Epigenomic signatures of sarcomatoid differentiation to guide the treatment of renal cell carcinoma.

Renal cell carcinoma with sarcomatoid differentiation (sRCC) is associated with poor survival and a heightened response to immune checkpoint inhibitors (ICIs). Two major barriers to improving outcomes for sRCC are the limited understanding of its gene regulatory programs and the low diagnostic yield of tumor biopsies due to spatial heterogeneity. Herein, we characterized the epigenomic landscape of sRCC by profiling 107 epigenomic libraries from tissue and plasma samples from 50 patients with RCC and healthy volunteers. By profiling histone modifications and DNA methylation, we identified highly recurrent epigenomic reprogramming enriched in sRCC. Furthermore, CRISPRa experiments implicated the transcription factor FOSL1 in activating sRCC-associated gene regulatory programs, and FOSL1 expression was associated with the response to ICIs in RCC in two randomized clinical trials. Finally, we established a blood-based diagnostic approach using detectable sRCC epigenomic signatures in patient plasma, providing a framework for discovering epigenomic correlates of tumor histology via liquid biopsy.

Safety and efficacy outcomes of early cessation of anti-PD1 therapy in patients 80 years or older: A retrospective cohort study.

Older patients have similar immune checkpoint inhibitor efficacy and rates of adverse events as younger patients, but appear to have decreased tolerability, particularly in the oldest patient cohort (>80 years), often leading to early cessation of therapy. We aimed to determine whether early discontinuation impacts efficacy of anti-PD-1 therapy in patients ≥80 years old. In this retrospective, multicenter, international cohort study, we examined 773 patients with 4 tumor types who were at least 80 years old and treated with anti-PD-1 therapy. We determined response rate, overall survival (OS), and progression-free survival (PFS) in patients who discontinued therapy early (<12 months) for reasons other than progression or death. We used descriptive statistics for demographics, response, and toxicity rates. Survival statistics were described using Kaplan Meier curves. Median (range) age at anti-PD-1 initiation was 83.0 (75.8-97.0) years. The cancer types included were melanoma (n = 286), non-small cell lung cancer (NSCLC) (n = 345), urothelial cell carcinoma (UCC) (n = 108), and renal cell carcinoma (RCC) (n = 34). Of these, 102 met the primary endpoint of <12 months to discontinuation for reasons other than death or progression. Median PFS and OS, respectively, for these patients were 34.4 months and 46.6 months for melanoma, 15.8 months and 23.4 months for NSCLC, and 10.4 months and 15.8 months for UCC. This study suggests geriatric patients who have demonstrated therapeutic benefit and discontinued anti-PD-1 therapy at less than 12 months of duration for reasons other than progression may have durable clinical benefit without additional therapy.

Clinical Outcomes Among Immunotherapy-Treated Patients With Primary Cardiac Soft Tissue Sarcomas: A Multicenter Retrospective Study.

Background: Primary cardiac soft tissue sarcomas (CSTS) affect young adults, with dismal outcomes. Objectives: The aim of this study was to investigate the clinical outcomes of patients with CSTS receiving immune checkpoint inhibitors (ICIs). Methods: A retrospective, multi-institutional cohort study was conducted among patients with CSTS between 2015 and 2022. The patients were treated with ICI-based regimens. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Objective response rates were determined according to Response Evaluation Criteria in Solid Tumors version 1.1. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events version 5.0. Results: Among 24 patients with CSTS, 17 (70.8%) were White, and 13 (54.2%) were male. Eight patients (33.3%) had angiosarcoma. At the time of ICI treatment, 18 patients (75.0%) had metastatic CSTS, and 4 (16.7%) had locally advanced disease. ICIs were administered as the first-line therapy in 6 patients (25.0%) and as the second-line therapy or beyond in 18 patients (75.0%). For the 18 patients with available response data, objective response rate was 11.1% (n = 2 of 18). The median PFS and median OS in advanced and metastatic CSTS (n = 22) were 5.7 months (95% CI: 2.8-13.3 months) and 14.9 months (95% CI: 5.7-23.7 months), respectively. The median PFS and OS were significantly shorter in patients with cardiac angiosarcomas than in those with nonangiosarcoma CSTS: median PFS was 1.7 vs 11 months, respectively (P < 0.0001), and median OS was 3.0 vs 24.0 months, respectively (P = 0.008). Any grade treatment-related adverse events occurred exclusively in the 15 patients with nonangiosarcoma CSTS (n = 7 [46.7%]), of which 6 (40.0%) were grade ≥3. Conclusions: Although ICIs demonstrate modest activity in CSTS, durable benefit was observed in a subset of patients with nonangiosarcoma, albeit with higher toxicity.

