Conditional cancer-specific mortality in T4, N1, or M1 prostate cancer: implications for long-term prognosis

Background: The risk of prostate cancer-specific mortality (PCSM) following a diagnosis of prostate cancer may improve after patients have survived a number of years after diagnosis. We sought to determine long-term conditional PCSM for patients with stage T4, N1, or M1 prostate cancer. Methods: We identified 66,817 patients diagnosed with stage IV (T4N0M0, N1M0, or M1) prostate cancer between 1973 and 2011 using the Surveillance, Epidemiology, and End Results (SEER) database. Conditional five-year PCSM was evaluated for each group of patients at 5, 10, and 15 years of survival according to the Fine & Gray model for competing risks after adjusting for tumor grade, age, income level, and marital status. Race-stratified analyses were also performed. Results: There were 13,345 patients with T4 disease, 12,450 patients with N1 disease, and 41,022 patients with M1 disease. Median follow-up among survivors in the three groups was 123 months (range: 0-382 months), 61 months (range: 0-410 months), and 30 months (range: 0-370 months), respectively. Conditional PCSM improved in all three groups over time. Among patients with T4 disease, 5-year PCSM improved from 13.9% at diagnosis to 11.2%, 8.1%, and 6.5% conditioned on 5, 10, or 15 years of survival, respectively (p < 0.001 in all cases). In patients with N1 disease, 5-year PCSM increased within the first five years and decreased thereafter, from 18.9% at diagnosis to 21.4% (p < 0.001), 17.6% (p = 0.055), and 13.8% (p <0.001), respectively. In patients with metastatic disease, 5-year PCSM improved from 57.2% at diagnosis to 41.1%, 28.8%, and 20.8%, respectively (p < 0.001). White race was associated with Conditional mortality after T4, N1, or M1 prostate cancer--2 a greater increase in conditional survival compared to non-white race among those with T4 or N1 disease. Conclusions: While patients with T4, N1, or M1 prostate cancer are never “cured,” their odds of cancer-specific survival increase substantially after they have survived for 5 or more years. Physicians who take care of patients with prostate cancer can use this data to guide follow-up decisions and to counsel newly diagnosed patients and survivors regarding their long-term prognosis

Prostate cancer incidence across stage, NCCN risk groups, and age before and after USPSTF Grade D recommendations against prostateâ specific antigen screening in 2012

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153721/1/cncr32604.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153721/2/cncr32604_am.pd

Genomic and clinical characterization of stromal infiltration markers in prostate cancer

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154519/1/cncr32688_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154519/2/cncr32688.pd

Conservative management of lowâ risk prostate cancer among young versus older men in the United States: Trends and outcomes from a novel national database

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151903/1/cncr32332.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151903/2/cncr32332_am.pd

Influence of Pyruvate Kinase Isoform Expression on Primary Cell Proliferation and Metabolism

Although it has been known for almost 90 years that cancer cells metabolize glucose differently than normal cells, the reason for this difference has been poorly understood and controversial. Unlike healthy cells, which completely oxidize most of their glucose to carbon dioxide, cancer cells metabolize most of their glucose to lactate even in the presence of oxygen. Paradoxically, despite cancer proliferation needing more energy, this metabolism generates less ATP per glucose. This phenomenon, also known as the Warburg Effect, is influenced by the differential isoform expression of pyruvate kinase (PK). PK catalyzes the final step of glycolysis, generating pyruvate and ATP from phosphoenolpyruvate (PEP) and ADP. While many differentiated cells express the M1 isoform (PKM1), cancer cells and other rapidly dividing tissues express the M2 isoform (PKM2). PKM2 has regulatable and overall less activity than PKM1, but it remains unclear how PKM2 benefits rapid proliferation. To study the importance of PKM2 in rapidly dividing cells, we examined the changes to proliferation and metabolism that occur following deletion of PKM2 in primary cells derived from mice harboring a PKM2 conditional allele. We find that acute deletion of PKM2 results in expression of PKM1 and a concomitant arrest in proliferation that is independent of senescence induction and cell death. Co-expression of PKM1 and PKM2 mimics the effect of expressing PKM1 alone, suggesting that gain of PKM1, not loss of PKM2, is responsible for the arrest. Slowed proliferation after exposure of cells to small molecule activators of PKM2 further argues that gain of pyruvate kinase activity is responsible for proliferation arrest. Metabolic flux analysis using U-13C-glucose and mass spectrometry reveals that PKM1 expression reduces flux to specific biosynthetic pathways and increases flux to the TCA cycle. Consistently, U-14C-glucose labeling of CO2 reveals increased glucose oxidation in PKM1-expressing MEFs. Exogenously supplied deoxyribonucleosides were able to rescue the proliferation arrest of PKM1-expressing MEFs. These data suggest that in comparison to PKM1, PKM2 expression promotes anabolism in proliferating cells by favoring metabolic flux that supports nucleotide biosynthesis

