Carsten Denkert1, Gunter von Minckwitz2, Silvia Darb-Esfahani3, Bianca Lederer2, Barbara I Heppner3, Karsten E Weber2, Jan Budczies4, Jens Huober5, Frederick Klauschen3, Jenny Furlanetto2, Wolfgang D Schmitt3, Jens-Uwe Blohmer6, Thomas Karn7, Berit M Pfitzner3, Sherko Kümmel8, Knut Engels9, Andreas Schneeweiss10, Arndt Hartmann11, Aurelia Noske12, Peter A Fasching13, Christian Jackisch14, Marion van Mackelenbergh2, Peter Sinn15, Christian Schem16, Claus Hanusch17, Michael Untch18, Sibylle Loibl2. 1. Institute of Pathology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany. Electronic address: carsten.denkert@charite.de. 2. GBG German Breast Group, Neu-Isenburg, Germany. 3. Institute of Pathology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany. 4. Institute of Pathology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany. 5. Department of Gynecology, University of Ulm, Ulm, Germany. 6. Breast Cancer Center, Charité Universitätsmedizin Berlin, Germany. 7. Department of Gynecology and Obstetrics, University of Frankfurt, Frankfurt, Germany. 8. Breast Unit, Kliniken Essen-Mitte, Essen, Germany. 9. Zentrum für Pathologie, Zytologie und Molekularpathologie, Neuss, Germany. 10. Universität Heidelberg, Nationales Centrum für Tumorerkrankungen, Heidelberg, Germany. 11. Institute of Pathology, University of Erlangen-Nürnberg, Erlangen, Germany. 12. Institute of Pathology, Technical University of Munich, Munich, Germany. 13. Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany. 14. Sana Klinikum Offenbach, Offenbach, Germany. 15. Institute of Pathology, University of Heidelberg, Heidelberg, Germany. 16. Department of Gynecology and Obstetrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany. 17. Rotkreuzklinikum, Frauenklinik, München, Germany. 18. Breast Cancer Center, Department of Gynecology and Obstetrics, Helios-Klinikum Berlin Buch, Germany.
Abstract
BACKGROUND: 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. METHODS: 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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Deutsche Krebshilfe and European Commission.
BACKGROUND: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. METHODS: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. FINDINGS: 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). INTERPRETATION: 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. FUNDING: Deutsche Krebshilfe and European Commission.
Authors: Christer Larsson; Anna Ehinger; Sofia Winslow; Karin Leandersson; Marie Klintman; Ludvig Dahl; Johan Vallon-Christersson; Jari Häkkinen; Cecilia Hegardt; Jonas Manjer; Lao Saal; Lisa Rydén; Martin Malmberg; Åke Borg; Niklas Loman Journal: NPJ Breast Cancer Date: 2020-07-06
Authors: Zuzana Kos; Elvire Roblin; Rim S Kim; Stefan Michiels; Brandon D Gallas; Weijie Chen; Koen K van de Vijver; Shom Goel; Sylvia Adams; Sandra Demaria; Giuseppe Viale; Torsten O Nielsen; Sunil S Badve; W Fraser Symmans; Christos Sotiriou; David L Rimm; Stephen Hewitt; Carsten Denkert; Sibylle Loibl; Stephen J Luen; John M S Bartlett; Peter Savas; Giancarlo Pruneri; Deborah A Dillon; Maggie Chon U Cheang; Andrew Tutt; Jacqueline A Hall; Marleen Kok; Hugo M Horlings; Anant Madabhushi; Jeroen van der Laak; Francesco Ciompi; Anne-Vibeke Laenkholm; Enrique Bellolio; Tina Gruosso; Stephen B Fox; Juan Carlos Araya; Giuseppe Floris; Jan Hudeček; Leonie Voorwerk; Andrew H Beck; Jen Kerner; Denis Larsimont; Sabine Declercq; Gert Van den Eynden; Lajos Pusztai; Anna Ehinger; Wentao Yang; Khalid AbdulJabbar; Yinyin Yuan; Rajendra Singh; Crispin Hiley; Maise Al Bakir; Alexander J Lazar; Stephen Naber; Stephan Wienert; Miluska Castillo; Giuseppe Curigliano; Maria-Vittoria Dieci; Fabrice André; Charles Swanton; Jorge Reis-Filho; Joseph Sparano; Eva Balslev; I-Chun Chen; Elisabeth Ida Specht Stovgaard; Katherine Pogue-Geile; Kim R M Blenman; Frédérique Penault-Llorca; Stuart Schnitt; Sunil R Lakhani; Anne Vincent-Salomon; Federico Rojo; Jeremy P Braybrooke; Matthew G Hanna; M Teresa Soler-Monsó; Daniel Bethmann; Carlos A Castaneda; Karen Willard-Gallo; Ashish Sharma; Huang-Chun Lien; Susan Fineberg; Jeppe Thagaard; Laura Comerma; Paula Gonzalez-Ericsson; Edi Brogi; Sherene Loi; Joel Saltz; Frederick Klaushen; Lee Cooper; Mohamed Amgad; David A Moore; Roberto Salgado Journal: NPJ Breast Cancer Date: 2020-05-12
Authors: Sara M Tolaney; Romualdo Barroso-Sousa; Tanya Keenan; Tianyu Li; Lorenzo Trippa; Ines Vaz-Luis; Gerburg Wulf; Laura Spring; Natalie Faye Sinclair; Chelsea Andrews; Jessica Pittenger; Edward T Richardson; Deborah Dillon; Nancy U Lin; Beth Overmoyer; Ann H Partridge; Eliezer Van Allen; Elizabeth A Mittendorf; Eric P Winer; Ian E Krop Journal: JAMA Oncol Date: 2020-10-01 Impact factor: 31.777