The immunogram of inflammatory breast cancer.

Purpose of review Inflammatory breast cancer (IBC) is the most fatal type presentation of clinical breast cancer. The immune tumor microenvironment (TME) of IBC is characterized by signals of immune evasion but suggests actionable vulnerability to immune-checkpoint inhibitors (ICIs). In this review, we aimed to summarize the most important preclinical evidences of IBC immune-vulnerability and the first data from clinical trials evaluating ICIs in IBC. Recent findings IBC is characterized by a preexisting active immune TME suppressed by mechanisms of immune-escape, including inhibitory immune-checkpoints, whose expression is higher than in non-IBC. Clinical trials evaluating ICIs in patients with IBC are burdened by slow accrual and low enrollment. Summary Because of the limited data from clinical trials, no conclusions about the activity of ICIs in IBC can be drawn. Ongoing clinical trials are assessing many promising ICI-based combination approaches. An enhanced multicenter collaboration to evaluate ICIs in patients with this aggressive form of disease and to improve clinical outcomes is required.

Immunotherapy for inflammatory breast cancer: current evidences and future perspectives


 Background: Inflammatory breast cancer (IBC) is a rare but aggressive tumor type accounting for up to 10% of breast cancer deaths. One-third of IBCs express high PD-L1 that can be targeted by atezolizumab (Az). MEK inhibitor cobimetinib (Co) not only inhibits the RAS-MAPK pathway but can further enhance immune-mediated killing. Thus, we hypothesize that Az+Co may enhance the efficacy of chemotherapy in metastatic IBC (mIBC). We opened a trial to test this hypothesis with a comprehensive multi-omics biomarker assessment. Patients and Methods: In a single-center, open-label phase II study, cohort 1 received one cycle of Az+ Co, followed by four cycles of Az+Co+eribulin (E) to induce a maximum clinical response, followed by Az+Co maintenance. Pre and Post one cycle of Az+Co tumors were collected for immunohistochemistry (IHC), multiplex immunofluorescence (mIF), whole-exome sequencing (WES), and RNA sequencing (RNAseq). Blood was collected for circulating tumor DNA (ctDNA). Results: Seventeen patients were enrolled in cohort 1. Seven had PR, and three had SD as the best responses. Fourteen had pre, and six had pre/post tumors. The levels of PD-L1 expression at pre/post were not associated with responses. WES revealed the median tumor mutation burden at pre- was 9mt/Mb. More than 50% had TP53 and PI3K pathway mutations at pre. RTK-RAS and Notch pathways were altered in 4/9 cases. PRDM9 and DPY19L2 single-gene mutations were commonly noted in pre. No cancer-associated gene aberration, including potential biomarkers of anti-PDL1 agent response was associated with clinical outcomes. Transcriptomic gene set enrichment analysis demonstrated a greater degree of TNFa and TGFb signaling, Oxphos, angiogenesis, and epithelial-to-mesenchymal transition (EMT) processes in tumors from patients with poor response. Immune profiling by RNAseq revealed two responders to have elevated effector memory T cells, NK T cells, myeloid dendritic cells, and M1 macrophage signatures in pre-samples, but post-samples were not available. mIF confirmed a higher frequency of NK-T cells. The ctDNA analysis from serially collected blood samples is ongoing. Discussion: In this comprehensive multi-omics analysis of pre-and-post-Az+Co, we observed several novel findings, while conventional biomarkers for Az and Co did not correlate with clinical responses. EMT, Oxphos, Notch, and chronic inflammation pathways, which are not previously well reported, were observed in this IBC cohort. These markers warrant further validation to see if they carry significance as therapeutic targets in IBC.
 Citation Format: Bora Lim, Angela Alexander, Jie S. Willey, Huiming Sun, Suyu Liu, Anisha B. Patel, Edwin Roger Parra, Cara Haymaker, Luisa Solis Soto, Alejandra Serrano, Baohua Sun, Cibelle Freitas Pinto Lima, Auriole Tamegnon, Renganayaki K. Pandurengan, Dzifa Douse, Jessica Lan, Luthra Raja, Randy Chu, Mark Knafl, Scott E. Woodman, Haifeng Zhu, Katja Shulze, Katherine Fedenko, Walter Darbonne, Naoto T. Ueno, Vicente Valero. Biomarker analysis: Multi-omics elucidation of Cohort 1 from a phase II study of a triple combination of Atezolizumab + cobimetinib + eribulin in patients with metastatic inflammatory breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-19.

Abstract P4-08-19: Biomarker analysis: Multi-omics elucidation of Cohort 1 from a phase II study of a triple combination of Atezolizumab + cobimetinib + eribulin in patients with metastatic inflammatory breast cancer

98. Utility and feasibility of Molecular Profiling of Circulating Tumor RNA (ctRNA) from FNA Supernatants

PURPOSE
This study investigates the interplay between T-cell receptor (TCR) immune characteristics and microbiome profiles to explore the relationship between immune diversity and microbial composition in cervical samples from Ethiopia.


METHODS
Cervical specimens were collected from patients at Tikur Anbessa Specialized Hospital in Addis Ababa, and rural Butajira, south-central Ethiopia. Patient data, including age, human papillomavirus status, pathology, and TCR immune characteristics, were analyzed with a focus on the interactions between TCR profiles and microbiome compositions in malignant samples.


RESULTS
Three distinct TCR profiles were identified: Group 1 (TCR active) exhibited features of active immune engagement, including high diversity, clonal expansion, and repertoire richness. Group 2 (TCR restricted) showed reduced TCR diversity and expansion, suggesting a restricted repertoire. Group 3 (TCR balanced) had moderate diversity and clonal activity. TCR repertoire groups were linked with microbial diversity, with Group 1 (TCR active) showing the highest number of microbes (high operational taxonomic units and microbial diversity). Maximum TCR clonal expansion positivity associated with microbial richness, while Group 3 (TCR balanced) was linked to reduced microbial alpha diversity. Taxonomic analysis revealed specific organisms enriched in TCR repertoire group.


CONCLUSION
Variations in TCR profiles are linked to distinct microbial environments in cervical cancer with greater microbial richness in patients with greater maximum productive frequency. These findings underscore the interplay between TCR diversity, microbiome composition, and malignancy, offering insights into the potential implications for microbiome-targeted therapies and prognostic biomarkers in cervical cancer.

Linking Microbiome Diversity and Immune Profiles in Ethiopian Patients With Cervical Cancer.

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Abstract P4-08-19: Biomarker analysis: Multi-omics elucidation of Cohort 1 from a phase II study of a triple combination of Atezolizumab + cobimetinib + eribulin in patients with metastatic inflammatory breast cancer

98. Utility and feasibility of Molecular Profiling of Circulating Tumor RNA (ctRNA) from FNA Supernatants

Linking Microbiome Diversity and Immune Profiles in Ethiopian Patients With Cervical Cancer.