Effect of Radiotherapy After Breast-Conserving Surgery Depending on the Presence of Tumor-Infiltrating Lymphocytes: A Long-Term Follow-Up of the SweBCG91RT Randomized Trial

Kovács, Anikó; Tullberg, Axel Stenmark; Rönnerman, Elisabeth Werner; Holmberg, Erik; Hartman, Linda; Sjöström, Martin; Lundstedt, Dan; Malmström, Per; Fernö, Mårten; Karlsson, Per

doi:10.1200/jco.18.02157

Cited by 46 publications

(49 citation statements)

References 73 publications

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“…According to the guidelines for TIL assessment in breast carcinoma [36, 37], analysis on hematoxylin and eosin–stained slides were independently evaluated by 2 board certified breast pathologists. We used semi continuous variables (deciles): less than 1%, 1% to 9%, 10% to 19%, 20% to 49%, 50% to 74%, and 75% or greater [38]. All cases for which the discordance between the 2 pathologists reached greater than 15% were reviewed together until a consensus was reached.…”

Section: Methodsmentioning

confidence: 99%

JAK1 as a prognostic marker and its correlation with immune infiltrates in breast cancer

Chen

Lai

Dai

et al. 2019

Aging

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Clinical trials testing Janus kinase-1 (JAK1) inhibitors in cancers are under way. Whether the JAK1 mRNA levels in breast tumors correlates with outcome has not been evaluated. JAK1 expression was analyzed via the Oncomine database and Tumor IMmune Estimation Resource site. Tumor tissues from 57 breast cancer patients were used for qRT-PCR and immune infiltration assessment. JAK1 expression was significantly lower in breast invasive carcinoma compared with adjacent normal tissues. Public databases (Kaplan-Meier plotter and PrognoScan) showed that low JAK1 expression was associated with poorer survival. Data from The Cancer Genome Atlas (TCGA) showed that high JAK1 expression was associated with increased survival in both TNM I-II and TNM III-IV patients. JAK1 was inversely correlated with tumor size status, lymph node status, and TNM of breast cancer patients. JAK1 levels were correlated with the T cell transcript-enriched LYM metagene signature and was significantly lower in the low tumor infiltrating lymphocytes (TILs) group. JAK1 expression levels had significant positive correlations with infiltrating levels of CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells in breast cancer and not with other B cells. In conclusion, JAK1 mRNA levels were correlated with prognosis and immune infiltrating levels in breast cancer.

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Section: Methodsmentioning

confidence: 99%

JAK1 as a prognostic marker and its correlation with immune infiltrates in breast cancer

Chen

Lai

Dai

et al. 2019

Aging

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“…Recently, a high number of tumor-infiltrating lymphocytes was shown to independently reduce the recurrence risk of early stage breast cancer patients within a randomized RT trial. Consequently, patients with low levels of tumor-infiltrating lymphocytes may represent a subgroup with an increased RT benefit [3]. Preclinical studies have indicated that stroma cells can modulate radiosensitivity of tumor cells [4][5][6][7], but non-leukocytic stroma cells have not yet been explored as potential predictive markers for benefit of RT in invasive breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Prognostic and predictive impact of stroma cells defined by PDGFRb expression in early breast cancer: results from the randomized SweBCG91RT trial

Strell

Tullberg

Edelmann

et al. 2021

Breast Cancer Res Treat

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Purpose Predictive biomarkers are needed to aid the individualization of radiotherapy (RT) in breast cancer. Cancer-associated fibroblasts have been implicated in tumor radioresistance and can be identified by platelet-derived growth factor receptor-beta (PDGFRb). This study aims to analyze how PDGFRb expression affects RT benefit in a large randomized RT trial. Methods PDGFRb was assessed by immunohistochemistry on tissue microarrays from 989 tumors of the SweBCG91RT trial, which enrolled lymph node-negative, stage I/IIA breast cancer patients randomized to RT after breast-conserving surgery. Outcomes were analyzed at 10 years for ipsilateral breast tumor recurrence (IBTR) and any recurrence and 15 years for breast cancer specific death (BCSD). Results PDGFRb expression correlated with estrogen receptor negativity and younger age. An increased risk for any recurrence was noted in univariable analysis for the medium (HR 1.58, CI 95% 1.11–2.23, p = 0.011) or PDGFRb high group (1.49, 1.06–2.10, p = 0.021) compared to the low group. No differences in IBTR or BCSD risk were detected. RT benefit regarding IBTR risk was significant in the PDGFRb low (0.29, 0.12–0.67, p = 0.004) and medium (0.31, 0.16–0.59, p < 0.001) groups but not the PDGFRb high group (0.64, 0.36–1.11, p = 0.110) in multivariable analysis. Likewise, risk reduction for any recurrence was less pronounced in the PDGFRb high group. No significant interaction between RT and PDGFRb-score could be detected. Conclusion A higher PDGFRb-score conferred an increased risk of any recurrence, which partly can be explained by its association with estrogen receptor negativity and young age. Reduced RT benefit was noted among patients with high PDGFRb, however without significant interaction.

