Prostate cancer, a leading cause of cancer death, displays a broad range of clinical behavior from relatively indolent to aggressive metastatic disease. To explore potential molecular variation ...underlying this clinical heterogeneity, we profiled gene expression in 62 primary prostate tumors, as well as 41 normal prostate specimens and nine lymph node metastases, using cDNA microarrays containing ≈26,000 genes. Unsupervised hierarchical clustering readily distinguished tumors from normal samples, and further identified three subclasses of prostate tumors based on distinct patterns of gene expression. High-grade and advanced stage tumors, as well as tumors associated with recurrence, were disproportionately represented among two of the three subtypes, one of which also included most lymph node metastases. To further characterize the clinical relevance of tumor subtypes, we evaluated as surrogate markers two genes differentially expressed among tumor subgroups by using immunohistochemistry on tissue microarrays representing an independent set of 225 prostate tumors. Positive staining for MUC1, a gene highly expressed in the subgroups with "aggressive" clinicopathological features, was associated with an elevated risk of recurrence (P = 0.003), whereas strong staining for AZGP1, a gene highly expressed in the other subgroup, was associated with a decreased risk of recurrence (P = 0.0008). In multivariate analysis, MUC1 and AZGP1 staining were strong predictors of tumor recurrence independent of tumor grade, stage, and preoperative prostate-specific antigen levels. Our results suggest that prostate tumors can be usefully classified according to their gene expression patterns, and these tumor sub-types may provide a basis for improved prognostication and treatment stratification.
Most prostate cancer in African American men lacks the ETS (E26 transforming specific) family fusion event (ETS-). We aimed to establish clinically relevant biomarkers in African American men by ...studying ETS dependent gene expression patterns to identified race specific genes predictive of outcomes.
Two multicenter cohorts of a total of 1,427 men were used for the discovery and validation (635 and 792 men, respectively) of race specific predictive biomarkers. We used false discovery rate adjusted q values to identify race and ETS dependent genes which were differentially expressed in African American men who experienced biochemical recurrence within 5 years. Principal component modeling along with survival analysis was done to assess the accuracy of the gene panel in predicting recurrence.
We identified 3,047 genes which were differentially expressed based on ETS status. Of these genes 362 were differentially expressed in a race specific manner (false discovery rate 0.025 or less). A total of 81 genes were race specific and over expressed in African American men who experienced biochemical recurrence. The final gene panel included APOD, BCL6, EMP1, MYADM, SRGN and TIMP3. These genes were associated with 5-year biochemical recurrence (HR 1.97, 95% CI 1.27-3.06, p = 0.002) and they improved the predictive accuracy of clinicopathological variables only in African American men (60-month time dependent AUC 0.72).
In an effort to elucidate biological features associated with prostate cancer aggressiveness in African American men we identified ETS dependent biomarkers predicting early onset biochemical recurrence only in African American men. Thus, these ETS dependent biomarkers representing ideal candidates for biomarkers of aggressive disease in this patient population.
BACKGROUND:
Nonmedical factors may modify the biological risk of prostate cancer (PCa) and contribute to the differential use of early detection; curative care; and, ultimately, greater racial ...disparities in PCa mortality. In this study, the authors examined patients' usual source of care, continuity of care, and mistrust of physicians and their association with racial differences in PCa screening.
METHODS:
Study nurses conducted in‐home interviews of 1031 African‐American men and Caucasian‐American men aged ≥50 years in North Carolina and Louisiana within weeks of their PCa diagnosis. Medical records were ed, and the data were used to conduct bivariate and multivariate analyses.
RESULTS:
Compared with African Americans, Caucasian Americans exhibited higher physician trust scores and a greater likelihood of reporting a physician office as their usual source of care, seeing the same physician at regular medical encounters, and historically using any PCa screening. Seeing the same physician for regular care was associated with greater trust and screening use. Men who reported their usual source of care as a physician office, hospital clinic, or Veterans Administration facility were more likely to report prior PCa screening than other men. In multivariate regression analysis, seeing the same provider remained associated with prior screening use, whereas both race and trust lost their association with prior screening.
