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Aim The assessment of deep myometrial invasion (MI) and lymph node involvement is of utmost importance in the preoperative staging of endometrial cancer (EC). Imaging parameters derived respectively from MRI and PET have shown good predictive value. The main aim of the present study is to assess the diagnostic performance of hybrid 18F-FDG PET/MRI in EC staging, with particular focus on MI and lymphnodal involvement detection. Patients and Methods Prospective monocentric study including 35 patients with biopsy-proven EC undergoing preoperative 18F-FDG PET/MRI (December 2018-March 2021) for staging purpose. Histological examination was the reference standard. PET (SUVmax, SUVmean with a threshold of 40% of SUVmax-SUVmean40, metabolic tumor volume, total lesion glycolysis) and MRI (volume index [VI], total tumor volume, tumor volume ratio [TVR], mean apparent diffusion coefficient, minimum apparent diffusion coefficient) parameters were calculated on the primary tumor, and their role in predicting EC risk group, the presence of lymphovascular space invasion (LVSI), and MI was assessed. Receiver operating characteristics analysis was used to assess the predictive value of PET and MRI parameters on EC characteristics. Results Patients' median age was 66.57 years (SD, 10.21 years). 18F-FDG PET/MRI identified the primary tumor in all patients. Twenty-two of 35 patients had high-risk EC and 13/35 low-risk disease; 13/35 presented LVSI, 22/35 had deep MI at histological examination, and 13/35 had p53 hyperexpression. PET/MRI was able to detect lymphnodal involvement with high accuracy and high specificity (sensitivity of 0.8571, specificity of 0.9286, accuracy of 0.9143), also showing a high negative predictive value (NPV) for lymphnodal involvement (NPV of 0.9630, positive predictive value [PPV] of 0.7500). The assessment of deep MI using PET/MRI correctly staged 27 patients (77.1%; sensitivity of 0.7273, specificity of 0.8462, accuracy of 0.7714), with also a good PPV (PPV of 0.8889, NPV of 0.647). MRI-derived total tumor volume, VI, and TVR were significant in predicting EC groups (high-risk vs low-risk patients) (P = 0.0059, 0.0235, 0.0181, respectively). MRI-derived volume, VI, TVR, and PET-derived metabolic tumor volume and total lesion glycolysis were able to predict LVSI (P = 0.0023, 0.0068, 0.0068, 0.0027, 0.01394, respectively). Imaging was not able to predict grading, presence of deep MI, nor hyperexpression of p53. Conclusions 18F-FDG PET/MRI has good accuracy in preoperative staging of EC; PET and MRI parameters have synergic role in preoperatively predicting LVSI, with MRI parameters being also predictive for EC risk group.

Purpose. Assessment of deep myometrial invasion (MI) and lymphovascular space invasion (LVSI) is of utmost importance in preoperative staging of endometrial cancer (EC). Imaging parameters derived respectively from MRI and PET have shown good predictive value. Aim of the present study is to assess the diagnostic performance of hybrid 18F-FDG PET/MRI in EC staging, with particular focus on MI and LVSI detection.Methods. Prospective monocentric study including 35 patients with biopsy-proven EC undergoing preoperative 18F-FDG PET/MRI for staging purpose. Histological examination was the reference standard. PET (SUVmax, SUVmean40, MTV40, TLG40) and MRI (volume index-VI, total tumor volume-TTV, tumor volume ratio-TVR, ADCmean, ADCmin) parameters were calculated on the primary tumor, and their role in predicting histological findings (grade, high- vs. low-risk groups, LVSI, MI, p53 hyper-expression) was assessed through a ROC analysis.Results. 18F-FDG-PET/MRI identified the primary tumor in all patients. In the LVSI detection, PET/MRI demonstrated high accuracy, specificity and negative predictive value (sensitivity=0.8571, specificity=0.9286, accuracy=0.9143, NPV=0.9630, PPV=0.7500). Assessment of MI using PET/MRI correctly staged 27 patients, showing a good positive predictive value (77.1%; sensitivity= 0.7273, specificity=0.8462, accuracy=0.7714, PPV=0.8889, NPV=0.647). VI, TTV, and TVR significantly predicted risk groups (p=0.0059, 0.0235, 0.0181, respectively). VI, TTV, TVR, MTV40 and TLG40 significantly predicted LVSI (p=0.0023, 0.0068, 0.0068, 0.0027, 0.0139, respectively). Imaging was not able to predict grading, MI nor p53 hyper-expression.Conclusion. 18F-FDG-PET/MRI has good accuracy in preoperative staging of EC; PET and MRI parameters have synergic role in preoperatively predicting LVSI, with MRI parameters being also predictive for EC risk groups.

