{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T13:47:52Z","timestamp":1782395272830,"version":"3.54.5"},"reference-count":53,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T00:00:00Z","timestamp":1782345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Tumor-infiltrating lymphocytes (TILs) are recognized predictors of response to neoadjuvant chemotherapy (NACT) and prognosis in breast cancer, particularly in triple-negative (TN) and HER2-positive subtypes. However, the additional predictive value of morphological features of the inflammatory infiltrate beyond TIL quantification is not fully established. We aimed to assess the predictive value of TILs for response to NACT in breast cancer and to determine whether morphological characteristics of the inflammatory infiltrate enhance predictive accuracy. Methods: We analyzed 477 patients with stage II\u2013III breast cancer treated with NACT between 2009 and 2016. Diagnostic core needle biopsies were prospectively re-evaluated. TILs were quantified according to International TILs Working Group recommendations. Morphological features of the infiltrate, including cell composition (lymphocytic vs. plasma cell-rich), heterogeneity, and localization, were evaluated using standardized criteria. Pathologic complete response (pCR) was defined as absence of invasive tumor in the breast and in the axillary lymph nodes (ypT0\/Tis ypN0). Univariate and multivariate logistic regression analyses were performed to assess the predictive value of TILs (quantitative and morphological assessment) to achieve pCR for the entire cohort and by surrogate molecular subtype. Results: A TIL cutoff of &gt;20% was identified as optimal for predicting pCR. High TILs were significantly associated with high-grade tumors, elevatedKi67, HER2-positive and TN subtypes, presence of plasma cells, and intraepithelial and heterogeneous infiltrates. In the overall cohort, TILs &gt; 20% significantly increased the likelihood of pCR (OR 3.9, 95%IC 2.5\u20136.0, p &lt; 0.001) and was an independent predictor of pCR. A combined variable incorporating TIL level and homogeneity improved predictive performance, with homogeneously high TILs emerging as a strong predictor of pCR (OR 5.521, 95%CI 3.174\u20139.603, p &lt; 0.01). Plasma cell-rich and intraepithelial infiltrates were also associated with higher pCR rates (respectively, OR 2.7, 95%CI 1.5\u20135.0, p = 0.001 and OR 2.8, 95%CI 1.6\u20135.0, p &lt; 0.001). Subtype-specific analyses confirmed the predictive value of TILs in TN tumors, but not in HER2-positive ones. Notably, in luminal B-like tumors, high TILs were the only independent predictor of response (OR 17.982, 95%CI 3.115\u2013103.815, p = 0.001). Conclusions: TIL assessment on routine H&amp;E-stained biopsies is a robust predictor of response to NACT in breast cancer that is readily available, cost-neutral and does not require additional techniques. Integration of simple morphological features significantly enhances predictive accuracy and may refine treatment stratification, particularly in luminal B-like tumors.<\/jats:p>","DOI":"10.3390\/cancers18132065","type":"journal-article","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T12:37:55Z","timestamp":1782391075000},"page":"2065","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tumor-Infiltrating Lymphocytes as Predictors of Response to Neoadjuvant Chemotherapy in Breast Cancer: Added Value of Morphological Characterization Beyond Quantification"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6655-1874","authenticated-orcid":false,"given":"Juan","family":"Azc\u00e1rate","sequence":"first","affiliation":[{"name":"Multidisciplinary Breast Cancer Unit, Department of Pathology, Hospital Universitari Bellvitge, 08907 Barcelona, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge (IDIBELL), 08908 Barcelona, Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat de Barcelona, 08007 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Petit","sequence":"additional","affiliation":[{"name":"Multidisciplinary Breast Cancer Unit, Department of Pathology, Hospital Universitari Bellvitge, 08907 Barcelona, Spain"},{"name":"Department of Pathology, Hospital Universitari Arnau de Vilanova, 25198 Lleida, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5567-2590","authenticated-orcid":false,"given":"Teresa","family":"Soler-Mons\u00f3","sequence":"additional","affiliation":[{"name":"Multidisciplinary Breast Cancer Unit, Department