CONCLUSIONS:
The current results indicated that systems factors, including those that differ among different sources of care and those associated with the continuity of care, may provide tangible targets to address disparities in the use of PCa early detection, may attenuate racial differences in PCa screening use, and may contribute to reduced racial disparities in PCa mortality. Cancer 2009. Published 2009 by the American Cancer Society.
The results of the current study indicated that systems factors, including those that differ among different sources of care and those associated with care continuity, may provide tangible targets to address and potentially attenuate disparities in the use of prostate cancer early detection, and may contribute to reduced racial disparities in mortality from prostate cancer.
We observed that the frequency of prostate tumor molecular subtypes differed between Black and White patients and some subtypes showed differential associations with a genomic risk score by race. ...Further understanding of prostate tumor heterogeneity across racial groups may provide insights for the clinical use of subtyping classifiers.
Socioeconomic and health care utilization factors are major drivers of prostate cancer (PC) mortality disparities in the USA; however, tumor molecular heterogeneity may also contribute to the higher mortality among Black men.
To compare differences in PC subtype frequency and genomic aggressiveness by self-identified race.
Five molecular subtype classifiers were applied for 426 Black and 762 White PC patients in the Decipher Genomics Resource Information Database (GRID).
Differences in subtype frequency and tumor genomic risk (Decipher score >0.6) by race were evaluated using χ2 tests and multivariable-adjusted logistic regression models.
Subtype frequencies differed by race for four classifiers. Subtypes characterized by the presence of SPOP mutations, SPINK1 overexpression, and neuroendocrine differentiation were more common among Black men. ERG and ETS fusion-positive subtypes were more frequent among White men, with no clear differences for subtypes reflecting luminal versus basal lineage. The hypothesized low-risk Kamoun S2 subtype was associated with a lower Decipher score among White men only (p = 0.01 for heterogeneity), while the aggressive You PCS1 subtype was associated with a higher Decipher score among White men only (p = 0.001 for heterogeneity). The Tomlins ERG+ subtype was associated with a higher Decipher score relative to all other subtypes among Black men, with no association among White men (p = 0.007 for heterogeneity).
The frequency of PC molecular subtypes differed by self-identified race. Additional studies are required to evaluate whether our observations suggest differences in the tumor genomic risk of progression by self-identified race.
We studied five classifiers that identify subtypes of prostate tumors and found that subtypes differed in frequency between Black and White patients. Further research is warranted to evaluate how differences in tumor subtypes may contribute to disparities in prostate cancer mortality.
In primary hyperaldosteronism, discriminating bilateral adrenal
hyperplasia (BAH) from an aldosterone-producing adenoma (APA) is
important because adrenalectomy, which is usually curative in APA, is
...seldom effective in BAH. We analyzed the results from our most recent
7-yr series to evaluate the predictive value of preoperative
noninvasive tests compared with adrenal vein sampling (AVS).
Forty-eight patients with hypertensive hyperaldosteronism underwent
bedside testing, computed tomography (CT) imaging, and AVS. Those in
whom the results of AVS indicated APA underwent adrenalectomy. Twelve
(30%) and 14 (34%) of 41 patients with APA had paradoxical falls with
ambulation in plasma aldosterone concentration (PAC) and
18-hydroxycorticosterone (18-OH-B), respectively. Twenty-nine (70%)
and 26 (65%) APA patients had a rise in PAC and 18-OH-B, respectively,
as did all 8 BAH patients. Significant identifiers of BAH were supine
PAC values less than 15 ng/dL (P = 0.04), an
increase greater than 60% (P = 0.02) in PAC with
ambulation, and supine 18-OH-B values less than 60 ng/dL
(P = 0.04). CT imaging alone was not predictive for
BAH or APA. In our population, patients with a positive bedside test
result (e.g. a fall in PAC and/or 18-OH-B) and a
unilateral adrenal nodule on CT (10 of 41 patients) could have
proceeded directly to adrenalectomy for APA. However, a positive
bedside test result with a negative CT or a negative bedside test
result regardless of CT findings required AVS to confirm the diagnosis
and site of disease.
