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

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]

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

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 35-35 ◽  
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.

scholarly journals Cancer Type-Dependent Correlations betweenTP53Mutations and Antitumor Immunity

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.

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

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.

scholarly journals Complement System: Promoter or Suppressor of Cancer Progression?

Antibodies ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 57
Author(s):  
Margot Revel ◽  
Marie V. Daugan ◽  
Catherine Sautés-Fridman ◽  
Wolf H. Fridman ◽  
Lubka T. Roumenina
Keyword(s):  
Cancer Progression ◽  
Complement System ◽  
Current Knowledge ◽  
Prognostic Impact ◽  
Cancer Type ◽  
Human Cancers ◽  
Cancer Types ◽  
The Complement System

Constituent of innate immunity, complement is present in the tumor microenvironment. The functions of complement include clearance of pathogens and maintenance of homeostasis, and as such could contribute to an anti-tumoral role in the context of certain cancers. However, multiple lines of evidence show that in many cancers, complement has pro-tumoral actions. The large number of complement molecules (over 30), the diversity of their functions (related or not to the complement cascade), and the variety of cancer types make the complement-cancer topic a very complex matter that has just started to be unraveled. With this review we highlight the context-dependent role of complement in cancer. Recent studies revealed that depending of the cancer type, complement can be pro or anti-tumoral and, even for the same type of cancer, different models presented opposite effects. We aim to clarify the current knowledge of the role of complement in human cancers and the insights from mouse models. Using our classification of human cancers based on the prognostic impact of the overexpression of complement genes, we emphasize the strong potential for therapeutic targeting the complement system in selected subgroups of cancer patients.

scholarly journals Hierarchical Classification of Cancers of Unknown Primary Using Multi-Omics Data

2019 ◽  
Vol 18 ◽  
pp. 117693511987216 ◽  
Author(s):  
Elham Bavafaye Haghighi ◽  
Michael Knudsen ◽  
Britt Elmedal Laursen ◽  
Søren Besenbacher
Keyword(s):  
Metastatic Cancer ◽  
Hierarchical Classification ◽  
Molecular Data ◽  
Unknown Primary ◽  
Cancer Type ◽  
Omics Data ◽  
Data Types ◽  
Cancer Types ◽  
Hierarchical Classifier

A cancer of unknown primary (CUP) is a metastatic cancer for which standard diagnostic tests fail to locate the primary cancer. As standard treatments are based on the cancer type, such cases are hard to treat and have very poor prognosis. Using molecular data from the metastatic cancer to predict the primary site can make treatment choice easier and enable targeted therapy. In this article, we first examine the ability to predict cancer type using different types of omics data. Methylation data lead to slightly better prediction than gene expression and both these are superior to classification using somatic mutations. After using 3 data types independently, we notice some differences between the classes that tend to be misclassified, suggesting that integrating the data might improve accuracy. In light of the different levels of information provided by different omics types and to be able to handle missing data, we perform multi-omics classification by hierarchically combining the classifiers. The proposed hierarchical method first classifies based on the most informative type of omics data and then uses the other types of omics data to classify samples that did not get a high confidence classification in the first step. The resulting hierarchical classifier has higher accuracy than any of the single omics classifiers and thus proves that the combination of different data types is beneficial. Our results show that using multi-omics data can improve the classification of cancer types. We confirm this by testing our method on metastatic cancers from the MET500 dataset.

Correlation between biopsy type and insufficient tissue availability for biomarker testing in five solid cancer types.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22136-e22136 ◽  
Author(s):  
Pieter De Richter ◽  
Jackie Ilacqua
Keyword(s):  
Breast Cancer ◽  
Core Biopsy ◽  
Online Survey ◽  
Cancer Tissue ◽  
Solid Cancer ◽  
Cancer Type ◽  
Multiple Cancer ◽  
Tissue Samples ◽  
Biomarker Testing ◽  
Cancer Types

e22136 Background: Limited tissue availability is a known barrier to conducting biomarker testing on cancer tissue specimens. It has been assumed that the frequency of insufficient tissue being available is correlated with type of tissue biopsy performed, but this has not previously been quantified across multiple cancer types. Methods: A panel of pathologists in the US (N=90) were asked to report on recent cancer tissues they prepared/handled for biomarker testing. The physicians were asked to report on the cancer type, biopsy method, molecular diagnostics tests conducted, and whether sufficient tissue was available for all requested tests. If insufficient tissue was available, they were asked to report on which tests they were unable to perform as a result. All data was collected through an online survey between August and November 2012. Results: In total, 99 breast cancer samples, 85 NSCLC samples, 60 CRC samples, 30 gastric cancer samples and 40 melanoma samples were reported on. Insufficient tissue was available in 5 (6%) of all NSCLC samples, 2 of which were obtained through fine needle aspirations (14% of all FNAs), a further 2 through core biopsies (5%), and a further 1 through a bronchoscopy (8%). Insufficient tissue was available in 1 (1%) of all breast cancer samples (core biopsy, 1% of all core biopsies), 1 (3%) of all melanoma samples (core biopsy, 13% of all core biopsies) and 1 (2%) of all CRC samples (core biopsy, 11% of all core biopsies). Conclusions: Insufficient cancer tissue for biomarker testing occurred across 4 out of 5 cancer types reported on, though was rare (<5%) in cancers other than NSCLC. The majority of tissue samples in which insufficient tissue was present were acquired through core biopsies (67% of all cases) or FNAs (22% of all cases).

