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Tumour-infiltrating lymphocytes (TILs)-related genomic signature predicts chemotherapy response in breast cancer

  • Preclinical study
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Abstract

Purpose

The present study evaluated whether morphological-measured stromal and intra-tumour tumour-infiltrating lymphocytes (TILs) levels were associated with gene expression profiles, and whether TILs-associated genomic signature (GS) could be used to predict clinical outcomes and response to therapies in several breast cancer subtypes.

Methods

We retrospectively evaluated haematoxylin eosin (HE)-TILs levels and gene expression profiling data from 40 patients with primary breast cancer and extracted the 22 overexpressed genes in cases with high TILs scores as the TILs-GS. The TILs-GS were compared with breast cancer subtype and were evaluated predictive values for prognosis and response to therapies.

Results

Higher TILs-GS expressions were observed for triple-negative and human epidermal growth factor receptor 2 (HER2) positive (+) breast cancers, compared to the luminal types (P < 0.001). With the exception of HER2+, the TILs-GS had no prognostic value in subtypes of breast cancers. The Wilcoxon test revealed significantly different TILs-GS levels between the cases with pathological complete response (pCR) and residual disease after anthracycline and taxane-based neoadjuvant chemotherapy, with the exception of the luminal-low proliferation subtype. In the multivariate analysis, pCR was independently associated with smaller tumour size, higher histological grade, ER negativity, HER2 positivity and higher TILs-GS scores (OR 2.02, 95% CI 1.30–3.14, P = 0.025).

Conclusions

TILs-GS was associated with stromal and intra-tumour TILs levels, as evaluated using HE, which predicted prognosis and chemotherapy response in several breast cancer subtypes. Further studies are needed to perform stratification according to TILs-GS levels and the conventional breast cancer subtypes.

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Abbreviations

HR:

Hormone receptor

HER2:

Human epidermal growth factor receptor 2

IHC:

Immunohistochemistry

TILs:

Tumour-infiltrating lymphocytes

HE:

Hematoxylin eosin

ER:

Estrogen receptor

NAC:

Neoadjuvant chemotherapy

TN:

ER−/HER2−

DEFS:

Distant event-free survival

pCR:

Pathological complete response

RD:

Residual disease

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, Okayama, Japan

    Mariko Kochi, Takayuki Iwamoto, Takayuki Motoki, Junji Matsuoka & Toshiyoshi Fujiwara

  2. Department of Breast and Endocrine Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kitaku, Okayama, 700-8558, Okayama, Japan

    Mariko Kochi, Takayuki Iwamoto, Taeko Mizoo, Tomohiro Nogami, Tadahiko Shien, Takayuki Motoki, Naruto Taira, Hiroyoshi Doihara & Junji Matsuoka

  3. Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Isehara, Japan

    Naoki Niikura & Yutaka Tokuda

  4. Department of Medical Oncology, San Raffaele Hospital, Milan, Italy

    Giampaolo Bianchini

  5. Department of Pathology, Nihon University School of Medicine, Tokyo, Japan

    Shinobu Masuda

  6. Department of Palliative and Supportive Medicine, Okayama University Hospital, Okayama, Japan

    Junji Matsuoka

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10549_2017_4502_MOESM1_ESM.pptx

Supplementry Fig. 1. Kaplan-Meier curves according to tumour-infiltrating lymphocytes gene signatures in the tamoxifen-treated data set. Kaplan-Meier curves for (a) luminal-low and (b) luminal-high breast cancer were compared using the log-rank test. Hazard ratios (HR) and 95% confidence intervals (CIs) for distant event-free survival were estimated using Cox regression analysis. Supplementry Fig. 2. Neoadjuvant therapy responses and tumour-infiltrating lymphocytes gene signatures among HER2 + cases in the trastuzumab-treated data set. The boxplots show the associations between tumour-infiltrating lymphocytes gene signatures (TILs-GS) and neoadjuvant therapy response. P-values were calculated using Wilcoxon’s test. pCR pathological complete response, RD residual disease. Supplementary material 1 (PPTX 86 kb)

Supplementary material 2 (XLSX 12 kb)

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Kochi, M., Iwamoto, T., Niikura, N. et al. Tumour-infiltrating lymphocytes (TILs)-related genomic signature predicts chemotherapy response in breast cancer. Breast Cancer Res Treat 167, 39–47 (2018). https://doi.org/10.1007/s10549-017-4502-3

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