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  • 1
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    Association of enfortumab vedotin (EV) toxicity with baseline parameters and clinical outcomes in patients (pts) with metastatic urothelial carcinoma (mUC).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e16585-e16585
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e16585-e16585
    Abstract: e16585 Background: EV is an antibody-drug conjugate approved for the treatment of mUC. Toxicities of special interest with EV are neuropathy, rash, and hyperglycemia. While it has been reported that EV-related skin toxicity may be associated with better responses to EV, the relationship of EV-related adverse events (AEs) with clinical outcomes is still unclear. The aim of this study is to investigate the association of EV-related toxicity and clinical outcomes among pts with mUC. Methods: We retrospectively reviewed demographic, clinical and laboratory data from pts with mUC who were treated with 〉 1 dose of EV at Dana-Farber Cancer Institute. AEs were graded per the CTCAE V5.0. A multivariable Cox regression analysis was performed to analyze overall survival (OS) and the occurrence of AEs while accounting for age, sex, and baseline peripheral neuropathy (BPN). A landmark analysis was performed to evaluate the association of toxicity occurrence and clinical outcomes, accounting for guarantee-time bias. Results: Our cohort included 54 pts with a median age of 72 years, of which 72.2% (n = 39) were male. Median follow-up was 18.6 months. Neuropathy was the most common AE occurring in 66.7% (n = 36) pts with 7.4% (n = 4) grade 3-4. Skin toxicity occurred in 57.4% (n = 31) pts with 3.7% (n = 2) grade 3-4. There were no recorded grade 5 AEs. Worse baseline Eastern Cooperative Oncology Group Performance Status (ECOG-PS) was associated with the development of more AEs (HR = 2.8; 95% CI = 1.2-6.3; p = 0.01). Decreased baseline hemoglobin (Hb) was associated with more EV-related neuropathy (1/HR = 1.25; 95% CI = 1.1-1.4; p = 0.01) and higher neuropathy grade (1/HR = 1.7; 95% CI = 1.1-2.5; p = 0.01). Moreover, pts who have previously received immune checkpoint inhibitors (ICI) were more likely to develop EV-related rash (HR = 5.4; 95% CI = 1.1-26.2; p = 0.03; Table 1). Overall, 30 deaths were observed, and median OS was 13.3 months (95% CI = 9.5-NA). A landmark analysis at 2 weeks of therapy (marking the final infusion of the 1st cycle of EV therapy) showed that in 16 pts who developed early skin toxicity, OS was improved vs. 38 pts who did not develop early skin toxicity (HR = 0.4; 95% CI = 0.2-0.9; p = 0.04). Conclusions: To our knowledge, this is the first study to investigate the association of EV-related AEs and clinical outcomes of pts with mUC using a landmark analysis. ECOG-PS and baseline Hb may be predictors of EV-related AEs. The incidence of early skin toxicity may be associated with improved OS. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.e16585
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 2
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    Association of neutrophil to eosinophil ratio (NER) with clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with first-line (1L) immune checkpoint inhibitors (ICI) –based regimens.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 4557-4557
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 4557-4557
    Abstract: 4557 Background: ICI-based regimens (ICI + ICI or ICI + VEGF targeted therapy [VEGF-TT]) represent current standard of care systemic therapies for the management of patients with mRCC. Robust biomarkers capable of predicting the therapeutic efficacy and safety of such regimens are still lacking. Eosinophils have been shown to play an important role in the response to immunotherapy. While recent investigations in RCC evaluated NER as a biomarker of poor response to immunotherapy, they did not fully account for the impact of different lines of therapy and the therapeutic classes of ICI-based