Sarcomatoid Dedifferentiation in Metastatic Clear Cell Renal Cell Carcinoma and Outcome on Treatment With Anti–Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors: A Retrospective Analysis

Beuselinck, Benoît; Lerut, Evelyne; Wolter, Pascal; Dumez, Herlinde; Berkers, Joost; Poppel, Hendrik Van; Joniau, Steven; Oyen, Raymond; Wever, Liesbeth De; Strijbos, Michiel; Paridaens, Robert; Schöffski, Patrick

doi:10.1016/j.clgc.2014.04.004

Cited by 39 publications

(32 citation statements)

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“…The presence of an important component of sarcomatoid dedifferentiation (25% of the tumor volume) was associated with short PFS and OS only on univariate analysis, and not on multivariate analysis. This is probably due to the fact that this factor is highly associated with other factors, among them the duration of PFS on first-line therapy [12]. Patients with one of the following prognostic markers: elevated corrected calcium levels, low albumin, elevated LDH levels or a sarcomatoid component 25% had a very reduced survival after start of second-line therapy.…”

Section: Summary Of Our Resultsmentioning

confidence: 99%

“…The IMDC and MSKCC prognostic scores were calculated at start of second-line therapy, as well as the different factors that form the basis for these established scores (interval between diagnosis and systemic treatment, performance status, hemoglobin levels, corrected serum calcium levels, serum LDH levels, neutrophil and platelet count), presence of sarcomatoid dedifferentiation in 25% of the tumor volume [12], PFS [13] and best response on first-line therapy, the presence of bone metastases [14], brain metastases [15] or glandular metastases (defined as pancreatic, adrenal or thyroid metastases) [16], baseline C-reactive protein (CRP) levels ( or4inferior limit of normal, 5 mg/dl) [17] and albumin levels ( or4inferior limit of normal, 3.5 g/dl) [18,19] at start of second-line therapy. Associations between PFS or OS and potential prognostic factors were assessed using Kaplan-Meier estimates and the logrank test in univariate analysis.…”

Section: Methodsmentioning

confidence: 99%

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Prognostic factors in second-line targeted therapy for metastatic clear-cell renal cell carcinoma after progression on an anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor

Sacré

Barthélémy²,

Korenbaum³

et al. 2015

Acta Oncologica

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Submit your article to this journal Background: About 40% of metastatic clear-cell renal cell carcinoma (m-ccRCC) patients receive a second-line targeted therapy after failure of anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (anti-VEGFR-TKI). Efficacy of second-line therapy is usually limited and prognostic and predictive factors at the start of second-line therapy are lacking. To identify the subgroup of patients that will benefit from such treatment remains a challenge. Methods: We performed a multi-institutional, retrospective study of patients who received a second-line therapy after progression on an anti-VEGFR-TKI. Univariate and multivariate analyses were performed in order to identify prognostic factors for progressive disease (PD) as best response, progression-free survival (PFS) and overall survival (OS) on second-line therapy. Results: For the whole cohort of 108 patients, mOS from the start of second-line therapy was 8.9 months while mPFS on second-line therapy was 2.8 months. A total of 49/105 (47%) patients had PD, 50/105 (48%) stable disease (SD) and 6/105 (6%) a partial response (PR). On multivariate analysis, the following markers were associated with improved outcome on second-line therapy: a PFS on first-line therapy 12 months (HR for PFS: 1.961; p ¼ 0.008) (HR for OS: 1.724; p ¼ 0.037) and Fuhrman grade 1-2 tumors (HR for OS: 2.198; p ¼ 0.007). Markers associated with poorer outcome on second-line therapy were: elevated serum lactate dehydrogenase (LDH) levels (HR for PFS: 0.511; p ¼ 0.04) (HR for OS: 0.392; p ¼ 0.017), low albumin (HR for OS: 0.392; p ¼ 0.01) and elevated corrected calcium levels (HR for OS: 0.416; p ¼ 0.01). The impact on OS of the Memorial Sloan Kettering Cancer Centre (MSKCC) and International Renal Cell Carcinoma Database Consortium (IMDC) prognostic scores as calculated at start of second-line therapy was validated in our patient series. Conclusions: Duration of first-line PFS, Fuhrman grade, serum LDH levels, albumin levels, corrected calcium levels and the MSKCC and IMDC scores calculated at start of second-line therapy are prognostic factors for m-ccRCC patients treated with second-line targeted therapy.

