Updates in combined approaches of radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer

Jungles, Kassidy M.; Holcomb, Erin A.; Pearson, Ashley N.; Jungles, Kalli R.; Bishop, Caroline R.; Pierce, Lori J.; Green, Michael D.; Speers, Corey

doi:10.3389/fonc.2022.1022542

Cited by 13 publications

(8 citation statements)

References 281 publications

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“…RT can affect the tumor microenvironment differently depending on the dose ( 68 ). Preclinical studies suggest high RT doses can turn an immunosuppressive tumor microenvironment proinflammatory ( 69 ).…”

Section: Discussionmentioning

confidence: 99%

Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial

Tullberg

Sjöström

Niméus

et al. 2023

Clinical Cancer Research

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Purpose: The local immune infiltrate's influence on tumor progression may be closely linked to tumor-intrinsic factors. The study aimed to investigate whether integrating immunologic and tumor-intrinsic factors can identify patients from a low-risk cohort who may be candidates for radiotherapy (RT) de-escalation. Experimental Design: The SweBCG91RT trial included 1,178 patients with stage I to IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median of 15.2 years. We trained two models designed to capture immunologic activity and immunomodulatory tumor-intrinsic qualities, respectively. We then analyzed if combining these two variables could further stratify tumors, allowing for identifying a subgroup where RT de-escalation is feasible, despite clinical indicators of a high risk of ipsilateral breast tumor recurrence (IBTR). Results: The prognostic effect of the immunologic model could be predicted by the tumor-intrinsic model (Pinteraction = 0.01). By integrating measurements of the immunologic- and tumor-intrinsic models, patients who benefited from an active immune infiltrate could be identified. These patients benefited from standard RT (HR, 0.28; 95% CI, 0.09–0.85; P = 0.025) and had a 5.4% 10-year incidence of IBTR after irradiation despite high-risk genomic indicators and a low frequency of systemic therapy. In contrast, high-risk tumors without an immune infiltrate had a high 10-year incidence of IBTR despite RT treatment (19.5%; 95% CI, 12.2–30.3). Conclusions: Integrating tumor-intrinsic and immunologic factors may identify immunogenic tumors in early-stage breast cancer populations dominated by ER-positive tumors. Patients who benefit from an activated immune infiltrate may be candidates for RT de-escalation.

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Section: Discussionmentioning

confidence: 99%

Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial

Tullberg

Sjöström

Niméus

et al. 2023

Clinical Cancer Research

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Section: Discussionmentioning

confidence: 99%

“…The introduction of checkpoint inhibitors has provided a new approach to the treatment of various malignancies. In breast cancer, however, checkpoint inhibitors have been significantly less effective (55, 92, 93). Immunosuppressive factors that reduce the efficacy of many cancer treatment strategies present a major obstacle to successful therapy.…”

Section: Discussionmentioning

confidence: 99%

Spatial analysis of NOS2 and COX2 interaction with T-effector cells reveals immunosuppressive landscapes associated with poor outcome in ER- breast cancer patients

Ridnour,

Cheng,

Heinz

et al. 2023

Preprint

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Multiple immunosuppressive mechanisms exist in the tumor microenvironment that drive poor outcomes and decrease treatment efficacy. The co-expression of NOS2 and COX2 is a strong predictor of poor prognosis in ER- breast cancer and other malignancies. Together, they generate pro-oncogenic signals that drive metastasis, drug resistance, cancer stemness, and immune suppression. Using an ER- breast cancer patient cohort, we found that the spatial expression patterns of NOS2 and COX2 with CD3+CD8+PD1- T effector (Teff) cells formed a tumor immune landscape that correlated with poor outcome. NOS2 was primarily associated with the tumor-immune interface, whereas COX2 was associated with immune desert regions of the tumor lacking Teff cells. A higher ratio of NOS2 or COX2 to Teff was highly correlated with poor outcomes. Spatial analysis revealed that regional clustering of NOS2 and COX2 was associated with stromal-restricted Teff, while only COX2 was predominant in immune deserts. Examination of other immunosuppressive elements, such as PDL1/PD1, Treg, B7H4, and IDO1, revealed that PDL1/PD1, Treg, and IDO1 were primarily associated with restricted Teff, whereas B7H4 and COX2 were found in tumor immune deserts. Regardless of the survival outcome, other leukocytes, such as CD4 T cells and macrophages, were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to a massive cell infiltration, thus validating the hypothesis that COX2 is an essential component of the Teff exclusion process and, thus, tumor evasion. Our study indicates that NOS2/COX2 expression plays a central role in tumor immunosuppression. Our findings indicate that new strategies combining clinically available NOS2/COX2 inhibitors with various forms of immune therapy may open a new avenue for the treatment of aggressive ER- breast cancers.

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“…The combination of new treatments with RT is complex due to the multiple factors involved. Both the technique and the dose and fractionation to be used can have a significant impact on clinical outcomes (Table 13) [206][207][208][209] .…”

Section: Rt-systemic Treatment Interactionsmentioning

confidence: 99%

Mexican breast cancer consensus. Management of early breast cancer

Bargalló-Rocha,

Aguilar-Villanueva,

Ahumada-Pámanes

et al. 2024

GAMO

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Breast cancer, in early stages, has specific surgical, radiotherapy, and systemic management. This type of cancer includes ductal carcinoma in situ and breast cancers in stages I, IIA, IIB, and IIIA. This tenth update of the Mexican Breast Cancer Consensus addressed the management of early stages. The dissemination of this consensus contributes to the updating and homogeneity of breast cancer management criteria. This article aims to present the update in the multidisciplinary management of breast cancer.

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Updates in combined approaches of radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer

Cited by 13 publications

References 281 publications

Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial

Integrating Tumor-Intrinsic and Immunologic Factors to Identify Immunogenic Breast Cancers from a Low-Risk Cohort: Results from the Randomized SweBCG91RT Trial

Spatial analysis of NOS2 and COX2 interaction with T-effector cells reveals immunosuppressive landscapes associated with poor outcome in ER- breast cancer patients

Mexican breast cancer consensus. Management of early breast cancer

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