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Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.

ABSTRACT: Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.

SUBMITTER: Bakouny Z

PROVIDER: S-EPMC7865061 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.

Bakouny Ziad Z Braun David A DA Shukla Sachet A SA Pan Wenting W Gao Xin X Hou Yue Y Flaifel Abdallah A Tang Stephen S Bosma-Moody Alice A He Meng Xiao MX Vokes Natalie N Nyman Jackson J Xie Wanling W Nassar Amin H AH Abou Alaiwi Sarah S Flippot Ronan R Bouchard Gabrielle G Steinharter John A JA Nuzzo Pier Vitale PV Ficial Miriam M Sant'Angelo Miriam M Forman Juliet J Berchuck Jacob E JE Dudani Shaan S Bi Kevin K Park Jihye J Camp Sabrina S Sticco-Ivins Maura M Hirsch Laure L Baca Sylvan C SC Wind-Rotolo Megan M Ross-Macdonald Petra P Sun Maxine M Lee Gwo-Shu Mary GM Chang Steven L SL Wei Xiao X XX McGregor Bradley A BA Harshman Lauren C LC Genovese Giannicola G Ellis Leigh L Pomerantz Mark M Hirsch Michelle S MS Freedman Matthew L ML Atkins Michael B MB Wu Catherine J CJ Ho Thai H TH Linehan W Marston WM McDermott David F DF Heng Daniel Y C DYC Viswanathan Srinivas R SR Signoretti Sabina S Van Allen Eliezer M EM Choueiri Toni K TK

Nature communications 20210205 1

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S ...[more]

PMID: 33547292

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Project description:BackgroundRenal cell carcinoma (RCC) with sarcomatoid and/or rhabdoid (S/R) dedifferentiation is a highly aggressive tumor with a poor prognosis. Immune checkpoint therapy (ICT) has shown significant treatment efficacy in this subtype. There remains uncertainly regarding the role of cytoreductive nephrectomy (CN) for patients with metastatic RCC (mRCC) with S/R who received ICT.ObjectiveHere, we report the outcomes with ICT for patients with mRCC and S/R dedifferentiation by CN status.Design, setting, and participantsA retrospective review was conducted of 157 patients with sarcomatoid, rhabdoid, or sarcomatoid plus rhabdoid dedifferentiation who received an ICT-based regimen at two cancer centers.InterventionCN performed at any time point; nephrectomy with curative intent was excluded.Outcome measurements and statistical analysisICT treatment duration (TD) and overall survival (OS) from ICT initiation were recorded. To address the immortal time bias, a time-dependent Cox regression model was generated that accounted for confounders identified by a directed acyclic graph as well as a time-dependent nephrectomy variable.Results and limitationsA total of 118 patients underwent CN, and of them, 89 underwent upfront CN. The results did not contradict the supposition that CN does not improve ICT TD (hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.65-1.47, p = 0.94) or OS from ICT initiation (HR 0.79, 95% CI 0.47-1.33, p = 0.37). In patients who underwent upfront CN compared with those who did not undergo CN, there was no association with ICT duration or OS (HR 0.61, 95% CI 0.35-1.06, p = 0.08). A detailed clinical summary of 49 patients with mRCC and rhabdoid dedifferentiation is provided.ConclusionsIn this multi-institutional cohort of mRCC with S/R dedifferentiation treated with ICT, CN was not significantly associated with improved TD or superior OS when accounting for the lead time bias. There appears to be a subset of patients who derive meaningful benefit from CN, so improved tools for stratification prior to CN are needed to optimize outcomes.Patient summaryImmunotherapy has improved outcomes for patients with metastatic renal cell carcinoma (mRCC) who have sarcomatoid and/or rhabdoid (S/R) dedifferentiation, which is an aggressive and uncommon feature; yet, the utility of a nephrectomy in this setting is unclear. We found that nephrectomy did not significantly improve survival or time on immunotherapy for these patients with mRCC and S/R dedifferentiation; yet, there may be a subset of patients who benefit from this surgical approach.

Project description:BackgroundSarcomatoid differentiation in renal cell carcinoma (RCC) with vena caval tumour thrombus has been shown to be associated with aggressive behaviours and poor prognosis; however, evidence of the impact of rhabdoid differentiation on prognosis is lacking. This study evaluated the impact of sarcomatoid differentiation and rhabdoid differentiation on oncological outcomes for RCC with vena caval tumour thrombus treated surgically.MethodsWe retrospectively analysed patients treated surgically for RCC with vena caval tumour thrombus at our institute from Jan 2015 to Nov 2018. Prognostic variables were evaluated for associations with progression-free survival (PFS) and cancer-specific survival (CSS) by Kaplan-Meier survival analysis and log-rank test. Univariate and multivariate analyses were performed to determine independent prognostic variables.ResultsWe identified 125 patients with RCC and vena caval tumour thrombus, including 17 (13.6%) with sarcomatoid differentiation alone, 8 (6.4%) with rhabdoid differentiation alone and 3 (2.4%) with both sarcomatoid and rhabdoid differentiation. Compared to pure RCC, patients with sarcomatoid differentiation but not rhabdoid differentiation have worse PFS (p = 0.018 and p = 0.095, respectively). The univariate and multivariate analyses both showed sarcomatoid differentiation as a significant predictor of PFS. Compared to pure RCC, patients with sarcomatoid differentiation (p = 0.002) and rhabdoid differentiation (p = 0.001) both had significantly worse CSS. The univariate analysis showed sarcomatoid differentiation, rhabdoid differentiation, metastasis and blood transfusion as significant predictors of CSS (All, p < 0.05). In the multivariate analysis, sarcomatoid differentiation (HR 3.90, p = 0.008), rhabdoid differentiation (HR 3.01, p = 0.042), metastasis (HR 3.87, p = 0.004) and blood transfusion (HR 1.34, p = 0.041) all remained independent predictors of CSS.ConclusionsSarcomatoid differentiation and rhabdoid differentiation are both independent predictors of poor prognosis in RCC with vena caval tumour thrombus treated surgically.

Dataset Information

Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.

Publications

Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.

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