Characteristics and national trends of patients receiving treatment of the primary tumor for metastatic prostate cancer☆

Background: We sought to determine temporal trends in the receipt of prostatectomy or locoregional radiation to the prostate for patients with metastatic prostate cancer and to identify predictors of receipt of local treatment. Methods: We identified 39,976 patients with metastatic prostate cancer diagnosed in 2004–2012 using the National Cancer Database (NCDB). We used logistic multivariable regression to determine trends in the receipt of prostate and/or pelvic radiation or radical prostatectomy after adjusting for demographic and clinical factors. Results: Patients with metastatic disease were less likely to receive locoregional treatment over time [7.88% in 2004 vs. 5.53% in 2012, adjusted odds ratio (AOR) = 0.97 per year, 95% confidence interval (CI) = 0.95–0.98; P < 0.001]. Cofactors associated with decreased likelihood for locoregional treatment included older age (AOR = 0.96 per year, 95% CI = 0.96–0.96, P < 0.001) and increased comorbidity level (1 comorbidity: AOR = 0.82, 95% CI = 0.73–0.93, P = 0.001; two or more comorbidities: AOR = 0.49, 95% CI = 0.39–0.61, P < 0.001). Decreasing utilization of both radiation and surgery of the primary site contributed to this trend. More specifically, patients with metastatic disease were less likely to receive radiation to the prostate and/or pelvis over time (5.9% in 2004 vs. 4.2% in 2012, AOR = 0.97 per year, 95% CI = 0.95–0.99, P < 0.001). Similarly, there was a trend toward decreased use of radical prostatectomy (2.17% in 2004 compared to 1.31% in 2012, AOR = 0.96 per year, 95% CI 0.93–0.99, P = 0.01). Conclusion: Despite recent evidence of the possible benefit for locoregional treatment of prostate cancer in the setting of metastatic disease, rates of prostate radiation and radical prostatectomy among this population have actually declined over the 8-year period between 2004 and 2012, suggesting slow adoption of this novel treatment paradigm

Socioeconomic disparities in the receipt of radiation for node-positive prostate cancer

53 Background: Radiation therapy in the setting of node-positive prostate cancer has been controversial, although some recent data suggests a survival benefit to radiation in this setting. We evaluated socioeconomic disparities in the receipt of radiation for node-positive prostate cancer to identify groups that may be less likely to receive this potentially life-saving treatment. Methods: We identified 3,283 patients with N1M0 prostate cancer diagnosed 1982-2011 using the Surveillance, Epidemiology, and End Results database who were treated with radiation or no local therapy. We conducted multivariable logistic regression to determine socioeconomic predictors of not receiving radiation treatment. Results: Several patient and demographic factors were associated with a reduced likelihood of receiving radiation: African American (AA) vs non-AA race (31.7% vs. 37.7%, adjusted odds ratio [AOR] 0.74, p = 0.012); unmarried vs married status (31.9% vs 38.6%, AOR 0.72, p < 0.001); bottom third vs top third in income level (33.7% vs. 39.8%, AOR 0.72, p < 0.001); age over 65 versus < = 65 years (34.6% vs 39.8%, AOR 0.81, p = 0.005); diagnosis before 2000 versus starting in 2000 (31.6% vs 43.5%, AOR 0.56, p < 0.001). In a separate analysis, patients under the age of 65 who had Medicaid or no insurance were less likely than patients with other insurance to receive radiation (43.5% vs 55.9%, OR 0.61, p = 0.041), although on multivariable analysis, no significant association persisted (p = 0.512). Conclusions: African American race, unmarried status, lower income level, older age, and insurance status were all associated with significantly reduced odds of receiving radiation therapy for node-positive prostate cancer compared with no local therapy. Given the accumulating data suggesting that radiation therapy can improve survival in node-positive patients, it is increasingly important to understand the reasons for these treatment disparities so that they can be reduced

