Corbin Jacobs

Prospective Analysis of Ki-67 as an Independent Predictor of Oncologic Outcomes in Patients with High Grade Upper Tract Urothelial Carcinoma

PURPOSE We determined the association of the proliferation marker Ki-67 with pathological parameters and oncologic outcomes in patients with high grade upper tract urothelial carcinoma. MATERIALS AND METHODS Immunohistochemical staining for Ki-67 was done prospectively in 101 consecutive patients undergoing radical nephroureterectomy/ureterectomy for high grade upper tract urothelial carcinoma. Data were compared based on Ki-67 status (normal vs over expressed). Survival was assessed by the Kaplan-Meier method. Cox regression analysis was done to identify independent predictors of time dependent outcomes. RESULTS Median patient age was 70.0 years and median followup was 22.0 months (range 1 to 77). Overall, 30.2% of the population experienced recurrence and 24.8% died of upper tract urothelial carcinoma. Organ confined disease (T2 or less and lymph node negative), lymphovascular invasion and sessile architecture were present in 56.3%, 33.3% and 20.8% of patients, respectively. Ki-67 was over expressed in 73.3% of patients and associated with adverse pathological features. Patients with over expressed Ki-67 had significantly worse recurrence-free survival (43.2 vs 69.0 months, p = 0.006) and cancer specific survival (48.9 vs 68.9 months, p = 0.031) than patients with normal Ki-67. Patients with nonmetastatic disease similarly had worse recurrence-free survival (40.7 vs 71.8 months, p = 0.003) and cancer specific survival (41 months vs not attained, p = 0.008) for over expressed vs normal Ki-67. After adjusting for the effects of organ vs nonorgan confined disease Ki-67 over expression was an independent predictor of recurrence-free survival in the total cohort (HR 4.3, p = 0.05) and in patients with nonmetastatic disease (HR 8.5, p = 0.038). CONCLUSIONS Ki-67 over expression was associated with adverse pathological features in cases of upper tract urothelial carcinoma. It was also an independent predictor of recurrence-free survival in patients with high grade upper tract urothelial carcinoma.

Ablation of a Site of Progression With Stereotactic Body Radiation Therapy Extends Sunitinib Treatment From 14 to 22 Months

Introduction Historically, chemotherapy for clear-cell renal cell carcinoma (ccRCC) has not been effective, and fewer than 25% of patients respond to cytokine therapy. Recommended treatment for patients with advanced ccRCC includes molecularly targeted agents such as sunitinib, a kinase inhibitor that targets vascular endothelial growth factor and platelet-derived growth factor receptors. A randomized phase III study established the benefits of sunitinib over interferon alfa, demonstrating an improvement in median progression-free survival (PFS) from 5 to 11 months and a 31% response rate. When a patient progresses on a systemic agent, the typical course of action is to switch therapies. We present a patient with broadly metastatic ccRCC who experienced progression at a single site while receiving sunitinib. After 14 months of sunitinib treatment, stereotactic body radiation therapy (SBRT) to the progressing metastasis allowed the patient to continue on sunitinib for 8 additional months until progression.

Prolonged Survival of a Patient With Papillary Renal Cell Carcinoma and Brain Metastases Using Pazopanib

Introduction Renal cell carcinoma (RCC) accounts for 80% to 85% of primary neoplasms that arise in the kidney, with an estimated 65,000 new cases and 13,500 deaths each year in the United States. Papillary RCC (PRCC) is the second most common type of RCC with a 5:1 male predominance. PRCC is classified into two groups; type 2 tumors are high grade and associated with a poor prognosis. The prevalence of brain metastases (BM) from RCC ranges from 6% to 10%, and the reported median survival time is 5 months for patients who are treated with whole-brain radiotherapy (WBRT) alone. We present a patient who developed more than 20 BM plus multiple bone, lymph node, and soft tissue metastases roughly one decade after removal of the primary tumor, and who remarkably survived 23 months.

Aspirin improves outcome in high risk prostate cancer patients treated with radiation therapy

Purpose High-risk prostate cancer (PC) has poor outcomes due to therapeutic resistance to conventional treatments, which include prostatectomy, radiation, and hormone therapy. Previous studies suggest that anticoagulant (AC) use may improve treatment outcomes in PC patients. We hypothesized that AC therapy confers a freedom from biochemical failure (FFBF) and overall survival (OS) benefit when administered with radiotherapy in patients with high-risk PC. Materials and Methods Analysis was performed on 74 high-risk PC patients who were treated with radiotherapy from 2005 to 2008 at UT Southwestern. Of these patients, 43 were on AC including aspirin (95.6%), clopidogrel (17.8%), warfarin (20%), and multiple ACs (31.1%). Associations between AC use and FFBF, OS, distant metastasis, and toxicity were analyzed. Results Median follow-up was 56.6 mo for all patients. For patients taking any AC compared with no AC, there was improved FFBF at 5 years of 80% vs. 62% (P = 0.003), and for aspirin the FFBF was 84% vs. 65% (P = 0.008). Aspirin use was also associated with reduced rates of distant metastases at 5 years (12.2% vs. 26.7%, P = 0.039). On subset analysis of patients with Gleason score (GS) 9–10 histology, aspirin resulted in improved 5-year OS (88% vs. 37%, P = 0.032), which remained significant on multivariable analysis (P < 0.05). Conclusions AC use was associated with a FFBF benefit in high-risk PC which translated into an OS benefit in the highest risk PC patients with GS 9–10, who are most likely to experience mortality from PC. This hypothesis-generating result suggests AC use may represent an opportunity to augment current therapy.

