Megan M. Merrill

Autotaxin-Lysophosphatidic Acid Signaling Axis Mediates Tumorigenesis and Development of Acquired Resistance to Sunitinib in Renal Cell Carcinoma.

Purpose: Sunitinib is currently considered as the standard treatment for advanced renal cell carcinoma (RCC). We aimed to better understand the mechanisms of sunitinib action in kidney cancer treatment and in the development of acquired resistance. Experimental Design: Gene expression profiles of RCC tumor endothelium in sunitinib-treated and -untreated patients were analyzed and verified by quantitative PCR and immunohistochemistry. The functional role of the target gene identified was investigated in RCC cell lines and primary cultures in vitro and in preclinical animal models in vivo. Results: Altered expression of autotaxin, an extracellular lysophospholipase D, was detected in sunitinib-treated tumor vasculature of human RCC and in the tumor endothelial cells of RCC xenograft models when adapting to sunitinib. ATX and its catalytic product, lysophosphatidic acid (LPA), regulated the signaling pathways and cell motility of RCC in vitro. However, no marked in vitro effect of ATX-LPA signaling on endothelial cells was observed. Functional blockage of LPA receptor 1 (LPA1) using an LPA1 antagonist, Ki16425, or gene silencing of LPA1 in RCC cells attenuated LPA-mediated intracellular signaling and invasion responses in vitro. Ki16425 treatment also dampened RCC tumorigenesis in vivo. In addition, coadministration of Ki16425 with sunitinib prolonged the sensitivity of RCC to sunitinib in xenograft models, suggesting that ATX-LPA signaling in part mediates the acquired resistance against sunitinib in RCC. Conclusions: Our results reveal that endothelial ATX acts through LPA signaling to promote renal tumorigenesis and is functionally involved in the acquired resistance of RCC to sunitinib. Clin Cancer Res; 19(23); 6461–72. ©2013 AACR.

Clinically nonmetastatic renal cell carcinoma with sarcomatoid dedifferentiation: Natural history and outcomes after surgical resection with curative intent

PURPOSE Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is an aggressive malignancy associated with a poor prognosis. Although existing literature focuses on patients presenting with metastatic disease, characteristics and outcomes for patients with localized disease are not well described. We aimed to evaluate postnephrectomy characteristics, outcomes, and predictors of survival in patients with sRCC who presented with clinically localized disease. PATIENTS AND METHODS An institutional review board-approved review from 1986 to 2011 identified 77 patients who presented with clinically localized disease, underwent nephrectomy, and had sRCC in their primary kidney tumor. Clinical and pathologic variables were captured for each patient. Overall survival (OS) and recurrence-free survival (RFS) were calculated for all patients and those who had no evidence of disease (NED) following nephrectomy, respectively. Comparisons were made with categorical groupings in proportional hazards regression models for univariable and multivariable analyses. RESULTS OS for the entire cohort (n = 77) at 2 years was 50%. A total of 56 (77%) patients of the 73 who has NED following nephrectomy experienced a recurrence, with a median time to recurrence of 26.2 months. On multivariable analysis, tumor stage, pathologically positive lymph nodes, and year of nephrectomy were significant predictors of both OS and recurrence-free survival. Limitations include the retrospective nature of this study and relatively small sample size. CONCLUSIONS Long-term survival for patients with sRCC, even in clinically localized disease, is poor. Aggressive surveillance of those who have NED following nephrectomy is essential, and further prospective studies evaluating the benefit of adjuvant systemic therapies in this cohort are warranted.

Preoperative multivariable prognostic models for prediction of survival and major complications following surgical resection of renal cell carcinoma with suprahepatic caval tumor thrombus

OBJECTIVE Surgical resection for renal cell carcinoma (RCC) with suprahepatic inferior vena cava tumor thrombus is associated with significant morbidity, yet there are currently no tools for preoperative prognostic evaluation. Our goal was to develop a preoperative multivariable model for prediction of survival and risk of major complications in patients with suprahepatic thrombi. METHODS We identified patients who underwent surgery for RCC with suprahepatic tumor thrombus extension from 2000 to 2013 at 4 tertiary centers. A Cox proportional hazard model was used for analysis of overall survival (OS) and logistic regression was used for major complications within 90 days of surgery (Clavien ≥ 3A). Nomograms were internally calibrated by bootstrap resampling method. RESULTS A total of 49 patients with level III thrombus and 83 patients with level IV thrombus were identified. During median follow-up of 24.5 months, 80 patients (60.6%) died and 46 patients (34.8%) experienced major complication. Independent prognostic factors for OS included distant metastases at presentation (hazard ratio = 2.52, P = 0.002) and Eastern Cooperative Oncology Group (ECOG) performance status (hazard ratio = 1.84, P<0.0001). Variables associated with increased risk of major complications on univariate analysis included preoperative systemic symptoms, level IV thrombus, and elevated preoperative alkaline phosphatase and aspartate transaminase levels; however, only systemic symptoms (odds ratio = 8.45, P<0.0001) was an independent prognostic factor. Preoperative nomograms achieved a concordance index of 0.72 for OS and 0.83 for major complications. CONCLUSIONS We have developed and internally validated multivariable preoperative models for the prediction of survival and major complications in patients with RCC who have a suprahepatic inferior vena cava thrombus. If externally validated, these tools may aid in patient selection for surgical intervention.