Abstract Disparities based on race and ethnicity still exist in the US healthcare system. Such disparities are reflected in the diagnosis and treatment of benign prostatic hyperplasia (BPH) and lower ...urinary tract symptoms (LUTS) among African Americans and Latinos. The prevalence of risk factors for BPH and LUTS and symptom progression are higher in these populations, but treatment is less common. African American men and Latinos frequently have other serious comorbidities, such as cardiovascular disease, diabetes mellitus, and metabolic syndrome. Health plan constraints and variabilities, race/ethnicity, socioeconomic status, language, healthcare-seeking behaviors, and cultural beliefs and practices influence the treatment of BPH and LUTS, oftentimes resulting in unequal access to care or inferior quality of care. The provision of nondiscriminatory treatment poses a challenge to clinicians that can partially be addressed by improving the cultural competence of practitioners in minority communities. An awareness of the customs and healing traditions of African Americans and Latinos may also facilitate culturally appropriate care and improve outcomes, and the participation of clinicians in continuing education/professional development programs to increase knowledge about minority health issues is recommended. Conversely, improving the health literacy of African American and Latino patients with BPH and LUTS can help avoid ineffective nontraditional methods of treatment.
Abstract only
222
Background: AA men often present with more aggressive prostate cancer and are less likely to receive treatment, negatively affecting quality-of-life and overall survival (OS). ...Sipuleucel-T is an autologous cellular immunotherapy approved for asymptomatic or minimally symptomatic mCRPC. Data from the PROCEED registry showed that OS for AA pts treated with SIP-T was 9.3 mo longer than OS for Caucasian pts. In a prior subgroup analysis of Phase III data, AA pts realized a 30.7-mo difference in OS with SIP-T vs. placebo (PBO). We calculated the NNTB to further interpret the OS benefit in AA pts. Methods: Data were pooled from 3 Phase III mCRPC SIP-T trials (D9901, D9902A, and IMPACT). The absolute risk reduction (ARR) is calculated from Kaplan-Meier estimates at 12-, 24-, and 36-mo for all SIP-T subjects, and an AA cohort, receiving ≥1 infusion. NNTB, the inverse of the ARR, represents the number of pts needed to be treated with SIP-T to prevent 1 additional death compared to PBO. All NNTB values are rounded up. Results: Of the 737 pooled mCRPC pts enrolled, 488 men were randomized to SIP-T (n=33 AA), and 249 to PBO. Baseline clinical characteristics between the SIP-T and PBO groups were well balanced; however, compared to overall SIP-T and PBO, AA SIP-T pts were more likely to have received prior chemotherapy, lower hemoglobin, and better performance status. The NNTB at 12-mo was the same (13) for both the pooled SIP-T and AA treated cohort. At 24-mo, the NNTB values were 10 for pooled and 5 for AA. At 36-mo, an NNTB of 8 (pooled) and 3 (AA) SIP-T treatments prevented 1 additional death (Table). Conclusions: This NNTB analysis shows a favorable survival benefit for AA men treated with SIP-T and all treated SIP-T subjects. NNTB values declined over 3-years, suggesting durability of clinical benefit with SIP-T, and that it may address a known survival disparity in AA with prostate cancer. Studies with larger sample sizes may confirm if AA pts derive a greater OS benefit from SIP-T. Clinical trial information: NCT00065442. Table: see text
Prostate cancer patients who have a detectable prostate-specific antigen (PSA) postprostatectomy may harbor pre-existing metastatic disease. To our knowledge, none of the commercially available ...genomic biomarkers have been investigated in such men.
To evaluate if a 22-gene genomic classifier can independently predict development of metastasis in men with PSA persistence postoperatively.
A multi-institutional study of 477 men who underwent radical prostatectomy (RP) between 1990 and 2015 from three academic centers. Patients were categorized as detectable PSA (n=150) or undetectable (n=327) based on post-RP PSA nadir ≥0.1 ng/ml.
Cumulative incidence curves for metastasis were constructed using Fine-Gray competing risks analysis. Penalized Cox univariable and multivariable (MVA) proportional hazards models were performed to evaluate the association of the genomic classifier with metastasis.