regimens. We aimed to comprehensively evaluate the association of NER with clinical outcomes in patients with mRCC treated with 1L ICI regimens. Methods: We retrospectively reviewed data from patients with mRCC treated with first line ICI-based regimens (dual ICI or ICI + VEGF-TT) at Dana-Farber Cancer Institute. Clinicodemographic information was collected, including tumor histology, ECOG performance status, IMDC risk score. We examined NER at baseline and at 6, 12, and 24 weeks while patients were still receiving treatment. The primary endpoint was overall survival (OS). Time to treatment failure (TTF) was a secondary endpoint. The association of NER with OS and TTF was evaluated using Cox regression models, adjusted for age, gender, BMI, histology, IMDC risk score and autoimmune disease. Results: Overall, 156 patients were included in the current analysis, with a median age of 61 years (IQR: 54-67). 60 patients received dual ICI therapy, while 96 were treated with ICI + VEGF-TT combinations. In the ICI+ICI group, a higher NER at baseline, 6 and 12 weeks was associated with worse OS. In the ICI + VEGF group, a higher NER only at 6 weeks appeared to be associated with worse OS. No association between NER and TTF was found. Conclusions: To our knowledge, this is the first study to investigate, across therapeutic classes, the association of NER with clinical outcomes in patients with mRCC treated with 1L ICI-based regimens. Higher NER was linked to poor survival outcomes, especially in patients receiving dual ICI therapy. Future translational studies are needed to clarify these findings. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.4557
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Impact of smoking status (SS) on the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with first line (1L) immuno-oncology (IO)-combination regimens: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 4555-4555
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 4555-4555
    Abstract: 4555 Background: Active smoking is associated with decreased overall survival (OS) in patients (pts) with mRCC treated with VEGF targeted therapy (VEGF-TT) (Kroeger N. et al. 2019, IMDC investigators). Conversely, smoking history has been linked to improved OS in pts with advanced non-small cell lung carcinoma (NSCLC) receiving 1L pembrolizumab monotherapy (Popat S. et al., 2022). Herein, we assess the association between SS and outcomes in pts with mRCC treated with 1L standard of care (SOC) IO-based regimens. Methods: Real-world data from the IMDC were collected retrospectively. We included mRCC pts who received either dual IO therapy or IO + VEGF-TT in the 1L setting and known SS at disease diagnosis. Pts were categorized as current, former and non-smokers. The primary outcomes were OS, time to treatment failure (TTF) and objective response rate (ORR) on 1L IO-based regimens. OS and TTF were evaluated using Cox regression, adjusting for age at 1L treatment, IMDC risk groups, BMI, histological type and time from diagnosis to 1L treatment initiation. ORR was compared between the SS groups using a logistic regression, adjusting for the same confounders. Results: 989 pts were eligible and included. 438 (44.3%), 415 (42%), and 136 (13.7%) pts were non-smokers, former, and current smokers at diagnosis, respectively. Median time from diagnosis to initiation of 1L IO-based treatment was 0.47 years (IQR 0.13-2.15). At baseline, there were no significant differences in age at 1L, IMDC risk groups, KPS status, BMI, and presence of sarcomatoid features across the 3 groups (p 〉 0.05). Median follow up was 21.2 months from 1L IO-based treatment initiation. On multivariable analysis, no significant differences in OS, TTF or ORR were seen between the SS groups (p 〉 0.05). Conclusions: To our knowledge, this represents the first and largest effort to evaluate the impact of smoking on clinical outcomes in pts with mRCC treated with IO-based regimens. There was no association between SS at diagnosis and the clinical outcomes of patients with mRCC receiving current 1L SOC IO-based regimens. As opposed to other cancer types (i.e., NSCLC), current or past smoking history did not appear to be predictive of benefit from IO-based therapy. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.4555