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Section: Summary Of Our Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Prognostic factors in second-line targeted therapy for metastatic clear-cell renal cell carcinoma after progression on an anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor

Sacré

Barthélémy²,

Korenbaum³

et al. 2015

Acta Oncologica

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“…Although the advent of targeted therapies has significantly improved survival in patients with metastatic renal cell carcinoma (RCC) in the past decade, the efficacy of these new drugs is limited in patients with sarcomatoid RCC (sRCC), as these patients experience the worst outcomes of all patients with RCC 1–3 .…”

Section: Introductionmentioning

confidence: 99%

Programmed cell death ligand 1 and tumor‐infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation

Kawakami

Sircar

Rodriguez‐Canales

et al. 2017

Cancer

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Background The immune profile of sarcomatoid renal cell carcinoma (RCC) (sRCC), including PD-L1 and PD-1 status, has not been well characterized. Methods PD-L1, PD-1, CD4, and CD8 immunohistochemical digital analysis was performed on nephrectomy specimens of 118 sRCC and 92 non-sarcomatoid clear cell RCC (ccRCC) patients. Clinical characteristics of the population were compared between sRCC and ccRCC. Overall survival was estimated and was compared between PD-L1–positive and PD-L1–negative groups as well as tumor infiltrating lymphocytes (TIL)–high and TIL–low groups. Results The PD-L1 H-score of sRCC (mean, 3.7; range, 0–192.1) was significantly higher than that of grade 4 ccRCC (P=0.001), and 41.3% of sRCC showed PD-L1 H-score≥10. PD-1–positive cell density was significantly higher in sRCC than in ccRCC within the tumor and at the invasive front. Intratumoral CD8-positive cell density was significantly higher in sRCC than in ccRCC. 41% in sarcomatoid component of sRCC and 8% in epithelioid component of sRCC had an adaptive immune resistance (PD-L1 positive and TIL positive) phenotype, while only 1% in pure epithelioid RCC had Type I phenotype. Conclusions sRCC showed higher PD-L1 expression and higher PD-1 and CD8–positive cell density than grade 4 ccRCC. Our results indicate a notable immunosuppressive environment in sRCC. Despite advances in the treatment of advanced-stage RCC, sRCC still has a poor prognosis. In this work, we describe highly immunosuppressive characteristics of sRCC compared with an appropriate ccRCC control. Our results suggest PD-1/PD-L1 blockade therapy as a potential therapeutic approach for sRCC.

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“…Regardless of the underlying histology, sarcomatoid differentiation is associated with a more aggressive disease phenotype . In most series, patients with metastatic sarcomatoid RCC had an estimated overall survival (OS) of 6 to 10 months …”

Section: Introductionmentioning

confidence: 99%

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

Michaelson

McKay

Werner

et al. 2015

Cancer

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BACKGROUND: Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poorrisk 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. METHODS: This was a phase 2, single-arm trial of sunitinib and gemcitabine in patients with sarcomatoid or poor-risk RCC. The primary endpoint was the objective response rate (ORR). Secondary endpoints included the time to progression (TTP), overall survival (OS), safety, and biomarker correlatives. RESULTS: Overall, 39 patients had sarcomatoid RCC, and 33 had poor-risk RCC. The ORR was 26% for patients with sarcomatoid RCC and 24% for patients with poor-risk RCC. The median TTP and OS for patients with sarcomatoid RCC were 5 and 10 months, respectively. For patients with poor-risk disease, the median TTP and OS were 5.5 and 15 months, respectively. Patients whose tumors had >10% sarcomatoid histology had a higher clinical benefit rate (ORR plus stable disease) than those with 10% sarcomatoid histology (P 5.04). The most common grade 3 or higher treatment-related adverse events included neutropenia (n 5 20), anemia (n 5 10), and fatigue (n 5 7). CONCLUSIONS: These results suggest that antiangiogenic therapy and cytotoxic chemotherapy are an active and well-tolerated combination for patients with aggressive RCC. The combination may be more efficacious than either therapy alone and is currently under further investigation. Cancer 2015;121:3435-43. V C 2015 American Cancer Society.KEYWORDS: chemotherapy, poor risk, renal cell carcinoma, sarcomatoid, vascular endothelial growth factor (VEGF), targeted. INTRODUCTIONRenal cell carcinoma (RCC) consists of a biologically heterogeneous group of tumors with distinct histopathologic and clinical features. Sarcomatoid RCC, a morphologic feature that can be identified across all RCC histologies, is characterized by the occurrence of spindle-shaped mesenchymal cells. The presence of sarcomatoid features has been reported in up to 29% of collecting duct carcinomas, in 9% to 11% of clear cell, chromophobe, and unclassified RCCs, and less frequently in papillary RCC (3%).1 Regardless of the underlying histology, sarcomatoid differentiation is associated with a more aggressive disease phenotype. 2,3 In most series, patients with metastatic sarcomatoid RCC had an estimated overall survival (OS) of 6 to 10 months.

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Sarcomatoid Dedifferentiation in Metastatic Clear Cell Renal Cell Carcinoma and Outcome on Treatment With Anti–Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors: A Retrospective Analysis

Cited by 39 publications

References 26 publications

Prognostic factors in second-line targeted therapy for metastatic clear-cell renal cell carcinoma after progression on an anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor

Prognostic factors in second-line targeted therapy for metastatic clear-cell renal cell carcinoma after progression on an anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor

Programmed cell death ligand 1 and tumor‐infiltrating lymphocyte status in patients with renal cell carcinoma and sarcomatoid dedifferentiation

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

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