Clinical spectrum of Transthyretin amyloidogenic mutations among diverse population origins.

PURPOSE: Coding mutations in the Transthyretin (TTR) gene cause a hereditary form of amyloidosis characterized by a complex genotype-phenotype correlation with limited information regarding differences among worldwide populations. METHODS: We compared 676 diverse individuals carrying TTR amyloidogenic mutations (rs138065384, Phe44Leu; rs730881165, Ala81Thr; rs121918074, His90Asn; rs76992529, Val122Ile) to 12,430 non-carriers matched by age, sex, and genetically-inferred ancestry to assess their clinical presentations across 1,693 outcomes derived from electronic health records in UK biobank. RESULTS: In individuals of African descent (AFR), Val122Ile mutation was linked to multiple outcomes related to the circulatory system (fold-enrichment = 2.96, p = 0.002) with the strongest associations being cardiac congenital anomalies (phecode 747.1, p = 0.003), endocarditis (phecode 420.3, p = 0.006), and cardiomyopathy (phecode 425, p = 0.007). In individuals of Central-South Asian descent (CSA), His90Asn mutation was associated with dermatologic outcomes (fold-enrichment = 28, p = 0.001). The same TTR mutation was linked to neoplasms in European-descent individuals (EUR, fold-enrichment = 3.09, p = 0.003). In EUR, Ala81Thr showed multiple associations with respiratory outcomes related (fold-enrichment = 3.61, p = 0.002), but the strongest association was with atrioventricular block (phecode 426.2, p = 2.81 × 10- 4). Additionally, the same mutation in East Asians (EAS) showed associations with endocrine-metabolic traits (fold-enrichment = 4.47, p = 0.003). In the cross-ancestry meta-analysis, Val122Ile mutation was associated with peripheral nerve disorders (phecode 351, p = 0.004) in addition to cardiac congenital anomalies (fold-enrichment = 6.94, p = 0.003). CONCLUSIONS: Overall, these findings highlight that TTR amyloidogenic mutations present ancestry-specific and ancestry-convergent associations related to a range of health domains. This supports the need to increase awareness regarding the range of outcomes associated with TTR mutations across worldwide populations to reduce misdiagnosis and delayed diagnosis of TTR-related amyloidosis.

Epigenomic charting and functional annotation of risk loci in renal cell carcinoma.

While the mutational and transcriptional landscapes of renal cell carcinoma (RCC) are well-known, the epigenome is poorly understood. We characterize the epigenome of clear cell (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) by using ChIP-seq, ATAC-Seq, RNA-seq, and SNP arrays. We integrate 153 individual data sets from 42 patients and nominate 50 histology-specific master transcription factors (MTF) to define RCC histologic subtypes, including EPAS1 and ETS-1 in ccRCC, HNF1B in pRCC, and FOXI1 in chRCC. We confirm histology-specific MTFs via immunohistochemistry including a ccRCC-specific TF, BHLHE41. FOXI1 overexpression with knock-down of EPAS1 in the 786-O ccRCC cell line induces transcriptional upregulation of chRCC-specific genes, TFCP2L1, ATP6V0D2, KIT, and INSRR, implicating FOXI1 as a MTF for chRCC. Integrating RCC GWAS risk SNPs with H3K27ac ChIP-seq and ATAC-seq data reveals that risk-variants are significantly enriched in allelically-imbalanced peaks. This epigenomic atlas in primary human samples provides a resource for future investigation.

Ancestry-driven recalibration of tumor mutational burden and disparate clinical outcomes in response to immune checkpoint inhibitors.

