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10.1172/JCI180516
1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
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1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
Find articles by Ortiz, E. in: JCI | PubMed | Google Scholar
1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
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Jiang, C.
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1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
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1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
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1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
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1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
Find articles by Pagano, A. in: JCI | PubMed | Google Scholar
1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
Find articles by Plodkowski, A. in: JCI | PubMed | Google Scholar
1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
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1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
Find articles by Mueller, J. in: JCI | PubMed | Google Scholar
1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
Find articles by Aghajanian, C. in: JCI | PubMed | Google Scholar
1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
Find articles by Weigelt, B. in: JCI | PubMed | Google Scholar
1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
Find articles by Makker, V. in: JCI | PubMed | Google Scholar
1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
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Cohen, P.
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1Laboratory of Molecular Metabolism, The Rockefeller University, New York, New York, USA.
2Division of Endocrinology, Department of Medicine, Memorial Sloan Kettering Cancer Center (MSK), New York, New York, USA.
3Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Weill Cornell Medicine, New York, New York, USA.
4Department of Radiology, MSK, New York, New York, USA.
5Center for Clinical and Translational Science, The Rockefeller University, New York, New York, USA.
6Department of Surgery, Gynecology Service,
7Department of Medicine, and
8Department of Pathology and Laboratory Medicine, MSK, New York, New York, USA.
9Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, New York, USA.
Address correspondence to: Juan Carlos Osorio, Memorial Sloan Kettering Cancer Center, 300 E. 66th Street, New York, New York 10065, USA. Phone: 646.888.6852; Email: osorioj@mskcc.org. Or to: Paul Cohen, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA. Phone: 212.327.7918; Email: pcohen@rockefeller.edu.
Authorship note: JCO and PC shared supervision of this work.
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Osorio, J.
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Authorship note: JCO and PC shared supervision of this work.
Published June 20, 2024 - More info
Published in Volume 134, Issue 17 on September 3, 2024
Related article:
Abstract
Obesity is a known driver of endometrial cancer. In this issue of the JCI, Gómez-Banoy and colleagues investigated a cohort of patients with advanced endometrial cancer treated with immune checkpoint inhibitors targeting the interaction between programmed cell death receptor-1 (PD-1) and its ligand (PD-L1). Notably, a BMI in the overweight or obese range was paradoxically associated with improved progression-free and overall survival. A second paradox emerged from CT analyses of visceral adipose tissue, viewed as an unhealthy fat depot in most other contexts, the quantity of which was also associated with improved treatment outcomes. Though visceral adiposity may have value as a biomarker to inform personalized treatment strategies, of even greater impact would be if a therapeutic strategy emerges from the future identification of adipose-derived mediators of this putative anticancer immune-priming effect.
Authors
× AbstractBACKGROUND. Obesity is the foremost risk factor in the development of endometrial cancer (EC). However, the impact of obesity on the response to immune checkpoint inhibitors (ICI) in EC remains poorly understood. This retrospective study investigates the association among BMI, body fat distribution, and clinical and molecular characteristics of EC patients treated with ICI.
METHODS. We analyzed progression-free survival (PFS) and overall survival (OS) in EC patients treated with ICI, categorized by BMI, fat-mass distribution, and molecular subtypes. Incidence of immune-related adverse events (irAEs) after ICI was also assessed based on BMI status.
RESULTS. 524 EC patients were included in the study. Overweight and obese patients exhibited a significantly prolonged PFS and OS compared with normal BMI patients after treatment with ICI. Multivariable Cox’s regression analysis confirmed the independent association of overweight and obesity with improved PFS and OS. Elevated visceral adipose tissue (VAT) was identified as a strong independent predictor for improved PFS to ICI. Associations between obesity and OS/PFS were particularly significant in the copy number–high/TP53abnormal (CN-H/TP53abn) EC molecular subtype. Finally, obese patients demonstrated a higher irAE rate compared with normal BMI individuals.
CONCLUSION. Obesity is associated with improved outcomes to ICI in EC patients and a higher rate of irAEs. This association is more pronounced in the CN-H/TP53abn EC molecular subtype.
FUNDING. NIH/NCI Cancer Center; MSK Gerstner Physician Scholars Program; National Center for Advancing Translational Sciences (NCATS); Cycle for Survival; Breast Cancer Research Foundation.
