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Expected population impacts of discontinued prostate-specific antigen screening.
BackgroundProstate-specific antigen (PSA) screening for prostate cancer has high risks of overdiagnosis, particularly among older men, and reports from screening trials indicate that it saves few lives after 11 to 13 years of follow-up. New clinical guidelines recommend against PSA screening for all men or for men aged >70 years, but, to the authors' knowledge, the expected population effects of these guidelines have not been studied to date.MethodsTwo models of prostate cancer natural history and diagnosis were previously developed using reconstructed PSA screening patterns and prostate cancer incidence in the United States. Assuming a survival benefit of PSA screening consistent with the screening trials, the authors used the models to predict incidence and mortality rates for the period from 2013 through 2025 under continued PSA screening and under discontinued PSA screening for all men or for men aged >70 years.ResultsThe models predicted that continuation of recent screening rates will overdiagnose 710,000 to 1,120,000 men (range between models) but will avoid 36,000 to 57,000 cancer deaths over the period 2013 through 2025. Discontinued screening for all men eliminated 100% of overdiagnoses but failed to prevent 100% of avoidable cancer deaths. Continued screening for men aged <70 years eliminated 64% to 66% of overdiagnoses but failed to prevent 36% to 39% of avoidable cancer deaths.ConclusionsDiscontinuing PSA screening for all men may generate many avoidable cancer deaths. Continuing PSA screening for men aged <70 years could prevent greater than one-half of these avoidable cancer deaths while dramatically reducing overdiagnoses compared with continued PSA screening for all ages
Advanced Imaging and Receipt of Guideline Concordant Care in Women with Early Stage Breast Cancer
Objective. It is unknown whether advanced imaging (AI) is associated with higher quality breast cancer (BC) care. Materials and Methods. Claims and Surveillance Epidemiology and End Results data were linked for women diagnosed with incident stage I-III BC between 2002 and 2008 in western Washington State. We examined receipt of preoperative breast magnetic resonance imaging (MRI) or AI (defined as computed tomography [CT]/positron emission tomography [PET]/PET/CT) versus mammogram and/or ultrasound (M-US) alone and receipt of guideline concordant care (GCC) using multivariable logistic regression. Results. Of 5247 women, 67% received M-US, 23% MRI, 8% CT, and 3% PET/PET-CT. In 2002, 5% received MRI and 5% AI compared to 45% and 12%, respectively, in 2008. 79% received GCC, but GCC declined over time and was associated with younger age, urban residence, less comorbidity, shorter time from diagnosis to surgery, and earlier year of diagnosis. Breast MRI was associated with GCC for lumpectomy plus radiation therapy (RT) (OR 1.55, 95% CI 1.08–2.26, and p=0.02) and AI was associated with GCC for adjuvant chemotherapy for estrogen-receptor positive (ER+) BC (OR 1.74, 95% CI 1.17–2.59, and p=0.01). Conclusion. GCC was associated with prior receipt of breast MRI and AI for lumpectomy plus RT and adjuvant chemotherapy for ER+ BC, respectively
Relationship of time to testosterone (T) and PSA rises during the first “off treatment” interval (1OFF) of intermittent androgen deprivation (IAD) with time to castration resistance (CRPC) and prostate cancer mortality (PCM) in men with biochemical relapse (BR).
Is prostate cancer different in black men? Answers from 3 natural history models
BACKGROUND: Black men in the United States have substantially higher prostate cancer incidence rates than the general population. The extent to which this incidence disparity is because prostate cancer is more prevalent, more aggressive, and/or more frequently diagnosed in black men is unknown.
METHODS: The authors estimated 3 independently developed models of prostate cancer natural history in black men and in the general population using an updated reconstruction of prostate-specific antigen screening, based on the National Health Interview Survey in 2005 and on prostate cancer incidence data from the Surveillance, Epidemiology, and End Results program during 1975 through 2000. By using the estimated models, the natural history of prostate cancer was compared between black men and the general population.
RESULTS: The models projected that from 30% to 43% (range across models) of black men develop preclinical prostate cancer by age 85 years, a risk that is (relatively) 28% to 56% higher than that in the general population. Among men who had preclinical disease onset, black men had a similar risk of diagnosis (range, 35%-49%) compared with the general population (32%-44%), but their risk of progression to metastatic disease by the time of diagnosis was from 44% to 75% higher than that in the general population.
CONCLUSIONS: Prostate cancer incidence patterns implicate higher incidence of preclinical disease and higher risk of metastatic progression among black men. The findings suggest screening black men earlier than white men and support further research into the benefit-harm tradeoffs of more aggressive screening policies for black men
Prostate cancer characteristics associated with response to pre-receptor targeting of the androgen axis.
