Reproducibility and predictive value of scoring stromal tumour infiltrating lymphocytes in triple-negative breast cancer: a multi-institutional study

Mark O’Loughlin, Xavier Andreu, Simonetta Bianchi, Ewa Chemielik, Alicia Cordoba, Gábor Cserni, Paulo Figueiredo, Giuseppe Floris, Maria P. Foschini, Päivi Heikkilä, Janina Kulka, Inta Liepniece-Karele, Peter Regitnig, Angelika Reiner, Ales Ryska, Anna Sapino, Aliaa Shalaby, Elisabeth Specht Stovgaard, Cecily Quinn, Elaine M. WalshVicky Zolota, Sharon A. Glynn, Grace Callagy

Research output: Contribution to journalEditorial

4 Citations (Scopus)

Abstract

Background: Several studies have demonstrated a prognostic role for stromal tumour infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC). The reproducibility of scoring sTILs is variable with potentially excellent concordance being achievable using a software tool. We examined agreement between breast pathologists across Europe scoring sTILs on H&E-stained sections without software, an approach that is easily applied in clinical practice. The association between sTILs and response to anthracycline-taxane NACT was also examined. Methodology: Pathologists from the European Working Group for Breast Screening Pathology scored sTILs in 84 slides from 75 TNBCs using the immune-oncology biomarker working group guidance in two circulations. There were 16 participants in the first and 19 in the second circulation. Results: Moderate agreement was achieved for absolute sTILs scores (intraclass correlation coefficient (ICC) = 0.683, 95% CI 0.601–0.767, p-value < 0.001). Agreement was less when a 25% threshold was used (ICC 0.509, 95% CI 0.416–0.614, p-value < 0.001) and for lymphocyte predominant breast cancer (LPBC) (ICC 0.504, 95% CI 0.412–0.610, p-value < 0.001). Intra-observer agreement was strong for absolute sTIL values (Spearman ρ = 0.727); fair for sTILs ≥ 25% (κ = 0.53) and for LPBC (κ = 0.49), but poor for sTILs as 10% increments (κ = 0.24). Increasing sTILs was significantly associated with an increased likelihood of a pathological complete response (pCR) on multivariable analysis. Conclusion: Increasing sTILs in TNBCs improves the likelihood of a pCR. However, inter-observer agreement is such that H&E-based assessment is not sufficiently reproducible for clinical application. Other methodologies should be explored, but may be at the cost of ease of application.

Original languageEnglish
JournalBreast Cancer Research and Treatment
Volume171
Issue number1
DOIs
Publication statusPublished - Aug 1 2018

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Triple Negative Breast Neoplasms
Tumor-Infiltrating Lymphocytes
Breast
Software
Lymphocytes
Breast Neoplasms
Anthracyclines

Keywords

  • Inter-observer agreement
  • Neoadjuvant chemotherapy
  • Pathological complete response
  • sTILs
  • Stromal tumour infiltrating lymphocytes
  • Triple-negative breast cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Reproducibility and predictive value of scoring stromal tumour infiltrating lymphocytes in triple-negative breast cancer : a multi-institutional study. / O’Loughlin, Mark; Andreu, Xavier; Bianchi, Simonetta; Chemielik, Ewa; Cordoba, Alicia; Cserni, Gábor; Figueiredo, Paulo; Floris, Giuseppe; Foschini, Maria P.; Heikkilä, Päivi; Kulka, Janina; Liepniece-Karele, Inta; Regitnig, Peter; Reiner, Angelika; Ryska, Ales; Sapino, Anna; Shalaby, Aliaa; Stovgaard, Elisabeth Specht; Quinn, Cecily; Walsh, Elaine M.; Zolota, Vicky; Glynn, Sharon A.; Callagy, Grace.

In: Breast Cancer Research and Treatment, Vol. 171, No. 1, 01.08.2018.