IntroductionEndometrial cancer (EC) constitutes the leading cause of gynecologic cancer–related death in the United States and one of the few cancer types with increasing incidence and disease-associated mortality (1). Obesity is one of the main drivers in the development of EC (2, 3), with a clear stepwise correlation between BMI and the risk of developing EC (4). Elevated body weight is also associated with worse prognosis in patients with this malignancy (5). Mechanistically, obesity induces dysfunction in the adipose tissue (AT), which has been implicated in promoting the progression and growth of EC cells (6) and triggering a dysregulated inflammatory state (7). However, there is a paucity of data regarding the influence of obesity on the response to immune-based therapies. This gap in knowledge is particularly important given that 80% of EC-diagnosed women are obese (8) and immune checkpoint inhibitors (ICIs) are becoming a cornerstone for the treatment of EC (9).
Monoclonal antibodies blocking inhibitory checkpoints have recently changed the frontline treatment paradigm for advanced and recurrent EC. Dorstarlimab, a programmed cell death receptor-1 (PD-1) blocker, is now firstline therapy in conjunction with chemotherapy for patients with advanced EC based on results from the RUBY trial (10). Similarly, pembrolizumab, another PD-1 inhibitor, in combination with chemotherapy, has recently shown improved progression-free survival (PFS) in the frontline setting when compared with chemotherapy alone in the NRG-GY018 trial (11). In the second-line setting, ICI alone or in combination with the tyrosine kinase inhibitor (TKI) lenvatinib is FDA approved in recurrent EC after treatment with platinum-based chemotherapy in mismatch repair–deficient (MMR–deficient) and MMR-proficient EC, respectively (12, 13). Despite these clinical advances, there is a lack of validated clinical, molecular, and immunological biomarkers that can predict response to these therapies. To this end, one of the most intriguing findings in patients treated with ICI for non-EC malignancies is the “obesity paradox,” in which obese patients treated with ICI have improved outcomes compared with lean patients (14). Furthermore, higher BMI may also correlate with the rate of immune-related adverse events (irAEs) (15), suggesting that obesity might promote disruption of immune tolerance against both tumor and normal cells. While these observations have been described in a few solid tumors (16–20), the heterogeneity across different studies and the attenuation of these associations after adjusting for relevant clinical factors underscore the need for further investigation (18, 21). Importantly, this clinical association has yet to be explored in the context of EC.
Given the high prevalence of obesity in EC and the prominence of ICI in its management, this retrospective study aims to show whether obesity influences clinical outcomes in women with EC after treatment with ICI. By characterizing clinical markers for obesity, body fat distribution, and molecular EC subtypes, we found a strong association between overweight/obesity and improved clinical outcomes in EC patients treated with ICI alone or in combination with lenvatinib. Notably, this favorable prognostic impact remained independent of clinicopathological and molecular subtyping of EC. Additionally, after assessment of body fat distribution, we found that increased visceral adipose tissue (VAT) is particularly associated with the improved clinical outcomes observed in our cohort. Finally, obesity was also linked to elevated rates of irAEs after immunotherapy. Collectively, these findings highlight the role of increased adiposity in modulating the response to ICIs and their side effect profile in EC.
ResultsCharacteristics of patients with EC treated with ICI categorized by BMI. We retrospectively screened 768 patients diagnosed with EC that underwent treatment with ICI at MSK from November 2015 to November 2022. Out of these, 524 patients with recurrent, advanced, or metastatic EC were included in the final analysis (Figure 1). The main reason for exclusion was patients receiving ICI therapy to treat a non-EC malignancy. Underweight patients (BMI < 18.5 kg/m2) were also excluded from the analysis (Figure 1). The baseline clinical characteristics (at the start of ICI) of the patients included in the final analysis are shown in Table 1. Across the entire study cohort, the median age was 67 years (range 30–94), and the median BMI was 29.1 kg/m2. Most patients (85%) received anti–PD-1 therapy, while 15% received anti–PD-L1 therapy. Regarding the combination of ICI with other anticancer therapies, 307 patients (59%) were treated with pembrolizumab in combination with lenvatinib. The majority of patients received ICI therapy as a second (54%) or third line (27%) of treatment. Additionally, 437 patients (83%) underwent molecular subtyping, and 500 (95%) had a baseline CT for determination of fat distribution. When categorized by BMI before the start of ICI therapy, 128 patients (24%) had a normal BMI (18.5–24.9 kg/m2), whereas 163 (31%) were overweight (BMI 25–29.9 kg/m2) and 233 (44%) were obese (BMI ≥ 30 kg/m2). Except for self-reported race and age, no significant differences in baseline characteristics were observed among the BMI groups. The number of patients with elevated subcutaneous adipose tissue (SAT), VAT, and VAT/SAT ratio increased from normal BMI to overweight to obese patients (Table 1).