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., Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

Purpose: We sought to validate levels of CD8+ tumor-infiltrating cells (TIC) expressing PD-1 but not TIM-3 and LAG-3 (IF biomarker; Pignon and colleagues, 2019) and to investigate human endogenous retroviruses (hERV) as predictors of response to anti–PD-1 in a randomized trial of nivolumab (nivo) versus everolimus (evero) in patients with metastatic clear cell renal cell carcinoma (mccRCC; CheckMate-025). Experimental Design: Tumor tissues (nivo: n = 116, evero: n = 107) were analyzed by multiparametric immunofluorescence (IF) and qRT-PCR. Genomic/transcriptomic analyses were performed in a subset of samples. Clinical endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and durable response rate (DRR, defined as complete response or partial response with a PFS ≥ 12 months). Results: In the nivo (but not evero) arm, patients with high-IF biomarker density (24/116, 20.7%) had higher ORR (45.8% vs. 19.6%, P = 0.01) and DRR (33.3% vs. 14.1%, P = 0.03) and longer median PFS (9.6 vs. 3.7 months, P = 0.03) than patients with low-IF biomarker. By RNA sequencing, several inflammatory pathways (q < 0.1) and immune-related gene signature scores (q < 0.05) were enriched in the high-IF biomarker group. When combined with the IF biomarker, tumor cell (TC) PD-L1 expression (≥1%) further separated clinical outcomes in the nivo arm. ERVE-4 expression was associated with increased DRR and longer PFS in nivo-treated patients. Conclusions: High levels of CD8+ TIC expressing PD-1 but not TIM-3 and LAG-3 and ERVE-4 expression predicted response to nivo (but not to evero) in patients with mccRCC. Combination of the IF biomarker with TC PD-L1 improved its predictive value, confirming our previous findings.

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 tumors1–3, 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 shed light on the molecular drivers of aggressivity and responsiveness to immune checkpoint inhibitors of S/R RCC tumors.