Research output: Contribution to journalEditorial

O’Loughlin, M, Andreu, X, Bianchi, S, Chemielik, E, Cordoba, A, Cserni, G, Figueiredo, P, Floris, G, Foschini, MP, Heikkilä, P, Kulka, J, Liepniece-Karele, I, Regitnig, P, Reiner, A, Ryska, A, Sapino, A, Shalaby, A, Stovgaard, ES, Quinn, C, Walsh, EM, Zolota, V, Glynn, SA & Callagy, G 2018, 'Reproducibility and predictive value of scoring stromal tumour infiltrating lymphocytes in triple-negative breast cancer: a multi-institutional study', Breast Cancer Research and Treatment, vol. 171, no. 1. https://doi.org/10.1007/s10549-018-4825-8
O’Loughlin, Mark ; Andreu, Xavier ; Bianchi, Simonetta ; Chemielik, Ewa ; Cordoba, Alicia ; Cserni, Gábor ; Figueiredo, Paulo ; Floris, Giuseppe ; Foschini, Maria P. ; Heikkilä, Päivi ; Kulka, Janina ; Liepniece-Karele, Inta ; Regitnig, Peter ; Reiner, Angelika ; Ryska, Ales ; Sapino, Anna ; Shalaby, Aliaa ; Stovgaard, Elisabeth Specht ; Quinn, Cecily ; Walsh, Elaine M. ; Zolota, Vicky ; Glynn, Sharon A. ; Callagy, Grace. / Reproducibility and predictive value of scoring stromal tumour infiltrating lymphocytes in triple-negative breast cancer : a multi-institutional study. In: Breast Cancer Research and Treatment. 2018 ; Vol. 171, No. 1.
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abstract = "Background: Several studies have demonstrated a prognostic role for stromal tumour infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC). The reproducibility of scoring sTILs is variable with potentially excellent concordance being achievable using a software tool. We examined agreement between breast pathologists across Europe scoring sTILs on H&E-stained sections without software, an approach that is easily applied in clinical practice. The association between sTILs and response to anthracycline-taxane NACT was also examined. Methodology: Pathologists from the European Working Group for Breast Screening Pathology scored sTILs in 84 slides from 75 TNBCs using the immune-oncology biomarker working group guidance in two circulations. There were 16 participants in the first and 19 in the second circulation. Results: Moderate agreement was achieved for absolute sTILs scores (intraclass correlation coefficient (ICC) = 0.683, 95{\%} CI 0.601–0.767, p-value < 0.001). Agreement was less when a 25{\%} threshold was used (ICC 0.509, 95{\%} CI 0.416–0.614, p-value < 0.001) and for lymphocyte predominant breast cancer (LPBC) (ICC 0.504, 95{\%} CI 0.412–0.610, p-value < 0.001). Intra-observer agreement was strong for absolute sTIL values (Spearman ρ = 0.727); fair for sTILs ≥ 25{\%} (κ = 0.53) and for LPBC (κ = 0.49), but poor for sTILs as 10{\%} increments (κ = 0.24). Increasing sTILs was significantly associated with an increased likelihood of a pathological complete response (pCR) on multivariable analysis. Conclusion: Increasing sTILs in TNBCs improves the likelihood of a pCR. However, inter-observer agreement is such that H&E-based assessment is not sufficiently reproducible for clinical application. Other methodologies should be explored, but may be at the cost of ease of application.",
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T1 - Reproducibility and predictive value of scoring stromal tumour infiltrating lymphocytes in triple-negative breast cancer

T2 - a multi-institutional study

AU - O’Loughlin, Mark

AU - Andreu, Xavier

AU - Bianchi, Simonetta

AU - Chemielik, Ewa

AU - Cordoba, Alicia

AU - Cserni, Gábor

AU - Figueiredo, Paulo

AU - Floris, Giuseppe

AU - Foschini, Maria P.

