Leonora de Boo1, Ashley Cimino-Mathews2, Yoni Lubeck3, Antonios Daletzakis4, Mark Opdam1, Joyce Sanders3, Erik Hooijberg3, Annelot van Rossum1, Zuzana Loncova5, Dietmar Rieder5, Zlatko Trajanoski5, Marieke Vollebergh6, Marcelo Sobral-Leite7, Koen van de Vijver8, Annegien Broeks9, Rianne van der Wiel9, Harm van Tinteren4, Sabine Linn10, Hugo Mark Horlings11, Marleen Kok12. 1. Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. 2. Departments of Pathology and Oncology, The Johns Hopkins Hospital, Baltimore, USA. 3. Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. 4. Biometrics Department, The Netherlands Cancer Institute, Amsterdam, the Netherlands. 5. Division of Bioinformatics, Medical University of Innsbruck, Innsbruck, Austria. 6. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. 7. Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, RJ, Brazil. 8. Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Pathology, Ghent University Hospital, Ghent, Belgium. 9. Core Facility Molecular Pathology and Biobanking, The Netherlands Cancer Institute, Amsterdam, the Netherlands. 10. Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Pathology, University Medical Centre, Utrecht, the Netherlands. 11. Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. 12. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Electronic address: m.kok@nki.nl.
Abstract
BACKGROUND: The prognostic value of tumour-infiltrating lymphocytes (TILs) differs by breast cancer (BC) subtype. The aim of this study was to evaluate TILs in stage III BC in the context of BRCA1/2-like phenotypes and association with outcome and benefit of intensified platinum-based chemotherapy. PATIENTS AND METHODS: Patients participated in a randomised controlled trial of adjuvant intensified platinum-based chemotherapy versus conventional anthracycline-based chemotherapy carried out between 1993 and 1999 in stage III BC. Stromal TILs were scored according to International guidelines in these human epidermal growth factor receptor 2 (HER2)-negative tumours. BRCA-profiles were determined using Comparative Genomic Hybridization. RESULTS:TIL levels were evaluated in 248 BCs. High TILs were associated with Triple Negative BC (TNBC). BRCA-like tumours harboured higher TILs compared to non-BRCA-like tumours (median TILs of 20% versus 10%, p < 0.01). TIL levels in BRCA1-like tumours were higher compared to BRCA2-like tumours (median TILs of 20% versus 10%, p < 0.001). These correlations remained significant within the oestrogen (ER)-positive subgroup, however not within the TNBC subgroup. In this stage III BC cohort, high TIL level was associated with favourable outcome (TILs per 10% increment, recurrence-free survival (RFS): multivariate hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.71-0.94, p = 0.01; overall survival (OS): multivariate HR 0.80, 95% CI 0.68-0.94, p = 0.01). There was no significant interaction between TILs and benefit of intensified platinum-based chemotherapy. CONCLUSION: In this high-risk breast cancer cohort, high TILs were associated with TNBC and BRCA1-like status. Within the ER-positive subgroup, TIL levels were higher in BRCA1-like compared to BRCA2-like tumours. When adjusted for clinical characteristics, TILs were significantly associated with a more favourable outcome in stage III BC patients.
RCT Entities:
BACKGROUND: The prognostic value of tumour-infiltrating lymphocytes (TILs) differs by breast cancer (BC) subtype. The aim of this study was to evaluate TILs in stage III BC in the context of BRCA1/2-like phenotypes and association with outcome and benefit of intensified platinum-based chemotherapy. PATIENTS AND METHODS: Patients participated in a randomised controlled trial of adjuvant intensified platinum-based chemotherapy versus conventional anthracycline-based chemotherapy carried out between 1993 and 1999 in stage III BC. Stromal TILs were scored according to International guidelines in these humanepidermal growth factor receptor 2 (HER2)-negative tumours. BRCA-profiles were determined using Comparative Genomic Hybridization. RESULTS: TIL levels were evaluated in 248 BCs. High TILs were associated with Triple Negative BC (TNBC). BRCA-like tumours harboured higher TILs compared to non-BRCA-like tumours (median TILs of 20% versus 10%, p < 0.01). TIL levels in BRCA1-like tumours were higher compared to BRCA2-like tumours (median TILs of 20% versus 10%, p < 0.001). These correlations remained significant within the oestrogen (ER)-positive subgroup, however not within the TNBC subgroup. In this stage III BC cohort, high TIL level was associated with favourable outcome (TILs per 10% increment, recurrence-free survival (RFS): multivariate hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.71-0.94, p = 0.01; overall survival (OS): multivariate HR 0.80, 95% CI 0.68-0.94, p = 0.01). There was no significant interaction between TILs and benefit of intensified platinum-based chemotherapy. CONCLUSION: In this high-risk breast cancer cohort, high TILs were associated with TNBC and BRCA1-like status. Within the ER-positive subgroup, TIL levels were higher in BRCA1-like compared to BRCA2-like tumours. When adjusted for clinical characteristics, TILs were significantly associated with a more favourable outcome in stage III BCpatients.
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