PURPOSE: Triple-negative breast cancer (TNBC) is considered aggressive, and therefore, virtually all young patients with TNBC receive (neo)adjuvant chemotherapy. Increased stromal tumor-infiltrating lymphocytes (sTILs) have been associated with a favorable prognosis in TNBC. However, whether this association holds for patients who are node-negative (N0), young (< 40 years), and chemotherapy-naïve, and thus can be used for chemotherapy de-escalation strategies, is unknown. METHODS: We selected all patients with N0 TNBC diagnosed between 1989 and 2000 from a Dutch population-based registry. Patients were age < 40 years at diagnosis and had not received (neo)adjuvant systemic therapy, as was standard practice at the time. Formalin-fixed paraffin-embedded blocks were retrieved (PALGA: Dutch Pathology Registry), and a pathology review including sTILs was performed. Patients were categorized according to sTILs (< 30%, 30%-75%, and ≥ 75%). Multivariable Cox regression was performed for overall survival, with or without sTILs as a covariate. Cumulative incidence of distant metastasis or death was analyzed in a competing risk model, with second primary tumors as competing risk. RESULTS: sTILs were scored for 441 patients. High sTILs (≥ 75%; 21%) translated into an excellent prognosis with a 15-year cumulative incidence of a distant metastasis or death of only 2.1% (95% CI, 0 to 5.0), whereas low sTILs (< 30%; 52%) had an unfavorable prognosis with a 15-year cumulative incidence of a distant metastasis or death of 38.4% (32.1 to 44.6). In addition, every 10% increment of sTILs decreased the risk of death by 19% (adjusted hazard ratio: 0.81; 95% CI, 0.76 to 0.87), which are an independent predictor adding prognostic information to standard clinicopathologic variables (χ2 = 46.7, P < .001). CONCLUSION: Chemotherapy-naïve, young patients with N0 TNBC with high sTILs (≥ 75%) have an excellent long-term prognosis. Therefore, sTILs should be considered for prospective clinical trials investigating (neo)adjuvant chemotherapy de-escalation strategies.

Cancer Center University Medical Center Utrecht Utrecht the Netherlands

Candiolo Cancer Institute FPO IRCCS Candiolo Italy

Charles University Medical Faculty and University Hospital Hradec Kralove Czech Republic

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

Departement of Pathology and Molecular Pathology University Hospital Zurich Zurich Switzerland

Department of Clinical Genetics Leiden University Medical Centre Leiden the Netherlands

Department of Epidemiology Maastricht University Maastricht the Netherlands

Department of Health Technology and Services Research Technical Medical Centre University of Twente Enschede the Netherlands

Department of Medical Oncology Netherlands Cancer Institute Amsterdam the Netherlands

Department of Medical Sciences University of Torino Torino Italy

Department of Molecular Pathology Netherlands Cancer Institute Amsterdam the Netherlands

Department of Pathology Canisius Wilhelmina Ziekenhuis Nijmegen the Netherlands

Department of Pathology Complejo Hospitalario 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 GZA ZNA Hospitals Antwerp Belgium

Department of Pathology Leiden University Medical Center Leiden the Netherlands

Department of Pathology Netherlands Cancer Institute Amsterdam the Netherlands

Department of Pathology Rion University Hospital Patras Greece

Department of Research and Development Netherlands Comprehensive Cancer Organization Utrecht the Netherlands

Division of Clinical Medicine and Research Peter MacCallum Cancer Centre Melbourne Australia

Division of Pathology University Medical Center Utrecht Utrecht the Netherlands

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

Service de Biostatistique et d'Epidémiologie Gustave Roussy Oncostat U1018 Inserm Paris Saclay University labeled Ligue Contre le Cancer Villejuif France

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

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

Zobrazit více v PubMed

Johnson RH, Anders CK, Litton JK, et al. : Breast cancer in adolescents and young adults. Pediatr Blood Cancer 65:e27397, 2018 PubMed PMC

Tung N, Lin NU, Kidd J, et al. : Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol 34:1460-1468, 2016 PubMed PMC

Early Breast Cancer Trialists' Collaborative Group : Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: A patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials. Lancet 393:1440-1452, 2019 PubMed PMC

Poorvu PD, Frazier AL, Feraco AM, et al. : Cancer treatment-related infertility: A critical review of the evidence. JNCI Cancer Spectr 3:pkz008, 2019 PubMed PMC

Menning S, de Ruiter MB, Kieffer JM, et al. : Cognitive impairment in a subset of breast cancer patients after systemic therapy-results from a longitudinal study. J Pain Symptom Manage 52:560-569 e1, 2016 PubMed

Piccart M, van 't Veer LJ, Poncet C, et al. : 70-gene signature as an aid for treatment decisions in early breast cancer: Updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. Lancet Oncol 22:476-488, 2021 PubMed

Sparano JA, Gray RJ, Makower DF, et al. : Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med 379:111-121, 2018 PubMed PMC

Champion VL, Wagner LI, Monahan PO, et al. : Comparison of younger and older breast cancer survivors and age-matched controls on specific and overall quality of life domains. Cancer 120:2237-2246, 2014 PubMed PMC

Salgado R, Denkert C, Demaria S, et al. : The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: Recommendations by an International TILs Working Group 2014. Ann Oncol 26:259-271, 2015 PubMed PMC

Adams S, Gray RJ, Demaria S, et al. : Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol 32:2959-2966, 2014 PubMed PMC

Park JH, Jonas SF, Bataillon G, et al. : Prognostic value of tumor-infiltrating lymphocytes in patients with early-stage triple-negative breast cancers (TNBC) who did not receive adjuvant chemotherapy. Ann Oncol 30:1941-1949, 2019 PubMed