of Pathology, Hospital Universitari Bellvitge, 08907 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugenia","family":"Quir\u00f3s","sequence":"additional","affiliation":[{"name":"Multidisciplinary Breast Cancer Unit, Department of Pathology, Hospital Universitari Bellvitge, 08907 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Vethencourt","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge (IDIBELL), 08908 Barcelona, Spain"},{"name":"Multidisciplinary Breast Cancer Unit, Department of Medical Oncology, Institut Catal\u00e0 d\u2019Oncologia, 08908 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agostina","family":"Stradella","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge (IDIBELL), 08908 Barcelona, Spain"},{"name":"Multidisciplinary Breast Cancer Unit, Department of Medical Oncology, Institut Catal\u00e0 d\u2019Oncologia, 08908 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3398-0570","authenticated-orcid":false,"given":"Amparo","family":"Garc\u00eda-Tejedor","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge (IDIBELL), 08908 Barcelona, Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat de Barcelona, 08007 Barcelona, Spain"},{"name":"Multidisciplinary Breast Cancer Unit, Department of Gynecology, Hospital Universitari Bellvitge, 08907 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7119-4031","authenticated-orcid":false,"given":"Maria Jes\u00fas","family":"Pla-Farnos","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge (IDIBELL), 08908 Barcelona, Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat de Barcelona, 08007 Barcelona, Spain"},{"name":"Multidisciplinary Breast Cancer Unit, Department of Gynecology, Hospital Universitari Bellvitge, 08907 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9756-5088","authenticated-orcid":false,"given":"H\u00e9ctor","family":"P\u00e9rez-Montero","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge (IDIBELL), 08908 Barcelona, Spain"},{"name":"Multidisciplinary Breast Cancer Unit, Department of Radiation Oncology, Institut Catal\u00e0 d\u2019Oncologia, 08908 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Gum\u00e0","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge (IDIBELL), 08908 Barcelona, Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat de Barcelona, 08007 Barcelona, Spain"},{"name":"Multidisciplinary Breast Cancer Unit, Department of Radiology, Hospital Universitari Bellvitge, 08907 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ra\u00fal","family":"Ortega","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge (IDIBELL), 08908 Barcelona, Spain"},{"name":"Multidisciplinary Breast Cancer Unit, Department of Radiology, Hospital Universitari Bellvitge, 08907 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Multidisciplinary Breast Cancer Unit, Department of Reparative Surgery, Hospital Universitari Bellvitge, 08907 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Cap\u00f3","sequence":"additional","affiliation":[{"name":"Multidisciplinary Breast Cancer Unit, Department of Gynecology, Hospital de Viladecans, 08840 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2129-6336","authenticated-orcid":false,"given":"Mar","family":"Varela","sequence":"additional","affiliation":[{"name":"Multidisciplinary Breast Cancer Unit, Department of Pathology, Hospital Universitari Bellvitge, 08907 Barcelona, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge (IDIBELL), 08908 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5447-6803","authenticated-orcid":false,"given":"Luis M.","family":"Molinos-Albert","sequence":"additional","affiliation":[{"name":"ISGlobal, 08036 Barcelona, Spain"},{"name":"CIBER Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda del Rosario","family":"Taco-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Multidisciplinary Breast Cancer Unit, Department of Pathology, Hospital Universitari Bellvitge, 08907 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esther","family":"Guerra","sequence":"additional","affiliation":[{"name":"Multidisciplinary Breast Cancer Unit, Department of Pathology, Hospital Universitari Bellvitge, 08907 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7888-6810","authenticated-orcid":false,"given":"Jan","family":"Bosch-Schips","sequence":"additional","affiliation":[{"name":"Multidisciplinary Breast Cancer Unit, Department of Pathology, Hospital Universitari Bellvitge, 08907 