Background: Pathologic complete response (pCR) – (ypT0/is ypN0) is an important treatment outcome in neoadjuvant systemic therapy (NST) for breast cancer. In our study, we wanted to investigate the impact of the tumour microenvironment, composed of pro‑ and anti‑
tumour immune cells, on the attainment of pCR, in patients with localized breast cancer, treated with NST.
Aim: We aimed to evaluate whether tumor infiltrating lymphocyte (TIL) density and the cellular subtype composition thereof in core needle biopsy (CNB) samples of breast cancer, influences attainment of pCR.
Patients and Methods: Between February 2018 and March 2021 we enrolled 171 patients with localized breast cancer – triple negative (TN), HER2 positive and luminal B‑like subtypes into a prospective, non‑interventional study at the Institute of Oncology Ljubljana. All patients were diagnosed with CNB of breast cancer prior to treatment. They received standard NST as per the European Society of Clinical Oncology – ESMO guidelines. TIL density was estimated on a tissue section prepared from a CNB paraffin block, and expressed
as the percentage of intratumoral stroma surface area occupied by TILs – in accordance with the International TIL Working Group guidelines. Cellular composition of TIL was determined on a second CNB sample, based on the proportions of presumably antitumor (CD8+, CXCL13+) and protumor (PD‑1+, FOXP3+) lymphocytes, using specific
monoclonal antibodies against CD8, CXCL13, PD‑1 and FOXP3.
Results: Median patient age was 48 years (IQR: 41.7–57.4). 91 (53%) patients had luminal B‑like, 32 (19%) HER2+ luminal, 16 (9%) HER2+ non‑luminal, and 32 (19%) TN breast cancer subtype. 59 (35%) patients attained pCR. Median TIL density for the entire cohort was
10% (IQR: 3.5–23.8), the median percentage of CD8+ TILs was 40.0% (IQR: 30.0–50.0), of CXCL13+ TILs 1% (IQR: 0.5–2.0), of PD‑1+ TILs 2% (IQR: 0.0–5.0), and that of FOXP3+ TILs 4% (IQR 1.0–7.0). TIL density (expressed as a numeric variable) was positively asso‑
ciated with the attainment of pCR (univariately and multivariably). In the multivariable logistic regression model, TIL density was an independent predictor of pCR attainment (p = 0.012, OR 1.27; 95% CI: 1.05–1.54) – controlled for age (p = 0.232), proliferation index
Kiel 67 expression (p = 0.001), lymph node status (p = 0.024), and breast cancer subtype, dichotomized to HER2+ luminal, HER2+ non‑luminal and TN against the luminal B‑like subtype (p < 0.001). In our sample, higher proportions of PD‑1+ and FOXP3+ TILs were
associated with a higher probability of attaining pCR. However, the association was not statistically significant. In the exploratory multivariable analysis, we showed that higher proportions of CD8+ TILs were associated with a higher probability of attaining pCR.
Conclusion: Higher TIL density (expressed as a numeric variable) is associated with a higher probability of attaining pCR. From among the presumably antitumor lymphocytes, a higher CD8+ TIL density was found to be associated with a higher probability of attaining pCR, whereas no clear association be tween the proportions of CXCL13+, PD‑1+ andFOXP3+ TILs and pCR was apparent.
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