Active surveillance and watchful waiting for low-risk prostate cancer in black patients: A population-based analysis

10 Background: Evidence from clinical trials supports conservative management as an acceptable alternative to definitive therapy for low-risk prostate cancer (LRPC). The optimal approach for Black men, however, remains unclear given trial underrepresentation and concern about racial differences in disease aggressiveness. We therefore sought to determine U.S. conservative management utilization rates for Black men with LRPC. Methods: The Surveillance, Epidemiology, and End Results (SEER) Program Prostate with Active Surveillance/Watchful Waiting (AS/WW) Database queried 50,302 LRPC patients (N = 5218 Black), diagnosed from 2010-2015. Trends in AS/WW utilization over time were determined, stratified by race (Black versus non-Black) and number of positive biopsy cores (≤2 versus ≥3). Results: From 2010 to 2015, AS/WW utilization increased from 12.6% to 36.4% among Black men (Ptrend< 0.001) and from 14.8% to 43.3% among non-Black men (Ptrend< 0.001). AS/WW rates reached 52.0% and 57.3% by 2015 for Black (Ptrend< 0.001) and non-Black (Ptrend< 0.001) men with ≤2 positive biopsy cores, respectively. Rates continually increased for all subgroups except Black men with ≥3 positive biopsy cores, where rates plateaued at 22.9% by 2013. Conclusions: In this report from the largest U.S. population of Black LRPC patients with quality assured AS/WW data, AS/WW rates have nearly tripled for Black men from 2010-2015, suggesting AS/WW is viewed as a safe management option in all races

Characteristics of radiation-associated bladder cancer compared to primary bladder cancer

582 Background: Radiation-associated muscle-invasive bladder cancer (RA-MIBC) has been suggested to represent a more aggressive disease variant compared to primary (non-radiation associated) MIBC. We sought to characterize the presentation, patterns of care, and outcomes of RA-MIBC compared to primary MIBC. Methods: We identified 60,117 patients diagnosed with non-metastatic or metastatic MIBC between 1988 and 2015 using the Surveillance, Epidemiology, and End Results (SEER) database and stratified patients based on whether radiation had been administered to a pelvic primary prior to the development of bladder cancer. We used logistic regression to compare rates of chemotherapy, surgery, or radiation for patients with RA-MIBC compared to primary MIBC. We used Fine-Gray competing risks regression to compare adjusted bladder cancer-specific mortality (BCSM) for RA-MIBC and primary MIBC. Results: There were 1,093 patients with RA-MIBC and 59,024 patients with primary MIBC. Patients with RA-MIBC were older compared to patients with primary MIBC (mean age 77.4 years vs 72.4 years, p < 0.001) and more likely to be male (86.8% vs 73.3%, p<0.001). RA-MIBCs were more likely to be high-grade (57.5% vs 47.6%, p<0.001), more likely to have T4 disease at diagnosis (21.0% vs 17.3%, p<0.001), and less likely to be node-positive (4.2% vs 8.1%, p < 0.001). In terms of treatment, non-metastatic primary MIBC patients were more likely to undergo radiation (14.0% vs 3.1%, p<0.001) as well as radiation with cystectomy (1.9% vs 0.8%, p<0.001) compared to those with RA-MIBC. Median survival was significantly shorter for patients with RA-MIBC (13 mo. vs 19 mo.; p<0.001). Conclusions: RA-MIBCs tend to present with higher grade and higher stage disease and are less likely to receive curative treatment. Even when adjusting for stage, grade, and receipt of treatment, patients with RA-MIBC have worse survival compared to those with primary MIBC. These findings raise the possibility that RA-MIBC represents a biologically more aggressive disease compared to primary MIBC. Future research is needed to better understand biological differences between RA-MIBC and primary MIBC and develop improved therapeutics for radiation-associated cancers

Racial disparities in treatment delay among younger men with prostate cancer

Young men (6 months since diagnosis. Of the 89,196 men <= 55 years included, young Black men experienced treatment delays beyond six months more frequently than young White men (7.39% vs. 3.96%; AOR 1.95, 95% CI 1.81-2.09, p < 0.001), a disparity that was greater than that among men ages 56-64 (p(interaction) < 0.001). This result persisted upon restricting the sample to men with private insurance/managed care. The finding that Black men with localized PC experienced treatment delays almost twice as frequently as White men underscores access barriers that may go beyond the direct costs of care