AU - Heikkilä, Päivi

AU - Kulka, Janina

AU - Liepniece-Karele, Inta

AU - Regitnig, Peter

AU - Reiner, Angelika

AU - Ryska, Ales

AU - Sapino, Anna

AU - Shalaby, Aliaa

AU - Stovgaard, Elisabeth Specht

AU - Quinn, Cecily

AU - Walsh, Elaine M.

AU - Zolota, Vicky

AU - Glynn, Sharon A.

AU - Callagy, Grace

PY - 2018/8/1

Y1 - 2018/8/1

N2 - Background: Several studies have demonstrated a prognostic role for stromal tumour infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC). The reproducibility of scoring sTILs is variable with potentially excellent concordance being achievable using a software tool. We examined agreement between breast pathologists across Europe scoring sTILs on H&E-stained sections without software, an approach that is easily applied in clinical practice. The association between sTILs and response to anthracycline-taxane NACT was also examined. Methodology: Pathologists from the European Working Group for Breast Screening Pathology scored sTILs in 84 slides from 75 TNBCs using the immune-oncology biomarker working group guidance in two circulations. There were 16 participants in the first and 19 in the second circulation. Results: Moderate agreement was achieved for absolute sTILs scores (intraclass correlation coefficient (ICC) = 0.683, 95% CI 0.601–0.767, p-value < 0.001). Agreement was less when a 25% threshold was used (ICC 0.509, 95% CI 0.416–0.614, p-value < 0.001) and for lymphocyte predominant breast cancer (LPBC) (ICC 0.504, 95% CI 0.412–0.610, p-value < 0.001). Intra-observer agreement was strong for absolute sTIL values (Spearman ρ = 0.727); fair for sTILs ≥ 25% (κ = 0.53) and for LPBC (κ = 0.49), but poor for sTILs as 10% increments (κ = 0.24). Increasing sTILs was significantly associated with an increased likelihood of a pathological complete response (pCR) on multivariable analysis. Conclusion: Increasing sTILs in TNBCs improves the likelihood of a pCR. However, inter-observer agreement is such that H&E-based assessment is not sufficiently reproducible for clinical application. Other methodologies should be explored, but may be at the cost of ease of application.

AB - Background: Several studies have demonstrated a prognostic role for stromal tumour infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC). The reproducibility of scoring sTILs is variable with potentially excellent concordance being achievable using a software tool. We examined agreement between breast pathologists across Europe scoring sTILs on H&E-stained sections without software, an approach that is easily applied in clinical practice. The association between sTILs and response to anthracycline-taxane NACT was also examined. Methodology: Pathologists from the European Working Group for Breast Screening Pathology scored sTILs in 84 slides from 75 TNBCs using the immune-oncology biomarker working group guidance in two circulations. There were 16 participants in the first and 19 in the second circulation. Results: Moderate agreement was achieved for absolute sTILs scores (intraclass correlation coefficient (ICC) = 0.683, 95% CI 0.601–0.767, p-value < 0.001). Agreement was less when a 25% threshold was used (ICC 0.509, 95% CI 0.416–0.614, p-value < 0.001) and for lymphocyte predominant breast cancer (LPBC) (ICC 0.504, 95% CI 0.412–0.610, p-value < 0.001). Intra-observer agreement was strong for absolute sTIL values (Spearman ρ = 0.727); fair for sTILs ≥ 25% (κ = 0.53) and for LPBC (κ = 0.49), but poor for sTILs as 10% increments (κ = 0.24). Increasing sTILs was significantly associated with an increased likelihood of a pathological complete response (pCR) on multivariable analysis. Conclusion: Increasing sTILs in TNBCs improves the likelihood of a pCR. However, inter-observer agreement is such that H&E-based assessment is not sufficiently reproducible for clinical application. Other methodologies should be explored, but may be at the cost of ease of application.

KW - Inter-observer agreement

KW - Neoadjuvant chemotherapy

KW - Pathological complete response

KW - sTILs

KW - Stromal tumour infiltrating lymphocytes

KW - Triple-negative breast cancer

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