Percentage of sarcomatoid component as a prognostic indicator for survival in renal cell carcinoma with sarcomatoid dedifferentiation

OBJECTIVE Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is associated with higher stage of presentation and worse survival. The objective of this study was to examine the clinicopathologic characteristics associated with overall survival (OS), specifically examining the percentage of sarcomatoid component (PSC). METHODS We reviewed clinicopathologic data for all nephrectomized patients with confirmed sRCC. Histologic slides were rereviewed by dedicated genitourinary pathologists to ascertain PSC. Patient characteristics were tabulated overall and by disease stage. Cutpoints in the PSC providing a meaningful difference in OS were identified by recursive partitioning analysis (RPA). Factors selected included age group, gender, race, clinical stage, tumor histology, presurgical systemic therapy, lymphovascular invasion, and tumor size. The Kaplan-Meier method and log-rank test were used to assess differences in OS. RESULTS Among 186 patients with sRCC, 64 (34%) had localized, and 122 (66%) had metastatic disease at presentation. Patients had primarily clear cell histology (73%). Median follow-up was 12.1 months (range: 0.1-242.2mo). Median OS was 12.6 months (95% CI: 10.7-14.9mo). Univariate RPA identified a PSC cutpoint of 10% as prognostically significant. Patients with PSC>10% were at higher risk of death when compared with patients with PSC≤10% (45% vs. 61% 1-y OS; P = 0.04). Multivariate RPA revealed that tumor size, presence of metastatic disease, and PSC were significantly associated with OS. Among 4 identified groups, patients with localized disease and tumor size≤10cm were most likely to be alive at 1 year (89%), and patients with metastatic disease and PSC>40% were least likely to be alive at 1 year (28%; P<0.001). CONCLUSION PSC appears to be a prognostic factor in patients with sRCC, with larger percentage of involvement portending a worse survival, especially in patients with metastatic disease.

PARTIAL NEPHRECTOMY IN THE SETTING OF METASTATIC RENAL CELL CARCINOMA

PURPOSE Cytoreductive nephrectomy remains the standard of care for appropriately selected patients with metastatic renal cell carcinoma. Although the role of partial nephrectomy is well accepted in patients with localized disease, limited data are available on partial nephrectomy in the metastatic setting. We identified the indications for and outcomes of partial nephrectomy in the setting of metastatic renal cell carcinoma with particular attention to partial nephrectomy subgroups. MATERIALS AND METHODS We analyzed data on a consecutive cohort of 33 patients with metastatic renal cell carcinoma who underwent partial nephrectomy at a single institution between 1996 and 2011. Nonparametric statistics were used to compare partial nephrectomy subgroups. Overall survival was estimated using the Kaplan-Meier method and survival functions were compared using the log rank test. RESULTS At presentation 8 patients had bilateral synchronous renal masses, 20 had a metachronous contralateral renal mass and 5 had a unilateral renal mass. A total of 22 patients (67%) died of disease a median of 27 months postoperatively. Patients who underwent partial nephrectomy for a metachronous contralateral renal mass and a renal mass 4 cm or less had the best overall survival (61 and 42 months, respectively). Median overall survival in patients with vs without metastatic disease at original diagnosis was 27 vs 63 months (p = 0.003). CONCLUSIONS Our findings suggest that metastasis at the original diagnosis and the timing of presentation of the partial nephrectomy index lesion have an important role in survival. These factors should be considered when determining which patients would benefit from partial nephrectomy in the setting of metastatic renal cell carcinoma.

Postoperative Surveillance Protocols for Renal Cell Carcinoma

Patients with renal cell carcinoma (RCC) are at risk of recurrence even after definitive surgical extirpation. Without prompt identification and treatment of recurrent disease, prognosis is poor. Literature suggests that early intervention in the form of metastasectomy and/or targeted therapy can lead to prolonged survival in those who develop recurrent or metastatic RCC. Therefore, surveillance in the postoperative setting is of paramount importance.

Characteristics and clinical outcomes of patients with renal cell carcinoma with sarcomatoid dedifferentiation (sRCC).

401 Background: sRCC is an aggressive subset of renal cell carcinomas that is associated with poor prognosis. We describe clinical and pathological characteristics and outcomes of the largest single-institutional cohort of patients with sRCC who underwent nephrectomy. METHODS Data were collected from 1986 to 2011 for patients identified as having sRCC. 221 patients with complete data who underwent a radical or partial nephrectomy and had a sarcomatoid component in the primary kidney tumor were included in the analysis. Clinical and pathologic variables were reviewed and Kaplan-Meier curves were used to compare differences in overall survival. RESULTS Mean age at diagnosis was 57 years and median tumor size was 11 cm (range 1.5-27.0 cm). 93% of patients were symptomatic at presentation and 96% had an ECOG performance status of 0 or 1. 12 patients had a preoperative biopsy that showed sRCC. 75% of patients were pT3 or higher at time of nephrectomy and 69% presented with metastatic disease. Of these, 11.8% had radiographic evidence of regional nodal involvement alone and 88.2% had distant metastatic disease. The associated epithelial component was clear cell in 72% of the patients, papillary in 12.7% and chromophobe in 3.1%. 29 patients received presurgical systemic therapy, while 161 patients received postoperative systemic therapy. During a median follow-up of 20.5 months, 187 patients (84%) died. Overall survival for the entire cohort at 1 year was 48%. Overall 1-, 2-, and 3-year survival rates for patients with metastatic disease at presentation versus no metastatic disease were 36, 20, and 16% versus 74, 51, and 44% respectively (p < 0.001). Patients with clear cell RCC epithelial component had a survival advantage over those with non-clear cell components with 1-, 2-, and 3-year survival rates of 52, 34, and 31% versus 38, 19, and 12% (p = 0.0057). CONCLUSIONS The majority of patients with sRCC who underwent nephrectomy present with metastatic disease and outcomes are dismal despite surgical intervention and multimodal therapy. Overall survival is better for patients who present without metastatic disease and have clear cell histology at time of nephrectomy.