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 4
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    Association of host immune signatures with response to immunotherapy-based regimens in patients with metastatic renal cell carcinoma (mRCC).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 4550-4550
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 4550-4550
    Abstract: 4550 Background: Treatment options for mRCC have evolved to include VEGF targeted therapies (VEGF-TT), immune checkpoint inhibitors (ICIs), or combinations of both. The interaction between the tumor and its immune microenvironment has been shown to influence clinical outcomes in patients treated with immunotherapy-based regimens. The aim of this study was to characterize the T-cell and B-cell immune repertoires in patients with mRCC treated with VEGF-TT, ICI or a combination of both, and evaluate their associations with clinical outcomes. Methods: We identified patients with mRCC at Dana-Farber Cancer Institute treated with VEGF-TT, ICI or both, and for whom tumor and/or blood samples were available. Bulk RNA-sequencing (RNA-seq) and T-cell receptor sequencing (TCR-seq) were performed on peripheral blood mononuclear cells (PBMCs), collected before and during therapy. Bulk RNA-seq was additionally performed on available pre-treatment primary tumor samples. Immunoglobulin heavy chain (IgH) isotypes were inferred from bulk RNA-seq data using TRUST4. Parameters of the T-cell and B-cell repertoires were evaluated in responders vs. non-responders to systemic therapies, and between pre- and on-treatment samples within patient subgroups. Results: In total, blood (PBMC) samples from 386 patients were available across all treatment cohorts. Following quality-control, TCR-seq and RNA-seq data were available for 367 and 134 patient samples, respectively. Responders to ICI-based regimens (ICI or VEGF-TT+ICI) presented a trend towards an increased baseline (pre-treatment) TCR clonality as compared to non-responders (p=0.06), corresponding to a less polyclonal T cell repertoire in responders at baseline. No significant changes in clonality were seen between pre- and on-treatment samples among responders to ICI regimens (p=0.14), as opposed to non-responders where a significant increase was identified (p=0.001). The analysis of IgH isotypes in baseline blood samples showed higher fraction of IgG1 in responders (vs. non-responders) to ICI regimens (p=0.01). This was further confirmed in the analysis of IgH isotypes inferred from tumor samples (p=0.04). No significant differences in IgH isotype fractions were identified between responders and non-responders to VEGF-TT. Conclusions: We were successfully able to characterize T-cell receptor and IgH repertoires in a large cohort of patients with mRCC and evaluate their associations with ICI response. Our results show that baseline TCR clonality and IgG1 antibody fraction are associated with the response to ICI regimens, suggesting a potential role for immune biomarker development.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.4550
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Emerging Biomarkers of Response to Systemic Therapies in Metastatic Clear Cell Renal Cell Carcinoma
    Elsevier BV ; 2023
    In:  Hematology/Oncology Clinics of North America Vol. 37, No. 5 ( 2023-10), p. 937-942
    Details
    In: Hematology/Oncology Clinics of North America, Elsevier BV, Vol. 37, No. 5 ( 2023-10), p. 937-942
    Type of Medium: Online Resource
    ISSN: 0889-8588
    URL: Article
    DOI: 10.1016/j.hoc.2023.05.021
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 93115-9
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  • 6
