Akash Nanda

Hormonal Therapy Use for Prostate Cancer and Mortality in Men With Coronary Artery Disease–Induced Congestive Heart Failure or Myocardial Infarction

CONTEXT Hormonal therapy (HT) when added to radiation therapy (RT) for treating unfavorable-risk prostate cancer leads to an increase in survival except possibly in men with moderate to severe comorbidity. However, it is unknown which comorbid conditions eliminate this survival benefit. OBJECTIVE To assess whether neoadjuvant HT use affects the risk of all-cause mortality in men with prostate cancer and coronary artery disease (CAD)-induced congestive heart failure (CHF) or myocardial infarction (MI), CAD risk factors, or no comorbidity. DESIGN, SETTING, AND PATIENTS A total of 5077 men (median age, 69.5 years) with localized or locally advanced prostate cancer were consecutively treated with or without a median of 4 months of neoadjuvant HT followed by RT at a suburban cancer center between 1997 and 2006 and were followed up until July 1, 2008. Cox regression multivariable analyses were performed assessing whether neoadjuvant HT use affected the risk of all-cause mortality, adjusting for age, year and type of RT, treatment propensity score, and known prostate cancer prognostic factors in each comorbidity group. MAIN OUTCOME MEASURE Risk of all-cause mortality. RESULTS Neoadjuvant HT use was not associated with an increased risk of all-cause mortality in men with no comorbidity (9.6% vs 6.7%, adjusted hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.72-1.32; P = .86) or a single CAD risk factor (10.7% vs 7.0%, adjusted HR, 1.04; 95% CI, 0.75-1.43; P = .82) after median follow-ups of 5.0 and 4.4 years, respectively. However, for men with CAD-induced CHF or MI, after a median follow-up of 5.1 years, neoadjuvant HT use was significantly associated with an increased risk of all-cause mortality (26.3% vs 11.2%, adjusted HR, 1.96; 95% CI, 1.04-3.71; P = .04). CONCLUSION Neoadjuvant HT use is significantly associated with an increased risk of all-cause mortality among men with a history of CAD-induced CHF or MI but not among men with no comorbidity or a single CAD risk factor.

TEM8 Interacts with the Cleaved C5 Domain of Collagen α3(VI)

Tumor endothelial marker (TEM)8 was uncovered as a gene expressed predominantly in tumor endothelium, and its protein product was recently identified as the receptor for anthrax toxin. Here, we demonstrate that TEM8 protein is preferentially expressed in endothelial cells of neoplastic tissue. We used the extracellular domain of TEM8 to search for ligands and identified the α3 subunit of collagen VI as an interacting partner. The TEM8-interacting region on collagen α3(VI) was mapped to its COOH-terminal C5 domain. Remarkably, collagen α3(VI) is also preferentially expressed in tumor endothelium in a pattern concordant with that of TEM8. These results suggest that the TEM8/C5 interaction may play an important biological role in tumor angiogenesis.

Tumor endothelial markers: new targets for cancer therapy.

Purpose of review Targeting the endothelial cells that line tumor infiltrating blood vessels is a new anticancer strategy that has gained widespread support from biologists and clinicians. Here we highlight different approaches currently being used to target tumor endothelium and discuss new avenues for intervention that have been opened through the recent identification of tumor endothelial markers (TEMs). Recent findings The ability of Avastin to prolong survival in a Phase III clinical trial of human colorectal cancer has established the validity of the anti-angiogenic approach. However, realization of the full potential of a vascular targeting strategy may require the exploitation of molecules which are highly restricted in expression to tumor endothelium. Here we explore the potential of TEMs as new targets for cancer therapy. Current knowledge of these markers and their relation to other family members in the context of tumor angiogenesis is discussed. In particular, we highlight those molecules which, by virtue of their structure, cell-surface location and expression pattern, appear to hold promise as targets for future drug development. The identification of TEM8 as the anthrax toxin receptor and the successful targeting of this receptor in preclinical tumor models make this molecule a particularly attractive candidate for future vascular targeting studies. Summary Technological advances in cellular fractionation and genomics enabled the identification of several markers preferentially expressed on human tumor endothelium. Studies of these TEMs are expected to aid in our understanding of angiogenesis and could lead to the development of new imaging and diagnostic agents for cancer.

