Associations between Pretreatment Body Composition Features and Clinical Outcomes among Patients with Metastatic Clear Cell Renal Cell Carcinoma Treated with Immune Checkpoint Blockade.

PURPOSE: High body mass index (BMI) may lead to improved immune-checkpoint blockade (ICB) outcomes in metastatic clear cell renal cell carcinoma (mccRCC). However, BMI is a crude body size measure. We investigated BMI and radiographically assessed body composition (BC) parameters association with mccRCC ICB outcomes. EXPERIMENTAL DESIGN: Retrospective study of ICB-treated patients with mccRCC. BMI and BC variables [skeletal muscle index (SMI) and multiple adiposity indexes] were determined using pretreatment CT scans. We examined the associations between BMI and BC variables with ICB outcomes. Therapeutic responses per RECIST v1.1 were determined. We compared whole-transcriptomic patterns with BC variables in a separate cohort of 62 primary tumor samples. RESULTS: 205 patients with mccRCC were included in the cohort (74% were male, 71% were overweight/obese, and 53% were classified as low SMI). High-BMI patients experienced longer overall survival (OS) than normal-weight patients [unadjusted HR, 0.66; 95% confidence interval (CI), 0.45-0.97; P = 0.035]. The only BC variable associated with OS was SMI [unadjusted HR comparing low vs. high SMI 1.65 (95% CI: 1.13-2.43); P = 0.009]. However, this OS association became nonsignificant after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium score and line of therapy. No OS association was seen for adiposity and no BC variable was associated with progression-free survival or radiological responses. Tumors from patients with low SMI displayed increased angiogenic, inflammatory, and myeloid signals. CONCLUSIONS: Our findings highlight the relevance of skeletal muscle in the BMI paradox. Future studies should investigate if addressing low skeletal muscle in metastatic patients treated with ICB can improve survival.

Cytotoxic innate lymphoid cells sense cancer cell-expressed interleukin-15 to suppress human and murine malignancies.

Malignancy can be suppressed by the immune system. However, the classes of immunosurveillance responses and their mode of tumor sensing remain incompletely understood. Here, we show that although clear cell renal cell carcinoma (ccRCC) was infiltrated by exhaustion-phenotype CD8+ T cells that negatively correlated with patient prognosis, chromophobe RCC (chRCC) had abundant infiltration of granzyme A-expressing intraepithelial type 1 innate lymphoid cells (ILC1s) that positively associated with patient survival. Interleukin-15 (IL-15) promoted ILC1 granzyme A expression and cytotoxicity, and IL-15 expression in chRCC tumor tissue positively tracked with the ILC1 response. An ILC1 gene signature also predicted survival of a subset of breast cancer patients in association with IL-15 expression. Notably, ILC1s directly interacted with cancer cells, and IL-15 produced by cancer cells supported the expansion and anti-tumor function of ILC1s in a murine breast cancer model. Thus, ILC1 sensing of cancer cell IL-15 defines an immunosurveillance mechanism of epithelial malignancies.

Genomic and Metabolic Hallmarks of SDH- and FH-deficient Renal Cell Carcinomas.

BACKGROUND: Succinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC and FHRCC) are rare kidney cancers driven by loss of TCA cycle enzymes. OBJECTIVE: To define and compare the genomic and metabolomic hallmarks of SDHRCC and FHRCC. DESIGN, SETTING, AND PARTICIPANTS: We analyzed SDHRCC and FHRCC tumors with either immunohistochemical evidence of loss of protein expression or genomically confirmed biallelic inactivation of SDHA/B/C/D/AF2 or FH. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Somatic alterations were identified using clinical pipelines, with allele-specific copy number alterations (CNAs) identified using FACETS. Mass spectrometry-based metabolomic profiling was performed on available SDHRCC and FHRCC tumors. RESULTS AND LIMITATIONS: Tumors were analyzed for 42 patients (25 FHRCC, 17 SDHRCC). In the germline analysis, 16/17 SDHRCCs harbored a germline alteration in SDHB, whereas only 17/22 FHRCCs had pathogenic germline FH variants. SDHRCCs had a lower mutation burden (p = 0.02) and CNA burden (p = 0.0002) than FHRCCs. All SDHRCCs presented with deletion of chromosome 1p (overlapping SDHB), whereas FHRCCs demonstrated high but not ubiquitous loss of 1q (FH locus). Both SDHRCCs and FHRCCs exhibited significant idiopathic accumulation of the metabolite guanine. FHRCC tumors had elevated levels of urea cycle metabolites (argininosuccinate, citrulline, and fumarate), whereas SDHRCC tumors had elevation of numerous acylcarnitines. These characteristic metabolic changes allowed identification of a previously unrecognized SDH-deficient RCC. CONCLUSIONS: Despite sharing similar genetic etiology, SDHRCC and FHRCC represent distinct molecular entities with unique genetic and metabolic abnormalities. PATIENT SUMMARY: Kidney cancers driven by loss of the gene encoding either the succinate dehydrogenase or fumarate hydratase enzyme are rare. We sought to define and compare the genetic and metabolic features of these cancer entities.