scholarly journals Survival after bone metastasis by primary cancer type: a Danish population-based cohort study

BMJ Open ◽  
2017 ◽  
Vol 7 (9) ◽  
pp. e016022 ◽  
Author(s):  
Elisabeth Svensson ◽  
Christian F Christiansen ◽  
Sinna P Ulrichsen ◽  
Mikael R Rørth ◽  
Henrik T Sørensen
Keyword(s):  
Breast Cancer ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Population Based ◽  
Solid Cancer ◽  
Cancer Type ◽  
Adjusted Relative Risk ◽  
Primary Cancer ◽  
Cancer Types ◽  
Synchronous Metastases

ObjectiveIn the 10 most common primary types with bone metastases, we aimed to examine survival, further stratifying on bone metastases only or with additional synchronous metastases.MethodsWe included all patients aged 18 years and older with incident hospital diagnosis of solid cancer between 1994 and 2010, subsequently diagnosed with BM until 2012. We followed patients from date of bone metastasis diagnosis until death, emigration or 31 December 2012, whichever came first. We computed 1-year, 3-year and 5-year survival (%) and the corresponding 95% CIs stratified on primary cancer type. Comparing patients with bone metastasis only and patients with other synchronous metastases, we estimated crude and adjusted HRs and corresponding 95% CI for mortality.ResultsWe included 17 251 patients with bone metastasis. The most common primary cancer types with bone metastasis were prostate (34%), breast (22%) and lung (20%). One-year survival after bone metastasis diagnosis was lowest in patients with lung cancer (10%, 95% CI 9% to 11%) and highest in patients with breast cancer (51%, 50% to 53%). At 5 years of follow-up, only patients with breast cancer had over 10% survival (13%, 11% to 14%). The risk of mortality was increased for the majority of cancer types among patients with bone and synchronous metastases compared with bone only (adjusted relative risk 1.29–1.57), except for cervix, ovarian and bladder cancer.ConclusionsWhile patients with bone metastases after most primary cancers have poor survival, one of ten patients with bone metastasis from breast cancer survived 5 years.

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

2021 ◽  
Vol 12 ◽  
Author(s):  
Anshuman Panda ◽  
Shridar Ganesan
Keyword(s):  
Clinical Trials ◽  
Phase Iii ◽  
Cancer Type ◽  
Over Expression ◽  
Indoleamine 2,3 Dioxygenase ◽  
Her2 Breast Cancer ◽  
Specific Subset ◽  
Pathway Expression ◽  
Mutation Burden ◽  
Cancer Types

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.

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

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.

scholarly journals Immune-Related Pneumonitis Was Decreased by Addition of Chemotherapy with PD-1/L1 Inhibitors: Systematic Review and Network Meta-Analysis of Randomized Controlled Trials (RCTs)

2022 ◽  
Vol 29 (1) ◽  
pp. 267-282
Author(s):  
Yi-Xiu Long ◽  
Yue Sun ◽  
Rui-Zhi Liu ◽  
Ming-Yi Zhang ◽  
Jing Zhao ◽  
...  
Keyword(s):  
Lower Risk ◽  
Meta Analysis ◽  
Treatment Method ◽  
Immunosuppressive Agent ◽  
Solid Cancer ◽  
Cancer Type ◽  
Cancer Types ◽  
Grade 3 ◽  
Nsclc Patients ◽  
Inhibitor Treatment

Purpose: Immune-related pneumonitis (IRP) has attracted extensive attention, owing to its increased mortality rate. Conventional chemotherapy (C) has been considered as an immunosuppressive agent and may thus reduce IRP’s risk when used in combination with PD-1/L1 inhibitors. This study aimed to assess the risk of IRP with PD-1/L1 inhibitors plus chemotherapy (I+C) versus PD-1/L1 inhibitors alone (I) in solid cancer treatment. Method: Multiple databases were searched for RCTs before January 2021. This NMA was performed among I+C, I, and C to investigate IRP’s risk. Subgroup analysis was carried out on the basis of different PD-1/L1 inhibitors and cancer types. Results: Thirty-one RCTs (19,624 patients) were included. The I+C group exhibited a lower risk of IRP in any grade (RR, 0.60; 95% CI, 0.38–0.95) and in grade 3–5 (RR, 0.42; 95% CI, 0.21–0.92) as opposed to the I group. The risk of any grade IRP with PD-1 plus chemotherapy was lower than that with PD-1 monotherapy (RR, 0.50; 95% CI, 0.28–0.89), although grade 3–5 IRP was similar. There was no statistically meaningful difference in the risk of any grade IRP between PD-L1 plus chemotherapy and PD-L1 inhibitors monotherapy (RR, 0.95; 95% CI, 0.43–2.09) or grade 3–5 IRP (RR, 0.71;95% CI, 0.24–2.07). In addition, compared with the I group, the I+C group was correlated with a decreased risk in IRP regardless of cancer type, while a substantial difference was only observed in NSCLC patients for grade 3–5 IRP (RR, 0.39; 95% CI, 0.15–0.98). Conclusion: In comparison to PD-1/L1 inhibitor treatment alone, combining chemotherapy with PD-1/L1 inhibitors might reduce the risk of IRP in the general population. Furthermore, PD-1 inhibitors in combination with chemotherapy were correlated with a decreased risk of IRP compared to PD-1 inhibitor treatment alone. In contrast to the I group, the I+C group exhibited a lower risk of IRP, especially for NSCLC patients.

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