Abstract Objective To determine the relationship of total PSA (tPSA), percent free PSA (%fPSA), and complexed PSA (cPSA) with prostate cancer detection and the diagnosis of poorly-differentiated ...cancers in the contemporary era. Methods We retrospectively reviewed the clinical and pathological records of 292 men who met the following inclusion criteria: (1) tPSA 2.5 to 10 ng/ml; (2) initial biopsy only; (3) extended biopsy scheme (≥10 peripheral zone cores); (4) no previous prostate surgeries. The ability of PSA-related markers to detect cancer was determined by area under the receiver operating characteristics curve analysis (AUC-ROC). Various clinically relevant %fPSA cutoffs and cPSA ranges were analyzed to determine the association with poorly-differentiated cancers. Results Cancer was detected in 126 (43%) men, with mean Gleason score of 7. The cancer detection rates for various cutoffs of tPSA, cPSA and %fPSA were very similar. On ROC analysis for cancer diagnosis, the AUCs for tPSA, %fPSA, and cPSA were 0.53, 0.54, and 0.52, respectively. Men with %fPSA <15 were more likely to have poorly-differentiated cancer than those with %fPSA ≥15 (66% vs. 41%, P < 0.005). Similarly, cPSA ranges (2–4, 4.1–6, and >6) were associated with the detection of poorly-differentiated cancers (37%, 57%, and 80% P < 0.003). Conclusions With the use of extended prostate sampling in the contemporary screening population, the addition of cPSA and %fPSA does not enhance the diagnostic performance of tPSA. However, the significant association between cPSA and poorly-differentiated cancers suggests that this may be a more useful initial test for prostate cancer screening.
Abstract
Background: CREB-binding protein (CBP), encoded by the CREBBP gene functions as an activator of a variety of transcription factors that play critical roles in normal embryonic growth and ...development, tumorigenesis and homeostasis by coupling chromatin remodeling to transcription factor recognition. Whether CBP functions as a tumor suppressor or an oncogene in cancer progression remains unclear. In this study, we assessed the prognostic significance of CBP protein expression in PACs.
Design: Formalin-fixed paraffin-embedded tissue sections from 115 PACs were immunostained by a manual method (DAKO EnVision+ Dual Link System-HRP) using rabbit polyclonal CBP (Santa Cruz Biotech, Santa Cruz, CA). Cytoplasmic and/or nuclear immunoreactivity was scored based on intensity and percentage of positive cells in both the tumor (T) and adjacent benign (B) epithelium in each case. Cases were assessed as tumor>benign (T>B), tumor = benign (T = B), tumor<benign (T<B) or negative (N). Results were correlated with clinicopathologic variables.
Results: Cytoplasmic CBP immunoreactivity was observed as follows: T>B 41%, T = B 37%, T<B 2% N 20%; and correlated with high (HG> = Gleason 7) vs low (LG< = Gleason 6) tumor grade T>B 52% HG vs 33% LG, T = B 19% HG vs 51% LG, T<B 2% HG vs 1% LG, N 27% HG vs 15% LG; p = 0.006 and advanced (stage III,IV) vs early (stage I, II) tumor stage T>B 51% adv vs 31% early, T = B 23% adv vs 52% early, T<B 2% adv vs 2% early, N 24% adv vs 15% early; p = 0.016; and biochemical disease recurrence T>B 53% recurr vs 28% non recurr, T = B 26% recurr vs 49% non recurr, T<B 2% recurr vs 2% non recurr, N 19% recurr vs 21% non recurr; p = 0.033. Nuclear CBP immunoreactivity was observed as follows: T>B 42%, T = B 7%, T<B 0% N 51%; and correlated with high (HG> = Gleason 7) vs low (LG< = Gleason 6) tumor grade T>B 58% HG vs 30% LG, T = B 6% HG vs 7% LG, N 36% HG vs 63% LG; p = 0.008 and advanced (stage III, IV) vs early (stage I, II) tumor stage T>B 54% adv vs 29% early, T = B 7% adv vs 7% early, N 39% adv vs 64% early; p = 0.019. On multivariate analysis, high tumor grade independently predicted biochemical disease recurrence (p = 0.006).
Conclusion: CBP immunoreactivity is a biomarker of adverse prognosis in PAC, correlating with high tumor grade and advanced stage disease. Cytoplasmic CBP expression is also associated with biochemical disease recurrence. Further study of CBP expression and its potential role in prostate cancer appears warranted.
Citation Format: Jeffrey S. Ross, Olga Voronel, Siddhartha Dalvi, Gregory M. Sheehan, Christine E. Sheehan, Tipu Nazeer, Bhaskar VS Kallakury. Prognostic significance of CBP (CREB-binding protein) in prostatic adenocarcinomas (PACs): CBP is associated with high grade, advanced stage and biochemical disease recurrence. abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4343. doi:10.1158/1538-7445.AM2015-4343
Abstract
Background: RUNX2, a member of the RUNX family of transcription factors, regulates normal bone, cartilage and skeletal muscle morphogenesis. Aberrant RUNX2 expression has correlated with ...malignant cell migration, invasion and bone metastases. In the following study, we evaluated the prognostic significance of RUNX2 protein expression in a large cohort of tumors from each of three sites of origin - prostate, colon and breast.