EGF Receptor Inhibition Radiosensitizes NSCLC Cells by Inducing Senescence in Cells Sustaining DNA Double-Strand Breaks

The mechanisms by which inhibition of the epidermal growth factor receptor (EGFR) sensitizes non-small cell lung cancer (NSCLC) cells to ionizing radiation remain poorly understood. We set out to characterize the radiosensitizing effects of the tyrosine kinase inhibitor erlotinib and the monoclonal antibody cetuximab in NSCLC cells that contain wild-type p53. Unexpectedly, EGFR inhibition led to pronounced cellular senescence but not apoptosis of irradiated cells, both in vitro and in vivo. Senescence was completely dependent on wild-type p53 and associated with a reduction in cell number as well as impaired clonogenic radiation survival. Study of ten additional NSCLC cell lines revealed that senescence is a prominent mechanism of radiosensitization in 45% of cell lines and occurs not only in cells with wild-type p53 but also in cells with mutant p53, where it is associated with an induction of p16. Interestingly, senescence and radiosensitization were linked to an increase in residual radiation-induced DNA double-strand breaks irrespective of p53/p16 status. This effect of EGFR inhibition was at least partially mediated by disruption of the MEK-ERK pathway. Thus, our data indicate a common mechanism of radiosensitization by erlotinib or cetuximab across diverse genetic backgrounds. Our findings also suggest that assays that are able to capture the initial proliferative delay that is associated with senescence should be useful for screening large cell line panels to identify genomic biomarkers of EGFR inhibitor-mediated radiosensitization.

Gleason Pattern 5 prostate cancer: further stratification of patients with high-risk disease and implications for future randomized trials

PURPOSE To compare prostate-specific antigen (PSA) outcomes in a cohort of men with high-risk prostate cancer based on the presence or absence of any Gleason Grade 5 component (primary, secondary, or tertiary). METHODS AND MATERIALS Our study cohort consisted of 312 men with T1c-T3N0M0 prostate cancer with Gleason Scores of 7 with tertiary Grade 5, 8, or 9-10 who underwent radical prostatectomy or external beam radiotherapy with or without androgen suppression therapy. Cox regression multivariable analysis was used to assess whether a difference existed in risk of PSA recurrence in men with Gleason Score of 9-10 compared with those with Gleason Score of 8 and 7 with tertiary Grade 5, adjusting for treatment, age, and known prostate cancer prognostic factors. RESULTS After a median follow-up of 5.7 years, men with a Gleason Score of 8 had a lower risk of PSA recurrence than those with a Gleason Score of 9-10 (hazard ratio, 0.74; 95% confidence interval, 0.52-1.05; p = 0.09). Conversely, men with a Gleason Score of 7 with tertiary Grade 5 had a similar risk of PSA recurrence compared with men with a Gleason Score of 9-10 (hazard ratio, 1.08; 95% confidence interval, 0.60-1.94; p = 0.81). Median times to PSA failure for men with Gleason Scores of 9-10, 7 with tertiary Grade 5, and 8 were 4.5, 5.0, and 5.4 years, respectively. CONCLUSIONS Our results highlight the importance of further substratification of the high-risk Gleason Score category of 8-10 into 8 vs. 9, 10, and 7 with tertiary Grade 5.

Identification of a Binding Partner for the Endothelial Cell Surface Proteins TEM7 and TEM7R

Tumor endothelial marker 7 (TEM7) was recently identified as an mRNA transcript overexpressed in the blood vessels of human solid tumors. Here, we identify several new variants of TEM7, derived by alternative splicing, that are predicted to be intracellular (TEM7-I), secreted (TEM7-S), or on the cell surface membrane (TEM7-M) of tumor endothelium. Using new antibodies against the TEM7 protein, we confirmed the predicted expression of TEM7 on the cell surface and demonstrated that TEM7-M protein, like its mRNA, is overexpressed on the endothelium of various tumor types. We then used an affinity purification strategy to search for TEM7-binding proteins and identified cortactin as a protein capable of binding to the extracellular region of both TEM7 and its closest homologue, TEM7-related (TEM7R), which is also expressed in tumor endothelium. The binding domain of cortactin was mapped to a unique nine-amino acid region in its plexin-like domain. These studies establish the overexpression of TEM7 protein in tumor endothelium and provide new opportunities for the delivery of therapeutic and imaging agents to the vessels of solid tumors.