DOC-2/DAB2 Interacting Protein Status in High-Risk Prostate Cancer Correlates With Outcome for Patients Treated With Radiation Therapy

PURPOSE This pilot study investigates the role of DOC-2/DAB2 Interacting Protein (DAB2IP) and enhancer of zeste homolog 2 (EZH2) as prognostic biomarkers in high-risk prostate cancer patients receiving definitive radiation therapy. METHODS AND MATERIALS Immunohistochemistry was performed and scored by an expert genitourinary pathologist. Clinical endpoints evaluated were freedom from biochemical failure (FFBF), castration resistance-free survival (CRFS), and distant metastasis-free survival (DMFS). Log-rank test and Cox regression were used to determine significance of biomarker levels with clinical outcome. RESULTS Fifty-four patients with high-risk prostate cancer (stage ≥ T3a, or Gleason score ≥ 8, or prostate-specific antigen level ≥ 20 ng/mL) treated with radiation therapy from 2005 to 2012 at our institution were evaluated. Nearly all patients expressed EZH2 (98%), whereas 28% of patients revealed DAB2IP reduction and 72% retained DAB2IP. Median follow-up was 34.0 months for DAB2IP-reduced patients, 29.9 months for DAB2IP-retained patients, and 32.6 months in the EZH2 study. Reduction in DAB2IP portended worse outcome compared with DAB2IP-retained patients, including FFBF (4-year: 37% vs 89%, P=.04), CRFS (4-year: 50% vs 90%, P=.02), and DMFS (4-year: 36% vs 97%, P=.05). Stratified EZH2 expression trended toward significance for worse FFBF and CRFS (P=.07). Patients with reduced DAB2IP or highest-intensity EZH2 expression exhibited worse FFBF (4-year: 32% vs 95%, P=.02), CRFS (4-year: 28% vs 100%, P<.01), and DMFS (4-year: 39% vs 100%, P=.04) compared with the control group. CONCLUSION Loss of DAB2IP is a potent biomarker that portends worse outcome despite definitive radiation therapy for patients with high-risk prostate cancer. Enhancer of zeste homolog 2 is expressed in most high-risk tumors and is a less potent discriminator of outcome in this study. The DAB2IP status in combination with degree of EZH2 expression may be useful for determining patients with worse outcome within the high-risk prostate cancer population.

Pretreatment biopsy analysis of DAB2IP identifies subpopulation of high-risk prostate cancer patients with worse survival following radiation therapy.

Decreased expression of tumor suppressor DAB2IP is linked to aggressive cancer and radiation resistance in several malignancies, but clinical survival data is largely unknown. We hypothesized that pretreatment DAB2IP reduction would predict worse prostate cancer‐specific survival (PCSS). Immunohistochemistry of pretreatment biopsies was scored by an expert genitourinary pathologist. Other endpoints analyzed include freedom from biochemical failure (FFBF), castration resistance‐free survival (CRFS), and distant metastasis‐free survival (DMFS). Seventy‐nine patients with NCCN‐defined high‐risk prostate cancer treated with radiotherapy from 2005 to 2012 at our institution were evaluated. Twenty‐eight percent (22/79) of pretreatment biopsies revealed DAB2IP‐reduction. The median follow up times were 4.8 years and 5.3 years for patients in the DAB2IP‐reduced group and DAB2IP‐retained group, respectively. Patients with reduced DAB2IP demonstrated worse outcome compared to patients retaining DAB2IP, including FFBF (4‐year: 34 vs. 92%; P < 0.0001), CRFS (4‐year: 58 vs. 96%; P = 0.0039), DMFS (4‐year: 58 vs. 100%; P = 0.0006), and PCSS (5‐year: 83 vs. 100%; P = 0.0102). Univariate analysis showed T stage, N stage, and Gleason score were statistically significant variables. Pretreatment tumor DAB2IP status remained significant in multivariable analyses. This study suggests that about one‐fourth of men with high‐risk prostate cancer have decreased tumor expression of DAB2IP. This subpopulation with reduced DAB2IP has a suboptimal response and worse malignancy‐specific survival following radiation therapy and androgen deprivation. DAB2IP loss may be a genetic explanation for the observed differences in aggressive tumor characteristics and radiation resistance. Further study into improving treatment response and survival in this subpopulation is warranted.