Rana R. McKay

Impact of Bone and Liver Metastases on Patients with Renal Cell Carcinoma Treated with Targeted Therapy

BACKGROUND The skeleton and liver are frequently involved sites of metastasis in patients with metastatic renal cell carcinoma (RCC). OBJECTIVE To analyze outcomes based on the presence of bone metastases (BMs) and/or liver metastases (LMs) in patients with RCC treated with targeted therapy. DESIGN, SETTING, AND PARTICIPANTS We conducted a review from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) of 2027 patients with metastatic RCC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We analyzed the impact of the site of metastasis on overall survival (OS) and time-to-treatment failure. Statistical analyses were performed using multivariable Cox regression. RESULTS AND LIMITATIONS The presence of BMs was 34% overall, and when stratified by IMDC risk groups was 27%, 33%, and 43% in the favorable-, intermediate-, and poor-risk groups, respectively (p<0.001). The presence of LMs was 19% overall and higher in the poor-risk patients (23%) compared with the favorable- or intermediate-risk groups (17%) (p=0.003). When patients were classified into four groups based on the presence of BMs and/or LMs, the hazard ratio, adjusted for IMDC risk factors, was 1.4 (95% confidence interval [CI], 1.22-1.62) for BMs, 1.42 (95% CI, 1.17-1.73) for LMs, and 1.82 (95% CI, 1.47-2.26) for both BMs and LMs compared with other metastatic sites (p<0.0001). The prediction model performance for OS was significantly improved when BMs and LMs were added to the IMDC prognostic model (likelihood ratio test p<0.0001). Data in this analysis were collected retrospectively. CONCLUSIONS The presence of BMs and LMs in patients treated with targeted agents has a negative impact on survival. Patients with BMs and/or LMs may benefit from earlier inclusion on clinical trials of novel agents or combination-based therapies.

Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway

VEGF signaling pathway inhibitor (anti‐VEGF) therapy is associated with hypertension, but little is known about predisposing clinical characteristics. This study describes the real‐world association between baseline clinical characteristics, blood pressure (BP) response, and survival in patients prescribed anti‐VEGF therapies.

Angiotensin System Inhibitors and Survival Outcomes in Patients with Metastatic Renal Cell Carcinoma

Purpose: The renin-angiotensin system may play a role in carcinogenesis. The purpose of this study was to evaluate the impact of angiotensin system inhibitors (ASI) on outcomes in metastatic renal cell carcinoma (mRCC) patients treated in the targeted therapy era. Experimental Design: We conducted a pooled analysis of mRCC patients treated on phase II and III clinical trials. Statistical analyses were performed using Cox regression adjusted for several risk factors and the Kaplan–Meier method. Results: A total of 4,736 patients were included, of whom 1,487 received ASIs and 783 received other antihypertensive agents. Overall, ASI users demonstrated improved overall survival (OS) compared with users of other antihypertensive agents (adjusted HR, 0.838, P = 0.0105, 26.68 vs. 18.07 months) and individuals receiving no antihypertensive therapy (adjusted HR, 0.810, P = 0.0026, 26.68 vs. 16.72 months). When stratified by therapy type, a benefit in OS was demonstrated in ASI users compared with nonusers in individuals receiving VEGF therapy (adjusted HR, 0.737, P < 0.0001, 31.12 vs. 21.94 months) but not temsirolimus or IFNα. An in vitro cell viability assay demonstrated that sunitinib in combination with an ASI significantly decreased RCC cell viability compared with control at physiologically relevant doses. This effect was not observed with either agent alone or with other non-ASI antihypertensives or temsirolimus. Conclusions: In the largest analysis to date, we demonstrate that ASI use improved survival in mRCC patients treated in the targeted therapy era. Further studies are warranted to investigate the mechanism underlying this interaction and verify our observations to inform clinical practice. Clin Cancer Res; 21(11); 2471–9. ©2015 AACR.

Depth of remission is a prognostic factor for survival in patients with metastatic renal cell carcinoma.

