Genomic and Immunologic Correlates of Indoleamine 2,3-Dioxygenase Pathway Expression in Cancer

Immune checkpoint blockade leads to unprecedented responses in many cancer types. An alternative method of unleashing anti-tumor immune response is to target immunosuppressive metabolic pathways like the indoleamine 2,3-dioxygenase (IDO) pathway. Despite promising results in Phase I/II clinical trials, an IDO-1 inhibitor did not show clinical benefit in a Phase III clinical trial. Since, a treatment can be quite effective in a specific subset without being effective in the whole cancer type, it is important to identify the subsets of cancers that may benefit from IDO-1 inhibitors. In this study, we looked for the genomic and immunologic correlates of IDO pathway expression in cancer using the Cancer Genome Atlas (TCGA) dataset. Strong CD8+ T-cell infiltration, high mutation burden, and expression of exogenous viruses [Epstein-Barr virus (EBV), Human papilloma virus (HPV), and Hepatitis C virus (HCV)] or endogenous retrovirus (ERV3-2) were associated with over-expression of IDO-1 in most cancer types, IDO-2 in many cancer types, and TDO-2 in a few cancer types. High mutation burden in ER+ HER2− breast cancer, and ERV3-2 expression in ER− HER2− and HER2+ breast, colon, and endometrial cancers were associated with over-expression of all three genes. These results may have important implications for guiding development clinical trials of IDO-1 inhibitors.

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Mutation burden as a biomarker of response to immune checkpoint therapy in nine solid cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.7_suppl.35 ◽

2017 ◽

Vol 35 (7_suppl) ◽

pp. 35-35 ◽

Cited By ~ 1

Author(s):

Shridar Ganesan ◽

Gyan Bhanot ◽

Janice M. Mehnert ◽

Ann W. Silk ◽

Jeffrey S. Ross ◽

...

Keyword(s):

Gene Expression ◽

Immune Response ◽

T Cells ◽

Immune Checkpoint ◽

Solid Cancer ◽

Cancer Type ◽

Her2 Breast Cancer ◽

Mutation Burden ◽

Gene Expression Signatures ◽

Cancer Types

35 Background: A high mutation burden a biomarker of response to immune checkpoint therapy in melanoma, non-small cell lung cancer, and colorectal cancer. It is unknown whether mutation burden is predictive of response in other cancer types, and whether it is identifiable using available clinical assays. Methods: Using data for 10,745 tumors from 33 solid cancer types in TCGA, we looked for a mutation burden threshold (iCAM) in each cancer type associated with gene expression signatures of a blocked immune response of robust CD8+T cell response and up-regulation of immune checkpoint genes. Results: A unique iCAM threshold was identified in nine cancers: melanoma and lung, colon, endometrial, and gastric adenocarcinoma; serous ovarian, bladder urothelial, cervical, and ER+ HER2− breast cancer. iCAM thresholds applied to published clinical data for patients treated with immune checkpoint therapy showed that iCAM+ patients had significantly better response. iCAM+ tumors can be identified from clinical-grade NGS assays with high accuracy . In a prospective melanoma cohort of patients treated with anti- PD-1 patients with iCAM+ tumors had significantly better objective response rates, progression free survival, and overall survival compared patients to iCAM− tumors. Pattern of somatic mutations were different in iCAM+ and iCAM− tumors, suggesting different mechanism of carcinogenesis in iCAM+ versus iCAM− tumors. Higher fractions of leukocytes were NK (Natural Killer) cells and macrophages were M1 polarized, and a lower fraction of T cells were regulatory T cells in iCAM+ tumors compared to iCAM− tumors. Over 75% of the genes significantly up-regulated in iCAM+ tumors in every cancer types were in the immune response pathway, confirming immune response to be the main differentiator in iCAM+ veruss iCAM− tumors. Conclusions: In nine cancer types, a clinically useful mutation burden threshold (iCAM) associated with gene expression signatures of blocked immune response can identify likely responders to immune checkpoint therapy, and iCAM status is identifiable using currently available clinical NGS assays.

