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Combining histological grade, TILs, and the PD-1/PD-L1 pathway to identify immunogenic tumors and de-escalate radiotherapy in early breast cancer : A secondary analysis of a randomized clinical trial

Stenmark Tullberg, Axel ; Sjöström, Martin LU ; Tran, Lena LU ; Niméus, Emma LU ; Killander, Fredrika LU ; Kovács, Anikó ; Lundstedt, Dan ; Holmberg, Erik and Karlsson, Per (2023) In Journal for ImmunoTherapy of Cancer 11(5).
Abstract

Background The implementation of immunological biomarkers for radiotherapy (RT) individualization in breast cancer requires consideration of tumor-intrinsic factors. This study aimed to investigate whether the integration of histological grade, tumor-infiltrating lymphocytes (TILs), programmed cell death protein-1 (PD-1), and programmed death ligand-1 (PD-L1) can identify tumors with aggressive characteristics that can be downgraded regarding the need for RT. Methods The SweBCG91RT trial included 1178 patients with stage I-IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median time of 15.2 years. Immunohistochemical analyses of TILs, PD-1, and PD-L1 were performed. An activated... (More)

Background The implementation of immunological biomarkers for radiotherapy (RT) individualization in breast cancer requires consideration of tumor-intrinsic factors. This study aimed to investigate whether the integration of histological grade, tumor-infiltrating lymphocytes (TILs), programmed cell death protein-1 (PD-1), and programmed death ligand-1 (PD-L1) can identify tumors with aggressive characteristics that can be downgraded regarding the need for RT. Methods The SweBCG91RT trial included 1178 patients with stage I-IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median time of 15.2 years. Immunohistochemical analyses of TILs, PD-1, and PD-L1 were performed. An activated immune response was defined as stromal TILs ≥10% and PD-1 and/or PD-L1 expression in ≥1% of lymphocytes. Tumors were categorized as high-risk or low-risk using assessments of histological grade and proliferation as measured by gene expression. The risk of ipsilateral breast tumor recurrence (IBTR) and benefit of RT were then analyzed with 10 years follow-up based on the integration of immune activation and tumor-intrinsic risk group. Results Among high-risk tumors, an activated immune infiltrate was associated with a reduced risk of IBTR (HR 0.34, 95% CI 0.16 to 0.73, p=0.006). The incidence of IBTR in this group was 12.1% (5.6-25.0) without RT and 4.4% (1.1-16.3) with RT. In contrast, the incidence of IBTR in the high-risk group without an activated immune infiltrate was 29.6% (21.4-40.2) without RT and 12.8% (6.6-23.9) with RT. Among low-risk tumors, no evidence of a favorable prognostic effect of an activated immune infiltrate was seen (HR 2.0, 95% CI 0.87 to 4.6, p=0.100). Conclusions Integrating histological grade and immunological biomarkers can identify tumors with aggressive characteristics but a low risk of IBTR despite a lack of RT boost and systemic therapy. Among high-risk tumors, the risk reduction of IBTR conferred by an activated immune infiltrate is comparable to treatment with RT. These findings may apply to cohorts dominated by estrogen receptor-positive tumors.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Clinical Trials, Phase III as Topic, Genome Instability, Radiotherapy, Tumor Biomarkers, Tumor Microenvironment
in
Journal for ImmunoTherapy of Cancer
volume
11
issue
5
article number
e006618
publisher
BMJ Publishing Group
external identifiers
  • pmid:37208129
  • scopus:85159690343
ISSN
2051-1426
DOI
10.1136/jitc-2022-006618
language
English
LU publication?
yes
id
749f501c-3e33-49c3-8960-ca1509eeaa06
date added to LUP
2023-08-22 12:21:31
date last changed
2024-04-20 01:14:18
@article{749f501c-3e33-49c3-8960-ca1509eeaa06,
  abstract     = {{<p>Background The implementation of immunological biomarkers for radiotherapy (RT) individualization in breast cancer requires consideration of tumor-intrinsic factors. This study aimed to investigate whether the integration of histological grade, tumor-infiltrating lymphocytes (TILs), programmed cell death protein-1 (PD-1), and programmed death ligand-1 (PD-L1) can identify tumors with aggressive characteristics that can be downgraded regarding the need for RT. Methods The SweBCG91RT trial included 1178 patients with stage I-IIA breast cancer, randomized to breast-conserving surgery with or without adjuvant RT, and followed for a median time of 15.2 years. Immunohistochemical analyses of TILs, PD-1, and PD-L1 were performed. An activated immune response was defined as stromal TILs ≥10% and PD-1 and/or PD-L1 expression in ≥1% of lymphocytes. Tumors were categorized as high-risk or low-risk using assessments of histological grade and proliferation as measured by gene expression. The risk of ipsilateral breast tumor recurrence (IBTR) and benefit of RT were then analyzed with 10 years follow-up based on the integration of immune activation and tumor-intrinsic risk group. Results Among high-risk tumors, an activated immune infiltrate was associated with a reduced risk of IBTR (HR 0.34, 95% CI 0.16 to 0.73, p=0.006). The incidence of IBTR in this group was 12.1% (5.6-25.0) without RT and 4.4% (1.1-16.3) with RT. In contrast, the incidence of IBTR in the high-risk group without an activated immune infiltrate was 29.6% (21.4-40.2) without RT and 12.8% (6.6-23.9) with RT. Among low-risk tumors, no evidence of a favorable prognostic effect of an activated immune infiltrate was seen (HR 2.0, 95% CI 0.87 to 4.6, p=0.100). Conclusions Integrating histological grade and immunological biomarkers can identify tumors with aggressive characteristics but a low risk of IBTR despite a lack of RT boost and systemic therapy. Among high-risk tumors, the risk reduction of IBTR conferred by an activated immune infiltrate is comparable to treatment with RT. These findings may apply to cohorts dominated by estrogen receptor-positive tumors.</p>}},
  author       = {{Stenmark Tullberg, Axel and Sjöström, Martin and Tran, Lena and Niméus, Emma and Killander, Fredrika and Kovács, Anikó and Lundstedt, Dan and Holmberg, Erik and Karlsson, Per}},
  issn         = {{2051-1426}},
  keywords     = {{Clinical Trials, Phase III as Topic; Genome Instability; Radiotherapy; Tumor Biomarkers; Tumor Microenvironment}},
  language     = {{eng}},
  number       = {{5}},
  publisher    = {{BMJ Publishing Group}},
  series       = {{Journal for ImmunoTherapy of Cancer}},
  title        = {{Combining histological grade, TILs, and the PD-1/PD-L1 pathway to identify immunogenic tumors and de-escalate radiotherapy in early breast cancer : A secondary analysis of a randomized clinical trial}},
  url          = {{http://dx.doi.org/10.1136/jitc-2022-006618}},
  doi          = {{10.1136/jitc-2022-006618}},
  volume       = {{11}},
  year         = {{2023}},
}