The immune checkpoint inhibitor (ICI) pembrolizumab is US FDA approved for treatment of solid tumors with high tumor mutational burden (TMB-high; ≥10 variants/Mb). However, the extent to which TMB-high generalizes as an accurate biomarker in diverse patient populations is largely unknown. Using two clinical cohorts, we investigated the interplay between genetic ancestry, TMB, and tumor-only versus tumor-normal paired sequencing in solid tumors. TMB estimates from tumor-only panels substantially overclassified individuals into the clinically important TMB-high group due to germline contamination, and this bias was particularly pronounced in patients with Asian/African ancestry. Among patients with non-small cell lung cancer treated with ICIs, those misclassified as TMB-high from tumor-only panels did not associate with improved outcomes. TMB-high was significantly associated with improved outcomes only in European ancestries and merits validation in non-European ancestry populations. Ancestry-aware tumor-only TMB calibration and ancestry-diverse biomarker studies are critical to ensure that existing disparities are not exacerbated in precision medicine.

The Prostate Cancer Androgen Receptor Cistrome in African American Men Associates with Upregulation of Lipid Metabolism and Immune Response.

African-American (AA) men are more likely to be diagnosed with and die from prostate cancer than European American (EA) men. Despite the central role of the androgen receptor (AR) transcription factor in prostate cancer, little is known about the contribution of epigenetics to observed racial disparities. We performed AR chromatin immunoprecipitation sequencing on primary prostate tumors from AA and EA men, finding that sites with greater AR binding intensity in AA relative to EA prostate cancer are enriched for lipid metabolism and immune response genes. Integration with transcriptomic and metabolomic data demonstrated coinciding upregulation of lipid metabolism gene expression and increased lipid levels in AA prostate cancer. In a metastatic prostate cancer cohort, upregulated lipid metabolism associated with poor prognosis. These findings offer the first insights into ancestry-specific differences in the prostate cancer AR cistrome. The data suggest a model whereby increased androgen signaling may contribute to higher levels of lipid metabolism, immune response, and cytokine signaling in AA prostate tumors. Given the association of upregulated lipogenesis with prostate cancer progression, our study provides a plausible biological explanation for the higher incidence and aggressiveness of prostate cancer observed in AA men. SIGNIFICANCE: With immunotherapies and inhibitors of metabolic enzymes in clinical development, the altered lipid metabolism and immune response in African-American men provides potential therapeutic opportunities to attenuate racial disparities in prostate cancer.

Impact of renin-angiotensin system inhibitors on outcomes in patients with metastatic renal cell carcinoma treated with immune-checkpoint inhibitors.

BACKGROUND: Renin-angiotensin system inhibitors (RASi) have been shown to improve outcomes in studies of multiple malignancies by effects on the tumor microenvironment to enhance the immune repertoire and improve drug delivery. Repurposing RASi to treat metastatic renal cell carcinoma (mRCC) in combination with immune-checkpoint inhibitors (ICI) may improve survival coupled with tolerability and cost efficacy. We evaluated the impact of RASi on outcomes in mRCC patients receiving ICI. METHODS: This multicenter, retrospective cohort study included mRCC patients treated with ICI with or without RASi. The patients from Dana-Farber Cancer Institute (DFCI) were used as a discovery cohort, and the patients from University of California San Diego (UCSD) were used for validation. Receipt of an ICI (PD1/L1 and/or CTLA-4 inhibitors) was required. RASi use was defined as receipt of a RASi at baseline and for a minimum of 30 days after ICI initiation. For both the discovery and validation cohorts, the primary outcome assessed was overall survival (OS) and the secondary endpoints were time-to-treatment failure (TTF), and objective response rate (ORR). RESULTS: Overall, 229 patients who received an ICI were included: 100 patients from DFCI and 129 patients from UCSD. Concomitant RASi were administered in 30 patients (30%) in the DFCI cohort and 59 (45%) in the UCSD cohort. Median age at ICI initiation was 62.5 years in both cohorts. Median follow-up was 3.8 [IQR 3-5.3] years in the DFCI cohort, and 2.3 [IQR 1.4-3.6] years in the UCSD cohort. In the DFCI cohort, RASi was significantly associated with longer OS (adjusted-HR 0.35 [95% CI, 0.17-0.70], P = .003) and TTF (adjusted-HR 0.57 [0.36-0.92], P = .02). In the validation cohort, RASi was associated with TTF (adjusted HR, 0.60 [0.39-0.92], P = .02) and not statistically associated with OS (adjusted-HR 0.60 [0.34-1.06], P = .07). The propensity analysis, matching 83 patients from both cohorts receiving RASi while on ICI with 83 who did not, showed that RASi significantly improved OS (HR 0.59 [0.37-0.95], P = .03) and TTF (HR 0.60 [0.43-0.85], P = .0034). CONCLUSIONS: RASi was associated with improved OS and TTF in mRCC patients receiving ICI. This provides a rationale for prospective randomized studies combining ICI and RASi in mRCC patients.