Improved prediction of immune checkpoint blockade efficacy across multiple cancer types.

Only a fraction of patients with cancer respond to immune checkpoint blockade (ICB) treatment, but current decision-making procedures have limited accuracy. In this study, we developed a machine learning model to predict ICB response by integrating genomic, molecular, demographic and clinical data from a comprehensively curated cohort (MSK-IMPACT) with 1,479 patients treated with ICB across 16 different cancer types. In a retrospective analysis, the model achieved high sensitivity and specificity in predicting clinical response to immunotherapy and predicted both overall survival and progression-free survival in the test data across different cancer types. Our model significantly outperformed predictions based on tumor mutational burden, which was recently approved by the U.S. Food and Drug Administration for this purpose1. Additionally, the model provides quantitative assessments of the model features that are most salient for the predictions. We anticipate that this approach will substantially improve clinical decision-making in immunotherapy and inform future interventions.

Evolving biological associations of upfront cytoreductive nephrectomy in metastatic renal cell carcinoma.

BACKGROUND: Systemic responses to cytoreductive nephrectomy (CN) in the management of metastatic renal cell carcinoma (mRCC) are variable and difficult to anticipate. The authors aimed to determine the association of CN with modifiable International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors and oncological outcomes. METHODS: Consecutive patients with mRCC referred for potential CN (2009-2019) were reviewed. The primary outcome was overall survival (OS); variables of interest included undergoing CN and the baseline number of modifiable IMDC risk factors (anemia, hypercalcemia, neutrophilia, thrombocytosis, and reduced performance status). For operative cases, the authors evaluated the effects of IMDC risk factor dynamics, measured 6 weeks and 6 months after CN, on OS and postoperative treatment disposition. RESULTS: Of 245 treatment-naive patients with mRCC referred for CN, 177 (72%) proceeded to surgery. The CN cases had fewer modifiable IMDC risk factors (P = .003), including none in 71 of 177 patients (40.1%); fewer metastases (P = .011); and higher proportions of clear cell histology (P = .012). In a multivariable analysis, surgical selection, number of IMDC risk factors, metastatic focality, and histology were associated with OS. Total risk factors changed for 53.8% and 57.2% of the patients from the preoperative period to 6 weeks and 6 months after CN, respectively. Adjusted for preoperative IMDC risk scores, an increase in IMDC risk factors at 6 weeks and 6 months was associated with adverse OS (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.13-2.19; P = .007; HR, 2.52; 95% CI, 1.74-3.65; P < .001). CONCLUSIONS: IMDC risk factors are dynamic clinical variables that can improve after upfront CN in select patients, and this suggests a systemic benefit of cytoreduction, which may confer clinically meaningful prognostic implications.

High Response Rate and Durability Driven by HLA Genetic Diversity in Patients with Kidney Cancer Treated with Lenvatinib and Pembrolizumab.

Immune checkpoint blockade (ICB) therapy has substantially improved the outcomes of patients with many types of cancers, including renal cell carcinoma (RCC). Initially studied as monotherapy, immunotherapy-based combination regimens have improved the clinical benefit achieved by ICB monotherapy and have revolutionized RCC treatment. While biomarkers like PD-L1 and tumor mutational burden (TMB) are FDA approved as biomarkers for ICB monotherapy, there are no known biomarkers for combination immunotherapies. Here, we describe the clinical outcomes and genomic determinants of response from a phase Ib/II clinical trial on patients with advanced RCC evaluating the efficacy of lenvatinib, a multi-kinase inhibitor mainly targeting VEGFR and FGFR plus pembrolizumab, an anti-PD1 immunotherapy. Concurrent treatment with lenvatinib and pembrolizumab resulted in an objective response rate of 79% (19/24) and tumor shrinkage in 96% (23/24) of patients. While tumor mutational burden (TMB) did not predict for clinical benefit, germline HLA-I diversity strongly impacted treatment efficacy. Specifically, HLA-I evolutionary divergence (HED), which measures the breadth of a patient's immunopeptidome, was associated with both improved clinical benefit and durability of response. Our results identify lenvatinib plus pembrolizumab as a highly active treatment strategy in RCC and reveal HLA-I diversity as a critical determinant of efficacy for this combination. HED also predicted better survival in a separate cohort of patients with RCC following therapy with anti-PD-1-based combination therapy. IMPLICATIONS: These findings have substantial implications for RCC therapy and for understanding immunogenetic mechanisms of efficacy and warrants further investigation.

A qualitative framework of non-selection factors for cytoreductive nephrectomy.

