parameters for Individual Discordant Cases With Repeat Biopsy

The complex biology and heterogeneity of prostate cancer presents a challenge to choose appropriate management strategies, ranging from aggressive decisive intervention to conservative watchful waiting or active surveillance. An aggressive approach potentially lowers the risk of developing advanced disease but comes with a high risk of treatment-associated adverse effects. In contrast, a conservative approach significantly reduces treatment-related adverse effects but may exert an increased risk of progression to advanced disease. Multiple patient factors are involved in the categorization of cancers into aggressive versus indolent.14 

The NCCN has established prostate cancer risk stratification guidelines using clinicopathologic parameters in order to avoid overtreatment and unnecessary adverse effects for low-risk prostate cancers. Patients with very low– and low-risk disease are candidates for active surveillance. Active surveillance comprises utilizing clinical examination, serum PSA levels, MRI, and prostate biopsies. Active surveillance protocols have significant variation, but the main goal is to delay or avoid treatment in such candidates until there is evidence of reclassification to higher-risk disease. Triggers for intervention include upgrade from Gleason score 6 to Gleason score 7 (with primary Gleason pattern 4),15,16  increased volume of cancer (number or proportion of positive cores), increased PSA kinetic thresholds (serum PSA, PSA doubling time, PSA velocity),17  and change in patient preference. Patients with intermediate-favorable disease are increasingly being considered for active surveillance, as randomized trials did not demonstrate a survival advantage in such men managed with radical prostatectomy versus conservative management.18,19  Definitive intervention is associated with reduced prostate cancer mortality in men with unfavorable and high-risk disease19,20  and is therefore the preferred initial therapy for these patients. Modalities for curative treatment include radical prostatectomy, radiation, ADT, chemotherapy, or combination modalities (NCCN Prostate Cancer Guidelines). Practically, the transition from intermediate-favorable to intermediate-unfavorable risk would serve as the trigger for intervention. Thus, to aid in the reclassification to higher-risk disease and validate low-risk disease, clinicians have started utilizing gene expression studies on tumor tissue.

However, molecular diagnostic assays are recent developments in the clinical management of prostate cancer, and multiplex genomic assays are currently not strongly recommended in the NCCN or American Urological Association guidelines for prostate cancer. The estimated increase in prostate cancer care costs represented the greatest relative increase for all cancer types between 2010 and 2020.21  Molecular assays may reduce the net costs in managing low-risk cancers by increasing the utilization of active surveillance. However, overreliance on genomic tests for intermediate-risk patients may lead to significantly increased out-of-pocket and intervention-related expenses for patients.9  We aimed to study the effectiveness of one such test—the Oncotype DX assay—to predict the aggressiveness of prostate cancer, comparing its analysis to the data from concurrent routinely obtained prostate biopsy and clinical parameters such as serum PSA and stage. We observed a high degree of concordance between clinicopathologically determined and Oncotype DX–derived risk groups, particularly among the low-risk patients. Discordance was observed in patients who were reclassified into intermediate-unfavorable or high-risk by Oncotype DX, while the surgical pathologic and clinical criteria for the same patients had classified them as intermediate-favorable risk. As a result, the clinical decision of choosing active surveillance versus definitive therapy was challenging. Per provider protocol and patient preference, the majority of the patients were actively surveilled, while few underwent definitive therapy. Notably, all the discordant cases followed the clinical course predicted by the surgical pathology report and serum PSA levels. The limitations encountered in our study include the small sample size of discordant cases (future studies are necessary to investigate a larger discordant patient cohort) and the duration of follow-up. While the median active surveillance follow-up interval in our study was 24 months, the assessment of failure of active surveillance (progression to higher-risk disease) may require long-term, extended-outcome assessment. Of the cases that received definitive therapy, it is challenging to predict their outcome had they not been subject to the intervention. However, the mean biochemical recurrence-free interval of 36 months for radical prostatectomy and 21 months for radiation therapy with or without ADT is highly indicative of the favorable tumor risk behavior as predicted by the pathology report.

Overall, our study has the advantage of consistent reporting by one pathologist, thus reducing interexaminer variability of tumor grade. Notably, 130 of 131 cases (99%) from the total cohort and 18 of 18 (100%) cases from the discordant cohort were diagnosed and graded by one of the authors. It demonstrates that the risk stratification criteria determined by accurate pathologic reporting of biopsy Gleason grade, along with serum PSA levels, is equivalent to that determined by Oncotype DX testing in low-risk patients. Importantly, the clinicopathologic stratification is superior to Oncotype DX in predicting the outcome of intermediate-favorable risk patients, as demonstrated by the success of active surveillance and biochemical recurrence-free interval in the initial years of follow-up.

Table 2.

Clinical and Pathologic Parameters for Individual Discordant Cases With Radical Prostatectomy

Clinical and Pathologic Parameters for Individual Discordant Cases With Radical Prostatectomy
Clinical and Pathologic Parameters for Individual Discordant Cases With Radical Prostatectomy
Table 3.

Clinical and Pathologic Parameters for Individual Discordant Cases With Radiation Therapy

Clinical and Pathologic Parameters for Individual Discordant Cases With Radiation Therapy
Clinical and Pathologic Parameters for Individual Discordant Cases With Radiation Therapy

The authors would like to acknowledge Dave Varga, BS (Department of Pathology and Microbiology, University of Nebraska Medical Center), for his help in obtaining patient and genomic test information.

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Author notes

Supplemental digital content is available for this article at https://meridian.allenpress.com/aplm in the October 2023 table of contents.

The authors have no relevant financial interest in the products or companies described in this article.

A portion of our work was presented as a poster at the United States and Canadian Academy of Pathology (USCAP) annual meeting; March 15, 2021; virtual.

Supplementary data