Response to supraphysiological testosterone is predicted by a distinct androgen receptor cistrome.

The androgen receptor (AR) is a master transcription factor that regulates prostate cancer (PC) development and progression. Inhibition of AR signaling by androgen deprivation is the first-line therapy with initial efficacy for advanced and recurrent PC. Paradoxically, supraphysiological levels of testosterone (SPT) also inhibit PC progression. However, as with any therapy, not all patients show a therapeutic benefit, and responses differ widely in magnitude and duration. In this study, we evaluated whether differences in the AR cistrome before treatment can distinguish between SPT-responding (R) and -nonresponding (NR) tumors. We provide the first preclinical evidence to our knowledge that SPT-R tumors exhibit a distinct AR cistrome when compared with SPT-NR tumors, indicating a differential biological role of the AR. We applied an integrated analysis of ChIP-Seq and RNA-Seq to the pretreatment tumors and identified an SPT-R signature that distinguishes R and NR tumors. Because transcriptomes of SPT-treated clinical specimens are not available, we interrogated available castration-resistant PC (CRPC) transcriptomes and showed that the SPT-R signature is associated with improved survival and has the potential to identify patients who would respond to SPT. These findings provide an opportunity to identify the subset of patients with CRPC who would benefit from SPT therapy.

Variation in targetable genomic alterations in non-small cell lung cancer by genetic ancestry, sex, smoking history, and histology.

BACKGROUND: Genomic alterations in 8 genes are now the targets of FDA-approved therapeutics in non-small cell lung cancer (NSCLC), but their distribution according to genetic ancestry, sex, histology, and smoking is not well established. METHODS: Using multi-institutional genetic testing data from GENIE, we characterize the distribution of targetable genomic alterations in 8 genes among 8675 patients with NSCLC (discovery cohort: DFCI, N = 3115; validation cohort: Duke, Memorial Sloan Kettering Cancer Center, Vanderbilt, N = 5560). For the discovery cohort, we impute genetic ancestry from tumor-only sequencing and identify differences in the frequency of targetable alterations across ancestral groups, smoking pack-years, and histologic subtypes. RESULTS: We identified variation in the prevalence of KRASG12C, sensitizing EGFR mutations, MET alterations, ALK, and ROS1 fusions according to the number of smoking pack-years. A novel method for computing continental (African, Asian, European) and Ashkenazi Jewish ancestries from panel sequencing enables quantitative analysis of the correlation between ancestry and mutation rates. This analysis identifies a correlation between Asian ancestry and EGFR mutations and an anti-correlation between Asian ancestry and KRASG12C mutation. It uncovers 2.7-fold enrichment for MET exon 14 skipping mutations and amplifications in patients of Ashkenazi Jewish ancestry. Among never/light smokers, targetable alterations in LUAD are significantly enriched in those with Asian (80%) versus African (49%) and European (55%) ancestry. Finally, we show that 5% of patients with squamous cell carcinoma (LUSC) and 17% of patients with large cell carcinoma (LCLC) harbor targetable alterations. CONCLUSIONS: Among patients with NSCLC, there was significant variability in the prevalence of targetable genomic alterations according to genetic ancestry, histology, and smoking. Patients with LUSC and LCLC have 5% rates of targetable alterations supporting consideration for sequencing in those subtypes.

Prevalence of pathogenic germline cancer risk variants in testicular cancer patients: Identifying high risk groups.