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“…HER2 + and TNBC are more likely to be infiltrated by tumor-infiltrating lymphocytes (TILs) and to express programmed death ligand-1 (PD-L1) in the TME than ER- or PR-expressing luminal tumors ( 93 – 95 ). Moreover, the quantity of TILs is a prognostic indicator of disease recurrence-free survival and overall survival, especially for TNBC ( 96 – 98 ). Higher TIL concentration is also predictive of response to neoadjuvant chemotherapy in all subtypes of breast cancer ( 99 ).…”

Section: Discussionmentioning

confidence: 99%

Physical Activity and Breast Cancer Prevention: Possible Role of Immune Mediators

Rogers

2020

Front. Nutr.

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There is strong evidence that physical activity (PA) reduces risk, recurrence, and mortality from breast cancer. Emerging data suggest that PA induces changes in inflammatory and immune mediators that may contribute to beneficial effects on breast cancer outcomes. Thus, the goal of this review was to evaluate the evidence linking the protective benefit of PA to modulation of immune responses in breast cancer. A literature search was conducted to identify studies that evaluated the impact of PA on tumor and immune outcomes in breast cancer patients and in mammary tumor models. Nineteen studies investigated the effect of PA interventions on cancer immune outcomes using preclinical breast cancer models. Tumor growth was reduced in 11 studies, unchanged in three studies, and increased in one study. Spontaneous metastasis was reduced in two studies and survival was improved in four studies. Frequently assessed immune outcomes include splenic cell number and function, circulating inflammatory cytokines, and intratumoral immune cells and inflammatory markers. Circulating inflammatory cytokine responses were heterogeneous in preclinical models. Within the tumor microenvironment (TME), several studies documented a change in the infiltration of immune cells with an increase in effector cells and a reduction in immune suppressive cells. Twenty-three studies investigated the effect of PA interventions on immune outcomes in breast cancer patients. Thirteen studies used aerobic PA interventions and 10 studies used a combination of aerobic and resistance exercise interventions. Cycling and treadmill activities were the most commonly used PA modalities. Circulating immune cells and inflammatory cytokines were the most frequently assessed immune outcomes in the clinical studies. Among the 19 studies that evaluated a PA intervention during the post treatment period, 10 reported a reduction in the levels of at least one inflammatory cytokine. No inflammatory cytokines were quantified in the three studies that evaluated a PA intervention during treatment with chemotherapy. Immune outcomes within the tumor were assessed in only one study performing a PA intervention prior to surgery. Results from preclinical and clinical studies suggest that PA exerts heterogeneous effects on inflammatory cytokines, but may alter the gene expression profile and immune infiltrates in the tumor which may result in a reduction in immunosuppressive factors. However, additional studies are needed to better understand the effect of PA on immune outcomes in the TME.

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Effect of Radiotherapy After Breast-Conserving Surgery Depending on the Presence of Tumor-Infiltrating Lymphocytes: A Long-Term Follow-Up of the SweBCG91RT Randomized Trial

Cited by 46 publications

References 73 publications

JAK1 as a prognostic marker and its correlation with immune infiltrates in breast cancer

JAK1 as a prognostic marker and its correlation with immune infiltrates in breast cancer

Prognostic and predictive impact of stroma cells defined by PDGFRb expression in early breast cancer: results from the randomized SweBCG91RT trial

Physical Activity and Breast Cancer Prevention: Possible Role of Immune Mediators

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