BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

Cancer Center University Medical Center Utrecht Utrecht The Netherlands

Charles University Medical Faculty and University Hospital Hradec Kralove Czech Republic

Core Facility Molecular Pathology and Biobanking Netherlands Cancer Institute Amsterdam The Netherlands

Department of Biometrics The Netherlands Cancer Institute Amsterdam The Netherlands

Department of Epidemiology Maastricht University Maastricht The Netherlands; Department of Research and Development Netherlands Comprehensive Cancer Organization Utrecht The Netherlands

Department of Internal Medicine Deventer Hospital Deventer The Netherlands

Department of Internal Medicine Zaans Medical Centre Zaandam The Netherlands

Department of Medical Oncology Amsterdam UMC Amsterdam The Netherlands

Department of Medical Oncology Amsterdam UMC Cancer Center Amsterdam Amsterdam The Netherlands

Department of Medical Oncology Dijklander Ziekenhuis Hoorn The Netherlands

Department of Medical Oncology OLVG Amsterdam The Netherlands

Department of Medical Oncology Rijnstate Medical center Arnhem The Netherlands

Department of Medical Oncology Rode Kruis Hospital Beverwijk The Netherlands

Department of Medical Oncology Saxenburgh Medical Center Hardenberg The Netherlands

Department of Medical Oncology Sint Antonius Hospital Utrecht The Netherlands

Department of Medical Oncology Spaarne Gasthuis Hoofddorp The Netherlands

Department of Medical Oncology The Netherlands Cancer Institute Amsterdam The Netherlands; Department of Tumorbiology and Immunology The Netherlands Cancer Institute Amsterdam The Netherlands

Department of Medical Oncology UMC Utrecht Cancer Center Utrecht The Netherlands

Department of Medical Sciences University of Torino Torino Italy; Candiolo Cancer Institute FPO IRCCS Candiolo Italy

Department of Molecular Pathology the Netherlands Cancer Institute Amsterdam The Netherlands

Department of Molecular Pathology the Netherlands Cancer Institute Amsterdam The Netherlands; Department of Clinical Genetics Leiden University Medical Centre Leiden The Netherlands

Department of Molecular Pathology the Netherlands Cancer Institute Amsterdam The Netherlands; Department of Pathology Netherlands Cancer Institute Amsterdam The Netherlands; Department of Pathology Leiden University Medical Center Leiden The Netherlands

Department of Molecular Pathology the Netherlands Cancer Institute Amsterdam The Netherlands; Department of Pathology University Medical Center Utrecht Utrecht The Netherlands

Department of Molecular Pathology the Netherlands Cancer Institute Amsterdam The Netherlands; Department of Pathology University Medical Center Utrecht Utrecht The Netherlands; Department of Medical Oncology The Netherlands Cancer Institute Amsterdam The Netherlands

Department of Pathology and Medical Biology University Medical Center Groningen Groningen The Netherlands

Department of Pathology and Molecular Pathology University Hospital Zurich Zurich Switzerland

Department of Pathology Canisius Wilhelmina Ziekenhuis Nijmegen The Netherlands

Department of Pathology Complejo Hospitalaria de Navarra Pamplona Spain

Department of Pathology Erasmus University Medical Center Rotterdam Rotterdam The Netherlands

Department of Pathology Gelre Ziekenhuizen Apeldoorn The Netherlands

Department of Pathology Netherlands Cancer Institute Amsterdam The Netherlands

Department of Pathology Rion University Hospital Patras Greece

Department of Pathology University Medical Center Utrecht Utrecht The Netherlands

Department of Research and Development Netherlands Comprehensive Cancer Organization Utrecht The Netherlands; Department of Health Technology and Services Research Technical Medical Centre University of Twente Enschede The Netherlands

Department of Surgery Diakonessenhuis Utrecht Utrecht The Netherlands

Division of Clinical Medicine and Research Peter MacCallum Cancer Centre Melbourne Australia; Department of Pathology GZA ZNA Hospitals Antwerp Belgium

Institute of Biostatistics and Registry Research Brandenburg Medical School Theodor Fontane Neuruppin Germany

Tumor Pathology Department Maria Sklodowska Curie Memorial National Research Institute of Oncology Gliwice Poland

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