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Cancer Type-Dependent Correlations betweenTP53Mutations and Antitumor Immunity

10.1101/692715 ◽

2019 ◽

Author(s):

Lin Li ◽

Mengyuan Li ◽

Xiaosheng Wang

Keyword(s):

Antitumor Immunity ◽

Colon Adenocarcinoma ◽

Joint Effect ◽

The Cancer Genome Atlas ◽

Cancer Type ◽

Mutation Burden ◽

Cancer Genome Atlas ◽

Negative Role ◽

Stomach Adenocarcinoma ◽

Cancer Types

AbstractMany studies have shown thatTP53mutations play a negative role in antitumor immunity. However, a few studies reported thatTP53mutations could promote antitumor immunity. To explain these contradictory findings, we analyzed five cancer cohorts from The Cancer Genome Atlas (TCGA) project. We found thatTP53-mutated cancers had significantly higher levels of antitumor immune signatures thanTP53-wildtype cancers in breast invasive carcinoma (BRCA) and lung adenocarcinoma (LUAD). In contrast,TP53-mutated cancers had significantly lower antitumor immune signature levels thanTP53-wildtype cancers in stomach adenocarcinoma (STAD), colon adenocarcinoma (COAD), and head and neck squamous cell carcinoma (HNSC). Moreover,TP53-mutated cancers likely had higher tumor mutation burden (TMB) and tumor aneuploidy level (TAL) thanTP53-wildtype cancers. However, the TMB differences were more marked betweenTP53-mutated andTP53-wildtype cancers than the TAL differences in BRCA and LUAD, and the TAL differences were more significant in STAD and COAD. Furthermore, we showed that TMB and TAL had a positive and a negative correlation with antitumor immunity and that TMB affected antitumor immunity more greatly than TAL did in BRCA and LUAD while TAL affected antitumor immunity more strongly than TMB in STAD and HNSC. These findings indicate that the distinct correlations betweenTP53mutations and antitumor immunity in different cancer types are a consequence of the joint effect of the altered TMB and TAL caused byTP53mutations on tumor immunity. Our data suggest that theTP53mutation status could be a useful biomarker for cancer immunotherapy response depending on cancer types.

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Tumor mutation burden analysis in a 5,660 cancer patient cohort reveals cancer type-specific mechanisms for high mutation burden.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2589 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2589-2589

Author(s):

Xiaodong Jiao ◽

Xiaochun Zhang ◽

Baodong Qin ◽

Dong Liu ◽

Liang Liu ◽

...

Keyword(s):

Effective Means ◽

Lung Squamous Cell Carcinoma ◽

Biological Pathways ◽

Formalin Fixed Paraffin Embed ◽

Cancer Type ◽

Biological Mechanisms ◽

Tumor Mutation Burden ◽

Molecular Features ◽

Mutation Burden ◽

Cancer Types

2589 Background: Tumor mutation burden (TMB), calculated by whole-exome sequencing (WES) or large NGS panels, has an important association with immunotherapy responses. Elucidating the underlying biological mechanisms of high TMB might help develop more precise and effective means for TMB and immunotherapy response prediction. Meanwhile, the landscape of TMB across different cancer types and its association with other molecular features have not been well investigated in large cohorts in China. Methods: Cancer patients whose fresh tissue (n = 1556), formalin-fixed, paraffin-embed (FFPE) specimen (n = 1794), and pleural fluid (n = 84) were profiled using 295- or 520-gene NGS panel. The association of the TMB status with a series of molecular features and biological pathways was interrogated using bootstrapping. Results: TMB, measured by 295- or 520-cancer-related gene panels, were correlated with WES TMB based on in silico simulation in the TCGA cohort. We compared the TMB landscape across 11 cancer type groups and found the highest average TMB in lung squamous cell carcinoma, whereas the lowest TMB was established in sarcoma. High microsatellite instability, DNA damage response deficiency, and homologous recombination repair deficiency indicated significantly higher TMB. The independent predictive power for TMB of twenty-six biological pathways was tested in 10 cancer groups. FoxO signaling pathway most commonly correlated with low-TMB; significant association was identified in four cancer groups. In contrast, no pathway was significantly correlated with high-TMB in more than two cancer groups. Overall, we discovered that the underlying pathways which may be the main drivers of TMB status varied greatly and sometimes had an opposite association with TMB across different cancer types. Moreover, we developed a 14- and 22-gene signature for TMB prediction for LUAD and LUSC, respectively, with only 10 genes shared by both signatures, indicating a histology-specific mechanism for driving high-TMB in lung cancer. Conclusions: The findings extended the knowledge of the underlying biological mechanisms for high TMB and might be helpful for developing more precise and accessible TMB assessment panels and algorithms in more cancer types.