BACKGROUND: Germline studies in testicular cancer have focused on unselected populations but so far have not led to recommendations for testicular cancer screening. OBJECTIVE: Herein, we hypothesized that men with testicular cancer and an additional risk factor for hereditary cancer predisposition carry a higher rate of pathogenic variants than men with testicular cancer without another risk factor. METHODS AND RESULTS: 187 patients with a personal history of testicular cancer underwent germline testing via Invitae. Patients were divided into low-risk and high-risk patients. Low-risk patients (n=83) had testicular cancer as their only primary malignancy without a family history of testicular cancer. High-risk patients (n=104) had additional primary malignancies and/or a family history of testicular cancer. 23.1% of patients harbored pathogenic germline variants with 19.6% carrying actionable variants. Among low-risk patients, 13.5% carried pathogenic variants versus 29.9% in the high-risk cohort. Of patients with a family history of non-testicular cancers and a personal history of additional primary malignancies, 32% harbored pathogenic variants. CONCLUSION: High-risk patients are twice as likely to harbor pathogenic variants compared to low-risk patients. Importantly, patients with a family history of cancer and other primary malignancies represent a subset of patients that may benefit from genetic evaluation.

Clonal hematopoiesis is associated with increased risk of progression of asymptomatic Waldenström macroglobulinemia.

Clonal hematopoiesis (CH) is associated with adverse outcomes in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma undergoing autologous stem cell transplantation. Still, its implications for patients with indolent NHL have not been well studied. We report the prevalence of CH in patients with Waldenström macroglobulinemia (WM) and its association with clinical outcomes. To unambiguously differentiate CH mutations from those in the WM clone, CH was defined by the presence of somatic mutations in DNMT3A, TET2, or ASXL1 (DTA) and was detected in 14% of 587 patients with IgM monoclonal gammopathy of undetermined significance (MGUS), smoldering WM (SWM) or WM. The presence and size of DTA clones were associated with older age. Patients with CH had an increased risk of progression from MGUS or SWM to WM, but not worse overall survival in this cohort. These findings further illuminate the clinical effects of CH in patients with indolent NHL such as WM.

CDH1 germline variants are enriched in patients with colorectal cancer, gastric cancer, and breast cancer.

BACKGROUND AND AIMS: CDH1 germline variants have been linked to heritability in diffuse gastric (DGC) and lobular breast cancer (LBC). Studies have not yet assessed whether CDH1 is a cancer-susceptibility gene in other cancers. Herein, we mapped the landscape of pathogenic and likely pathogenic (P/LP) germline variants in CDH1 across various cancers and ethnicities. METHODS: We evaluated CDH1 germline P/LP variants in 212,944 patients at one CLIA-certified laboratory (Invitae) and described their frequency in 7 cancer types. We screened for CDH1 variant enrichment in each cancer relative to a cancer-free population from The Genome Aggregation Database version 3 (gnomADv3). RESULTS: CDH1 P/LP variants were identified in 141 patients, most commonly in patients with DGC (27/408, 6.6%) followed by colorectal signet-ring cell cancer (CSRCC; 3/79, 3.8%), gastric cancer (56/2756, 2%), and LBC (22/6809, 0.3%). CDH1 P/LP variants were enriched in specific ethnic populations with breast cancer, gastric cancer, CRC, LBC, DGC, and CSRCC compared to matched ethnicities from gnomADv3. CONCLUSION: We report for the first time the prevalence of P/LP CDH1 variants across several cancers and show significant enrichment in CDH1 P/LP variants for patients with CSRCC, DGC, and LBC across various ethnicities. Future prospective studies are warranted to validate these findings.

Clinical Outcomes and Toxic Effects of Single-Agent Immune Checkpoint Inhibitors Among Patients Aged 80 Years or Older With Cancer: A Multicenter International Cohort Study.

