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Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy

Tumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer, but their role in luminal breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the rel... Full description

Journal Title: The lancet oncology 2018-01, Vol.19 (1), p.40-50
Main Author: Denkert, Carsten
Other Authors: von Minckwitz, Gunter , Darb-Esfahani, Silvia , Lederer, Bianca , Heppner, Barbara I , Weber, Karsten E , Budczies, Jan , Huober, Jens , Klauschen, Frederick , Furlanetto, Jenny , Schmitt, Wolfgang D , Blohmer, Jens-Uwe , Karn, Thomas , Pfitzner, Berit M , Kümmel, Sherko , Engels, Knut , Schneeweiss, Andreas , Hartmann, Arndt , Noske, Aurelia , Fasching, Peter A , Jackisch, Christian , van Mackelenbergh, Marion , Sinn, Peter , Schem, Christian , Hanusch, Claus , Untch, Michael , Loibl, Sibylle
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: England: Elsevier Ltd
ID: ISSN: 1470-2045
Link: https://www.ncbi.nlm.nih.gov/pubmed/29233559
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title: Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy
format: Article
creator:
  • Denkert, Carsten
  • von Minckwitz, Gunter
  • Darb-Esfahani, Silvia
  • Lederer, Bianca
  • Heppner, Barbara I
  • Weber, Karsten E
  • Budczies, Jan
  • Huober, Jens
  • Klauschen, Frederick
  • Furlanetto, Jenny
  • Schmitt, Wolfgang D
  • Blohmer, Jens-Uwe
  • Karn, Thomas
  • Pfitzner, Berit M
  • Kümmel, Sherko
  • Engels, Knut
  • Schneeweiss, Andreas
  • Hartmann, Arndt
  • Noske, Aurelia
  • Fasching, Peter A
  • Jackisch, Christian
  • van Mackelenbergh, Marion
  • Sinn, Peter
  • Schem, Christian
  • Hanusch, Claus
  • Untch, Michael
  • Loibl, Sibylle
subjects:
  • Adjuvant treatment
  • Analysis
  • Biomarkers
  • Breast cancer
  • Cancer
  • Cancer therapies
  • Chemotherapy
  • Clinical trials
  • ErbB-2 protein
  • Estrogens
  • Immune system
  • Immunogenicity
  • Immunology
  • Immunomodulation
  • Lymphocytes
  • Mathematical models
  • Medical prognosis
  • Pathology
  • Patients
  • Prognosis
  • Statistical analysis
  • Tumors
ispartof: The lancet oncology, 2018-01, Vol.19 (1), p.40-50
description: Tumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer, but their role in luminal breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the relevance of TILs for chemotherapy response and prognosis in patients with TNBC, HER2-positive breast cancer, and luminal–HER2-negative breast cancer. Patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were included from six randomised trials done by the German Breast Cancer Group. Pretherapeutic core biopsies from 3771 patients included in these studies were assessed for the number of stromal TILs by standardised methods according to the guidelines of the International TIL working group. TILs were analysed both as a continuous parameter and in three predefined groups of low (0–10% immune cells in stromal tissue within the tumour), intermediate (11–59%), and high TILs (≥60%). We used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2560 patients from five of the six clinical trial cohorts. In the luminal–HER2-negative breast cancer subtype, a pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs. In the HER2-positive subtype, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 1470-2045
fulltext: fulltext
issn:
  • 1470-2045
  • 1474-5488
url: Link


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titleTumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy
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creatorDenkert, Carsten ; von Minckwitz, Gunter ; Darb-Esfahani, Silvia ; Lederer, Bianca ; Heppner, Barbara I ; Weber, Karsten E ; Budczies, Jan ; Huober, Jens ; Klauschen, Frederick ; Furlanetto, Jenny ; Schmitt, Wolfgang D ; Blohmer, Jens-Uwe ; Karn, Thomas ; Pfitzner, Berit M ; Kümmel, Sherko ; Engels, Knut ; Schneeweiss, Andreas ; Hartmann, Arndt ; Noske, Aurelia ; Fasching, Peter A ; Jackisch, Christian ; van Mackelenbergh, Marion ; Sinn, Peter ; Schem, Christian ; Hanusch, Claus ; Untch, Michael ; Loibl, Sibylle
