Tumour-infiltrating lymphocytes as a prognostic and tamoxifen predictive marker in premenopausal breast cancer: data from a randomised trial with long-term follow-up.

Abstract

BACKGROUND:

Tumour-infiltrating lymphocytes (TILs) are of important prognostic and predictive value in human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) and triple-negative breast cancer (TNBC), but their clinical relevance in oestrogen receptor-positive/HER2-negative (ER+/HER2-) remains unknown. The primary study aim was to analyse the prognostic effect of TILs on the BC-free interval (BCFi) in premenopausal patients stratified by BC subtypes. The secondary aim was to investigate if TILs are predictive of tamoxifen (TAM) benefit.

METHODS:

Archival tissues from primary breast tumours were collected from patients from the SBII:2pre trial, in which 564 premenopausal women were randomised to 2 years of adjuvant TAM or no systemic treatment, regardless of hormone receptor status. TILs were scored on whole tissue sections from 447 patients with available ER status. Tumours were divided into ER+/HER2-, HER2+ and TNBC subtypes by immunohistochemistry and in situ hybridisation. The prognostic value of TILs was analysed in systemically untreated patients (n = 221); the predictive information was investigated in the ER+ subgroup (n = 321) by cumulative incidence curves and Cox regression analyses. The median follow-up was 28 years.

RESULTS:

High (≥ 50%) infiltration of TILs was a favourable prognostic factor in terms of BCFi (univariable analysis: hazard ratioBCFi (HRBCFi) 0.40; 95% confidence interval (CI) 0.22-0.71; P = 0.002). Similar effects were observed across all BC subtypes. The effect of adjuvant TAM was stronger in patients with ER+ tumours and TILs < 50% (HRBCFi 0.63; 95% CI 0.47-0.84; P = 0.002) than in patients with high immune infiltration (≥ 50%) (HRBCFi 0.84; 95% CI (0.24-2.86); P = 0.77). However, evidence for differential effects of TAM in categories of TILs, i.e. interaction, was weak.

CONCLUSIONS:

We demonstrate a long-term favourable prognostic value of high infiltration of TILs in a cohort of premenopausal BC patients and the positive prognostic effect was extended to the ER+/HER2- subgroup. A beneficial effect of TAM in ER+ patients was observed in patients with tumours of low TIL infiltration, but evidence for a treatment predictive effect was weak.

TRIAL REGISTRATION:

This trial is registered in the ISRCTN database, trial ID: ISRCTN12474687 .

• Authors: Christine Lundgren, Pär-Ola Bendahl, Maria Ekholm, Mårten Fernö, Carina Forsare, Ute Krüger, Bo Nordenskjöld, Olle Stål, Lisa Rydén
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 22 Issue 1 Pg. 140 (12 23 2020) ISSN: 1465-542X [Electronic] England
• PMID: 33357231 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Receptors, Estrogen
• Tamoxifen
• ERBB2 protein, human
• Receptor, ErbB-2

Topics

• Adult
• Aged
• Biomarkers, Tumor (analysis, metabolism)
• Breast (immunology, pathology, surgery)
• Breast Neoplasms (diagnosis, immunology, mortality, therapy)
• Chemotherapy, Adjuvant (methods)
• Disease-Free Survival
• Drug Resistance, Neoplasm (immunology)
• Female
• Follow-Up Studies
• Humans
• Immunohistochemistry
• Lymphocytes, Tumor-Infiltrating (immunology)
• Mastectomy
• Middle Aged
• Neoplasm Recurrence, Local (epidemiology, immunology, pathology, prevention & control)
• Neoplasm Staging
• Premenopause
• Prognosis
• Prospective Studies
• Receptor, ErbB-2 (analysis)
• Receptors, Estrogen (analysis, metabolism)
• Retrospective Studies
• Tamoxifen (pharmacology, therapeutic use)