Christine Horak's research while affiliated with Bristol-Myers Squibb and other places
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Publications (84)
Immune-checkpoint inhibitors (ICI), although revolutionary in improving long-term survival outcomes, are mostly effective in patients with immune-responsive tumors. Most patients with cancer either do not respond to ICIs at all or experience disease progression after an initial period of response. Treatment resistance to ICIs remains a major challe...
Background: Inhibition of immune-checkpoint targets including PD1 is clinically effective in a variety of cancers. However, only a subset of patients respond and complete response remains uncommon. To understand the mechanisms of response and resistance, recent studies have focused on neoantigens, copy-number alterations, and transcriptional signat...
Despite remarkable success of immune checkpoint inhibitors, the majority of cancer patients have yet to receive durable benefits. Here, in order to investigate the metabolic alterations in response to immune checkpoint blockade, we comprehensively profile serum metabolites in advanced melanoma and renal cell carcinoma patients treated with nivoluma...
4568
Background: hERV levels positively correlate with tumor immune infiltrate and were recently shown to be associated with clinical benefit to PD-1/PD-L1 blockade in two small cohorts of patients (pts) with mccRCC (Smith C.C. et al and Panda A. et al; 2018). We tested whether hERV levels correlate with efficacy of nivolumab in a prospective phase...
Purpose:
Immune-related RECIST (irRECIST) were designed to capture atypical responses seen with immunotherapy. We hypothesized that, in patients with metastatic clear cell renal cell carcinoma (mccRCC), candidate biomarkers for nivolumab response would show improved association with clinical endpoints capturing atypical responders (irRECIST) compa...
To understand prognostic factors for outcome between differentially sequenced nivolumab and ipilimumab in a randomized phase II trial, we measured T-cell infiltration and PD-L1 by immunohistochemistry, T-cell repertoire metrics, and mutational load within the tumor. We used next-generation sequencing (NGS) and assessed the association of those para...
Combination anti–cytotoxic T lymphocyte antigen 4 (CTLA-4) and anti–programmed cell death protein 1 (PD-1) therapy promotes antitumor immunity and provides superior benefit to patients with advanced-stage melanoma compared with either therapy alone. T cell immunity requires recognition of antigens in the context of major histocompatibility complex...
619
Background: Development of predictive biomarkers would help select patients more likely to respond to nivolumab (nivo) in mccRCC. Here we evaluated biomarkers for nivo using endpoints based on either RECIST 1.1 (ORR and PFS) or irRECIST (irORR and irPFS), which were proposed to more accurately predict benefit of immunotherapy. Methods: We retro...
A deepened understanding of the cellular and molecular processes in the tumor microenvironment is necessary for the development of precision immunotherapy (IT). We simultaneously investigated CD3, PDL1, and IDO by immunohistochemistry in paired biopsies from various organs of 43 metastatic melanoma patients treated with IT and targeted therapy (TT)...
SNF'ing out antitumor immunity
Immune checkpoint inhibitors induce durable tumor regressions in some, but not all, cancer patients. Understanding the mechanisms that determine tumor sensitivity to these drugs could potentially expand the number of patients who benefit (see the Perspective by Ghorani and Quezada). Pan et al. discovered that tumor ce...
Introduction
L’association de NIVO et d’IPI a amélioré la survie sans progression (SSP) et le taux de réponse objective par rapport à l’IPI seul dans l’essai de phase II CheckMate 069 et l’essai de phase III CheckMate 067 chez des patients atteints de mélanome avancé naïf de traitement. Nous présentons ici les premiers résultats de survie globale (...
Purpose
The clinical activity observed in a phase I dose-escalation study of concurrent therapy with nivolumab (NIVO) and ipilimumab (IPI) in patients with previously treated or untreated advanced melanoma led to subsequent clinical development, including randomized trials. Here, we report long-term follow-up data from study CA209-004, including 3-...
The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, an...
Purpose
Until recently, limited options existed for patients with advanced melanoma who experienced disease progression while receiving treatment with ipilimumab. Here, we report the coprimary overall survival (OS) end point of CheckMate 037, which has previously shown that nivolumab resulted in more patients achieving an objective response compare...
Introduction: Nivolumab and ipilimumab (NIVO+IPI) in combination was more efficacious than nivolumab (NIVO) alone in advanced melanoma patients (pts) in the phase 3 CheckMate 067 study (Larkin et al, NEJM. 2015). To elucidate the differential mechanisms of action of NIVO+IPI vs NIVO, we assessed biomarkers in pts with advanced melanoma treated with...