Design: Formalin-fixed paraffin-embedded tissue sections from 121 PAC, 104 CRC and 82 invasive BC 64 ductal (IDC); 18 lobular (ILC) were immunostained by a manual method (DAKO LSAB+ System-HRP) using mouse monoclonal RUNX2 (Santa Cruz). Nuclear and/or cytoplasmic immunoreactivity was scored based on intensity and percentage of positive cells in both the tumor (T) and adjacent benign (B) epithelium in each case. Cases were assessed as tumor>benign (T>B), tumor = benign (T = B), tumor<benign (T<B) or negative (N). Results were correlated with clinicopathologic variables.
Results: RUNX2 immunoreactivity was predominately nuclear in PAC, CRC and BC and noted as follows: in PACs: T>B 58%, T = B 31%, T<B 3% N 8%; and correlated with high > = Gleason grade 7 vs low < = Gleason grade 6 tumor grade (p = 0.001), advanced stage III, IV vs early stage I, II tumor stage (p = 0.039) and biochemical disease recurrence (p = 0.008). In CRCs, immunoreactivity was noted as: T>B 61%, T = B 22%, T<B 15% N 2%; and correlated with advanced stage III, IV vs early stage I, II tumor stage (p<0.0001); positive lymph node status (p = 0.001); high grade 3 vs grade 2 vs grade 1 tumor grade (p = 0.012); and on Cox univariate analysis with shortened overall survival (p = 0.05). While in BCs: T>B 65% and T = B 35%; and correlated overall with early stage I, II vs advanced stage III, IV tumor stage (p = 0.05); ER positive status (p = 0.028); and on Cox univariate analysis, correlated with both lengthened recurrence free (p = 0.033) and overall (p = 0.042) survival; and showed a trend toward association with PR positive status (p = 0.075). Within the ER negative BC subgroup, RUNX2 immunoreactivity correlated with early tumor stage (p = 0.008) and PR positive status (p = 0.033). Conclusion: While RUNX2 protein expression correlates with adverse prognostic variables in prostate and colon cancers, RUNX2 immunoreactivity portends favorable prognosis in breast cancer. Further study of RUNX2 expression and its potential role as a therapeutic target particularly in PAC and CRC appear warranted.
Citation Format: Bhaskar V.S. Kallakury, Albert Huho, Ann B. Boguniewicz, David M. Jones, Tipu Nazeer, Hwa Jeong Lee, Christine E. Sheehan, Jeffrey S. Ross. Prognostic significance of RUNX2 protein expression in carcinomas of the prostate (PAC), colon (CRC), and breast (BC). abstract. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4355. doi:10.1158/1538-7445.AM2015-4355
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Background: Urothelial carcinoma of the upper tract (UTUC) has distinct clinical and pathologic features from UC of the bladder (UCB). We compared the comprehensive genomic profile ...(CGP) of UTUC with UCB. Methods: DNA was extracted from 40 microns of FFPE sections from 195 consecutive cases of relapsed/metastatic UTUC and 295 cases of UCB. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 627X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), insertions/deletions (INDELs), copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: The median age of the UTUC patients was 65.7 years (range, 35-86); 74 (38%) were female and 121 (62%) were male. There were 174 (89%) kidney and 21 (11%) ureteral UTUCs assessed. In total, 51 (26%) and 138 (71%) were stage III and IV, respectively, at the time of CGP. Samples for sequencing were obtained from primary tumor in 157 (81%) cases and from metastatic sites in 38 (19%) cases. There were 1,243 total GA (6.4 GA/sample) involving 203 individual genes and 384 CRGA (1.97 CRGA/sample) involving 51 genes. The most frequent GA were non-CRGA mutations in TP53 (46%), CDKN2A (43%) and CDKN2B (36%). The most frequent CRGA were in FGFR3 (28%), PIK3CA (15%) and CCND1 (12%). In comparison with UCB, statistically equivalent CRGA in FGFR3 (28% vs 21%), PIK3CA (15% vs 20%) and total ERBB2 (11% vs 16%) were identified. Of the 14 UTUC with ERBB2 non-amplification alterations, 6 (43%) featured a micropapillary growth pattern virtually identical to the frequency in UCB (40%). Conclusions: CGP of UTUC uncovers a wide variety of CRGA that can respond to targeted therapy including frequent CRGA in FGFR3, PIK3CA and ERBB2. CRGA in UTUC are generally similar to those found in UCB. Further study of targeted therapy for genomically characterized cases in a clinical trial setting for UTUC appears warranted.
