Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? High‐grade prostate cancers are associated with poor disease‐specific outcomes. A proportion of these tumours produce little PSA. This study demonstrates that among Gleason 8–10 prostate cancers, some of the worst survival outcomes are associated with the lowest PSA levels. OBJECTIVE To assess outcomes of patients with Gleason score 8–10 prostate cancer (CaP) with a low (≤2.5 ng/mL) vs higher preoperative serum PSA levels. PATIENTS AND METHODS From 1983 to 2003, 5544 patients underwent open radical prostatectomy, of whom 354 had a Gleason 8–10 tumour in the prostatectomy specimen. Patients were stratified according to preoperative PSA level into four strata: ≤2.5 ng/mL (n= 31), 2.6–4 ng/mL (n= 31), 4.1–10 ng/mL (n= 174), and >10 ng/mL (n= 118). We compared biochemical progression‐free survival (PFS), metastasis‐free survival (MFS), and cancer‐specific survival (CSS) as a function of preoperative PSA level. RESULTS Patients with PSA level ≤2.5 ng/mL were more likely to have seminal vesicle invasion (P= 0.003). On Kaplan–Meier survival analysis, patients with a PSA level ≤2.5 ng/mL had proportionately worse outcomes than their counterparts with higher PSA levels. The 7‐year PFS in the PSA ≤2.5 ng/mL stratum was lower than those of the PSA 2.6–4 ng/mL and 4–10 ng/mL strata (36% vs 50 and 42%, respectively); however, the lowest 7‐year PFS was found in those with a PSA level >10 ng/mL (32%, P= 0.02). Gleason score 8–10 tumours with a PSA level ≤2.5 ng/mL also tended to have the lowest 7‐year MFS (75, 93, 89 and 92% for PSA level ≤2.5, 2.6–4, 4.1–10 and >10 ng/mL, respectively, P= 0.2) and CSS (81, 100, 94 and 90% for PSA level ≤2.5, 2.6–4, 4.1–10 and >10 ng/mL, respectively, P= 0.3), although these differences were not statistically significant. In the subset with palpable disease, Gleason grade 8–10 disease with PSA level ≤2.5 ng/mL also was associated with a worse prognosis. CONCLUSIONS In patients with Gleason grade 8–10 disease, a proportion of these tumours are so poorly differentiated that they produce relatively little PSA. Patients with high‐grade, low‐PSA tumours had less favourable outcomes than many of those with higher PSA levels.
PURPOSE Recent studies have identified genetic variants associated with both increased serum PSA concentrations and prostate cancer risk, raising the possibility of diagnostic bias. By correcting for the effects of these variants on PSA levels, it may be possible to create a personalized PSA cutoff to more accurately identify individuals for whom biopsy is recommended. We therefore determined how many men would continue to meet common biopsy criteria after genetic correction of their measured PSA concentrations. MATERIALS AND METHODS The genotypes of 4 single nucleotide polymorphisms (SNPs) previously associated with serum PSA levels (rs2736098, rs10788160, rs11067228, and rs17632542) were determined in 964 healthy Caucasian volunteers without prostate cancer. Genetic correction of the PSA was performed by dividing an individual's PSA value by his combined genetic risk. Analyses were used to compare the percentage of men that would meet commonly used biopsy thresholds (≥2.5 or ≥4.0 ng/mL) before and after genetic correction. RESULTS Genetic correction of serum PSA results was associated with a significantly decreased frequency of men meeting biopsy thresholds. Genetic correction could lead to a 15% and 20% relative reduction in the total number of biopsies using a biopsy threshold of ≥2.5 or ≥4.0 ng/mL, respectively. In addition, genetic correction could result in an 18–22% reduction in the number of potentially unnecessary biopsies and a 3% decrease in potentially delayed diagnoses. CONCLUSIONS Our results suggest that 4 SNPs can be used to adjust a man's measured PSA concentration and potentially delay or prevent unnecessary prostate biopsies in Caucasian men.
Transcriptional and splicing anomalies have been observed in intron 8 of the CASP8 gene (encoding procaspase-8) in association with cutaneous basal-cell carcinoma (BCC) and linked to a germline SNP rs700635. Here, we show that the rs700635[C] allele, which is associated with increased risk of BCC and breast cancer, is protective against prostate cancer [odds ratio (OR) = 0.91, P = 1.0 × 10−6]. rs700635[C] is also associated with failures to correctly splice out CASP8 intron 8 in breast and prostate tumours and in corresponding normal tissues. Investigation of rs700635[C] carriers revealed that they have a human-specific short interspersed element-variable number of tandem repeat-Alu (SINE-VNTR-Alu), subfamily-E retrotransposon (SVA-E) inserted into CASP8 intron 8. The SVA-E shows evidence of prior activity, because it has transduced some CASP8 sequences during subsequent retrotransposition events. Whole-genome sequence (WGS) data were used to tag the SVA-E with a surrogate SNP rs1035142[T] (r2 = 0.999), which showed associations with both the splicing anomalies (P = 6.5 × 10−32) and with protection against prostate cancer (OR = 0.91, P = 3.8 × 10−7).
Background Associations have been documented recently between some of the 23 single nucleotide polymorphisms newly discovered with the Collaborative Oncological Gene-environment Study iCOGS array that indicate prostate cancer (PCa) risk and aspects of disease aggressiveness. The utility of these iCOGS SNPs remains to be determined in active surveillance (AS). Objective To determine associations between iCOGS SNPs and upgrading among men who underwent surgical treatment and AS for low-risk PCa. Design, setting, and participants The genotypes of the 23 iCOGS SNPs were determined for all white subjects with biopsy Gleason score (GS) 6 including 950 men who underwent definitive treatment with surgery and 209 men who elected AS. The clinical and pathologic characteristics were documented for all subjects. Outcome measures and statistical analysis Men who underwent surgery were grouped according to their pathologic GS (upgraded was defined as GS ≥ 7; nonupgraded remained GS 6). Men who were enrolled in AS were also grouped according to their GS on subsequent surveillance biopsies. Statistical analyses were performed comparing the genotypes between the upgraded and nonupgraded groups. Results and limitations Overall, 31% and 34% of men were upgraded in the surgery and AS cohorts, respectively. Three iCOGS SNPs were significantly associated with the risk of upgrading in the surgical cohort. After correction for multiple testing, only rs11568818 on chromosome 11q22 remained significantly associated with upgrading. Assessment of this allele in the AS cohort reveals that it was present at noteworthy higher frequencies in men with high-grade disease on surveillance biopsies compared with nonupgraded men (p = 0.003). This study was primarily limited by the homogeneous patient population. Conclusions This is the first report of a SNP on chromosome 11q22 associated with higher grade disease in a surgical cohort that is also validated for eventual upgrading in a prospective AS cohort. Patient summary We examined the relationship between a group of genetic markers and prostate cancer (PCa) aggressiveness in a group of patients who underwent surgery for PCa and a group of patients who were enrolled in active surveillance. We found that these genetic markers helped predict which patients had more aggressive disease in both groups.
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