IMPORTANCE: Geriatric (aged ≥80 years) patients are historically underrepresented in cancer clinical trials. Little is known about the efficacy of immune checkpoint inhibitors (ICIs) in geriatric patients. These agents are associated with immune-related adverse events (irAEs), which may be particularly associated with morbidity in this population. OBJECTIVE: To provide insight into the clinical outcomes and safety of ICIs among geriatric patients (aged ≥80 years) with cancer. DESIGN, SETTING, AND PARTICIPANTS: A Multicenter, international retrospective study of 928 geriatric patients with different tumors treated with single-agent ICIs between 2010 to 2019 from 18 academic centers in the US and Europe. Analyses were conducted from January 2021 to April 2021. MAIN OUTCOMES AND MEASURES: Clinical outcomes and irAE patterns in geriatric patients treated with single-agent ICIs. RESULTS: Median (range) age of the 928 patients at ICI initiation was 83.0 (75.8-97.0) years. Most patients (806 [86.9%]) were treated with anti-programmed cell death 1 therapy. Among the full cohort, the 3 most common tumors were non-small cell lung cancer (NSCLC, 345 [37.2%]), melanoma (329 [35.5%]), and genitourinary (GU) tumors (153 [16.5%]). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median PFS and OS, respectively, were 6.7 and 10.9 months (NSCLC), 11.1 and 30.0 months (melanoma), and 6.0 and 15.0 months (GU). Within histologically specific subgroups (NSCLC, melanoma, and GU), clinical outcomes were similar across age subgroups (aged <85 vs ≥85 years). Among all 928 patients, 383 (41.3%) experienced ≥1 irAE(s), including 113 (12.2%) that were reported to be grade (G) 3 to 4 based on Common Terminology Criteria for Adverse Events (version 5.0). The median time to irAE onset was 9.8 weeks; 219 (57%) occurred within the first 3 months after ICI initiation. Discontinuation of treatment with ICIs owing to irAEs occurred in 137 (16.1%) patients. There was no significant difference in the rate of irAEs among patients aged younger than 85, 85 to 89, and 90 years or older. Despite the similar rate of G3 or higher irAEs, ICIs were discontinued due to irAEs more than twice as often among patients aged 90 years or older compared with patients younger than 90 years (30.9% vs 15.1%, P = .008). CONCLUSIONS AND RELEVANCE: The findings of this international cohort study suggest that treatment with ICIs may be effective and generally well tolerated among older patients with cancer, though ICI discontinuation owing to irAEs was more frequent with increasing age.

Care disruptions among patients with lung cancer: A COVID-19 and cancer outcomes study.

INTRODUCTION: Patients with lung cancer (LC) are susceptible to severe outcomes from COVID-19. This study evaluated disruption to care of patients with LC during the COVID-19 pandemic. METHODS: The COVID-19 and Cancer Outcomes Study (CCOS) is a prospective cohort study comprised of patients with a current or past history of hematological or solid malignancies with outpatient visits between March 2 and March 6, 2020, at two academic cancer centers in the Northeastern United States (US). Data was collected for the three months prior to the index week (baseline period) and the following three months (pandemic period). RESULTS: 313 of 2365 patients had LC, 1578 had other solid tumors, and 474 had hematological malignancies. Patients with LC were not at increased risk of COVID-19 diagnosis compared to patients with other solid or hematological malignancies. When comparing data from the pandemic period to the baseline period, patients with LC were more likely to have a decrease in in-person visits compared to patients with other solid tumors (aOR 1.94; 95% CI, 1.46-2.58), but without an increase in telehealth visits (aOR 1.13; 95% CI 0.85-1.50). Patients with LC were more likely to experience pandemic-related treatment delays than patients with other solid tumors (aOR 1.80; 95% CI 1.13-2.80) and were more likely to experience imaging/diagnostic procedure delays than patients with other solid tumors (aOR 2.59; 95% CI, 1.46-4.47) and hematological malignancies (aOR 2.01; 95% CI, 1.02-3.93). Among patients on systemic therapy, patients with LC were also at increased risk for decreased in-person visits and increased treatment delays compared to those with other solid tumors. DISCUSSION: Patients with LC experienced increased cancer care disruption compared to patients with other malignancies during the early phase of the COVID-19 pandemic. Focused efforts to ensure continuity of care for this patient population are warranted.

CDKN2A Alterations and Response to Immunotherapy in Solid Tumors.