Figure 1Consort diagram of the study population selection including exclusion criteria.
Table 1Clinical characteristics of EC patients treated with ICI categorized by BMI
Association between BMI and clinical outcomes after treatment with ICI in patients with EC. First, we investigated whether an elevated BMI could influence the response to ICI in all EC patients included in the analysis. Survival analyses were performed after initiation of ICI therapy, revealing that patients categorized as overweight or obese exhibited a significantly prolonged PFS when compared with those with normal BMI after treatment with ICI (overweight versus normal BMI: median 6.5 versus 4.5 months, HR 0.71, 95% CI 0.55–0.93, P = 0.0112; obese versus normal BMI: median 7.8 versus 4.5 months, HR 0.61, 95% CI 0.47–0.78, P < 0.0001) (Figure 2A). Furthermore, patients with overweight and obesity demonstrated a significantly prolonged overall survival (OS) compared with patients with normal BMI after ICI (overweight versus normal BMI: median 27 versus 15.2 months, HR 0.61, 95% CI 0.45–0.83, P = 0.0018; obese versus normal BMI: median 22 versus 15.2 months, HR 0.65, 95% CI 0.49–0.86, P = 0.0026) (Figure 2B).
Figure 2Survival outcomes of EC patients treated with ICI categorized by BMI. Kaplan-Meier curves for (A) PFS and (B) OS in patients with EC treated with ICI and categorized by BMI (normal: BMI 18.5–24.9 kg/m2 in blue; overweight: BMI 25–29.9 kg/m2 in red; obese: BMI >30 kg/m2 in green) (n = 524). Kaplan-Meier curves for (C) PFS and (D) OS in the subgroup of EC patients treated with the ICI pembrolizumab in combination with lenvatinib (n = 307). P values in the PFS and OS plots were calculated using a log-rank test. HRs and 95% CIs for overweight and obese patients were calculated using normal BMI as a reference.
The combination of lenvatinib with the ICI pembrolizumab is the standard-of-care treatment for a substantial proportion of patients with MMR-proficient, advanced EC who have progressed after firstline platinum-based chemotherapy (12). As more than half of our cohort received this treatment combination (Table 1), we explored whether obesity was associated with clinical outcomes with this specific treatment regimen. Survival analyses in patients who received combination lenvatinib and pembrolizumab revealed that obese and overweight patients had significantly longer PFS (overweight versus normal BMI: median 7.3 versus 5.6 months, HR 0.62, 95% CI 0.45–0.87, P = 0.0052; obese versus normal BMI: median 8.2 versus 5.6 months, HR 0.57, 95% CI 0.42–0.79, P = 0.0005) and OS (overweight versus normal BMI: median 27.7 versus 14 months, HR 0.53, 95% CI 0.35–0.79, P = 0.0020; obese versus normal BMI: median 21.1 versus 14 months, HR 0.64, 95% CI 0.45–0.92, P = 0.0144) compared with patients with normal BMI (Figure 2, C and D).
We then explored the impact of other baseline clinical variables on the PFS and OS of EC patients after treatment with ICI therapy. Similarly to what was shown with BMI, univariable Cox’s regression analysis demonstrated that specific histological types, stage at diagnosis, number of previous lines of therapy, and molecular subtype were significantly associated with changes in PFS and OS in EC patients treated with ICI (Table 2 and Table 3). Thus, we investigated whether BMI was independently associated with improved PFS and OS in our study cohort by controlling for these and other clinical variables. Multivariable Cox’s regression analysis demonstrated that baseline overweight and obese states were independently associated with improved PFS when compared with patients with normal BMI (overweight versus normal BMI: adjusted HR 0.71, 95% CI 0.54–0.93; obese versus normal BMI: adjusted HR 0.54, 95% CI 0.42–0.71) (Figure 3A). Similarly, overweight and obesity were independently associated with extended OS compared with normal BMI (overweight versus normal BMI: adjusted HR 0.64, 95% CI 0.47–0.89; obese versus normal BMI: adjusted HR 0.64, CI 95% 0.48–0.87) (Figure 3B). As expected, distinct histological types (carcinosarcoma, serous, un/dedifferentiated) and poor baseline Eastern Cooperative Oncology Group (ECOG) performance status (22) were independent predictors of worse PFS and OS. Overall, these results suggest a paradoxical association between elevated BMI and improved responses to ICI in patients with EC, further supporting BMI as an independent predictor of clinical response to ICI.