Unusual tumor response and toxicity from radiation and concurrent erlotinib for non-small-cell lung cancer.

We report a case of a never-smoker female with non-small-cell lung cancer (NSCLC) who experienced a striking tumor response to combined low-dose radiation and the epidermal growth factor receptor inhibitor erlotinib, even though erlotinib alone was not effective in preventing tumor progression. Furthermore, the patient developed symptomatic pneumonitis, which is unusual for the small volume of lung that was exposed to a significant dose of radiation. This case demonstrates that combination therapy with radiation and erlotinib has the potential to significantly benefit a subset of patients with NSCLC in addition to those approximately 10% who have tumors which respond to erlotinib alone. It also highlights the potential risks of molecular targeted radiation therapy.

Neoadjuvant Hormonal Therapy Use and the Risk of Death in Men with Prostate Cancer Treated with Brachytherapy Who Have No or at Least a Single Risk Factor for Coronary Artery Disease

BACKGROUND Neoadjuvant hormone therapy (NHT) use is associated with an increased risk of all-cause mortality (ACM) in men with a history of coronary artery disease (CAD)-induced congestive heart failure (CHF) or myocardial infarction (MI). However, its effect in men with no or at least a single risk factor for CAD stratified by prostate cancer (PCa) aggressiveness is unknown. OBJECTIVE To assess whether NHT use affects the risk of ACM in men with low-, intermediate-, and high-risk PCa treated with brachytherapy who have no or at least a single risk factor for CAD. DESIGN, SETTING, AND PARTICIPANTS This retrospective study cohort consisted of 5411 men with low-risk PCa (prostate-specific antigen [PSA] <10 ng/ml, Gleason score 6, and clinical stage T1-T2a); 4365 men with intermediate-risk PCa (PSA 10-20 ng/ml or Gleason score <8 or clinical stage <T3); and 1360 men with localized or locally advanced, high-risk PCa consecutively treated in a community-based, multi-institutional setting between 1991 and 2006. CAD risk factors included at least a history of diabetes mellitus, hypercholesterolemia, or hypertension. The median follow-up for men with low-, intermediate-, and high-risk PCa were 4.1, 4.4, and 4.6 yr, respectively. INTERVENTIONS Men were treated with or without a median duration of 4 mo of NHT followed by brachytherapy with or without supplemental external-beam radiation therapy (EBRT). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Cox regression multivariable analyses were performed to assess whether NHT use affected the risk of ACM in men with low-, intermediate-, and high-risk PCa, adjusting for age; year of brachytherapy; supplemental EBRT use; the presence of CAD risk factors; treatment propensity score; and known PCa prognostic factors, including pretreatment PSA level, biopsy Gleason score, and clinical stage. RESULTS AND LIMITATIONS NHT use was associated with a significantly increased risk of ACM in men with low-risk PCa (adjusted hazard ratio [HR]: 1.27; 95% confidence interval [CI], 1.07-1.51; p<0.01) but not in men with intermediate-risk (adjusted HR: 1.13; 95% CI, 0.96-1.35; p=0.15) or high-risk PCa (adjusted HR: 0.86; 95% CI, 0.66-1.13; p=0.28). Using an interaction model for the low-risk group, NHT use was associated with a significantly increased risk of ACM in the subgroup of men with at least a single CAD risk factor (adjusted HR: 1.36; 95% CI, 1.07-1.74; p=0.01) but not for men with no CAD risk factors (adjusted HR: 1.19; 95% CI, 0.95-1.51; p=0.13). CONCLUSIONS For men with no or at least a single risk factor for CAD, NHT use is associated with an increased risk of ACM in the setting of low-risk but not intermediate- or high-risk PCa. This effect is driven by the subgroup of men with at least a single risk factor for CAD. These results warrant prospective validation given the widespread use of NHT for prostate downsizing prior to brachytherapy.