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Background: Neuroendocrine carcinoma of the prostate (NCAP) is an aggressive high grade malignancy that often presents as metastatic disease. Current treatments of this tumor have ...only modest benefit leading investigators to query whether comprehensive genomic profiling (CGP) would have potential to discover novel targets of therapy. Methods: DNA was extracted from 40 microns of FFPE sections from 37 consecutive cases of relapsed/metastatic NCAP. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 583X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Genomic alterations (GA) included base substitutions (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. Clinically relevant GA (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: The median age of the men in this study was 65.1 years (range 43 to 83 years). All (100%) cases were positive for neuroendocrine markers on immunohistochemical staining and were Stage IV at the time of CGP. Samples used for sequencing were obtained from the primary tumor in 9 (24%) of NCAP and from metastatic sites in 28 (76%) of NCAP (12 liver, 6 LN, 2 each from bladder, pelvis and soft tissue, and 1 each from rectum, bone, urethra and ureter. There were 213 total GA (5.8 GA/sample) and 47 CRGA (1.3 CRGA/sample). The most frequent GA were non-CRGA mutations in TP53 (68%) and RB1 (51%). TMPRSS:ERG fusions were identified in 32% of cases whereas AR was altered in 8% (1 mutation and 2 amplifications). The most frequent CRGA involved PTEN (32%), BRCA2 (14%), FGFR1 (5%), PIK3CA (5%) and AKT2 (3%). No alterations in BRAF were identified. Clinical responses to MTOR inhibitors in patients with MTOR pathway alterations will be presented. Conclusions: NCAP has distinctive genomic alterations from classic acinar CAP including reduced frequencies of alterations in TMPRSS:ERG and AR and frequent RB1 mutations. Multiple alterations in the MTOR pathway identified in this infrequent tumor type suggest that these patients may be candidates for MTOR inhibitors and other targeted therapies.
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Background: Small cell neuroendocrine carcinoma of the bladder (SCCB) is rare but aggressive form of genitourinary cancer that can arise de novo or in conjunction with urothelial ...carcinoma (UCB). Methods: DNA was extracted from 40 microns of FFPE specimen from 29 cases of relapsed, refractory and metastatic SCCB and 1,113 UCB. Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of > 503X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations (GA), including base substitutions, insertions and deletions (short variants; SV), fusions, and copy number changes including amplifications (amp) and homozygous deletions. Results: 29 SCCB cases were confirmed on routine histology and featured positive IHC staining for chromogranin, synaptophysin or both. Patients had a mean age of 68.1 years (range 49-90 years) and 25 (86%) were male. At the time of CGP, 3 (10%) SCCB were Stage III and 26 (90%) were stage IV. The primary SCCB was used for sequencing in 14 (48%) of cases and a metastasis sample in 15 (52%). The 29 SCCB featured 2.86 GA/case.The genomics of SCCB differed significantly from UCB (Table). The most frequent clinically relevant GA in SCCB were RICTOR amp (21%) and PIK3CA (10%), BRCA1, HGF, FBXW7 and CCND2 SV (7% each). The relatively high TMB in SCCB (7% TMB > 20 mut/Mb and 28% TMB > 10 mut/Mb) is similar to that seen in UCB. No SCCB cases were MSI-high. ERBB2 and FGFR1 GA frequencies (both 3%) in SCCB were lower than in similarly studied UCB. Conclusions: SCCB differs in genomic landscape from UCB in having higher frequencies of TP53 and RB1 GA and lower frequencies of FGFR3 and ERBB2 GA. However, like UCB, SCCB shares the presence of multiple GA associated with potential responses to targeted therapies and high TMB associated with response to immune checkpoint inhibitor therapy. Table: see text
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Background: Relapsed and refractory urethral cancer (UrethC) is a rare form of genito-urinary malignancy that includes urothelial carcinoma (UC), squamous cell carcinoma (SCC), ...adenocarcinoma (AC) and clear cell carcinoma (CCC) subtypes. No standard treatment exists. Methods: DNA was extracted from 40 microns of FFPE specimen from 46 cases of mUrethC. Comprehensive genomic profiling (CGP) was performed using a hybrid-capture, adaptor ligation based next generation sequencing assay to a mean coverage depth of >500X. Tumor mutational burden (TMB) was calculated from a minimum of 1.11 Mb of sequenced DNA as previously described and reported as mutations/Mb. The results were analyzed for all classes of genomic alterations (GA), including base substitutions, insertions and deletions (short variants; SV), fusions, and copy number changes including amplifications (amp) and homozygous deletions. Results: The clinical features, GA, TMB findings in the mUrethC patients and the subtypes of UrethC are shown in the Table. In comparison with 1,183 similarly profiled UC of the bladder (UCB), all 46 mUrethC and the 21 urothelial mUrethC as a separate group widely differed in GA frequencies. With the exception of similar TP53 GA frequencies, there were significantly lower GA in ERBB2, FGFR1-3 and PIK3CAin the mUrethC cases (p<0.0001 for all comparisons) In addition, mUrethC featured as significantly lower frequency of TMB > 20 mut/Mb (4%; p=0.0001). Conclusions: CGP of mUrethC reveals distinctive genomic alteration frequencies among the 4 disease subtypes with higher numbers of GA in the AC than in the UC, SCC and CCC. The TMB appears to be lower in mUrethC than classically seen in UCB where checkpoint inhibition is now approved. Further study of this rare form of genitourinary cancer appears warranted. Table: see text