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5727-2099","authenticated-orcid":false,"given":"August","family":"Vidal","sequence":"additional","affiliation":[{"name":"Multidisciplinary Breast Cancer Unit, Department of Pathology, Hospital Universitari Bellvitge, 08907 Barcelona, Spain"},{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge (IDIBELL), 08908 Barcelona, Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat de Barcelona, 08007 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3463-5333","authenticated-orcid":false,"given":"Evelyn","family":"Mart\u00ednez-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge (IDIBELL), 08908 Barcelona, Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat de Barcelona, 08007 Barcelona, Spain"},{"name":"Multidisciplinary Breast Cancer Unit, Department of Radiation Oncology, Institut Catal\u00e0 d\u2019Oncologia, 08908 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1485-5080","authenticated-orcid":false,"given":"Sonia","family":"Pernas","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge (IDIBELL), 08908 Barcelona, Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat de Barcelona, 08007 Barcelona, Spain"},{"name":"Multidisciplinary Breast Cancer Unit, Department of Medical Oncology, Institut Catal\u00e0 d\u2019Oncologia, 08908 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1380-2718","authenticated-orcid":false,"given":"Miguel","family":"Gil-Gil","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge (IDIBELL), 08908 Barcelona, Spain"},{"name":"Multidisciplinary Breast Cancer Unit, Department of Medical Oncology, Institut Catal\u00e0 d\u2019Oncologia, 08908 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5714-6823","authenticated-orcid":false,"given":"Catalina","family":"Falo","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n Biom\u00e9dica de Bellvitge (IDIBELL), 08908 Barcelona, Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat de Barcelona, 08007 Barcelona, Spain"},{"name":"Multidisciplinary Breast Cancer Unit, Department of Medical Oncology, Institut Catal\u00e0 d\u2019Oncologia, 08908 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2206","DOI":"10.1093\/annonc\/mdt303","article-title":"Personalizing the treatment of women with early breast cancer: Highlights of the st gallen international expert consensus on the primary therapy of early breast Cancer 2013","volume":"24","author":"Goldhirsch","year":"2013","journal-title":"Ann. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2838","DOI":"10.1158\/1078-0432.CCR-19-3492","article-title":"Pathologic Complete Response after Neoadjuvant Chemotherapy and Impact on Breast Cancer Recurrence and Survival: A Comprehensive Meta-analysis","volume":"26","author":"Spring","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Falo, C., Azcarate, J., Fernandez-Gonzalez, S., Perez, X., Petit, A., Perez, H., Vethencourt, A., Vazquez, S., Laplana, M., and Ales, M. (2024). Breast Cancer Patient\u2019s Outcomes after Neoadjuvant Chemotherapy and Surgery at 5 and 10 Years for Stage II\u2013III Disease. Cancers, 16.","DOI":"10.3390\/cancers16132421"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"104120","DOI":"10.1016\/j.esmoop.2024.104120","article-title":"Tumor-infiltrating lymphocytes in HER2-positive breast cancer: Potential impact and challenges","volume":"10","author":"Schlam","year":"2025","journal-title":"ESMO Open"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2786","DOI":"10.1093\/annonc\/mdt350","article-title":"Ki67 levels as predictive and prognostic parameters in pretherapeutic breast cancer core biopsies: A translational investigation in the neoadjuvant gepartrio trial","volume":"24","author":"Denkert","year":"2013","journal-title":"Ann. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5678","DOI":"10.1158\/1078-0432.CCR-04-2421","article-title":"Breast cancer molecular subtypes respond differently to preoperative chemotherapy","volume":"11","author":"Rouzier","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2147\/CMAR.S316700","article-title":"The Characteristics of Tumor Microenvironment in Triple Negative Breast Cancer","volume":"14","author":"Fan","year":"2022","journal-title":"Cancer Manag. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1093\/annonc\/mdu450","article-title":"The evaluation of tumor-infiltrating lymphocytes (TILS) in breast cancer: Recommendations by an International TILS Working Group 2014","volume":"26","author":"Salgado","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1200\/JCO.2009.23.7370","article-title":"Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer","volume":"28","author":"Denkert","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/S1470-2045(17)30904-X","article-title":"Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: A pooled analysis of 3771 patients treated with neoadjuvant therapy","volume":"19","author":"Denkert","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1080\/13543784.2022.2008354","article-title":"Biomarkers for breast cancer immunotherapy: PD-L1, TILs, and beyond","volume":"31","author":"Rizzo","year":"2022","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1758835920940928","DOI":"10.1177\/1758835920940928","article-title":"Efficacy and predictive factors of immune checkpoint inhibitors in metastatic breast cancer: A systematic review and meta-analysis","volume":"12","author":"Zou","year":"2020","journal-title":"Ther. Adv. Med. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1001\/jamaoncol.2023.5033","article-title":"Clinical and Biomarker Findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-Negative Breast Cancer NeoPACT Phase 2 Clinical Trial","volume":"10","author":"Sharma","year":"2024","journal-title":"JAMA Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Lopez Janeiro, A., Miraval Wong, E., Jim\u00e9nez-S\u00e1nchez, D., Ortiz De Solorzano, C., Lozano, M.D., Teijeira, A., Schalper, K.A., Melero, I., and De Andrea, C.E. (2024). Spatially resolved tissue imaging to analyze the tumor immune microenvironment: Beyond cell-type densities. J. Immunother. Cancer, 12.","DOI":"10.1136\/jitc-2023-008589"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1097\/PAP.0000000000000162","article-title":"Assessing Tumor-infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immunooncology Biomarkers Working Group: Part 1: Assessing the Host Immune Response, TILs in Invasive Breast Carcinoma and Ductal Carcinoma in Situ, Metastatic Tumor Deposits and Areas for Further Research","volume":"24","author":"Hendry","year":"2017","journal-title":"Adv. Anat. Pathol."},{"key":"ref_16","unstructured":"WHO Classification of Tumours Editorial Board (2019). WHO Classification of Tumours: Breast Tumours, World Health Organization. [5th ed.]."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1111\/j.1365-2559.1991.tb00229.x","article-title":"Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: Experience from a large study with long-term follow-up","volume":"19","author":"Elston","year":"1991","journal-title":"Histopathology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4414","DOI":"10.1200\/JCO.2007.10.6823","article-title":"Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy","volume":"25","author":"Symmans","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_19","unstructured":"The University of Texas, MD Anderson Cancer Center (2021, December 31). Residual Cancer Burden Calculator. Available online: http:\/\/www3.mdanderson.org\/app\/medcalc\/index.cfm?pagename=jsconvert3."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Brierley, J., Gospodarowicz, M.K., and Wittekind, C.H. (2017). TNM Classification of Malignant Tumours, John Wiley & Sons, Inc. [8th ed.].","DOI":"10.1002\/9780471420194.tnmc26.pub3"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"27","DOI":"10.21037\/cco.2020.01.06","article-title":"Biomarkers of neoadjuvant\/adjuvant chemotherapy for breast cancer","volume":"9","author":"Iwamoto","year":"2020","journal-title":"Chin. Clin. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1796","DOI":"10.1200\/JCO.2011.38.8595","article-title":"Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes","volume":"30","author":"Untch","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.breast.2022.10.001","article-title":"Predictive and prognostic values of tumor infiltrating lymphocytes in breast cancers treated with neoadjuvant chemotherapy: A meta-analysis","volume":"66","author":"Li","year":"2022","journal-title":"Breast"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gao, Z.H., Li, C.X., Liu, M., and Jiang, J.Y. (2020). Predictive and prognostic role of tumour-infiltrating lymphocytes in breast cancer patients with different molecular subtypes: A meta-analysis. BMC Cancer, 20.","DOI":"10.1186\/s12885-020-07654-y"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Mao, Y., Qu, Q., Zhang, Y., Liu, J., Chen, X., and Shen, K. (2014). The value of tumor infiltrating lymphocytes (TILs) for predicting response to neoadjuvant chemotherapy in breast cancer: A systematic review and meta-analysis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115103"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1200\/JCO.18.01624","article-title":"Randomized Phase II Study Evaluating Palbociclib in Addition to Letrozole as Neoadjuvant Therapy in Estrogen Receptor-Positive Early Breast Cancer: PALLET Trial","volume":"37","author":"Johnston","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/S1470-2045(19)30786-7","article-title":"Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): An open-label, multicentre, randomised, phase 2 trial","volume":"21","author":"Prat","year":"2020","journal-title":"Lancet Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2342","DOI":"10.1200\/JCO.2010.31.6950","article-title":"Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: Clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype\u2014ACOSOG Z1031","volume":"29","author":"Ellis","year":"2011","journal-title":"J. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3808","DOI":"10.1200\/JCO.2001.19.18.3808","article-title":"Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for erbb 1 and or erbb-2","volume":"19","author":"Ellis","year":"2001","journal-title":"J. Clin. Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1002\/cncr.22789","article-title":"Phase 2 randomized trial of primary endocrine therapy versus chemotherapy in postmenopausal patients with estrogen receptor-positive breast cancer","volume":"110","author":"Semiglazov","year":"2007","journal-title":"Cancer"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.ctrv.2017.04.005","article-title":"Tumor-infiltrating lymphocytes in patients with HER2-positive breast cancer treated with neoadjuvant chemotherapy plus trastuzumab, lapatinib or their combination: A meta-analysis of randomized controlled trials","volume":"57","author":"Solinas","year":"2017","journal-title":"Cancer Treat. Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1001\/jamaoncol.2015.0830","article-title":"Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: A secondary analysis of the NeoALTTO trial","volume":"1","author":"Salgado","year":"2015","journal-title":"JAMA Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1200\/JCO.2014.58.1967","article-title":"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","volume":"33","author":"Denkert","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1360","DOI":"10.1001\/jamaoncol.2021.1932","article-title":"Neoadjuvant Trastuzumab, Pertuzumab, and Docetaxel vs Trastuzumab Emtansine in Patients with ERBB2-Positive Breast Cancer: A Phase 2 Randomized Clinical Trial","volume":"7","author":"Hatschek","year":"2021","journal-title":"JAMA Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1001\/jamaoncol.2023.7304","article-title":"Tumor Intrinsic Subtypes and Gene Expression Signatures in Early-Stage ERBB2\/HER2 -Positive Breast Cancer: A Pooled Analysis of CALGB 40601, NeoALTTO, and NSABP B-41 Trials","volume":"10","author":"Rediti","year":"2024","journal-title":"JAMA Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1093\/jnci\/djy076","article-title":"Tumor-infiltrating lymphocytes in patients receiving trastuzumab\/pertuzumab-based chemotherapy: A TRYPHAENA Substudy","volume":"111","author":"Ignatiadis","year":"2019","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1093\/annonc\/mdv395","article-title":"Immune modulation of pathologic complete response after neoadjuvant HER2-directed therapies in the NeoSphere trial","volume":"26","author":"Bianchini","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/s41523-024-00636-4","article-title":"Tumor-infiltrating lymphocytes in HER2-positive breast cancer treated with neoadjuvant chemotherapy and dual HER2-blockade","volume":"10","author":"Liefaard","year":"2024","journal-title":"npj Breast Cancer"},{"key":"ref_39","unstructured":"Badve, S.S. (2025, January 9\u201312). Tumor infiltrating lymphocytes (TILs) and pathologic complete response (pCR) in stage II\/III HER2 breast cancer treated with taxane, trastuzumab and pertuzumab (THP): Secondary results from the EA 1181\/CompassHER2 pCR trial. Proceedings of the San Antonio Breat Cancer Symposium, San Antonio, TX, USA."