creatorcontribDenkert, Carsten ; von Minckwitz, Gunter ; Darb-Esfahani, Silvia ; Lederer, Bianca ; Heppner, Barbara I ; Weber, Karsten E ; Budczies, Jan ; Huober, Jens ; Klauschen, Frederick ; Furlanetto, Jenny ; Schmitt, Wolfgang D ; Blohmer, Jens-Uwe ; Karn, Thomas ; Pfitzner, Berit M ; Kümmel, Sherko ; Engels, Knut ; Schneeweiss, Andreas ; Hartmann, Arndt ; Noske, Aurelia ; Fasching, Peter A ; Jackisch, Christian ; van Mackelenbergh, Marion ; Sinn, Peter ; Schem, Christian ; Hanusch, Claus ; Untch, Michael ; Loibl, Sibylle
descriptionTumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer, but their role in luminal breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the relevance of TILs for chemotherapy response and prognosis in patients with TNBC, HER2-positive breast cancer, and luminal–HER2-negative breast cancer. Patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were included from six randomised trials done by the German Breast Cancer Group. Pretherapeutic core biopsies from 3771 patients included in these studies were assessed for the number of stromal TILs by standardised methods according to the guidelines of the International TIL working group. TILs were analysed both as a continuous parameter and in three predefined groups of low (0–10% immune cells in stromal tissue within the tumour), intermediate (11–59%), and high TILs (≥60%). We used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2560 patients from five of the six clinical trial cohorts. In the luminal–HER2-negative breast cancer subtype, a pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs. In the HER2-positive subtype, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p<0·0001 for each subtype, χ2 test for trend). In the univariable analysis, a 10% increase in TILs was associated with longer disease-free survival in TNBC (hazard ratio [HR] 0·93 [95% CI 0·87–0·98], p=0·011) and HER2-positive breast cancer (0·94 [0·89–0·99], p=0·017), but not in luminal–HER2-negative tumours (1·02 [0·96–1·09], p=0·46). The increase in TILs was also associated with longer overall survival in TNBC (0·92 [0·86–0·99], p=0·032), but had no association in HER2-positive breast cancer (0·94 [0·86–1·02], p=0·11), and was associated with shorter overall survival in luminal–HER2-negative tumours (1·10 [1·02–1·19], p=0·011). Increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed, and was also associated with a survival benefit in HER2-positive breast cancer and TNBC. By contrast, increased TILs were an adverse prognostic factor for survival in luminal–HER2-negative breast cancer, suggesting a different biology of the immunological infiltrate in this subtype. Our data support the hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies. In light of the results in luminal breast cancer, further research investigating the interaction of the immune system with different types of endocrine therapy is warranted. Deutsche Krebshilfe and European Commission.
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1EISSN: 1474-5488
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3PMID: 29233559
languageeng
publisherEngland: Elsevier Ltd
subjectAdjuvant treatment ; Analysis ; Biomarkers ; Breast cancer ; Cancer ; Cancer therapies ; Chemotherapy ; Clinical trials ; ErbB-2 protein ; Estrogens ; Immune system ; Immunogenicity ; Immunology ; Immunomodulation ; Lymphocytes ; Mathematical models ; Medical prognosis ; Pathology ; Patients ; Prognosis ; Statistical analysis ; Tumors
ispartofThe lancet oncology, 2018-01, Vol.19 (1), p.40-50
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02018 Elsevier Ltd
1Copyright © 2017 Elsevier Ltd. All rights reserved.
2COPYRIGHT 2018 Elsevier B.V.