PURPOSE: Immune checkpoint inhibitors (ICI) have shown clinical benefit in many types of metastatic cancers with only a few predictive biomarkers identified so far. CDKN2A is commonly altered in human cancers, but prior studies have provided conflicting evidence regarding the association between CDKN2A genomic alterations (GA) and response to ICIs. Herein, we examined the impact of loss-of-function CDKN2A alterations on response and survival in patients treated with ICIs. EXPERIMENTAL DESIGN: We studied the association between loss-of-function CDKN2A alterations and the response to ICIs in two independent cohorts of six different cancer types. Seven hundred and eighty-nine patients treated at Dana-Farber Cancer Institute (DFCI; Boston, MA) and 1,250 patients treated at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY) were included in the final analysis. Patients' tumors were sequenced using Oncopanel or MSK-IMPACT. RNA sequencing data from The Cancer Genome Atlas and IMvigor210 were used to investigate differences in the tumor microenvironment. RESULTS: In the DFCI cohort, CDKN2A GAs were associated with poor response and survival in patients with urothelial carcinoma treated with ICIs, but not those treated with platinum-based therapy. Similarly, CDKN2A GAs were associated with worse outcomes in the MSKCC urothelial carcinoma cohort treated with ICIs. There was no association of CDKN2A status with ICI treatment outcome in five other cancers: esophagogastric, head and neck, non-small cell lung, renal cell carcinoma, and melanoma. Immuno-inflammatory pathways were significantly reduced in expression in CDKN2A-altered tumors. CONCLUSIONS: Our data show that CDKN2A GAs were associated with reduced benefit from ICI therapy in urothelial carcinoma as well as changes in the tumor-immune microenvironment.

Trans-ethnic variation in germline variants of patients with renal cell carcinoma.

Prior studies of the renal cell carcinoma (RCC) germline landscape investigated predominantly patients of European ancestry. We examine the frequency of germline pathogenic and likely pathogenic (P/LP) variants in 1,829 patients with RCC from various ancestries. Overall, P/LP variants are found in 17% of patients, among whom 10.3% harbor one or more clinically actionable variants with potential preventive or therapeutic utility. Patients of African ancestry with RCC harbor significantly more P/LP variants in FH compared to patients of non-African ancestry with RCC and African controls from the Genome Aggregation Database (gnomAD). Patients of non-African ancestry have significantly more P/LP variants in CHEK2 compared to patients of African ancestry with RCC and non-Finnish Europeans controls. Non-Africans with RCC have more actionable variants compared to Africans with RCC. This work helps understand the underlying biological differences in RCC between Africans and non-Africans and paves the way to more comprehensive genomic characterization of underrepresented populations.

Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma.

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.

Activity of cabozantinib after immune checkpoint blockade in metastatic clear-cell renal cell carcinoma.

BACKGROUND: Cabozantinib is approved for the first and subsequent line treatment of metastatic clear-cell renal cell carcinoma (ccRCC) based on trials in which most patients were immune checkpoint blockade (ICB) naive. With an expanding role of ICB in earlier lines of therapy, we assessed activity of cabozantinib in patients with metastatic ccRCC after progressing on anti-PD-1/PD-L1-based ICBs. METHODS: We retrospectively analysed the clinical outcomes of 86 patients from 2 academic centres who received cabozantinib after progression on ICB alone, ICB in combination with vascular endothelial growth factor inhibitors (VEGFis) or ICB in combination with other therapies. Overall response rate (ORR, investigator assessed), time to treatment failure (TTF), overall survival (OS) and toxicities leading to dose reductions or cessation were evaluated. RESULTS: Eighty-six patients were included in the analysis; the median age was 63 years (range 33-84) and the median number of prior therapies was 2 (range 1-10). The type of prior ICB therapy was ICBs alone (64%), an ICB in combination with a VEGFi (29%) or ICBs in combination with other therapies (7%). At the time of cabozantinib treatment, 71% of patients were in the International Metastatic RCC Database Consortium good- or intermediate-risk groups. Approximately half of patients (52%) were started on cabozantinib at the full 60 mg daily dose. The ORR was 36% (95% confidence interval [CI] = 26-47%) with no complete response and 43% achieving stable disease; 21% had primary progressive disease. The median TTF was 6.5 months (95% CI = 5.3-8.5.). The median OS was 13.1 months (95% CI = 8.7-NR) with 55% (95% CI = 41-66%) OS rate at 12 months. Most common reasons for dose reductions were fatigue (27%), palmar-plantar erythrodysesthesia (16%) and diarrhoea (10%). CONCLUSIONS: Cabozantinib is active in patients treated with prior ICB-based therapies, with no new safety signals. This study supports the use of cabozantinib after ICB-based therapies.