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Trends in pancreatic cancer clinical trials in the United States

Medical Research Archives ◽

10.18103/mra.v9i11.2578 ◽

2021 ◽

Vol 9 (11) ◽

Author(s):

Lynn Matrisian ◽

Maren Martinez ◽

Allison Rosenzweig ◽

Cassadie Moravek ◽

Anne-Marie Duliege

Keyword(s):

Pancreatic Cancer ◽

Clinical Trials ◽

The United States ◽

Phase Iii ◽

Cancer Type ◽

Fda Approval ◽

Treatment Type ◽

Phase Iii Trials ◽

Previously Treated Patients ◽

Previously Treated

Trends in clinical trials for pancreatic cancer between 2011-2020 were tracked in the Pancreatic Cancer Action Network database originally designed to assist in identifying open trials for eligible patients. More than 125 trials specific for pancreatic cancer or including no more than one additional cancer type have been open each year, the majority for patients with a diagnosis of pancreatic adenocarcinoma (PAC). The trends indicate an active and progressive pancreatic cancer research community and include an increasing number of trials for previously treated patients, the emergence of trials for post-adjuvant or maintenance therapy, an increasing number of research-intensive phase 0 trials, increasing seamless phase I/II and II/III trials to improve efficiency, and an increasing number of phase III trials despite historical failures. Trials were analyzed by treatment type and included trials to optimize standard chemotherapy or radiation therapy, trials targeting tumor pathways, the stroma, or the immune system, biomarker-specified trials, and a miscellaneous category of trials testing tumor metabolism, complementary medicine approaches, or alternate energy sources. There was a dramatic increase in immunotherapy trials over this time. Several biomarker-specified trials were initiated, and FDA approval was obtained for biomarker-specified targeted agents, many in a tissue-agnostic setting, indicating an increase in a precision medicine approach to pancreatic cancer treatment. An increasing number of trials tested non-standard approaches, many which progressed to phase III. The trends suggest an encouraging trajectory of pancreatic cancer clinical research.

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Global drug development in cancer: A cross-sectional study of clinical trial registries

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.2520 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 2520-2520

Author(s):

P. Hertz ◽

B. Seruga ◽

L. W. Le ◽

I. F. Tannock

Keyword(s):