3Copyright Elsevier Limited Jan 1, 2018
42018. Elsevier Ltd
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0Denkert, Carsten
1von Minckwitz, Gunter
2Darb-Esfahani, Silvia
3Lederer, Bianca
4Heppner, Barbara I
5Weber, Karsten E
6Budczies, Jan
7Huober, Jens
8Klauschen, Frederick
9Furlanetto, Jenny
10Schmitt, Wolfgang D
11Blohmer, Jens-Uwe
12Karn, Thomas
13Pfitzner, Berit M
14Kümmel, Sherko
15Engels, Knut
16Schneeweiss, Andreas
17Hartmann, Arndt
18Noske, Aurelia
19Fasching, Peter A
20Jackisch, Christian
21van Mackelenbergh, Marion
22Sinn, Peter
23Schem, Christian
24Hanusch, Claus
25Untch, Michael
26Loibl, Sibylle
title
0Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy
1The lancet oncology
addtitleLancet Oncol
descriptionTumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer, but their role in luminal breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the relevance of TILs for chemotherapy response and prognosis in patients with TNBC, HER2-positive breast cancer, and luminal–HER2-negative breast cancer. Patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were included from six randomised trials done by the German Breast Cancer Group. Pretherapeutic core biopsies from 3771 patients included in these studies were assessed for the number of stromal TILs by standardised methods according to the guidelines of the International TIL working group. TILs were analysed both as a continuous parameter and in three predefined groups of low (0–10% immune cells in stromal tissue within the tumour), intermediate (11–59%), and high TILs (≥60%). We used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2560 patients from five of the six clinical trial cohorts. In the luminal–HER2-negative breast cancer subtype, a pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs. In the HER2-positive subtype, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p<0·0001 for each subtype, χ2 test for trend). In the univariable analysis, a 10% increase in TILs was associated with longer disease-free survival in TNBC (hazard ratio [HR] 0·93 [95% CI 0·87–0·98], p=0·011) and HER2-positive breast cancer (0·94 [0·89–0·99], p=0·017), but not in luminal–HER2-negative tumours (1·02 [0·96–1·09], p=0·46). The increase in TILs was also associated with longer overall survival in TNBC (0·92 [0·86–0·99], p=0·032), but had no association in HER2-positive breast cancer (0·94 [0·86–1·02], p=0·11), and was associated with shorter overall survival in luminal–HER2-negative tumours (1·10 [1·02–1·19], p=0·011). Increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed, and was also associated with a survival benefit in HER2-positive breast cancer and TNBC. By contrast, increased TILs were an adverse prognostic factor for survival in luminal–HER2-negative breast cancer, suggesting a different biology of the immunological infiltrate in this subtype. Our data support the hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies. In light of the results in luminal breast cancer, further research investigating the interaction of the immune system with different types of endocrine therapy is warranted. Deutsche Krebshilfe and European Commission.
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1Analysis
2Biomarkers
3Breast cancer
4Cancer
5Cancer therapies
6Chemotherapy
7Clinical trials
8ErbB-2 protein
9Estrogens
10Immune system
11Immunogenicity
12Immunology
13Immunomodulation
14Lymphocytes
15Mathematical models
16Medical prognosis
17Pathology
18Patients
19Prognosis
20Statistical analysis
21Tumors
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8Klauschen, Frederick
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17Hartmann, Arndt
18Noske, Aurelia
19Fasching, Peter A
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titleTumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy
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9Estrogens
10Immune system
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abstractTumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer, but their role in luminal breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the relevance of TILs for chemotherapy response and prognosis in patients with TNBC, HER2-positive breast cancer, and luminal–HER2-negative breast cancer. Patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were included from six randomised trials done by the German Breast Cancer Group. Pretherapeutic core biopsies from 3771 patients included in these studies were assessed for the number of stromal TILs by standardised methods according to the guidelines of the International TIL working group. TILs were analysed both as a continuous parameter and in three predefined groups of low (0–10% immune cells in stromal tissue within the tumour), intermediate (11–59%), and high TILs (≥60%). We used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2560 patients from five of the six clinical trial cohorts. In the luminal–HER2-negative breast cancer subtype, a pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs. In the HER2-positive subtype, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p<0·0001 for each subtype, χ2 test for trend). In the univariable analysis, a 10% increase in TILs was associated with longer disease-free survival in TNBC (hazard ratio [HR] 0·93 [95% CI 0·87–0·98], p=0·011) and HER2-positive breast cancer (0·94 [0·89–0·99], p=0·017), but not in luminal–HER2-negative tumours (1·02 [0·96–1·09], p=0·46). The increase in TILs was also associated with longer overall survival in TNBC (0·92 [0·86–0·99], p=0·032), but had no association in HER2-positive breast cancer (0·94 [0·86–1·02], p=0·11), and was associated with shorter overall survival in luminal–HER2-negative tumours (1·10 [1·02–1·19], p=0·011). Increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed, and was also associated with a survival benefit in HER2-positive breast cancer and TNBC. By contrast, increased TILs were an adverse prognostic factor for survival in luminal–HER2-negative breast cancer, suggesting a different biology of the immunological infiltrate in this subtype. Our data support the hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies. In light of the results in luminal breast cancer, further research investigating the interaction of the immune system with different types of endocrine therapy is warranted. Deutsche Krebshilfe and European Commission.
copEngland
pubElsevier Ltd
pmid29233559
doi10.1016/S1470-2045(17)30904-X