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Pancreatic Metastases in Advanced Renal Cell Carcinoma: An Evolving Prognostic Paradox - Beyond the Abstract

In patients with metastatic renal cell carcinoma (mRCC), the pancreas is a rare site of metastasis with limited data regarding its prognostic significance.1-3  Although pancreatic metastasis (PM) has been associated with improved clinical outcomes in mRCC patients, this has not been extensively studied in the context of systemic therapy.1,3,4  The purpose of this study was to further understand the outcomes of mRCC patients with PM who receive systemic therapy.


We performed a pooled analysis of 4736 patients with mRCC who were enrolled in phase II/III clinical trials. Systemic therapies included cytokine therapy, mammalian target of rapamycin-targeted therapy, and anti-vascular endothelial growth factor (VEGF) targeted therapy. The primary endpoint was to evaluate overall survival (OS), comparing patients with versus without PM. The Kaplan-Meier method and Cox regression were used for statistical analyses.

Within the pool of 4736 patients with mRCC, 235 (5%) of patients were documented to have PM at the initiation of systemic therapy. Patients with PM had significantly prolonged median OS (41.7 vs. 19.0 months; adjusted hazard ratio, 0.52; P<0.001) and progression-free survival (10.9 vs. 6.9 months; adjusted hazard ratio, 0.72; P=0.004) compared to patients without PM. These OS and progression-free survival (PFS) results were independent of the International mRCC Database Consortium (IMDC) risk group and other sites of metastasis.

This study demonstrated an increase in OS, PFS, and overall response rate (ORR) in mRCC patients with PM. This supports previous findings that certain metastases patterns within mRCC may predict prognosis, which could aid in therapy selection and clinical decision-making. Within the small cohort of PM patients (5%) extracted from our overall pool, there was a higher prevalence of patients that had IMDC favorable risk compared to patients without PM. This aligns with previous findings in several mRCC cohort analyses that demonstrated more indolent disease when PM is present.5-7

When categorized by IMDC risk group, OS was improved in the favorable and intermediate-risk group while PFS was improved only in the favorable risk group amongst patients with PM compared to without PM.8  Though the number of poor risk mRCC with PM was low, OS and PFS were similar between patients with and without PM.

Different therapy regimens should be considered when studying these improved outcomes. Our study demonstrated improved PFS in patients with PM who received cytokine therapy and VEGF-targeted therapy compared to patients without PM. However, this finding was exclusive to first-line therapy, which could indicate the development of resistance to therapy with subsequent lines.

The mechanism underlying these observations remains under investigation. In clear cell mRCC patients with PM, a whole-exome sequencing analysis of both primary and metastatic sites revealed increased genomic alterations associated with improved outcomes (PBRM1 mutations, 3q loss, and 5q amplification).9,10  The exact tropism for the spread of RCC to the pancreas remains unknown, with a seed and soil mechanism being previously proposed.11  It is possible that more indolent subtypes of RCC have an increased tropism for the pancreas, which could explain more favorable outcomes when PM is present. Additionally, the underlying pathogenesis of PM could account for varying outcomes to therapy. A biomarker analysis demonstrated limited immune infiltrate and increased vascularity on biopsy specimens extracted from mRCC patients with PM, which could indicate greater sensitivity to VEGF-targeted therapy.9  This finding is complemented by a phase II, multicenter trial (IMmotion150) which compared atezolizumab with and without bevacizumab to sunitinib in advanced clear cell RCC.12  The study correlated angiogenesis signatures with outcomes and demonstrated that patients with angiogenesishigh signatures had improved outcomes when treated with sunitinib compared with atezolizumab/bevacizumab and atezolizumab alone. Patients with IMDC favorable risk were also associated with angiogenesishigh , which supports that they may have increased sensitivity to VEGF-targeted therapy. Our study showed improved PFS with cytokine therapy in patients with PM. Considering that combination immunotherapy is now being administered as first-line therapy, it will be crucial to assess its unique effects on mRCC patients with PM.

Despite PM being rare in the context of RCC, their presence is associated improved clinical outcomes. However, further research must evaluate a more granular mechanism to understand the indolent disease behavior and integrate more recently emerging treatment regimens to comprehensively evaluate response to anti-VEGF therapy versus immunotherapy.

Written by: Justine Panian & Rana R. Mckay, MD, Department of Medicine, Division of Hematology/Oncology, University of California San Diego, San Diego, CA

References:

  1. Bianchi M, Sun M, Jeldres C et al. Distribution of metastatic sites in renal cell carcinoma: A population-based analysis. Ann Oncol. 2012; 23(4): 973-80.
  2. Gong J, Maia MC, Dizman N et al. Metastasis in renal cell carcinoma: Biology and implications for therapy. Asian J Urol. 2016; 3(4): 286-92.
  3. Ballarin R, Spaggiari M, Cautero N et al. Pancreatic metastases from renal cell carcinoma: The state of the art. World J Gastroenterol. 2011; 17(43): 4747-56.
  4. Jo S, Yang IJ and Song S. Surgery for metastatic renal cell carcinoma in the pancreatic head: A case report and literature review. Ann Hepatobiliary Pancreat Surg. 2019; 23(1): 91-95.
  5. Yuasa T, Inoshita N, Saiura A et al. Clinical outcome of patients with pancreatic metastases from renal cell cancer. BMC Cancer. 2015; 15: 46.
  6. Kalra S, Atkinson BJ, Matrana MR et al. Prognosis of patients with metastatic renal cell carcinoma and pancreatic metastases. BJU Int. 2016; 117(5): 761-5.
  7. Grassi P, Doucet L, Giglione P et al. Clinical impact of pancreatic metastases from renal cell carcinoma: A multicenter retrospective analysis. PLoS One. 2016; 11(4): e0151662.
  8. Heng DY, Xie W, Regan MM et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a large, multicenter study. J Clin Oncol. 2009; 27(34): 5794-9.
  9. Singla N, Xie Z, Zhang Z et al. Pancreatic tropism of metastatic renal cell carcinoma. JCI Insight. 2020; 5(7).
  10. Ricketts CJ, De Cubas AA, Fan H et al. The cancer genome atlas comprehensive molecular characterization of renal cell carcinoma. Cell Rep. 2018; 23(12): 3698.
  11. Sellner F. Observations on solitary versus multiple isolated pancreatic metastases of renal cell carcinoma: Another indication of a seed and soil mechanism? Cancers (Basel). 2019; 11(9).
  12. Rini BI, Powles T, Atkins MB et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (immotion151): A multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019; 393(10189): 2404-15.


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