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"110220","DOI":"10.1016\/j.ejrad.2022.110220","article-title":"A model combining pretreatment MRI radiomic features and tumor-infiltrating lymphocytes to predict response to neoadjuvant systemic therapy in triple-negative breast cancer","volume":"149","author":"Jimenez","year":"2022","journal-title":"Eur. J. Radiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1186\/s13000-018-0743-7","article-title":"Predictive value of tumor-infiltrating lymphocytes to pathological complete response in neoadjuvant treated triple-negative breast cancers","volume":"13","author":"Ruan","year":"2018","journal-title":"Diagn. Pathol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"van den Ende, N.S., Nguyen, A.H., Jager, A., Kok, M., Debets, R., and van Deurzen, C.H.M. (2023). Triple-Negative Breast Cancer and Predictive Markers of Response to Neoadjuvant Chemotherapy: A Systematic Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032969"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1097\/PAI.0000000000000466","article-title":"Prognostic Significance of Stromal Versus Intratumoral Infiltrating Lymphocytes in Different Subtypes of Breast Cancer Treated With Cytotoxic Neoadjuvant Chemotherapy","volume":"26","author":"Khoury","year":"2018","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1093\/ajcp\/aqy069","article-title":"Tumor-infiltrating lymphocytes in breast cancer: Evaluating interobserver variability, heterogeneity, and fidelity of scoring core biopsies","volume":"150","author":"Khoury","year":"2018","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1097\/SLA.0000000000005954","article-title":"Intratumoral Tumor Infiltrating Lymphocytes (TILs) are Associated With Cell Proliferation and Better Survival But Not Always With Chemotherapy Response in Breast Cancer","volume":"278","author":"Wu","year":"2023","journal-title":"Ann. Surg."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Li, M., Quintana, A., Alberts, E., Hung, M.S., Boulat, V., Ripoll, M.M., and Grigoriadis, A. (2023). B Cells in Breast Cancer Pathology. Cancers, 15.","DOI":"10.3390\/cancers15051517"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.humpath.2023.07.010","article-title":"Characterization and spatial distribution of the immune cell infiltrate in triple-negative breast cancer: A novel classification based on plasma cells and CD8+ T cells","volume":"139","author":"Gibert","year":"2023","journal-title":"Hum. Pathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s13058-021-01477-w","article-title":"Plasma cell infiltration and treatment effect in breast cancer patients treated with neoadjuvant chemotherapy","volume":"23","author":"Sakaguchi","year":"2021","journal-title":"Breast Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s12282-016-0698-z","article-title":"Immune infiltrates in the breast cancer microenvironment: Detection, characterization and clinical implication","volume":"24","author":"Burugu","year":"2017","journal-title":"Breast Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1158\/2326-6066.CIR-23-0076","article-title":"Spatial Distribution of Immune Cells Drives Resistance to Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer","volume":"12","author":"Donati","year":"2024","journal-title":"Cancer Immunol. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1038\/s41523-025-00728-9","article-title":"Spatial proximity of CD8+ T cells to tumor cells predicts neoadjuvant therapy efficacy in breast cancer","volume":"11","author":"Liang","year":"2025","journal-title":"npj Breast Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Tzoras, E., Zerdes, I., Tsiknakis, N., Manikis, G.C., Mezheyeuski, A., Bergh, J., Matikas, A., and Foukakis, T. (2022). Dissecting Tumor-Immune Microenvironment in Breast Cancer at a Spatial and Multiplex Resolution. Cancers, 14.","DOI":"10.3390\/cancers14081999"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1186\/s13058-024-01932-4","article-title":"Characterization of tumor-infiltrating lymphocytes and their spatial distribution in triple-negative breast cancer","volume":"26","author":"Han","year":"2024","journal-title":"Breast Cancer Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/13\/2065\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T13:01:42Z","timestamp":1782392502000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/13\/2065"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,25]]},"references-count":53,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cancers18132065"],"URL":"https:\/\/doi.org\/10.3390\/cancers18132065","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,25]]}}}