Factors influencing differential responses of prostate tumors to androgen receptor (AR) axis-directed therapeutics are poorly understood, and predictors of treatment efficacy are needed. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth.We characterized two androgen-sensitive prostate cancer xenograft models after androgen suppression by castration in combination with the SRD5A inhibitor, dutasteride, as well as a panel of castration resistant metastases obtained via rapid autopsy.In LuCaP35 tumors (intra-tumoral T:DHT ratio 2:1) dutasteride suppressed DHT to 0.02 ng/gm and prolonged survival vs. castration alone (337 vs.152 days, HR 2.8, p = 0.0015). In LuCaP96 tumors (T:DHT 10:1), survival was not improved despite similar DHT reduction (0.02 ng/gm). LuCaP35 demonstrated higher expression of steroid biosynthetic enzymes maintaining DHT levels (5-fold higher SRD5A1, 41 fold higher, 99-fold higher RL-HSD, p<0.0001 for both), reconstitution of intra-tumoral DHT (to ∼30% of untreated tumors), and ∼2 fold increased expression of full length AR. In contrast, LuCaP96 demonstrated higher levels of steroid catabolizing enzymes (6.9-fold higher AKR1C2, 3000-fold higher UGT2B15, p = 0.002 and p<0.0001 respectively), persistent suppression of intra-tumoral DHT, and 6-8 fold induction of full length AR and the ligand independent V7 AR splice variant. Human metastases demonstrated bio-active androgen levels and AR full length and AR splice-variant expression consistent with the range observed in xenografts.Intrinsic differences in basal steroidogenesis, as well as variable expression of full length and splice-variant AR, associate with response and resistance to pre-receptor AR ligand suppression. Expression of steroidogenic enzymes and AR isoforms may serve as potential biomarkers of sensitivity to potent AR-axis inhibition and should be validated in additional models
Relationships Between Times to Testosterone and Prostate-Specific Antigen Rises During the First Off-Treatment Interval of Intermittent Androgen Deprivation are Prognostic for Castration Resistance in Men With Nonmetastatic Prostate Cancer
Characterization of LuCaP35 and LuCaP96 prostate cancer xenografts and responses to systemic androgen suppression.
<p>(<b>A</b>) Representative FFPE samples of each xenograft were stained with hematoxylin and eosin (H&E) and for expression of the androgen receptor (AR) and PSA as indicated. The scale bar (depicted on the PSA figures for ease of visualization) are 50µm. Kaplan-Meier plots of progression free survival (defined as tumor size <750 mm<sup>3</sup>) in mice bearing LuCaP35 (<b>B</b>) or LuCaP96 (<b>C</b>) xenografts. Intact male SCID mice were implanted subcutaneously with 30 mm<sup>3</sup> pieces of the indicated xenografts. When tumors reached ∼300 mm<sup>3</sup>, mice were randomly enrolled into cohorts that were either left intact (No Cx) or castrated (Cx). P-values for curve comparisons were generated using the Mantel-Haenszel logrank test. (<b>D</b>) Mean and standard deviation of tissue testosterone (T, black bar) and DHT (gray bar) levels measured by mass spectrometry in tumors of the indicated xenograft (passaged in intact mice). (<b>E</b>) Relative expression of transcripts for the indicated steroidogenic genes was calculated using the delta dCt method (fold change = 2∧ddCt). Genes differentially expressed in LuCaP35 vs. LuCaP96 within one order of magnitude are indicated within the gray lines. Significant differences (by Welch’s t test; p<0.05) are indicated by black circles; white circles indicate genes that were not significantly different between LuCaP35 and LuCaP96 (all values given in Supplementary Data 2).Upward triangles indicate highly differentially expressed genes specifically leading to increased T (AKR1C3, 40 fold) or increased DHT levels (SRD5A1, 5.0 fold; 17BHSD10 4.8 fold; RLHSD, 99 fold). Downward triangles indicate highly differentially expressed genes specifically mediating DHT catabolism (AKR1C2, 7 fold; UGT2B15, 3000 fold).</p
Androgen levels and AR expression in prostate cancer xenografts treated with castration and dutasteride.
<p>Tissue testosterone (T, black bars) and DHT (gray bars) levels were measured by mass spectrometry in LuCaP35 (<b>A</b>) and LuCap96 (<b>B</b>) tumors resected from intact mice (No Cx), and from mice treated with castration alone (Cx) or castration + dutasteride (Cx+Dut) at early time points (d3-21, while still on therapy, indicated by double-headed arrows), or at castration-resistant re-growth (defined as >750 mm<sup>3</sup>). P values computed from Welch’s two sample t test (p<0.05 were considered significant). Single stars indicate a statistically significant difference in DHT levels between Cx vs. Cx+Dut treated samples at d3-21 of treatment. Double stars indicate a significant difference in DHT levels between Cx vs. Cx+Dut treated samples even after castration-recurrent re-growth. No other comparisons between Cx vs. Cx + Dut treated groups were significant. Expression of full length (FL) AR and the AR variant 7 (ARV7) truncated splice variant was measured in LuCaP35 (<b>C</b>) and LuCaP96 (<b>D</b>) at the time of tumor re-growth to 750 mm<sup>3</sup>. Transcript expression was measured by qRT-PCR and normalized to expression of the housekeeping gene RPL13A within each sample to yield the delta cycle threshold (dCt). The relative difference in expression between the indicated treatment groups was calculated using the delta dCt method (fold change = 2∧ddCt). P values computed from Welch’s two sample t test (p<0.05 were considered significant).</p