Targeted Therapy has not Substantially Improved Outcomes in Patients with Sarcomatoid Renal Cell Carcinoma: Beyond the Abstract

Renal cell carcinomas (RCCs) of any histologic subtype can undergo sarcomatoid dedifferentiation which confers a poor prognosis. Over the past decade, targeted therapies against the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways have substantially improved outcomes in patients with advanced clear-cell RCC.1 

To determine whether these benefits are also evident in RCCs with sarcomatoid dedifferentiation (sRCCs), we performed a retrospective analysis of our institutional experience with sRCCs, and explored whether the survival of these patients improved since the introduction of targeted therapies.2 

Because biopsies are very insensitive in detecting the sarcomatoid component, we only included patients who had undergone nephrectomy either with curative or cytoreductive intent. In most cases (80.9%), the primary epithelial component was clear-cell RCC. Patients who were initially diagnosed with localized disesae had a significantly longer median overall survival compared with those who presented with metastatic disease at diagnosis (23.3 months vs 12.1 months; p=0.0064). Both the international metastatic renal cell carcinoma database consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic models were able to correctly risk-stratify patients into "intermediate-risk" and "poor-risk" groups. Very few patients were classified as "favorable-risk" by IMDC criteria, and none by MSKCC criteria, pointing again to the unfavorable prognosis associated with sRCC. Higher percentages of the sarcomatoid component were associated with shorter median overall survival (OS). In addition, patients with non-clear cell histology of the epithelial component demonstrated significantly worse OS compared with clear-cell histology (HR=1.76, 95% CI 1.11-2.77, p=0.015).2 

Although the number of intermediate-risk patients (by either IMDC or MSKCC criteria) patients surviving at 1 year has increased following the introduction of targeted therapies, this improvement was no longer evident by year 3 onwards. Of note, poor-risk patients did not gain any benefit in survival outcomes following the introduction of targeted therapies.2 Indeed, the outcomes of poor-risk patients with sRCC have remained dismal for over 2 decades based on our institutional experience2. Similarly, the treatment options for poor-risk RCC patients without sarcomatoid dedifferentiation have remained limited.3 Clearly, novel therapeutic strategies are urgently needed.

The recent introduction of immune checkpoint inhibitors in our therapeutic armamentarium, and the launch of several phase 3 trials combining these drugs with other targeted agents, may produce much-needed benefit in the survival outcomes of patients with sRCC. In addition, genomic characterization and immune profiling of sRCC tissues4, 5 may identify novel biological targets, as well as biomarkers of response to immunotherapy or other targeted approaches.

Written By: Pavlos Msaouel, MD, PhD, Chief Fellow, Hematology/Oncology Fellowship, University of Texs MD Anderson Cancer Center, Houston, TX;  Jose A. Karam, MD, FACS, Department of Urology, The University of Texas MD Anderson Cancer Center;  Christopher G. Wood, MD, FACS, Department of Urology, The University of Texas MD Anderson Cancer Center;  Nizar M. Tannir, MD, FACP, Department of Genitourinary Oncology, The University of Texas MD Anderson Cancer Center

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References:
1. Choueiri, T. K., Motzer, R. J.: Systemic Therapy for Metastatic Renal-Cell Carcinoma. N Engl J Med, 376: 354, 2017
2. Keskin, S. K., Msaouel, P., Hess, K. R. et al.: Outcomes of Patients with Renal Cell Carcinoma and Sarcomatoid Dedifferentiation Treated with Nephrectomy and Systemic Therapies Over Three Decades: Comparison Between the Cytokine (1987-2005) and the Targeted Therapy (2006-2015) Eras. J Urol, 2017
3. Porta, C., Tortora, G., Larkin, J. M. et al.: Management of poor-risk metastatic renal cell carcinoma: current approaches, the role of temsirolimus and future directions. Future Oncol, 12: 533, 2016
4. Malouf, G. G., Flippot, R., Mouawad, R. et al.: Integrative analysis of sarcomatoid clear-cell renal cell carcinomas reveals an immune subgroup. J Clin Oncol, 35: (suppl; abstr 4571), 2017
5. Malouf, G. G., Ali, S. M., Wang, K. et al.: Genomic Characterization of Renal Cell Carcinoma with Sarcomatoid Dedifferentiation Pinpoints Recurrent Genomic Alterations. Eur Urol, 70: 348, 2016