BACKGROUND Response remains an important endpoint in clinical cancer trials. However, the prognostic utility of best tumor response in metastatic renal cell carcinoma (mRCC) remains vague. OBJECTIVE To define the prognostic relevance of the depth of remission in mRCC. DESIGN, SETTING, AND PARTICIPANTS Pooled data from the Pfizer database for 2749 patients from phase 2 and 3 clinical trials in mRCC were analyzed. Tumor shrinkage was categorized according to the best percentage change in the sum of the largest diameter of target lesions. Outcome was computed using Kaplan-Meier curves and correlation was assessed via Cox regression, including a 6-mo landmark. INTERVENTION Sunitinib, sorafenib, axitinib, temsirolimus, or temsirolimus and interferon-α. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Categorized tumor shrinkage, overall survival (OS), progression free survival (PFS). RESULTS AND LIMITATIONS Major tumor shrinkage of 60% or more occurred in approximately 10% of patients and was associated with median OS of 54.5 mo. OS expectations steadily decreased with depth of remission (26.4, 16.6, 10.4, and 7.3 mo). The association was maintained when stratified by type of therapy, line of therapy, and performance status. Cox proportional regression analyses for the 6-mo landmark confirmed the prognostic relevance of major tumor shrinkage (hazard ratio 0.29, 95% confidence interval 0.22-0.39; p<0.001). The major limitation of our study is the variability of imaging intervals among studies. CONCLUSIONS This is the first and largest analysis of best tumor response in mRCC. We demonstrate that depth of remission is an independent prognostic factor in mRCC. PATIENT SUMMARY It remains unknown whether tumor shrinkage during therapy is needed to achieve clinical activity in metastatic renal cell carcinoma. Our analysis shows that the magnitude of tumor shrinkage correlates with better survival in patients. This observation may be used as a clinical research tool in future trials. TRIAL REGISTRATION NCT00054886, NCT00077974, NCT00267748, NCT00338884, NCT00137423, NCT00083889, NCT00065468, NCT00678392.

Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor‐risk metastatic renal cell carcinoma

Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poor‐risk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor‐risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC.

Prognostic Significance of Bone Metastases and Bisphosphonate Therapy in Patients with Renal Cell Carcinoma

BACKGROUND Bone metastases (BMs) are frequently present in patients with metastatic renal cell carcinoma (mRCC) and cause significant morbidity. OBJECTIVE The purpose of this analysis was to assess the impact of BMs and bisphosphonate therapy (BT) on outcomes in mRCC. DESIGN, SETTING, AND PARTICIPANTS We conducted a pooled analysis of patients with mRCC treated from 2003 to 2011 in phase 2 and 3 trials. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Statistical analyses were performed using Cox regression and the Kaplan-Meier method. RESULTS AND LIMITATIONS We identified 2749 patients treated with sunitinib (n=1059), sorafenib (n=355), axitinib (n=359), temsirolimus (n=208), temsirolimus plus interferon-α (IFN-α) (n=208), or IFN-α (n=560), with 28% (n=781) having BMs. A total of 285 patients (10.4%) received BT. The presence of BMs in patients was associated with shorter overall survival (OS) when compared with patients without BMs (13.2 vs 20.2 mo, respectively; p<0.0001) and shorter progression-free survival (PFS) (5.1 vs 6.7 mo, respectively; p<0.0008). When stratified by risk groups, the presence of BMs was associated with shorter OS in all risk groups. The use of BT in patients with BMs was not associated with improved OS compared with patients who did not receive BT (13.3 vs 13.1 mo, respectively; p=0.3801) or improved PFS (5.1 vs 4.9 mo, respectively; p=0.1785). Bisphosphonate users with BMs did not have a decreased rate of skeletal-related events (SREs) compared with nonusers (8.6% vs 5.8%, respectively; p=0.191). In addition, BT was associated with increased rates of hypocalcemia, renal insufficiency, and osteonecrosis of the jaw (p<0.0001). Data were analyzed retrospectively. CONCLUSIONS We confirm that the presence of BMs is associated with shorter survival in mRCC. BT did not affect survival or SRE prevention and was associated with increased toxicity. PATIENT SUMMARY In this analysis, we demonstrate that bone metastases are associated with shorter survival in patients with metastatic renal cell carcinoma. In addition, we call into question the utility of bisphosphonate therapy in this population.

Cytoreductive nephrectomy in patients with metastatic non-clear-cell renal cell carcinoma (RCC).

To determine whether patients with metastatic non‐clear‐cell renal cell carcinoma (RCC) benefit from cytoreductive nephrectomy (CN).