Figure 3Multivariable Cox’s regression analysis of BMI and other clinical variables associated with response to ICI in EC patients. Forest plots of adjusted HRs and 95% CIs for patients with normal BMI (BMI 18.5–24.9 kg/m2) (reference group) compared with overweight (BMI 25–29.9 kg/m2) and obese (BMI > 30 kg/m2) for (A) PFS and (B) OS (n = 524) Analysis was adjusted for age, self-reported race, histology, checkpoint inhibitor treatment, combination therapies, baseline performance status, stage at diagnosis, prior lines of therapy, and previous pelvic radiotherapy. Endo-LG, endometrial low grade; Endo-HG, endometrial high grade; Un-/dediff, un/dedifferentiated; Len/pem, lenvatinib/pembrolizumab; Treme/durva, tremelimumab/durvalumab.
Table 2Univariable Cox’s regression analysis for PFS in EC patients treated with ICI
Table 3Univariable Cox’s regression analysis for OS in EC patients treated with ICI
Association between fat distribution and clinical responses to ICI in patients with EC. While BMI serves as a well-established anthropometric indicator that is positively associated with cardiometabolic disease, it is important to recognize its inability to distinguish between fat and muscle mass (23). Furthermore, in the context of cancer, BMI may not precisely capture the association between AT and responses to distinct types of therapies (24). To address this limitation and assess whether specific fat distribution could predict clinical responses in patients with EC after ICI treatment, we performed 2D measurements of SAT and VAT at the level of L3/L4, which have shown a strong correlation with abdominal fat volumes and cardiometabolic risk factors (25). Out of the total cohort, 500 patients had available baseline CT scans to assess SAT and VAT areas.
BMI correlated with both SAT (r = 0.79, P < 0.0001) and VAT areas (r = 0.71, P < 0.0001) (Supplemental Figure 1; supplemental material available online with this article; https://doi.org/10.1172/JCI180516DS1). We then categorized EC patients based on their median VAT (112 cm2) or SAT (270 cm2) area and examined their response to ICI, as previously performed in other studies (18). In patients with high VAT area, the median PFS after ICI was significantly prolonged compared with those with low VAT area (median 7.8 versus 5.4 months, HR 0.69, 95% CI 0.56–0.85, P = 0.0003) (Figure 4A). Furthermore, a high VAT area was associated with significantly prolonged OS compared with patients with low VAT area (median 25.9 versus 19.2 months, HR 0.73, 95% CI 0.57–0.93, P = 0.0096) (Figure 4B). In contrast, the relationship between SAT and survival outcomes was less pronounced. Among patients with EC and high SAT area, there was a numerically but not statistically significant improvement in PFS after ICI treatment compared with those with low SAT area (median 7.2 versus 5.8 months, HR 0.82, 95% CI 0.67–1.01, P = 0.06) (Figure 4C). Similarly, an elevated SAT area was numerically associated with prolonged OS compared with EC patients with a low SAT area (median 23.1 versus 19.5 months, HR 0.79, 95% CI 0.62–1, P = 0.0531) (Figure 4D). To further characterize the association between body-fat composition and clinical outcomes, we stratified VAT and SAT by quartiles. We found an incremental association between VAT area and PFS, but not OS, with patients in the highest quartile of VAT area showing a significant increase in PFS compared with patients in the lowest VAT area quartile (median 8.3 versus 5.7 months, HR 0.65, 95% CI 0.48–0.87, P = 0.004) (Supplemental Figure 2, A and B); in contrast, no association with PFS or OS was observed in the analysis of SAT area by quartiles (Supplemental Figure 2, C and D). Prior studies have suggested that the ratio between VAT and SAT could be a better predictor of cardiometabolic risk compared with VAT area measurement and BMI (26, 27). Hence, we determined the VAT/SAT ratio in our cohort and stratified patients in high and low VAT/SAT ratio according to the median (0.3723). Patients with a high VAT/SAT ratio exhibited a significant improvement in PFS (median 7.25 versus 5.5 months, HR 0.75, 95% CI 0.61–0.92, P = 0.0049), but not OS (Supplemental Figure 3, A and B). In a subgroup analysis performed in patients treated with lenvatinib and pembrolizumab (n = 296), we observed a trend toward both high VAT and SAT being associated with improved PFS, aligning with the significant results obtained in the larger cohort (Supplemental Figure 4, A–D).
Figure 4Survival outcomes after ICI in EC stratified by VAT and SAT area. Kaplan-Meier curves for (A) PFS and (B) OS in patients with EC following ICI treatment stratified by low and high VAT area (
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