A-S Hamy1,2, J-Y Pierga3,4, A Sabaila5, E Laas5, H Bonsang-Kitzis1,2,5, C Laurent1,2, A Vincent-Salomon6, P Cottu3, F Lerebours3, R Rouzier5,7, M Lae6, F Reyal1,2,5. 1. Residual Tumor & Response to Treatment Laboratory, RT2Lab, Translational Research Department, PSL Research University, Institut Curie, Paris. 2. INSERM, U932 Immunity and Cancer, Paris. 3. Department of Medical Oncology, Institut Curie, Paris. 4. Faculty of Medicine, Paris Descartes University, Paris. 5. Departments of Surgery, Institut Curie, Paris. 6. Department of Pathology, Institut Curie, Paris, France. 7. Equipe d'Accueil 7285, Risk and Safety in Clinical Medicine for Women and Perinatal Health, University Versailles-Saint-Quentin, 2 av de la source de la Biévre, 78180 Montigny-le-Bretonneux, France.
Abstract
BACKGROUND: The role of tumor-infiltrating lymphocytes (TILs) in breast cancer has been extensively studied over the last decade. High TILs levels have been associated with pathological response rate in the neoadjuvant setting and with better outcomes in the adjuvant setting. However, little attention has been paid to changes in TILs and residual TIL levels after neoadjuvant chemotherapy (NAC). We investigated TIL levels before, after chemotherapy, and their dynamics during treatment; and we assessed the correlation of these levels with response to NAC and prognosis. MATERIALS AND METHODS: We identified 175 patients with primary HER2-positive breast cancers receiving NAC+/- trastuzumab between 2002 and 2011. Microbiopsy specimens and paired surgical samples were evaluated for stromal lymphocyte infiltration. Univariate and multivariate analyses were carried out to assess the association of clinical and pathological factors with pathological complete response (pCR) and disease-free survival. RESULTS: Baseline TIL levels were not significantly associated with pCR. TIL levels decreased during treatment in 78% of the patients. The magnitude of the decrease was strongly associated with pCR. After chemotherapy, TIL levels were high in tumors displaying aggressive patterns (high residual cancer burden score, mitotic index >22, tumor cellularity >5%). In the population with residual disease, TIL levels >25% at the end of NAC were significantly associated with an adverse outcome (TILs >25%, HR = 7.98, P = 0.009) after multivariate analyses including BMI, post-NAC mitotic index and tumor grade. CONCLUSION: A decrease in TIL levels during chemotherapy was positively associated with response to treatment. In tumor failing to achieve pCR, post-NAC lymphocytic infiltration was associated with higher residual tumor burden and adverse clinical outcome. Further studies are required to characterize immune infiltration in residual disease to identify candidates who could benefit from second-line therapy trials including immune checkpoint inhibitors.
BACKGROUND: The role of tumor-infiltrating lymphocytes (TILs) in breast cancer has been extensively studied over the last decade. High TILs levels have been associated with pathological response rate in the neoadjuvant setting and with better outcomes in the adjuvant setting. However, little attention has been paid to changes in TILs and residual TIL levels after neoadjuvant chemotherapy (NAC). We investigated TIL levels before, after chemotherapy, and their dynamics during treatment; and we assessed the correlation of these levels with response to NAC and prognosis. MATERIALS AND METHODS: We identified 175 patients with primary HER2-positive breast cancers receiving NAC+/- trastuzumab between 2002 and 2011. Microbiopsy specimens and paired surgical samples were evaluated for stromal lymphocyte infiltration. Univariate and multivariate analyses were carried out to assess the association of clinical and pathological factors with pathological complete response (pCR) and disease-free survival. RESULTS: Baseline TIL levels were not significantly associated with pCR. TIL levels decreased during treatment in 78% of the patients. The magnitude of the decrease was strongly associated with pCR. After chemotherapy, TIL levels were high in tumors displaying aggressive patterns (high residual cancer burden score, mitotic index >22, tumor cellularity >5%). In the population with residual disease, TIL levels >25% at the end of NAC were significantly associated with an adverse outcome (TILs >25%, HR = 7.98, P = 0.009) after multivariate analyses including BMI, post-NAC mitotic index and tumor grade. CONCLUSION: A decrease in TIL levels during chemotherapy was positively associated with response to treatment. In tumor failing to achieve pCR, post-NAC lymphocytic infiltration was associated with higher residual tumor burden and adverse clinical outcome. Further studies are required to characterize immune infiltration in residual disease to identify candidates who could benefit from second-line therapy trials including immune checkpoint inhibitors.
Authors: R Barroso-Sousa; W T Barry; H Guo; D Dillon; Y B Tan; K Fuhrman; W Osmani; A Getz; M Baltay; C Dang; D Yardley; B Moy; P K Marcom; E A Mittendorf; I E Krop; E P Winer; S M Tolaney Journal: Ann Oncol Date: 2019-04-01 Impact factor: 32.976
Authors: Adrienne G Waks; Daniel G Stover; Elizabeth A Mittendorf; Sara M Tolaney; Jennifer L Guerriero; Deborah Dillon; William T Barry; Evisa Gjini; Christina Hartl; Wesley Lo; Jennifer Savoie; Jane Brock; Robert Wesolowski; Zaibo Li; Adrienne Damicis; Anne V Philips; Yun Wu; Fei Yang; Amy Sullivan; Patrick Danaher; Heather Ann Brauer; Wafa Osmani; Mikel Lipschitz; Katherine A Hoadley; Michael Goldberg; Charles M Perou; Scott Rodig; Eric P Winer; Ian E Krop Journal: Clin Cancer Res Date: 2019-05-06 Impact factor: 12.531
Authors: Santiago Moragon; Cristina Hernando; Maria Teresa Martinez-Martinez; Marta Tapia; Belen Ortega-Morillo; Ana Lluch; Begoña Bermejo; Juan Miguel Cejalvo Journal: Cancers (Basel) Date: 2022-06-28 Impact factor: 6.575
Authors: Ciara C O'Sullivan; Karla V Ballman; Linda McCall; Anuhya Kommalapati; Tyler Zemla; Anna Weiss; Melissa Mitchell; Victoria Blinder; Nadine M Tung; William J Irvin; Myounghee Lee; Matthew P Goetz; William Fraser Symmans; Virginia F Borges; Ian Krop; Lisa A Carey; Ann H Partridge Journal: Future Oncol Date: 2021-10-12 Impact factor: 3.674
Authors: J Fay; S Toomey; A J Eustace; S F Madden; D M Collins; E W Kay; K M Sheehan; S Furney; B Moran; A Fagan; P G Morris; A Teiserskiene; A D Hill; L Grogan; J M Walshe; O Breathnach; C Power; D Duke; K Egan; W M Gallagher; N O'Donovan; J Crown; B T Hennessy Journal: Breast Cancer Res Treat Date: 2021-05-13 Impact factor: 4.872