Person:

Muralidhar, Vinayak

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.

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.

Purpose Recent retrospective data suggest that brachytherapy (BT) boost may confer a cancer-specific survival benefit in radiation-managed high-risk prostate cancer. We sought to determine whether this survival benefit would extend to the recently defined favorable high-risk subgroup of prostate cancer patients (T1c, Gleason 4 + 4 = 8, PSA < 10 ng/ml or T1c, Gleason 6, PSA > 20 ng/ml). Material and methods We identified 45,078 patients in the Surveillance, Epidemiology, and End Results database with cT1c-T3aN0M0 intermediate- to high-risk prostate cancer diagnosed 2004-2011 treated with external beam radiation therapy (EBRT) only or EBRT plus BT. We used multivariable competing risks regression to determine differences in the rate of prostate cancer-specific mortality (PCSM) after EBRT + BT or EBRT alone in patients with intermediate-risk, favorable high-risk, or other high-risk disease after adjusting for demographic and clinical factors. Results: EBRT + BT was not associated with an improvement in 5-year PCSM compared to EBRT alone among patients with favorable high-risk disease (1.6% vs. 1.8%; adjusted hazard ratio [AHR]: 0.56; 95% confidence interval [CI]: 0.21-1.52, p = 0.258), and intermediate-risk disease (0.8% vs. 1.0%, AHR: 0.83, 95% CI: 0.59-1.16, p = 0.270). Others with high-risk disease had significantly lower 5-year PCSM when treated with EBRT + BT compared with EBRT alone (3.9% vs. 5.3%; AHR: 0.73; 95% CI: 0.55-0.95; p = 0.022). Conclusions: Brachytherapy boost is associated with a decreased rate of PCSM in some men with high-risk prostate cancer but not among patients with favorable high-risk disease. Our results suggest that the recently-defined “favorable high-risk” category may be used to personalize therapy for men with high-risk disease.