Background: Response to checkpoint blockade may be dependent on tumor mutational load and the presence of antigen-specific effector T cells in the tumor microenvironment; however, how blockade modulates these features during therapy is unclear. We assessed genomic changes in tumors from patients (pts) with advanced melanoma receiving nivolumab (niv...
Background: NIVO plus IPI improved progression-free survival (PFS) and objective response rate (ORR) vs IPI alone in the phase II CheckMate 069 and phase III CheckMate 067 trials of treatment-naive patients (pts) with advanced melanoma (MEL). Here, we report the first OS results from CheckMate 067.
Methods: Treatment-naïve patients (N=945) were ran...
9571
Background: Checkpoint inhibitors have revolutionized the treatment of stage IV melanoma patients. Selection of patients for PD-1 monotherapy or CTLA4/PD1 combination remains an important challenge. We set out to perform a discovery study of pretreatment serum protein biomarkers to identify predictors of progression free survival (PFS) for ipi...
3036
Background: Immune-checkpoint inhibition has been shown to be effective in a variety of cancers, including renal cell carcinoma (RCC) and melanoma. However, only a subset of patients with RCC and melanoma respond to anti-PD1 therapy. Given the importance of metabolism in the tumor immune microenvironment, we performed serum metabolomics in niv...
3016
Background: Immune checkpoint inhibitors targeting programmed cell death-1 (PD-1) substantially improve patient survival in clear-cell renal cell carcinoma (ccRCC), but predictive biomarkers for efficacy have not yet been identified. Methods: We analyzed whole exome sequencing (WES) from a clinical trial of anti-PD-1 monotherapy (nivolumab) fo...
9515
Background: CheckMate 064 (open label, phase 2) randomized advanced melanoma pts to NIVO 3 mg/kg Q2W for 6 doses then IPI 3 mg/kg Q3W for 4 doses (n = 70; cohort A), or the reverse (IPI then NIVO; n = 70; cohort B). More cohort A than cohort B pts had complete or partial response (54% and 31%, respectively). We sought to determine whether comm...
Introduction
Dans le cadre de l’essai CheckMate 067, l’association de nivolumab (NIVO, anti-PD-1) et d’ipilimumab (IPI, anti-CTLA-4) a amélioré de manière significative la survie sans progression médiane (SSPm) et le taux de réponse objective (TRG) par rapport à l’IPI seul chez des patients atteints de mélanome avancé. Nous rapportons les résultats...
Introduction
Les résultats d’essais cliniques ont montré une amélioration significative du taux de réponse objective et de la survie sans progression (SSP) avec nivolumab (NIVO ; un anticorps anti-PD-1) plus ipilimumab (IPI ; un anticorps anti-CTLA-4) en comparaison avec IPI seul dans le mélanome avancé. Nous rapportons les premiers résultats de su...
Background:
Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone...
Background
Chemotherapy combined with radiotherapy is the standard treatment of “limited-stage” small-cell lung cancer. However, controversy persists over the optimal timing of thoracic radiotherapy and chemotherapy.
Material and methods
We performed a meta-analysis of individual patient data in randomised trials comparing earlier versus later rad...
Background: NIVO inhibits the interaction of the PD-1 receptor with its ligands, PD-L1 and PD-L2. While high tumor PD-L1 expression results in greater clinical benefit with NIVO, MEL patients (pts) with low-to-no PD-L1 expression also benefit from NIVO. This may be partially attributed to PD-L2. Here, we analyzed the association between PD-L1/PD-L2...
Background: This phase II trial (CheckMate 069) demonstrated a statistically significant improvement in objective response rate (ORR) and progression-free survival (PFS) with the combination of NIVO+IPI vs. IPI alone in treatment-naïve patients (pts) with wild-type MEL (Postow et al. N Engl J Med 2015;372:2006). ORR was 61% for NIVO+IPI vs 11% for...
Background: In previously treated MEL patients (pts), the results of an early phase I trial with NIVO monotherapy (CA209-003) demonstrated tumor responses that were durable even after treatment discontinuation (Topalian et al. J Clin Oncol 2014;32:1020). We report extended follow-up with 5-year overall survival (OS) data from this study.
Methods: I...
Table of contents
MELANOMA BRIDGE 2015
KEYNOTE SPEAKER PRESENTATIONS
Molecular and immuno-advances
K1 Immunologic and metabolic consequences of PI3K/AKT/mTOR activation in melanoma
Vashisht G. Y. Nanda, Weiyi Peng, Patrick Hwu, Michael A. Davies
K2 Non-mutational adaptive changes in melanoma cells exposed to BRAF and MEK inhibitors help the establi...