5010 Background: Immune checkpoint inhibitors targeting the PD-1 pathway have transformed the management of many advanced malignancies, including clear cell renal cell carcinoma (ccRCC), but the drivers and resistors of PD-1 response remain incompletely elucidated. Further, the common paradigm in solid tumor immunology that pre-existing CD8+ T cell infiltration, in combination with high numbers of nonsynonymous mutations (which, in the context of diverse HLA class I alleles, may be presented as neoantigens) drives response to PD-1 blockade, has not been thoroughly explored in ccRCC. Methods: We analyzed 592 tumors collected from advanced ccRCC patients enrolled in prospective clinical trials (CheckMate 009, CheckMate 010, CheckMate 025) of treatment with PD-1 blockade (n = 362) or mTOR inhibition (as control arm; n = 230) by whole-exome (n = 454) and RNA-sequencing (n = 311), integrated with CD8 immunofluorescence analysis (n = 219), to uncover the immunogenomic determinants of therapeutic response and survival. Wilcoxon rank-sum test was used to compare somatic alteration burden between clinical benefit (CB) v.s no CB (NCB); Fisher’s exact test was used to compare mutations and copy number alteration by infiltration state; and hazard ratio (HR) was calculated from Cox PH model for progression-free (PFS) and overall survival (OS) endpoints. All tests were at a significance level of p < 0.05. Results: Conventional genomic markers (tumor mutation burden, p = 0.81; neoantigen load, p = 0.47 for CB vs. NCB) and degree of CD8+ T cell infiltration (p = 0.88 for PFS; p = 0.65 for OS) were not associated with clinical response or altered survival with PD-1 blockade. These advanced ccRCC tumors were highly CD8+ T cell infiltrated, with only 22% having an immune desert phenotype and 5% with an immune excluded phenotype. Our analysis revealed that CD8+ T cell infiltrated tumors are depleted of clinically favorable PBRM1 mutations (p = 0.013) and enriched for unfavorable chromosomal losses of 9p21.3 (p < 0.001) when compared to non-infiltrated tumors. When found within infiltrated tumors, del(9p21.3) was associated with worse CB rate (36% (9/25) for del(9p21.3) vs. 88% (7/8) for wildtype at that locus, p = 0.017) and worse survival (HR = 2.38, p = 0.01 for PFS; HR = 2.44, p = 0.01 for OS) with PD-1 blockade. Conclusions: These data demonstrate how the potential interplay of immunophenotypes with somatic mutations and chromosomal alterations impacts therapeutic efficacy in advanced ccRCC.

5023 Background: We previously showed that levels of CD8+ tumor infiltrating cells (TIC) expressing PD-1 but not TIM-3 and LAG-3 (CD8+ PD1+TIM3−LAG3−) were associated with response to nivolumab (nivo) in pretreated mccRCC pts (Pignon et al, 2019). Here, we sought to validate these findings in a randomized Phase III trial of nivo versus everolimus (evero) (CM-025) and explore the association of the biomarker with transcriptomic profiles. Methods: Tumor tissues from the CM-025 trial were analyzed (nivo arm: n = 116, evero arm: n = 107). Density/percentage of CD8+ PD1+TIM3−LAG3− TIC was evaluated by immunofluorescence (IF) and PD-L1 expression on tumor cells (TC) was evaluated by IHC. Linear association with outcomes was assessed using binary logistic (ORR, clinical benefit (CB) defined as CR/PR and PFS≥12 months) and Cox PH (PFS, OS) regression models (1-sided p-values shown). Bulk RNA-seq was performed in a subset of samples (n = 71) and data analyzed using ssGSEA and Gene Signature Scores (GSS). Results: In the nivo arm, density of CD8+ PD1+TIM3−LAG3− TIC (IF biomarker) was associated with ORR (OR = 1.43, p = 0.03) and CB (OR = 1.54, p = 0.02) while a trend was observed with PFS (HR = 0.87, p = 0.06). At an optimized cutoff, nivo treated pts with high IF biomarker (24/116, 20.7%) had higher ORR (45.8% vs 19.6%, p = 0.01) and CB (33.3% vs 14.1%, p = 0.03) and longer median PFS (9.6 vs 3.7 months, p = 0.03) than pts with low IF biomarker. A significant interaction between the IF biomarker and treatment was seen for both PFS and OS (2-sided p = 0.02 and 2-sided p = 0.08, respectively; significance determined as p < 0.15). By bulk RNA-seq, several inflammatory pathways (FDR q < 0.1) and inflammatory GSS (FDR q < 0.05) were enriched in the high IF biomarker group. When combined with the IF biomarker, TC PD-L1 expression (≥1%) further separated clinical outcomes (ORR, CB and PFS) in the nivo arm. In the evero arm, the IF biomarker was neither prognostic nor predictive of any clinical outcome. Conclusions: High levels of CD8+ PD1+TIM3−LAG3− TIC predicted response to nivo (but not to control evero) in mccRCC pts and were associated with activation of inflammatory response. Combination with TC PD-L1 further improved its predictive value, confirming our previous findings (Pignon et al, 2019). Further validation in the setting of first-line anti-PD-1 therapy is ongoing.