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Peer-reviewedCC BY 4.0ESMO Open

Parity, breastfeeding, and reproductive timing are associated with tumour-infiltrating lymphocytes in hormone receptor-negative breast cancer: a population-based cohort study

  • E. Gabrielsen1,2
  • A. Wirsing3,4
  • T. Wilsgaard5
  • I. Thune1,6
  • H. Frydenberg6
  • T. Lofterød6
  • E. Mortensen3,4
  • H. Nalwoga7,8
  • L.A. Akslen7,9
  • H.S. Haugnes1,2
  • E.S. Blix1,2
9 affiliations
  1. 1Department of Clinical Medicine, UiT–The Arctic University of Norway, Tromsø, Norway
  2. 2Department of Oncology, University Hospital of North Norway, Tromsø, Norway
  3. 3Department of Pathology, University Hospital of North Norway, Tromsø, Norway
  4. 4Department of Medical Biology, UiT–The Arctic University of Norway, Tromsø, Norway
  5. 5Department of Community Medicine, UiT–The Arctic University of Norway, Tromsø, Norway
  6. 6Department of Oncology, Oslo University Hospital, Oslo, Norway
  7. 7Department of Clinical Medicine, Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway
  8. 8Department of Pathology, Makerere University College of Health Sciences, Kampala, Uganda
  9. 9Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
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Abstract

Background: Tumour-infiltrating lymphocytes (TILs) are established biomarkers of breast cancer immunogenicity and prognosis. Reproductive events induce durable immunological remodelling of the breast, but whether TIL levels at diagnosis reflect the immunological imprint of these events remains unclear.

Materials and methods: We included women diagnosed with invasive breast cancer between 1978 and 2012 in the Energy Balance and Breast Cancer Aspects throughout Life study, a substudy of the population-based Tromsø Study (Norway). Prediagnostic host factors were obtained. TILs were scored on an ordinal scale (1-4). Associations between host factors and the TIL score were analysed using ordinal logistic regression with interaction terms for hormone receptor (HR) status. Breast cancer-specific mortality was evaluated using Kaplan–Meier methods and Cox regression.

Results: A total of 425 women were included [median age at diagnosis 56.0 years, 360 (87.6%) parous], of whom 84 (19.8%) had HR-negative tumours. Among HR-negative cases, parity [odds ratio (OR) 10.14, 95% confidence interval (CI) 1.97-52.22], longer breastfeeding duration [OR 1.87 per standard deviation (SD), 95% CI 1.10-3.17], and higher age at first birth (OR 1.79 per SD, 95% CI 1.06-3.01) were associated with higher TIL scores, whereas higher mean arterial pressure (OR 0.59 per SD, 95% CI 0.41-0.86) was inversely associated. Significant interactions with HR status were observed for parity and breastfeeding duration. No associations were observed in HR-positive tumours. High-TIL levels (scores 3-4 versus 1-2) were associated with lower breast cancer-specific mortality in HR-negative tumours (adjusted hazard ratio 0.32, 95% CI 0.14-0.72) but not in HR-positive disease (hazard ratio 0.98, 95% CI 0.58-1.68; Pinteraction = 0.023).

Conclusions: These findings suggest that reproductive history and timing may shape the tumour immune microenvironment over the life course. If confirmed in larger studies, TILs may represent an intermediate phenotype linking upstream host characteristics to downstream clinical outcomes in breast cancer.

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Cite

BibTeXRIS
BibTeX
@article{gabrielsen2026parity,
  title = {{Parity, breastfeeding, and reproductive timing are associated with tumour-infiltrating lymphocytes in hormone receptor-negative breast cancer: a population-based cohort study}},
  author = {E. Gabrielsen and A. Wirsing and T. Wilsgaard and I. Thune and H. Frydenberg and T. Lofterød and E. Mortensen and H. Nalwoga and L.A. Akslen and H.S. Haugnes and E.S. Blix},
  journal = {ESMO Open},
  year = {2026},
  month = oct,
  doi = {10.1016/j.esmoop.2026.108604},
  url = {https://doi.org/10.1016/j.esmoop.2026.108604},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Parity, breastfeeding, and reproductive timing are associated with tumour-infiltrating lymphocytes in hormone receptor-negative breast cancer: a population-based cohort study
AU  - E. Gabrielsen
AU  - A. Wirsing
AU  - T. Wilsgaard
AU  - I. Thune
AU  - H. Frydenberg
AU  - T. Lofterød
AU  - E. Mortensen
AU  - H. Nalwoga
AU  - L.A. Akslen
AU  - H.S. Haugnes
AU  - E.S. Blix
PY  - 2026
DA  - 2026/10/21
JO  - ESMO Open
DO  - 10.1016/j.esmoop.2026.108604
UR  - https://doi.org/10.1016/j.esmoop.2026.108604
AB  - Background: Tumour-infiltrating lymphocytes (TILs) are established biomarkers of breast cancer immunogenicity and prognosis. Reproductive events induce durable immunological remodelling of the breast, but whether TIL levels at diagnosis reflect the immunological imprint of these events remains unclear.  Materials and methods: We included women diagnosed with invasive breast cancer between 1978 and 2012 in the Energy Balance and Breast Cancer Aspects throughout Life study, a substudy of the population-based Tromsø Study (Norway). Prediagnostic host factors were obtained. TILs were scored on an ordinal scale (1-4). Associations between host factors and the TIL score were analysed using ordinal logistic regression with interaction terms for hormone receptor (HR) status. Breast cancer-specific mortality was evaluated using Kaplan–Meier methods and Cox regression.  Results: A total of 425 women were included [median age at diagnosis 56.0 years, 360 (87.6%) parous], of whom 84 (19.8%) had HR-negative tumours. Among HR-negative cases, parity [odds ratio (OR) 10.14, 95% confidence interval (CI) 1.97-52.22], longer breastfeeding duration [OR 1.87 per standard deviation (SD), 95% CI 1.10-3.17], and higher age at first birth (OR 1.79 per SD, 95% CI 1.06-3.01) were associated with higher TIL scores, whereas higher mean arterial pressure (OR 0.59 per SD, 95% CI 0.41-0.86) was inversely associated. Significant interactions with HR status were observed for parity and breastfeeding duration. No associations were observed in HR-positive tumours. High-TIL levels (scores 3-4 versus 1-2) were associated with lower breast cancer-specific mortality in HR-negative tumours (adjusted hazard ratio 0.32, 95% CI 0.14-0.72) but not in HR-positive disease (hazard ratio 0.98, 95% CI 0.58-1.68; Pinteraction = 0.023).  Conclusions: These findings suggest that reproductive history and timing may shape the tumour immune microenvironment over the life course. If confirmed in larger studies, TILs may represent an intermediate phenotype linking upstream host characteristics to downstream clinical outcomes in breast cancer.
SN  - 2059-7029
ER  -