Predictors of Prostate Cancer-Specific Mortality in Elderly Men With Intermediate-Risk Prostate Cancer Treated With Brachytherapy With or Without External Beam Radiation Therapy

PURPOSE To identify clinical factors associated with prostate cancer-specific mortality (PCSM), adjusting for comorbidity, in elderly men with intermediate-risk prostate cancer treated with brachytherapy alone or in conjunction with external beam radiation therapy. METHODS AND MATERIALS The study cohort comprised 1,978 men of median age 71 (interquartile range, 66-75) years with intermediate-risk disease (Gleason score 7, prostate-specific antigen (PSA) 20 ng/mL or less, tumor category T2c or less). Fine and Grays multivariable competing risks regression was used to assess whether prevalent cardiovascular disease (CVD), age, treatment, year of brachytherapy, PSA level, or tumor category was associated with the risk of PCSM. RESULTS After a median follow-up of 3.2 (interquartile range, 1.7-5.4) years, the presence of CVD was significantly associated with a decreased risk of PCSM (adjusted hazard ratio, 0.20; 95% CI 0.04-0.99; p = 0.05), whereas an increasing PSA level was significantly associated with an increased risk of PCSM (adjusted hazard ratio 1.14; 95% CI 1.02-1.27; p = 0.02). In the absence of CVD, cumulative incidence estimates of PCSM were higher (p = 0.03) in men with PSA levels above as compared with the median PSA level (7.3 ng/mL) or less; however, in the setting of CVD there was no difference (p = 0.27) in these estimates stratified by the median PSA level (6.9 ng/mL). CONCLUSIONS In elderly men with intermediate-risk prostate cancer, CVD status is a negative predictor of PCSM and affects the prognostic capacity of pretreatment PSA level. These observations support the potential utility of prerandomization stratification by comorbidity to more accurately assess prognostic factors and treatment effects within this population.

Cardiovascular Comorbidity and Mortality in Men With Prostate Cancer Treated With Brachytherapy-Based Radiation With or Without Hormonal Therapy

PURPOSE To assess the impact of coronary artery disease (CAD) risk factors and sequelae on the risk of all-cause mortality (ACM) in men treated for prostate cancer (PC). METHODS AND MATERIALS The study cohort comprised 5077 men with PC consecutively treated with curative intent between 1997 and 2006 at the Chicago Prostate Cancer Center. Cox and Fine and Grays competing risks regression multivariable analyses were performed, assessing whether cardiovascular comorbidity impacted the risk of ACM and PC-specific mortality, respectively, adjusting for CAD risk factors (diabetes mellitus, hypercholesterolemia, or hypertension) and sequelae (congestive heart failure or myocardial infarction), age, year and type of treatment, and known PC prognostic factors. RESULTS When compared with men with no comorbidity there was a significantly increased risk of ACM in men with congestive heart failure or myocardial infarction (adjusted hazard ratio [AHR] 1.96, P<.001) and in men with diabetes mellitus (AHR 1.60, P=.03) and hypertension (AHR 1.25, P=.04). In contrast, men with hypercholesterolemia had a similar risk of ACM (AHR 0.68, P=.17) when compared with men with no comorbidity. Other factors associated with a significantly increased risk of ACM included age (AHR 1.09, P<.001), prostate-specific antigen level (AHR 1.25, P=.008), and Gleason score 8-10 disease (AHR 1.71, P=.003). Cardiovascular comorbidity did not impact the risk of PC-specific mortality. CONCLUSIONS In addition to age and unfavorable PC prognostic factors, select CAD risk factors and sequelae are associated with an increased risk of ACM in men treated for PC. These comorbidity prognostic factors predict time courses of mortality from competing causes, which may be factored into the decision-making process when considering management options for PC in a given individual.