PURPOSE: Cytoreductive nephrectomy (CN) benefits a subset of patients with metastatic renal cell carcinoma (mRCC), however proper patient selection remains complex and controversial. We aim to characterize urologists' reasons for not undertaking a CN at a quaternary cancer center. METHODS: Consecutive patients with mRCC referred to MSKCC urologists for consideration of CN between 2009 and 2019 were included. Baseline clinicopathologic characteristics were used to compare patients selected or rejected for CN. The reasons cited for not operating and the alternative management strategies recommended were extrapolated. Using an iterative thematic analysis, a framework of reasons for rejecting CN was designed. Kaplan-Meier estimates tested for associations between the reasons for not undertaking a CN and overall survival (OS). RESULTS: Of 297 patients with biopsy-proven mRCC, 217 (73%) underwent CN and 80 (27%) did not. Median follow-up of patients alive at data cut-off was 27.3 months. Non-operative patients were older (p = 0.014), had more sites of metastases (p = 0.008), harbored non-clear cell histology (p = 0.014) and reduced performance status (p < 0.001). The framework comprised seven distinct themes for recommending non-operative management: two patient-fitness considerations and five oncological considerations. These considerations were associated with OS; four of the oncological factors conferred a median OS of less than 12 months (p < 0.001). CONCLUSION: We developed a framework of criteria by which patients were deemed unsuitable candidates for CN. These new insights provide a novel perspective on surgical selection, could potentially be applicable to other malignancies and possibly have prognostic implications.

Pretreatment neutrophil-to-lymphocyte ratio and mutational burden as biomarkers of tumor response to immune checkpoint inhibitors.

Treatment with immune checkpoint inhibitors (ICI) has demonstrated clinical benefit for a wide range of cancer types. Because only a subset of patients experience clinical benefit, there is a strong need for biomarkers that are easily accessible across diverse practice settings. Here, in a retrospective cohort study of 1714 patients with 16 different cancer types treated with ICI, we show that higher neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poorer overall and progression-free survival, and lower rates of response and clinical benefit, after ICI therapy across multiple cancer types. Combining NLR with tumor mutational burden (TMB), the probability of benefit from ICI is significantly higher (OR = 3.22; 95% CI, 2.26-4.58; P < 0.001) in the NLR low/TMB high group compared to the NLR high/TMB low group. NLR is a suitable candidate for a cost-effective and widely accessible biomarker, and can be combined with TMB for additional predictive capacity.

The Clinicopathologic and Molecular Landscape of Clear Cell Papillary Renal Cell Carcinoma: Implications in Diagnosis and Management.

BACKGROUND: Clear cell papillary renal cell carcinoma (CCPRCC) is a recently described tumor entity. Several questions remain about its epidemiology, molecular features, and clinical behavior. OBJECTIVE: To comprehensively evaluate clinicopathologic and molecular features of CCPRCC, and compare it with more common kidney cancer subtypes. DESIGN, SETTING, AND PARTICIPANTS: We identified 89 CCPRCC patients and compared their clinicopathologic features with 1120 localized clear cell renal cell carcinoma (ccRCC) and 129 type 1 papillary renal cell carcinoma (pRCC) patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Nonparametric statistical testing was used to compare relevant features between tumor types. Overall, cancer-specific survival (CSS) and metastasis-free survival estimates were calculated from initial diagnosis using the Kaplan-Meier method. Patients with ipsilateral multifocal disease were explored further. A subset of CCPRCC tumors underwent genomic analysis and were compared with other RCC subtypes. RESULTS AND LIMITATIONS: A higher proportion of female (45% vs 32%) and African-American (19% vs 3%) patients were observed in the CCPRCC cohort than in the ccRCC and pRCC cohorts. CCPRCC tumors also had increased odds of presenting with additional ipsilateral masses (odds ratio [OR]: 4.41 [confidence interval {CI}: 2.34, 8.15], p < 0.001) and bilateral disease (OR: 4.80 [CI: 2.40, 9.59], p < 0.001) compared with ccRCC tumors. On molecular analysis, CCPRCC tumors showed fewer somatic aberrations and a greater degree of mitochondrial DNA depletion. In multifocal CCPRCC tumors, histologic concordance among the different renal cell carcinoma masses was estimated at 44% (7/16), and none of the individuals presenting exclusively with CCPRCC tumors developed metastatic disease after 5 yr. In contrast, multifocal tumors with CCPRCC and other nonconcordant histologies were more likely to experience adverse outcomes (CSS, log rank p = 0.034). CONCLUSIONS: CCPRCC is characterized by distinct molecular and epidemiologic features that could be used to refine current diagnostic approaches. Although their clinical course is generally indolent, multifocal CCPRCC tumors represent a unique diagnostic challenge. In this context, single-mass biopsies could miss concomitant aggressive disease, with a potential negative impact on patient outcomes. Furthermore, high discordance rates in multifocal CCPRCC tumors have important clinical implications in management. PATIENT SUMMARY: We explored the molecular and clinical features of clear cell papillary renal cell carcinoma (CCPRCC) relative to other kidney cancer subtypes. While CCPRCC generally conveys a good prognosis, additional caution should be taken when it is diagnosed using biopsy if multiple kidney masses are present.