The median follow-up for censored patients was 57 mo. The median time from RP to first postoperative PSA was 1.4 mo. Detectable PSA patients were more likely to have higher adverse pathologic features compared with undetectable PSA patients. On MVA, only genomic high-risk (hazard ratio HR: 5.95, 95% confidence interval CI: 2.02–19.41, p=0.001), detectable PSA (HR: 4.26, 95% CI: 1.16–21.8, p=0.03), and lymph node invasion (HR: 12.2, 95% CI: 2.46–70.7, p=0.003) remained prognostic factors for metastasis. Among detectable PSA patients, the 5-yr metastasis rate was 0.90% for genomic low/intermediate and 18% for genomic high risk (p<0.001). Genomic high risk remained independently prognostic on MVA (HR: 5.61, 95% CI: 1.48–22.7, p=0.01) among detectable PSA patients. C-index for Cancer of the Prostate Risk Assessment Postsurgical score, Gandaglia nomogram, and the genomic classifier plus either Cancer of the Prostate Risk Assessment Postsurgical score or Gandaglia were 0.69, 0.68, and 0.82 or 0.81, respectively. Sample size was a limitation.
Despite patients with a detectable PSA harboring significantly higher rates of aggressive clinicopathologic features, Decipher independently predicts for metastasis. Prospective validation of these findings is warranted and will be collected as part of the ongoing randomized trial NRG GU-002.
Decipher independently predicted metastasis for patients with detectable prostate-specific antigen after prostatectomy.
This article found that despite patients with a detectable prostate-specific antigen harboring significantly higher rates of aggressive clinicopathologic features, Decipher independently predicts for metastasis.
Abstract
Background: Racial disparities in prostate cancer (PCa) incidence and mortality are well known. PCa is known to be more aggressive in African American men (AAM) compared to European American ...men (EAM) in terms of higher incidence and mortality rates. Here we validate a tumor gene expression pan-cancer race model in men with PCa and further characterize genomic differences that may contribute to disparate clinical outcomes.
Methods: We obtained deidentified genome-wide expression profiles from clinical use of the Decipher RP test in 9,953 men from the GRID registry database. A subset of men (n=313) had known race status. A pan-cancer race model, developed to predict patient AAM race from analysis of gene expression patterns in 4,162 tumors from retrospective cohorts with known race status, was applied to the prospective cohort for race prediction. Hallmarks of cancer, immune modulators, AR activity, and prognostic gene signatures available in the GRID were used to gain a molecular perspective on PCa racial disparities.
Results: The race model was independently validated in the subset of men with known race and had an AUC of 0.98 for differentiating AAM from EAM. The model was then applied to the 9,640 GRID patients with unknown race status and classified 6,831 as EAM, 1,058 as AAM, and 1,751 as having indeterminate race. Characterizing the molecular subtypes, we found known and predicted AAM to be enriched with SPINK1+ tumors (21% and 24%, respectively) compared to predicted EAM (8%). In contrast, while ERG+ was found 22% and 19% in known and predicted AAM, respectively, compared to 46% in predicted EAM. Based on PAM50 prostate cancer classifier, 61% of AAM were classified as basal-like tumors, whereas 41% were basal-like in EAM. Similarly, 28% of AAM had low AR-A while only 11% of EAM had low AR-A. AAM tumors had higher levels of immune infiltration signatures as well as higher scores for inflammatory and interferon gamma responses, NF-KB mediated tumor necrosis factor (TNF) activity, and interleukin 6 (IL6) signaling activity scores. AAM had lower DNA repair glycolysis scores compared to EAM.
Conclusion: Known and predicted AAM were enriched with SPINK1+ tumors, higher immune infiltration and activation but lower ERG+, DNA repair, and AR activity tumors. Using such large GRID data with known race, we will further understand the underlying causes associated with prostate cancer racial disparities.
Citation Format: Walter Rayford, Jennifer Jordan, Mandeep Takhar, Mohammed Alshalalfa, Darlene Dai, Nicholas Erho, Mark D. Greenberger, Elai Davicioni. Genomic variations associated with prostate cancer in large cohort of African American men abstract. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B098.
PDF