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    Abstract B019: Clinical and molecular characterization of chromophobe renal cell carcinoma: A focus on immunotherapy based regimens and the tumor immune microenvironment
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 16_Supplement ( 2023-08-15), p. B019-B019
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 16_Supplement ( 2023-08-15), p. B019-B019
    Abstract: Background: Chromophobe renal cell carcinoma (ChRCC) represents 5% of all kidney cancers. In contrast to clear cell RCC (ccRCC), the immune landscape of ChRCC and its response to immunotherapy remain poorly characterized. We sought to evaluate the clinical outcomes of patients with ChRCC treated with immuno-oncology (IO)-based regimens, and assess the immune cell composition, phenotypic state, and T cell specificity in the tumor microenvironment of ChRCC. Methods: Using real-world data from the International Metastatic RCC Database Consortium, we analyzed the survival outcomes and objective responses of patients with advanced ChRCC to currently adopted IO-based regimens (i.e. dual IO therapy or IO + vascular endothelial growth factor targeted therapy [VEGF-TT]) in the first-line setting, as compared to patients with ccRCC. Single-cell RNA sequencing (scRNA-seq) and single-cell T-cell receptor sequencing (scTCR-seq) were performed on ChRCC and related oncocytic neoplasms (i.e. renal oncocytoma [RO] and low-grade oncocytic tumor [LOT]) samples with matched normal kidney specimens. The infiltration of CD45+ immune cells in renal oncocytic tumors and ccRCC samples was quantified using immunohistochemistry (IHC). Results: Compared to patients with ccRCC (n=856) treated with first-line IO-based regimens, patients with ChRCC (n=31) had a lower overall survival (median: 24.7 vs. 50.5 months, p & lt;0.001) and lower time to treatment failure (median: 4.5 vs. 11.0 months, p & lt;0.001). Similarly, patients with ChRCC had a significantly lower overall response rate than those with ccRCC (12.0 vs. 47.1%, respectively; p & lt;0.001). When evaluating immune cell infiltration, renal oncocytic tumors (ChRCC, RO, and LOT) exhibited a low density of CD45+ cells (mean: 739 ± 114 cells/mm2; n=5) compared to ccRCC (mean: 3,420 ± 1,979 cells/mm2; n=5) (p & lt;0.05). Single-cell analysis was performed on 46,817 cells from 5 tumors (ChRCC: n=3, RO: n=1 and LOT: n=1) and 4 samples from adjacent normal kidney. Across all tumors, CD8+ T cell clusters displayed a lower expression of immune checkpoints (i.e. PDCD1, CTLA4, LAG3, HAVCR2, and TIGIT) as compared to CD8+ T-cells from ccRCC. This was further validated in the analysis of bulk RNA-seq data from the TCGA, with a significantly lower expression of all immune checkpoints in ChRCC compared to both ccRCC (p & lt;0.01) and papillary RCC (pRCC; p & lt;0.01). Analysis of the T cell receptor repertoire (scTCR-seq) of ChRCC, RO and LOT samples did not show any pattern of clonal expansion, and a higher proportion of T cells in ChRCC were inferred to have a viral specificity, compared to ccRCC (0.79 vs. 0.1%, respectively). Conclusions: Patients with metastatic ChRCC appear to display poor clinical outcomes when treated with IO-based regimens, compared to ccRCC. Renal oncocytic tumors, including ChRCC, exhibit a low infiltration of immune cells, and a non-exhausted immune phenotype. Citation Format: Michel Alchoueiry, Chris Labaki, Long Zhang, Yue Hou, Kevin Bi, Charbel Hobeika, J. Connor Wells, Kosuke Takemura, Ziad Bakouny, Sabrina Camp, Carmen Priolo, Damir Khabibullin, Nicholas Schindler, Renee Maria Saliby, Eddy Saad, Samer Salem, Melissa Daou, Rana McKay, Sumanta Pal, Daniel Heng, Eliezer Van Allen, Sachet Shukla, Toni Choueiri, David Braun, Elizabeth Henske. Clinical and molecular characterization of chromophobe renal cell carcinoma: A focus on immunotherapy based regimens and the tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr B019.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.KIDNEY23-B019
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Host immune signatures as predictors of response to immunotherapy-based regimens in patients with metastatic renal cell carcinoma (mRCC)