Background:
Concurrent administration of the immune checkpoint inhibitors nivolumab and ipilimumab has shown greater efficacy than either agent alone in patients with advanced melanoma, albeit with more high-grade adverse events. We assessed whether sequential administration of nivolumab followed by ipilimumab, or the reverse sequence, could impro...
Strategies to help improve the efficacy of the immune system against cancer represent an important innovation, with recent attention having focused on anti-programmed death (PD)-1/PD-ligand 1 (L1) monoclonal antibodies. Clinical trials have shown objective clinical activity of these agents (e.g., nivolumab, pembrolizumab) in several malignancies, i...
The hazard ratio (HR) for death was 0.42 (99.79% CI 0.25–0.73; P < 0.0001) in favor of nivolumab, with 1year OS rate 73% (95% CI, 66%–79%) for nivolumab vs 42% (95% CI, 33%–51%) for dacarbazine. Median OS was not reached for nivolumab and was 10.8 months for dacarbazine. Median progression-free survival (PFS) was 5.1 months for nivolumab and 2.2 mo...
Methods:
Following IRB-approved informed consent, targeted NGS was performed on the pt's FFPE primary TNBC and on a C-refractory recurrent lung metastasis at a CLIA-certified laboratory (Foundation Medicine) to characterize all classes of genomic alterations across 287 cancer-related genes. RPPA was performed at a CLIA-certified laboratory (Theran...
Background: Blockade of the immune checkpoints PD-1 and CTLA-4 each results in improved overall survival in patients (pts) with metastatic melanoma using monotherapy. In a phase 1 dose-escalation study, dual inhibition of these pathways by nivolumab (NIVO) and ipilimumab (IPI) demonstrated encouraging antitumor activity.
Methods: Treatment-naïve pt...
Background: Nivolumab, a fully human anti-programmed death-1 (PD-1) immune checkpoint inhibitor antibody, has shown encouraging clinical activity in melanoma. We evaluated the pharmacodynamic effects of nivolumab on immune endpoints in patients (pts) with advanced melanoma in an exploratory phase 1 study (NCT01621490).
Methods: 85 pts (41 and 44 an...
The anti-PD-1 therapeutic antibody, nivolumab, has demonstrated clinical activity in patients with advanced melanoma. The activity of nivolumab in subgroups of patients with tumors which have wild-type BRAF kinase vs patients with tumors having mutant BRAF has not systematically been explored in a large dataset.
To evaluate the efficacy and safety...
Methods:
Treatment-naïve pts (N = 945) were randomized 1:1:1 to NIVO 1 mg/kg Q2W + IPI 3 mg/kg Q3W for 4 doses followed by NIVO 3 mg/kg Q2W, NIVO 3 mg/kg Q2W + placebo, or IPI 3 mg/kg Q3W for 4 doses + placebo, until progression or unacceptable toxicity. Pts were stratified by PD-L1 status, BRAF mutation status, and M-stage. Co-primary endpoints a...
Background:
Nivolumab (a programmed death 1 [PD-1] checkpoint inhibitor) and ipilimumab (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] checkpoint inhibitor) have been shown to have complementary activity in metastatic melanoma. In this randomized, double-blind, phase 3 study, nivolumab alone or nivolumab plus ipilimumab was compared with...
Background:
In a phase 1 dose-escalation study, combined inhibition of T-cell checkpoint pathways by nivolumab and ipilimumab was associated with a high rate of objective response, including complete responses, among patients with advanced melanoma.
Methods:
In this double-blind study involving 142 patients with metastatic melanoma who had not p...
Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients w...
Purpose: The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients. Experimental Design: HLA-A*0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected...
Background:
Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study.
Methods:
We randomly assigned 418 prev...
Aim: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, is active and tolerable in pts with advanced MEL (Topalian et al. NEJM 366:2443, 2012). We report long-term clinical activity, response duration off-therapy, tumor PD-1 ligand (PD-L1) expression associated with survival endpoints, and 3-yr overall survival (OS) for the ME...
Nivolumab, a human immunoglobulin G4-blocking antibody against the T-cell programmed death-1 checkpoint protein, has activity against metastatic melanoma. Its safety, clinical efficacy, and correlative biomarkers were assessed with or without a peptide vaccine in ipilimumab-refractory and -naive melanoma.
