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Thread: (C) Screening Diagnosis PSA Imaging Biopsies

  1. #151
    Genomic Assessment of a High Grade Low PSA Prostate Cancer Cohort

    (A MSK Study)


    High grade prostate cancer with a paradoxically low PSA has been associated with a more aggressive phenotype compared with high grade disease with a high PSA. We sought to examine the genomic landscape of these patients using next generation DNA sequencing to identify a characteristic biology that could explain their unique clinical presentation.

    A database search identified 19 patients with a Gleason score (GS) of 8 or higher and a PSA less than 4 who had prostate tissue that had undergone next-generation DNA sequencing of targeted gene panels using the MSK-IMPACT assay. A comparison cohort was identified of 146 patients with a GS of 8 or higher, PSA greater than 4, and sequenced prostate tissue. Chi square tests were used to assess the significance of different characteristics between the two groups. Genomic outcomes examined included tumor mutational burden (TMB), the fraction of the genome that is copy number altered (FCNA), and specific genomic alterations, including somatic and germline mutations.

    Median PSA was 2.35 in the low PSA group and 9.27 in the comparison group. All patients had Gleason 8 or 9 disease. All prostate samples were radical prostatectomy specimens, except for one which was a biopsy specimen. A minority of patients received androgen deprivation therapy prior to tissue collection: 21% in the low PSA group and 13% in the high PSA group (p=0.341). The 2 groups did not differ significantly in pathologic T stage (pT2, pT3, and pT4 were 5%, 68%, and 21% in the low PSA group vs 6%, 73% and 21%, p=0.996), pathologic N stage (pN1 37% vs 51%, p=0.233), and clinical M stage at diagnosis (M1 21% vs 18%, p=0.762). While the 2 groups did not differ with respect to TMB (2.1 vs 2.0) or FCNA (0.07 vs 0.07), there were some notable genomic differences. The low PSA cohort had more germline mutations in the DNA damage response (DDR) pathway, with 26% of patients harboring a germline DDR alteration versus 8% of patients in the high PSA cohort, p=0.0097. The difference in the incidence of both germline and somatic DDR alterations approached significance: 32% of low PSA patients versus 15% of high PSA patients, p=0.059. Genes considered as part of the DDR pathway included BRCA2, BRCA1, ATM, RAD50, CHEK2, FANCA, PALB2, and MUTYH. Notably, the low PSA cohort did not harbor an increased number of alterations in genes typically associated with small cell neuroendocrine prostate cancer, including TP53 (26% vs 32%), RB1 (0% vs 2%) and PTEN (5% vs 20%). Other genes with recurring alterations in these populations included APC (16% and 6%) and TMPRSS2-ERG fusions (26% and 23%).

    Patients presenting with high grade prostate cancer and a PSA <4 should undergo genomic testing since about one third harbor DDR mutations and may be future candidates for PARP inhibitor therapy. Alterations commonly associated with small cell neuroendocrine prostate cancer were not seen with increased frequency.

  2. #152
    Genetic correlates of prostate cancer visibility (and invisibility) on mpMRI: It’s time to take stock
    [2019, Comment, Full Text]



    Multiparametric magnetic resonance imaging (mpMRI) has enhanced risk stratification for men at risk of prostate cancer, through accurate pre‐biopsy detection of high‐risk disease [1]. However, it has become apparent that not all clinically significant prostate cancer is detected by mpMRI. Approximately 10‐20% of significant disease is invisible to mpMRI, depending on the threshold set for significance, and on the quality of mpMRI acquisition and interpretation. The threshold for significance has recently been challenged by the 29‐year follow‐up of the SPCG‐4 study, in which men with overall Gleason score 3 + 4 did not suffer prostate‐cancer‐related death [2], whilst those with overall Gleason score 4 + 3 did suffer prostate‐cancer related death (adjusted relative risk 5.73; 95% CI 1.59–20.67) potentially suggesting a new threshold for clinically significant disease. This finding is important, given that in PROMIS, no men with overall Gleason score 4 + 3 had negative pre‐biopsy mpMRI [1], indicating that actually mpMRI may identify all truly significant cancer (if SPCG‐4 is used to guide our threshold). Nonetheless, over the past two years, there has been increasing drive to better understand the nature of mpMRI‐inconspicuous disease, particularly at the molecular level.

  3. #153
    Use of 68Ga-PSMA PET for detecting lymph node metastases in primary and recurrent prostate cancer and location of recurrence after radical prostatectomy: an overview of the current literature
    [2019, Review]



    First, to review the literature to determine the sensitivity and specificity of 68 Ga-PSMA PET for detecting pelvic lymph node metastases in patients with primary prostate cancer, and the positive predictive value in patients with biochemical recurrence after initial curative treatment. Second, to determine the detection rate and management impact of 68 Ga-PSMA PET in patients with biochemical recurrence after radical prostatectomy.

    We performed a comprehensive literature search. Search terms used through Medline, Embase and Science Direct were '(PSMA, 68 Ga-PSMA, 68 Gallium-PSMA, Ga-68-PSMA or prostate-specific membrane antigen)' and '(histology, lymph node, staging, sensitivity, specificity, positive predictive value, recurrence, recurrent or detection)'. Relevant abstracts were reviewed and full-text articles obtained where possible. References to and from obtained articles were searched to identify further relevant articles.

    Nine retrospective and two prospective studies describe the sensitivity and specificity of 68 Ga-PSMA PET for detecting pelvic lymph node metastases before initial treatment which ranged from 33.3 to 100% and 80 to 100%, respectively. In eight retrospective studies, the positive predictive value of 68 Ga-PSMA PET in patients with biochemical recurrence before salvage lymph node dissection ranged from 70 to 100%. The detection rate of 68 Ga-PSMA PET in patients with biochemical recurrence after radical prostatectomy in the PSA subgroups <0.2 ng/ml, 0.2-0.49 ng/ml and 0.5-<1.0 ng/ml ranged from 11.3 to 50.0%, 20.0 to 72.7% and 25.0 to 87.5% respectively.

    68 Ga-PSMA PET demonstrates a high specificity for the detection of pelvic lymph node metastases in primary prostate cancer. Furthermore, 68 Ga-PSMA PET has a very high positive predictive value in detecting lymph node metastases in patients with biochemical recurrence. By contrast, sensitivity is only moderate. Therefore, based on the currently available literature, 68 Ga-PSMA PET cannot yet replace pelvic lymph node dissection to exclude lymph node metastases. In the salvage phase, 68 Ga-PSMA PET has both a high detection rate and impact on radiotherapy planning in early biochemical recurrence after radical prostatectomy.


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