    Oxford University Press (OUP) ; 2023
    In:  The Oncologist Vol. 28, No. Supplement_1 ( 2023-08-23), p. S4-S5
    Details
    In: The Oncologist, Oxford University Press (OUP), Vol. 28, No. Supplement_1 ( 2023-08-23), p. S4-S5
    Abstract: Treatment options for mRCC have evolved to include VEGF targeted therapies (VEGF-TT), immune checkpoint inhibitors (ICIs), or combinations of both. However, clinical responses to systemic therapies in mRCC remain largely unpredictable and robust biomarkers are still lacking. The interaction between the tumor and its immune microenvironment has been shown to influence clinical outcomes in patients treated with ICI-based regimens. The aim of this study was to characterize the T-cell and B-cell immune repertoires in patients with mRCC treated with VEGF-TT, ICI or a combination of both, and evaluate their associations with clinical outcomes. Methods We identified patients with mRCC at Dana-Farber Cancer Institute treated with VEGF-TT, ICI or both, and for whom tumor and/or blood samples were available. T-cell receptor sequencing (TCR-seq) was performed on peripheral blood mononuclear cells (PBMCs), collected before and during therapy. Bulk RNA-sequencing (RNA-seq) was performed on available pre-treatment PBMCs and primary tumor samples. Immunoglobulin heavy chain (IgH) isotypes were inferred from bulk RNA-seq data using TRUST4. Parameters of the T-cell and B-cell repertoires were evaluated in responders vs. non-responders to systemic therapies, and between pre- and on-treatment samples within patient subgroups. Results In total, blood (PBMC) samples from 386 patients were available across all treatment cohorts (186 VEGF-TT, 126 ICI and 74 ICI+VEGF-TT). Following quality-control, TCR-seq data were available for 367 patients (228 pre-treatment and 139 on-treatment), while RNA-seq data were available for 105 PBMC and 17 tumor-derived pre-treatment samples. In the TCR-seq analysis, responders to ICI-based regimens (ICI or VEGF-TT+ICI) presented a trend towards an increased baseline (pre-treatment) TCR clonality as compared to non-responders (p=0.06) (Fig. 1A), corresponding to a less polyclonal T cell repertoire in responders at baseline. No significant changes in clonality were seen between pre- and on-treatment samples among responders to ICI regimens (p=0.14), as opposed to non-responders where a significant increase was identified (p=0.001). Therefore, responders to ICI-based regimens seem to have a more oligoclonal TCR repertoire (increased clonality) at baseline with no treatment-induced changes, whereas non-responders to ICI-based regimens seem to evolve from a more polyclonal to a more oligoclonal TCR repertoire in response to treatment. The analysis of IgH isotypes in baseline blood samples showed higher fraction of IgG1 in responders (vs. non-responders) to ICI regimens (p=0.01) (Fig. 1B). This was further confirmed in the analysis of IgH isotypes inferred from tumor samples (p=0.04). No significant differences in IgH isotype fractions were identified between responders and non-responders to VEGF-TT. Furthermore, while shared clonotypes were detected between blood and tumor samples, there were no differences in the Jaccard similarity index between responders and non-responders to ICI-based or VEGF-TT regimens. Figure 1: (A) Evaluation of pre-treatment and post-treatment TCR clonality in responders vs. non-responders across treatment cohorts. (B) Differences in the fraction of IGH isotypes between responders and non-responders across treatment cohorts. Conclusions We were successfully able to characterize T-cell receptor and B-cell IgH repertoires in a large cohort of patients with mRCC, and evaluate their associations with ICI response. Our results show that baseline TCR clonality and IgG1 antibody fraction are associated with the response to ICI regimens, suggesting a potential role for immune biomarker development. CDMRP DOD Funding: yes
    Type of Medium: Online Resource