In this phase I study, 90 patients with unr...
Background:
Kirsten rat sarcoma virus (KRAS) wild-type status determined using a locked nucleic acid (LNA)-mediated quantitative polymerase chain reaction (qPCR) clamping assay (LNA assay) predicted response to therapy in the CRYSTAL (Cetuximab Combined With Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) study. A companion KRAS...
This randomized phase II trial was designed to compare the rate of pathologic complete response (pCR) induced by neoadjuvant cyclophosphamide plus doxorubicin (AC) followed by ixabepilone or paclitaxel in women with early stage breast cancer (BC). Expression of βIII-tubulin as a predictive marker was also evaluated.
Women with untreated, histologic...
Background:
In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and...
TPS3114
Background: Programmed death-1 (PD-1) is an immune checkpoint receptor expressed by T cells that negatively regulates T-cell activity and may promote tumor immune evasion by binding to its ligands (PD-L1/L2) on tumor cells and/or antigen-presenting cells. Nivolumab is a fully human IgG4 PD-1 receptor blocking monoclonal antibody that has sh...
3003^
Background: Nivolumab and ipilimumab are fully human monoclonal antibodies that block the immune checkpoint receptors PD-1 and CTLA-4, respectively. In a multi-cohort, phase I study of nivolumab/ipilimumab combination therapy in melanoma patients (pts), objective response rates up to 47% were observed (NCT01024231). Putative predictive biomar...
3016
Background: The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation. In a phase I study, nivolumab, a PD-1 receptor blocking antibody, demonstrated durable clinical activity. Evaluation of the expression of the PD-1 ligand, PD-L1, by IHC with the 5H1 Ab suggested a correlation between pretreatment tumor...
9012^
Background: CTLA-4 and PD-1 are critical immune checkpoint receptors. In MEL pts, ipilimumab (anti-CTLA-4) prolonged survival in two phase III trials, and nivolumab (anti-PD-1) produced an objective response rate (ORR) of 31% (n=106) in a phase I trial. PD-1 is induced by CTLA-4 blockade, and combined blockade of CTLA-4/PD-1 showed enhanced a...
Purpose:
Predictive biomarkers offer the potential to improve the benefit:risk ratio of a therapeutic agent. Ixabepilone achieves comparable pathologic complete response (pCR) rates to other active drugs in the neoadjuvant setting. This phase II trial was designed to investigate potential biomarkers that differentiate response to this agent.
Expe...
Context:
The therascreen KRAS RGQ polymerase chain reaction kit is being developed as a companion diagnostic to aid clinicians, through detection of KRAS mutations, in the identification of patients with metastatic colorectal cancer (mCRC) who are more likely to benefit from cetuximab.
Objectives:
To assess whether KRAS mutation status, determin...
1064 Background: Ixa is active in taxane-refractory metastatic and neoadjuvant BC. In the neoadjuvant ixa study CA163-080 (080), pre-treatment (tx) and post-tx tumor specimens were assessed by gene expression profiling. Standard neoadjuvant chemotherapy (ctx) may de-bulk tumor, leaving resistant TICs. We assessed the impact of ixa on gene expressio...
Background: Anthracyclines (A) and taxanes (T) are standard neoadjuvant treatments for breast cancer (BC), achieving pathologic complete response (pCR) rates of 20-30% in unselected patient (pt) populations. Ixabepilone (ixa) is approved for treatment of metastatic BC: plus capecitabine (Cap) in pts progressing after A and T or as monotherapy after...
Background: Overexpression of βIII tubulin has been shown to correlate with poor prognosis and reduced response to taxanes. Ixa exhibits activity in βIII overexpressing tumor models and BC patients (pts) with high βIII mRNA levels. We report the prevalence of βIII by a validated IHC assay and the correlation of βIII protein and mRNA expression in B...
Global miRNA expression profiling has become increasingly common in cancer research, and miRNA signatures that are correlated to stage of disease or to clinical outcomes are now available for a variety of cancer types. Expression profiling of miRNA may be useful also in identifying molecular markers for the prediction of drug-responses and for pros...
The anti-EGF receptor monoclonal antibody cetuximab provides a case study for the development of predictive biomarkers in oncology. The identification and validation of KRAS mutation status as a predictor of lack of benefit from cetuximab in metastatic colorectal cancer provides an important first step. However, KRAS mutation status does not appear...