Loi S, Drubay D, Adams S, et al. : Tumor-infiltrating lymphocytes and prognosis: A pooled individual patient analysis of early-stage triple-negative breast cancers. J Clin Oncol 37:559-569, 2019 PubMed PMC

Dackus GM, Ter Hoeve ND, Opdam M, et al. : Long-term prognosis of young breast cancer patients (≤40 years) who did not receive adjuvant systemic treatment: Protocol for the PARADIGM initiative cohort study. BMJ Open 7:e017842, 2017 PubMed PMC

Casparie M, Tiebosch AT, Burger G, et al. : Pathology databanking and biobanking in The Netherlands, a central role for PALGA, the nationwide histopathology and cytopathology data network and archive. Cell Oncol 29:19-24, 2007 PubMed PMC

Kos Z, Roblin E, Kim RS, et al. : Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer. NPJ Breast Cancer 6:17, 2020 PubMed PMC

Denkert C, Wienert S, Poterie A, et al. : Standardized evaluation of tumor-infiltrating lymphocytes in breast cancer: Results of the ring studies of the international immuno-oncology biomarker working group. Mod Pathol 29:1155-1164, 2016 PubMed

Slide Score. www.slidescore.com

The R Foundation: The R Project for Statistical Computing. https://www.R-project.org/

Loi S, Michiels S, Salgado R, et al. : Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: Results from the FinHER trial. Ann Oncol 25:1544-1550, 2014 PubMed

Loi S, Sirtaine N, Piette F, et al. : Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol 31:860-867, 2013 PubMed

Leon-Ferre RA, Polley MY, Liu H, et al. : Impact of histopathology, tumor-infiltrating lymphocytes, and adjuvant chemotherapy on prognosis of triple-negative breast cancer. Breast Cancer Res Treat 167:89-99, 2018 PubMed PMC

Denkert C, von Minckwitz G, Brase JC, et al. : Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol 33:983-991, 2015 PubMed

Aine M, Boyaci C, Hartman J, et al. : Molecular analyses of triple-negative breast cancer in the young and elderly. Breast Cancer Res 23:20, 2021 PubMed PMC

Fane M, Weeraratna AT: How the ageing microenvironment influences tumour progression. Nat Rev Cancer 20:89-106, 2020 PubMed PMC

de Boo L, Cimino-Mathews A, Lubeck Y, et al. : Tumour-infiltrating lymphocytes (TILs) and BRCA-like status in stage III breast cancer patients randomised to adjuvant intensified platinum-based chemotherapy versus conventional chemotherapy. Eur J Cancer 127:240-250, 2020 PubMed

Early Breast Cancer Trialists' Collaborative Group : Adjuvant chemotherapy in oestrogen-receptor-poor breast cancer: Patient-level meta-analysis of randomised trials. Lancet 371:29-40, 2008 PubMed

Tachi T, Teramachi H, Tanaka K, et al. : The impact of outpatient chemotherapy-related adverse events on the quality of life of breast cancer patients. PLoS One 10:e0124169, 2015 PubMed PMC

Rakha EA, Martin S, Lee AH, et al. : The prognostic significance of lymphovascular invasion in invasive breast carcinoma. Cancer 118:3670-3680, 2012 PubMed

WHO Classification of Tumours Editorial Board : Breast Tumours. Lyon, France, International Agency for Research on Cancer, 2019. pp 104-105

Nelson RA, Guye ML, Luu T, et al. : Survival outcomes of metaplastic breast cancer patients: Results from a US population-based analysis. Ann Surg Oncol 22:24-31, 2015 PubMed

Westreich D, Greenland S: The table 2 fallacy: Presenting and interpreting confounder and modifier coefficients. Am J Epidemiol 177:292-298, 2013 PubMed PMC

Graeser MK, Engel C, Rhiem K, et al. : Contralateral breast cancer risk in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 27:5887-5892, 2009 PubMed

Metcalfe K, Lynch HT, Ghadirian P, et al. : Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 22:2328-2335, 2004 PubMed

Bueno-de-Mesquita JM, Nuyten DS, Wesseling J, et al. : The impact of inter-observer variation in pathological assessment of node-negative breast cancer on clinical risk assessment and patient selection for adjuvant systemic treatment. Ann Oncol 21:40-47, 2010 PubMed

Timms KM, Abkevich V, Hughes E, et al. : Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res 16:475, 2014 PubMed PMC

Nik-Zainal S, Davies H, Staaf J, et al. : Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature 534:47-54, 2016 PubMed PMC

van den Broek AJ, de Ruiter K, van 't Veer LJ, et al. : Evaluation of the Dutch BRCA1/2 clinical genetic center referral criteria in an unselected early breast cancer population. Eur J Hum Genet 23:588-595, 2015 PubMed PMC

Copson ER, Maishman TC, Tapper WJ, et al. : Germline BRCA mutation and outcome in young-onset breast cancer (POSH): A prospective cohort study. Lancet Oncol 19:169-180, 2018 PubMed PMC

Baretta Z, Mocellin S, Goldin E, et al. : Effect of BRCA germline mutations on breast cancer prognosis: A systematic review and meta-analysis. Medicine (Baltimore) 95:e4975, 2016 PubMed PMC

Chao C, Bhatia S, Xu L, et al. : Incidence, risk factors, and mortality associated with second malignant neoplasms among survivors of adolescent and young adult cancer. JAMA Netw Open 2:e195536, 2019 PubMed PMC

Kassam F, Enright K, Dent R, et al. : Survival outcomes for patients with metastatic triple-negative breast cancer: Implications for clinical practice and trial design. Clin Breast Cancer 9:29-33, 2009 PubMed

TILs Working Group. www.tilsinbreastcancer.org

Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer