Immune Checkpoint Inhibitors in Triple Negative Breast Cancer: What is the Evidence?

Chok, Nora; Chokr, Samer

doi:10.21767/2576-3903.100031

Cited by 3 publications

(3 citation statements)

References 32 publications

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“…5c). These characteristics may indicate a susceptibility to immune checkpoint inhibitors and cyclooxygenase inhibitors in human claudin-low breast cancer [63, 64].…”

Section: Resultsmentioning

confidence: 99%

Claudin-low-like mouse mammary tumors show distinct transcriptomic patterns uncoupled from genomic drivers

et al. 2019

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Background: Claudin-low breast cancer is a molecular subtype associated with poor prognosis and without targeted treatment options. The claudin-low subtype is defined by certain biological characteristics, some of which may be clinically actionable, such as high immunogenicity. In mice, the medroxyprogesterone acetate (MPA) and 7, 12-dimethylbenzanthracene (DMBA)-induced mammary tumor model yields a heterogeneous set of tumors, a subset of which display claudin-low features. Neither the genomic characteristics of MPA/DMBA-induced claudinlow tumors nor those of human claudin-low breast tumors have been thoroughly explored. Methods: The transcriptomic characteristics and subtypes of MPA/DMBA-induced mouse mammary tumors were determined using gene expression microarrays. Somatic mutations and copy number aberrations in MPA/DMBAinduced tumors were identified from whole exome sequencing data. A publicly available dataset was queried to explore the genomic characteristics of human claudin-low breast cancer and to validate findings in the murine tumors. Results: Half of MPA/DMBA-induced tumors showed a claudin-low-like subtype. All tumors carried mutations in known driver genes. While the specific genes carrying mutations varied between tumors, there was a consistent mutational signature with an overweight of T>A transversions in TG dinucleotides. Most tumors carried copy number aberrations with a potential oncogenic driver effect. Overall, several genomic events were observed recurrently; however, none accurately delineated claudin-low-like tumors. Human claudin-low breast cancers carried a distinct set of genomic characteristics, in particular a relatively low burden of mutations and copy number aberrations. The gene expression characteristics of claudin-low-like MPA/DMBA-induced tumors accurately reflected those of human claudin-low tumors, including epithelial-mesenchymal transition phenotype, high level of immune activation, and low degree of differentiation. There was an elevated expression of the immunosuppressive genes PTGS2 (encoding COX-2) and CD274 (encoding PD-L1) in human and murine claudin-low tumors. Conclusions: Our findings show that the claudin-low breast cancer subtype is not demarcated by specific genomic aberrations, but carries potentially targetable characteristics warranting further research.

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“…5c). These characteristics may indicate a susceptibility to immune checkpoint inhibitors and cyclooxygenase inhibitors in human claudin-low breast cancer [63, 64].…”

Section: Resultsmentioning

confidence: 99%

Claudin-low-like mouse mammary tumors show distinct transcriptomic patterns uncoupled from genomic drivers

et al. 2019

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“…These features were also characteristic of human claudin-low tumors in the METABRIC cohort [6,7], which showed significantly higher expression levels of both PTGS2 and CD274 compared to non-claudin-low breast tumors (p < 0.001 for both, two-tailed Wilcoxon rank-sum test), and compared specifically to basal-like tumors (p = 0.004 and p < 0.001, respectively) (Fig 5C). These characteristics may indicate a susceptibility to immune checkpoint inhibitors and cyclooxygenase inhibitors in human claudin-low breast cancer [29,30].…”

Section: Resultsmentioning

confidence: 99%

Claudin-low-like mouse mammary tumors show distinct transcriptomic patterns uncoupled from genomic drivers

Sørlie

Fougner

Bergholtz

et al. 2019

Preprint

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Claudin-low breast cancer is a molecular subtype associated with poor prognosis and without targeted treatment options. The claudin-low subtype is defined by certain biological characteristics, some of which may be clinically actionable, such as high immunogenicity. In mice, the medroxyprogesterone acetate (MPA) and 7,12-dimethylbenzanthracene (DMBA) induced mammary tumor model yields a heterogeneous set of tumors, a subset of which display claudin-low features. Neither the genomic characteristics of MPA/DMBA-induced claudin-low tumors, nor those of human claudin-low breast tumors, have been thoroughly explored.The transcriptomic characteristics and subtypes of MPA/DMBA-induced mouse mammary tumors were determined using gene expression microarrays. Somatic mutations and copy number aberrations in MPA/DMBA-induced tumors were identified from whole exome sequencing data. A publicly available dataset was queried to explore the genomic characteristics of human claudin-low breast cancer and to validate findings in the murine tumors.Half of MPA/DMBA-induced tumors showed a claudin-low-like subtype. All tumors carried mutations in known driver genes. While the specific genes carrying mutations varied between tumors, there was a consistent mutational signature with an overweight of T>A transversions in TG dinucleotides. Most tumors carried copy number aberrations with a potential oncogenic driver effect. Overall, several genomic events were observed recurrently, however none accurately delineated claudin-low-like tumors. Human claudin-low breast cancers carried a distinct set of genomic characteristics, in particular a relatively low burden of mutations and copy number aberrations. The gene expression characteristics of claudin-low-like MPA/DMBA-induced tumors accurately reflected those of human claudin-low tumors, including epithelial-mesenchymal transition phenotype, high level of immune activation and low degree of differentiation. There was an elevated expression of the immunosuppressive genes PTGS2 (encoding COX-2) and CD274 (encoding PD-L1) in human and murine claudin-low tumors. Our findings show that the claudin-low breast cancer subtype is not demarcated by specific genomic aberrations, but carries potentially targetable characteristics warranting further research.Author SummaryBreast cancer is comprised of several distinct disease subtypes with different etiologies, prognoses and therapeutic targets. The claudin-low breast cancer subtype is relatively poorly understood, and no specific treatment exists targeting its unique characteristics. Animal models accurately representing human disease counterparts are vital for developing novel therapeutics, but for the claudin-low breast cancer subtype, no such uniform model exists. Here, we show that exposing mice to the carcinogen DMBA and the hormone MPA causes a diverse range of mammary tumors to grow, and half of these have a gene expression pattern similar to that seen in human claudin-low breast cancer. These tumors have numerous changes in their DNA, with clear differences between each tumor, however no specific DNA aberrations clearly demarcate the claudin-low subtype. We also analyzed human breast cancers and show that human claudin-low tumors have several clear patterns in their DNA aberrations, but no specific features accurately distinguish claudin-low from non-claudin-low breast cancer. Finally, we show that both human and murine claudin-low tumors express high levels of genes associated with suppression of immune response. In sum, we highlight claudin-low breast cancer as a clinically relevant subtype with a complex etiology, and with potential unexploited therapeutic targets.

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“…Aberrant signaling by VEGFR2 and cMET, as well as modifications of the immune cell population in response to an immune-suppressive phenotype, resulted in a failure of immunotherapy for TNBC [ 9 ]. In TNBC, multiple genomic instabilities and mutations have been associated with immune responses [ 10 ]. A comparative study between TNBC and non-TNBC (NTNBC) showed that TNBC is characterized by higher expression levels of functional gene sets associated with 15 types of immune cells [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Explainable Artificial Intelligence Reveals Novel Insight into Tumor Microenvironment Conditions Linked with Better Prognosis in Patients with Breast Cancer

Chakraborty

Ivan

Amero

et al. 2021

Cancers

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We investigated the data-driven relationship between immune cell composition in the tumor microenvironment (TME) and the ≥5-year survival rates of breast cancer patients using explainable artificial intelligence (XAI) models. We acquired TCGA breast invasive carcinoma data from the cbioPortal and retrieved immune cell composition estimates from bulk RNA sequencing data from TIMER2.0 based on EPIC, CIBERSORT, TIMER, and xCell computational methods. Novel insights derived from our XAI model showed that B cells, CD8+ T cells, M0 macrophages, and NK T cells are the most critical TME features for enhanced prognosis of breast cancer patients. Our XAI model also revealed the inflection points of these critical TME features, above or below which ≥5-year survival rates improve. Subsequently, we ascertained the conditional probabilities of ≥5-year survival under specific conditions inferred from the inflection points. In particular, the XAI models revealed that the B cell fraction (relative to all cells in a sample) exceeding 0.025, M0 macrophage fraction (relative to the total immune cell content) below 0.05, and NK T cell and CD8+ T cell fractions (based on cancer type-specific arbitrary units) above 0.075 and 0.25, respectively, in the TME could enhance the ≥5-year survival in breast cancer patients. The findings could lead to accurate clinical predictions and enhanced immunotherapies, and to the design of innovative strategies to reprogram the breast TME.

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Immune Checkpoint Inhibitors in Triple Negative Breast Cancer: What is the Evidence?

Cited by 3 publications

References 32 publications

Claudin-low-like mouse mammary tumors show distinct transcriptomic patterns uncoupled from genomic drivers

Claudin-low-like mouse mammary tumors show distinct transcriptomic patterns uncoupled from genomic drivers

Claudin-low-like mouse mammary tumors show distinct transcriptomic patterns uncoupled from genomic drivers

Explainable Artificial Intelligence Reveals Novel Insight into Tumor Microenvironment Conditions Linked with Better Prognosis in Patients with Breast Cancer

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