Purpose
The anti–epidermal growth factor receptor (EGFR) antibody cetuximab is efficacious in multiple tumor types. Patient selection with markers predictive of benefit may enhance its therapeutic index. This retrospective, correlative analysis of the phase III trial BMS099 of cetuximab in advanced non–small-cell lung cancer (NSCLC) was conducted t...
Background and rationale: Historically, patients with aggressive HER2+ BC have a poor response to chemotherapy, including antimicrotubule agents. Elevated III levels have been reported in HER2+ BC. Introduction of the HER2+ targeted agent TZ, in combination with taxane based chemotherapy, greatly improved the outcomes of these patients. The novel a...
8021
Background: This phase III study investigated cetuximab (C) plus taxane/carboplatin (TC) in 1 st -line advanced NSCLC. Progression-free survival (PFS) was not significantly different with the addition of C to TC; response rate (RR) was significantly higher; median overall survival (OS) was longer, with a difference (not statistically significa...
3587
Background: High βIII-tubulin (βIII) expression confers resistance to many anti-microtubule agents (Sève, Lancet 2008; 9: 168). The anti-microtubule agent ixabepilone (Ixa) demonstrates efficacy in βIII over-expressing tumor models resistant to taxanes and has clinical activity in patients with TN BC. The incidence and expression of βIII by BC...
Citations
... Investigators have previously defined eight emerging "hallmarks of resistance" to immunotherapy or immune-resistance nodes that should guide future research on this topic [5]. Studies have identified various mechanisms explaining primary and acquired resistance to immunotherapy [6]. ...
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... Atezolizumab plus chemotherapy and bevacizumab as first-line treatment for advancedstage NSCLC Incorporation of atezolizumab to a regimen consisting of Bev and chemotherapy significantly improves PFS in advanced non-squamous NSCLC (34). This result is not influenced by expression of EGFR or ALK. ...
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... This finding is not surprising, because KRAS mutations have been shown to be a poor predictor of response to EGFR inhibitor therapy in patients with NSCLC. 18,[38][39][40][41][42][43][44] However, a subgroup analysis of 90 patients in the SATURN study who had the KRAS mutation showed no significant difference in PFS between patients treated with erlotinib vs placebo (HR, 0.77; 95% CI, 0.50-1.19; P = .2246). ...
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... The documented activity of ixabepilone in breast can cer and other solid tumors refractory to taxanes prompted a clinical trial with this agent in patients with recurrent or persistent endometrial carcinoma who had failed in prior chemotherapy regimen [128,154]. A phase I trial of ixabepilone reported stable and minimal responses in patients with advanced ovarian and endometrial cancers [155]. A phase II study of ixabepilone in patients with recurrent or persistent endometrial adenocarcinoma is closed and results showed that the overall response rate was 12%. ...
... In addition to blocking co-inhibitory pathways, targeting the im- munosuppressive properties of cancer cells themselves is considered a promising approach especially in combination with antibody-based immunotherapy, in order to lead to greater depth of response and overall response rate ( Wolchok et al., 2013;Sznol et al., 2014). ...
... Unfortunately, the complete response (CR) rate is only about 20% and median progression-free survival (PFS) is about 18 months, with no evidence of plateau (7,8,10,11). In this view, several reports have highlighted the importance of patient immune-competence to achieve durable response with anti-PD-1 immunotherapy (12)(13)(14). Indeed, ASCT, especially in heavily pre-treated patients, leads to a prolonged and deep immunosuppression (12). ...
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... For example, programmed cell death 1 (PD1)/programmed cell death-ligand 1 (PD-L1) expression by immunohistochemistry is a Food and Drug Administration (FDA)approved companion diagnostic test for various cancer types 4 . Accordingly, many studies have reported a positive correlation between PD-L1 expression and the ICI response in non-small cell lung cancer [5][6][7] . Strikingly, however, other studies have reported no significant correlation between PD-L1 expression and the ICI treatment response 3,[8][9][10] , and some studies have even revealed that ICI responders display low PD-L1 expression levels 3,11 . ...
... Radiation therapy, chemotherapy and immunotherapy have been included in the treatment in addition to surgery (13,16). Immunotherapy has become the latest research hotspot in recent years, and new immune therapeutic targets have also been identified (17,18). Lymph node metastasis is one of the vital elements of the TNM stage. ...
... Conflicting or inconclusive evidence exists regarding whether mutated alleles in ERV [25] , mTOR [28] , and VHL [28] are prognostic for OS or PFS. Finally, SETD2 may be associated with metastatic spread to bone [34] . ...