    ISSN: 1083-7159 , 1549-490X
    URL: Article
    DOI: 10.1093/oncolo/oyad216.007
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 8
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    Epigenomic profiling nominates master transcription factors (TFs) driving sarcomatoid differentiation (SD) of renal cell carcinoma (RCC)
    Oxford University Press (OUP) ; 2023
    In:  The Oncologist Vol. 28, No. Supplement_1 ( 2023-08-23), p. S8-S8
    Details
    In: The Oncologist, Oxford University Press (OUP), Vol. 28, No. Supplement_1 ( 2023-08-23), p. S8-S8
    Abstract: Sarcomatoid differentiation of RCC (sRCC) is associated with poor survival. Recent studies showed marked response of sRCC to immune checkpoint blockade (ICB). While distinctive patterns of gene expression in sRCC have been identified, the gene regulatory programs and TFs that drive SD remain unknown. The aim of this study is to nominate TFs responsible for SD and to investigate their association with the clinical outcomes of patients with RCC. Methods Chromatin immunoprecipitation and sequencing (ChIP-seq) for H3K27ac – a histone modification associated with active regulatory elements – was performed on pathologically reviewed sRCC and non-sRCC samples collected at the Dana-Farber Cancer Institute. Regulatory elements that were differentially active between the two groups were identified based on levels of H3K27ac (Benjamini-Hochberg q & lt;0.01, log-fold change (LFC) threshold=1). Enrichment of specific TF binding motifs at activated regulatory elements in sRCC was assessed using HOMER. Differential gene expression analysis of TFs was performed using DESeq2 on RNA-seq data from TCGA. A Mann-Whitney U test was performed on RNA-seq data from the IMmotion151 and Javelin Renal 101 clinical trials to compare mean expression level of TFs in transcript per million (TPM) in these trials. Patients with non-sRCC enrolled in the IMmotion151 trials were divided into quartiles based on gene expression levels of candidate TFs. Progression-free survival (PFS) was compared between non-sRCC patients stratified by expression quartiles as well as patients with sRCC using a multivariable Cox proportional-hazards model accounting for age and IMDC risk score. To validate these findings, a similar analysis was performed in the Javelin Renal 101 trial. Results We obtained high-quality H3K27ac ChIP-seq profiles for 9 sRCC and 17 non-sRCC samples. We identified 278 candidate regulatory elements with increased H3K27ac levels in sRCC vs. non-sRCC. These regulatory elements were enriched for nucleotide motifs bound by the TFs FOSL1 and E2F7. Differential expression analysis between 48 sRCC vs. 493 non-sRCC samples showed that FOSL1 and E2F7 were significantly upregulated in sRCC vs. non-sRCC (LFC=1.7, q=5e-11; LFC=1.8, q=1.3e-20; resp.). Mean TPMs of FOSL1 and E2F7 were significantly increased in sRCC vs. non-sRCC in IMmotion151 cohort and Javelin Renal 101 (all p & lt;0.001). Among patients who received sunitinib, those with the highest quartile of FOSL1 and E2F7 expression showed significantly shorter PFS in IMmotion151 patients compared to patients with the lowest quartile of expression (HR=1.6, 95%CI=1.3-2.2, p=0.008 & HR=2.6, 95%CI=1.8-3.7, p & lt;0.001; resp.). Furthermore, patients with highest quartile of expression showed similar PFS compared to patients with sRCC (p=0.56 and p=0.64; resp.). These results were validated in the sunitinib arm of the Javelin Renal 101 cohort (Figure). Figure: Kaplan-Meier curves of progression-free survival (PFS) in patients with in the sunitinib arm of Javelin Renal 101 by sarcomatoid differentiation and FOSL1 expression levels. Conclusions This is the first study to characterize the epigenomic landscape of sRCC by integrating ChIP-seq and RNA-seq data. Our findings implicated FOSL1 and E2F7 as transcriptional regulators of SD with prognostic relevance. These TFs seems to be associated with aggressive behavior in non-sRCC as well. Further studies are underway to functionally validate these results.