Body Mass Index and Metastatic Renal Cell Carcinoma: Clinical and Biological Correlations.

PURPOSE Obesity is an established risk factor for clear cell renal cell carcinoma (RCC); however, some reports suggest that RCC developing in obese patients may be more indolent. We investigated the clinical and biologic effect of body mass index (BMI) on treatment outcomes in patients with metastatic RCC. METHODS The impact of BMI (high BMI: ≥ 25 kg/m2 v low BMI: < 25 kg/m2) on overall survival (OS) and treatment outcome with targeted therapy was investigated in 1,975 patients from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and in an external validation cohort of 4,657 patients. Gene expression profiling focusing on fatty acid metabolism pathway, in The Cancer Genome Atlas data set, and immunohistochemistry staining for fatty acid synthase (FASN) were also investigated. Cox regression was undertaken to estimate the association of BMI with OS, adjusted for the IMDC prognostic factors. RESULTS In the IMDC cohort, median OS was 25.6 months (95% CI, 23.2 to 28.6) in patients with high BMI versus 17.1 months (95% CI, 15.5 to 18.5) in patients with low BMI (adjusted hazard ratio, 0.84; 95% CI, 0.73 to 0.95). In the validation cohort, high BMI was associated with improved OS (adjusted hazard ratio, 0.83; 95% CI, 0.74 to 0.93; medians: 23.4 months [95% CI, 21.9 to 25.3 months] v 14.5 months [95% CI, 13.8 to 15.9 months], respectively). In The Cancer Genome Atlas data set (n = 61), FASN gene expression inversely correlated with BMI (P = .034), and OS was longer in the low FASN expression group (medians: 36.8 v 15.0 months; P = .002). FASN immunohistochemistry positivity was more frequently detected in IMDC poor (48%) and intermediate (34%) risk groups than in the favorable risk group (17%; P-trend = .015). CONCLUSION High BMI is a prognostic factor for improved survival and progression-free survival in patients with metastatic RCC treated with targeted therapy. Underlying biology suggests a role for the FASN pathway.

Programmed death ligand-1 expression in adrenocortical carcinoma: an exploratory biomarker study

BackgroundAdrenocortical carcinoma (ACC) is a rare tumor in which prognostic factors are still not well established. Programmed Death Ligand-1 (PD-L1) expression in ACC and its association with clinico-pathological features and survival outcomes are unknown.MethodsFormalin-fixed paraffin-embedded (FFPE) specimens were obtained from 28 patients with ACC. PD-L1 expression was evaluated by immunohistochemistry (IHC) in both tumor cell membrane and tumor infiltrating mononuclear cells (TIMC). PD-L1 positivity on tumor cells was defined as ≥5% tumor cell membrane staining. TIMC were evaluated by IHC using a CD45 monoclonal antibody. For PD-L1 expression in TIMC, a combined score based on the extent of infiltrates and percentage of positive cells was developed. Any score greater that zero was considered PD-L1 positive. Baseline clinico-pathological characteristics and follow up data were retrospectively collected. Comparisons between PD-L1 expression and clinico-pathological features were evaluated using unpaired t-test and Fisher’s exact test. Kaplan-Meier method and log-rank test were used to assess association between PD-L1 expression and 5-year overall survival (OS).ResultsAmong 28 patients with surgically treated ACC, 3 (10.7%) were considered PD-L1 positive on tumor cell membrane. On the other hand, PD-L1 expression in TIMC was performed in 27 specimens and PD-L1 positive staining was observed in 19 (70.4%) patients. PD-L1 positivity in either tumor cell membrane or TIMC was not significantly associated with higher stage at diagnosis, higher tumor grade, excessive hormone secretion, or OS.ConclusionsPD-L1 expression can exist in ACC in both tumor cell membrane and TIMC with no relationship to clinico-pathologic parameters or survival.

Risk factors and model for predicting toxicity-related treatment discontinuation in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor–targeted therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

Vascular endothelial growth factor (VEGF)–targeted therapies are standard treatment for metastatic renal cell carcinoma (mRCC); however, toxicities can lead to drug discontinuation, which can affect patient outcomes. This study was aimed at identifying risk factors for toxicity and constructing the first model to predict toxicity‐related treatment discontinuation (TrTD) in mRCC patients treated with VEGF‐targeted therapies.