Clinical Trial ◽

Clinical Trials ◽

Drug Development ◽

Phase Ii ◽

New Drugs ◽

Phase Iii ◽

Cancer Site ◽

Cancer Type ◽

Clinical Trial Registries ◽

Global Drug Development

2520 Background: Clinical trials are increasingly funded by industry. High costs of drug development may lead to attempts to develop new drugs in more ‘profitable’ (i.e., more prevalent) as compared to ‘less profitable’ (i.e., more deadly) cancers. Here we determine the focus of current global drug development. Methods: We determined characteristics of phase II and III clinical trials evaluating new drugs in oncology, which were registered with WHO International Clinical Trial Registries between 01/2008 and 06/2008. Estimates of incidence, mortality, and prevalence in the more- and less-developed world (MDW, LDW) were obtained from GLOBOCAN 2002. Simple correlation analysis was performed between the number of clinical trials and incidence, mortality and prevalence per cancer site after log transformation of variables. Results: We identified 399 newly registered trials. Of 374 trials with information about recruitment, 322 (86.1%) and 39 (10.4%) recruited patients only from the MDW and LDW, respectively, while 13 (3.5%) had worldwide recruitment. 229 (58%) of trials were sponsored by industry and 324 trials were phase II (81%). Most trials (and most phase III trials) evaluated treatments for globally prevalent cancers: breast, lung, prostate, and colorectal cancer (Table). Prevalence of a particular cancer type in both the MDW and LDW correlated significantly with the number of clinical trials (Pearson r = 0.63 and 0.55; p = 0.01 and 0.03, respectively). In contrast, mortality in the MDW (Pearson r = 0.73; p= 0.002), but not in the LDW (Pearson r = 0.38; p= 0.17), correlated significantly with the number of clinical trials. Conclusions: Global drug development in cancer predominates in globally prevalent cancers, which are a more important cause of mortality in the MDW than in the LDW. Cancer sites that are major killers globally, and especially in the LDW (e.g., stomach, liver, and esophageal cancer) should receive priority for clinical research. [Table: see text] No significant financial relationships to disclose.

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Pan-cancer opportunities for off-label immunotherapy based on nonsynonymous mutation burden.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.7_suppl.14 ◽

2017 ◽

Vol 35 (7_suppl) ◽

pp. 14-14

Author(s):

Todd Cory Knepper ◽

Jamie K. Teer ◽

Christine Marie Walko ◽

Howard L. McLeod

Keyword(s):

Clinical Benefit ◽

Solid Cancer ◽

Cancer Type ◽

Synonymous Mutation ◽

Nonsynonymous Mutation ◽

Off Label ◽

Action Committee ◽

Mutation Burden ◽

Cancer Types

14 Background: In an effort to better predict which cancer patients (pts) are more likely to derive clinical benefit from immunotherapy, an association between increased non-synonymous mutation burden and likelihood of clinical response has been described. This study reports the mutation burden of pts with a variety of advanced cancers within a real-world clinical genomics database in order to highlight opportunities where off-label immunotherapy can be considered. Methods: For each solid cancer assayed by FoundationOne within Moffitt’s Clinical Genomic Action Committee (CGAC) database, a non-synonymous mutation burden was determined. Pts were then grouped by cancer type and descriptive statistics used to describe the mutation burden. For cancers with at least 5 cases, the percentage of pts with a non-synonymous mutation burden exceeding a threshold shown to be suggestive of clinical benefit from immunotherapy ( ≥ 13) is reported. The threshold was derived via linear regression from the “intermediate-high” mutation burden classification of the FoundationOne assay. Results: 520 pts received a FoundationOne test. The median non-synonymous mutation burden was 7 and the mean was 11.4. More pts with cancers that have demonstrated response to immunotherapy had a mutation burden exceeding the threshold (19.7% for lung – 45.0% for melanoma). Pt tumors from cancer types without immunotherapy indications sometimes (5.0% for salivary gland – 10.5% for breast and colorectal cancer) exceeded mutation threshold suggestive of benefit. Conclusions: A meaningful proportion of pts with cancer types without FDA-approved immunotherapies have a mutation burden for which immunotherapy may represent a clinical consideration. [Table: see text]

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Representativeness of Black Patients in Cancer Clinical Trials Sponsored by the National Cancer Institute Compared With Pharmaceutical Companies

JNCI Cancer Spectrum ◽

10.1093/jncics/pkaa034 ◽

2020 ◽

Vol 4 (4) ◽

Cited By ~ 4

Author(s):

Joseph M Unger ◽

Dawn L Hershman ◽

Raymond U Osarogiagbon ◽

Anirudh Gothwal ◽

Seerat Anand ◽

...