    Type of Medium: Online Resource
    ISSN: 1083-7159 , 1549-490X
    URL: Article
    DOI: 10.1093/oncolo/oyad216.012
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
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  • 9
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    Characterization of the Cellular Origin and Oncogenic Mechanisms of Chromophobe Renal Cell Carcinoma (ChRCC) and Renal Oncocytic Neoplasms
    Oxford University Press (OUP) ; 2023
    In:  The Oncologist Vol. 28, No. Supplement_1 ( 2023-08-23), p. S7-S8
    Details
    In: The Oncologist, Oxford University Press (OUP), Vol. 28, No. Supplement_1 ( 2023-08-23), p. S7-S8
    Abstract: ChRCC is a rare form of kidney cancer and presents with a poor prognosis in the metastatic setting, with limited response to immune checkpoint inhibitors (ICI) and targeted therapy. While previous studies suggested that ChRCC originates from intercalated cells of the kidney, its exact cellular origin has not been clearly defined. We therefore investigated the cellular origin of ChRCC and renal oncocytic neoplasms at single-cell resolution. Methods ChRCC, renal oncocytoma (RO) and low-grade oncocytic tumor (LOT) samples with matched normal kidney specimens were analyzed using single-cell RNA sequencing (scRNA-seq). Epithelial cells from normal samples were clustered and annotated into the distinct known cellular types found in the adult healthy human kidney. A logistic regression model (Young M.D. et al., Science, 2018) was trained on the normal epithelial clusters, using a comprehensive set of 74 marker genes (features). Subsequently, the model was tested on tumor clusters from ChRCC, RO and LOT to investigate their cellular origin through the identification of the highest predicted probabilities of similarity between normal epithelial cellular types and tumor cells. Differential gene expression and pathway analyses between ChRCC and its cell of origin were then conducted to investigate mechanisms of oncogenesis. Results Following quality-control, 46,817 cells from 5 tumors (ChRCC: n=3, RO: n=1 and LOT: n=1) and 4 normal samples were isolated for scRNA-seq analysis. Among normal samples, 784 epithelial cells were clustered and annotated into the following cellular entities: proximal tubule (PT), loop of Henle – distal tubule (LOH-DT), principal cells (PC), α-intercalated cells (ICA) and β-intercalated cells (ICB). Across all ChRCC and oncocytic tumors, 7,573 tumor cells were identified, among which 7,425 corresponded to ChRCC. For ChRCC, RO, and LOT neoplasms, the highest predicted probability of similarity was consistently identified with ICA cells (ranging from 0.60 to 0.80). This finding was validated using an external and previously published (Zhang Y. et al., Proc Natl Acad Sci USA, 2021) scRNA-seq dataset from a patient with ChRCC (n=2,853 cells). Additionally, evaluation of previously defined ChRCC-specific markers (i.e. FOXI1, RHCG, KIT, CLCNKA, and CLCNKB) in scRNA-seq data of normal kidney epithelial cells consistently showed the highest expression in ICA cells. Differential gene expression between ChRCC and ICA cells revealed a significant downregulation of MHC class I genes (i.e. HLA-A , HLA-B, and HLA-C) and HSP70 (family A) genes (i.e. HSPA1A, HSPA1B, HSPA6, and HSPA8) in ChRCC. Differential pathway analysis between ChRCC and ICA cells showed a significant enrichment of the ferroptosis, glutathione metabolism, mTOR signaling and IL-15 pathways in ChRCC. Conclusions Renal oncocytic tumors, including ChRCC, appear to originate from the α-intercalated cells of the normal human kidney. As compared to α-intercalated cells, ChRCC downregulates MHC class I genes, which may be associated with its poor response to immunotherapy. Further, the selective downregulation of HSP70 genes may in part explain ChRCC’s increased sensitivity to ferroptosis. CDMRP DOD Funding: yes
    Type of Medium: Online Resource
    ISSN: 1083-7159 , 1549-490X
    URL: Article
    DOI: 10.1093/oncolo/oyad216.011
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 2023829-0
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    Novel Targeted Therapies for Renal Cell Carcinoma
    Elsevier BV ; 2023
    In:  Hematology/Oncology Clinics of North America Vol. 37, No. 5 ( 2023-10), p. 1015-1026
    Details
    In: Hematology/Oncology Clinics of North America, Elsevier BV, Vol. 37, No. 5 ( 2023-10), p. 1015-1026
    Type of Medium: Online Resource
    ISSN: 0889-8588
    URL: Article
    DOI: 10.1016/j.hoc.2023.05.022
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 93115-9
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