Keyword(s):

Clinical Trials ◽

Pharmaceutical Company ◽

Statistical Tests ◽

Research Network ◽

Cancer Clinical Trials ◽

Cancer Type ◽

New Drug ◽

Black Patients ◽

The Us ◽

Cancer Types

Abstract Background Many clinical trials supporting new drug applications underrepresent minority patients. Trials conducted by the National Cancer Institute’s National Clinical Trial’s Network (NCTN) have greater outreach to community sites, potentially allowing better representation. We compared the representation of Black patients in pharmaceutical company–sponsored cancer clinical trials with NCTN trials and with the US cancer population. Methods We established a large cohort of study publications representing the results of trials that supported new US Food and Drug Administration drug approvals from 2008 to 2018. NCTN trial data were from the SWOG Cancer Research Network. US cancer population rates were estimated using Surveillance, Epidemiology, and End Results survey data. We compared the proportion of Black patients by enrollment year for each cancer type and overall. Tests of proportions were used. All statistical tests were 2-sided. Results A total 358 trials (pharmaceutical company–sponsored trials, 85; SWOG trials, 273) comprised of 93 825 patients (pharmaceutical company–sponsored trials, 46 313; SWOG trials, 47 512) for 15 cancer types were analyzed. Overall, the proportion of Black patients was 2.9% for pharmaceutical company–sponsored trials, 9.0% for SWOG trials, and 12.1% for the US cancer population (P < .001 for each pairwise comparison). These findings were generally consistent across individual cancer types. Conclusions The poor representation of Black patients in pharmaceutical company–sponsored trials supporting new drug applications could result in the use of new drugs with little data about efficacy or side effects in this key population. Moreover, because pharmaceutical company–sponsored trials test the newest available therapies, limited access to these trials represents a disparity in access to potential breakthrough therapies.

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Differences in Funding Sources of Phase III Oncology Clinical Trials by Treatment Modality and Cancer Type

American Journal of Clinical Oncology ◽

10.1097/coc.0000000000000152 ◽

2017 ◽

Vol 40 (3) ◽

pp. 312-317 ◽

Cited By ~ 5

Author(s):

Vikram Jairam ◽

James B. Yu ◽

Sanjay Aneja ◽

Lynn D. Wilson ◽

Shane Lloyd

Keyword(s):

Clinical Trials ◽

Treatment Modality ◽

Phase Iii ◽

Cancer Type ◽

Funding Sources ◽

Oncology Clinical Trials

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Comprehensive analyses of m6A regulators and interactive coding and non-coding RNAs across 32 cancer types

Molecular Cancer ◽

10.1186/s12943-021-01362-2 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Sipeng Shen ◽

Ruyang Zhang ◽

Yue Jiang ◽

Yi Li ◽

Lijuan Lin ◽

...

Keyword(s):

Wnt Signaling Pathway ◽

Rna Modification ◽

Cancer Type ◽

Individual Level ◽

Mutation Burden ◽

Cancer Types ◽

Unsupervised Approach ◽

Single Cancer ◽

Non Coding Rnas ◽

Interactive Coding

AbstractN6-Methyladenosine (m6A) is an RNA modification that interacts with numerous coding and non-coding RNAs and plays important roles in the development of cancers. Nonetheless, the clinical impacts of m6A interactive genes on these cancers largely remain unclear since most studies focus only on a single cancer type. We comprehensively evaluated m6A modification patterns, including 23 m6A regulators and 83 interactive coding and non-coding RNAs among 9,804 pan-cancer samples. We used clustering analysis to identify m6A subtypes and constructed the m6A signature based on an unsupervised approach. We used the signatures to identify potential m6A modification targets across the genome. The prognostic value of one target was further validated in 3,444 samples from six external datasets. We developed three distinct m6A modification subtypes with different tumor microenvironment cell infiltration degrees: immunological, intermediate, and tumor proliferative. They were significantly associated with overall survival in 24 of 27 cancer types. Our constructed individual-level m6A signature was associated with survival, tumor mutation burden, and classical pathways. With the signature, we identified 114 novel genes as potential m6A targets. The gene shared most commonly between cancer types, BCL9L, is an oncogene and interacts with m6A patterns in the Wnt signaling pathway. In conclusion, m6A regulators and their interactive genes impact the outcome of various cancers. Evaluating the m6A subtype and the signature of individual tumors may inform the design of adjuvant treatments.

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