Tumor-Infiltrating Lymphocytes: A Predictive and Prognostic Biomarker in Neoadjuvant-Treated HER2-Positive Breast Cancer

Purpose: We elucidated the value of tumor-infiltrating lymphocytes (TIL) as an independent predictor for pathologic complete response (pCR) rate and as a prognostic marker for disease-free survival (DFS) in patients with HER2-positive breast cancer in the neoadjuvant setting. Experimental Design: We evaluated stromal TILs in 498 HER2-positive breast cancer samples of the neoadjuvant GeparQuattro (G4) and GeparQuinto (G5) trials. Levels of TILs were determined as a continuous parameter per 10% increase and as lymphocyte-predominant breast cancer (LPBC; ≥ 60% TILs), and correlated with pCR rate and DFS. Results: In the complete cohort, HER2-positive LPBC cases had a significantly increased pCR rates compared with non-LPBC types. They were significant predictors for pCR in univariate (10% TILs: OR 1.12, P = 0.002; LPBC: OR 2.02, P = 0.002) and multivariate analyses (10% TILs: OR 1.1, P = 0.014; LPBC: OR 1.87, P = 0.009). This effect was also detectable in the trastuzumab-treated (10% TILs: OR 1.12, P = 0.018; LPBC: OR 2.08, P = 0.013) but not in the lapatinib-treated subgroup. We identified a low-risk (pCR/LPBC) and a high-risk group (no pCR/no LPBC) regarding DFS. In triple-positive breast cancer, TILs are of more prognostic relevance than pCR. Conclusions: We could demonstrate the predictive and prognostic impact of TILs in HER2-positive breast cancer in the neoadjuvant setting. In combination with pCR rate, TILs may help to stratify prognostic subgroups, thereby guiding future therapy decisions. Clin Cancer Res; 22(23); 5747–54. ©2016 AACR.

[1]  M. Greene,et al.  The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. , 2010, Cancer cell.

[2]  C. Denkert The immunogenicity of breast cancer--molecular subtypes matter. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[3]  D. Berry,et al.  Molecular Heterogeneity and Response to Neoadjuvant Human Epidermal Growth Factor Receptor 2 Targeting in CALGB 40601, a Randomized Phase III Trial of Paclitaxel Plus Trastuzumab With or Without Lapatinib. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  M. Rezai,et al.  Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. , 2012, The Lancet. Oncology.

[5]  T. Fehm,et al.  Integrating bevacizumab, everolimus, and lapatinib into current neoadjuvant chemotherapy regimen for primary breast cancer. Safety results of the GeparQuinto trial. , 2011, Annals of oncology : official journal of the European Society for Medical Oncology.

[6]  M. Rezai,et al.  Survival after adding capecitabine and trastuzumab to neoadjuvant anthracycline-taxane-based chemotherapy for primary breast cancer (GBG 40--GeparQuattro). , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[7]  E. Perez,et al.  Association of Stromal Tumor-Infiltrating Lymphocytes With Recurrence-Free Survival in the N9831 Adjuvant Trial in Patients With Early-Stage HER2-Positive Breast Cancer. , 2016, JAMA oncology.

[8]  M. Berger,et al.  Lapatinib plus capecitabine for HER2-positive advanced breast cancer. , 2006, The New England journal of medicine.

[9]  S Michiels,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. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[10]  Giulia Bianchi,et al.  Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. , 2012, The Lancet. Oncology.

[11]  S. Loi,et al.  Anti–ErbB-2 mAb therapy requires type I and II interferons and synergizes with anti–PD-1 or anti-CD137 mAb therapy , 2011, Proceedings of the National Academy of Sciences.

[12]  M. Rezai,et al.  Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  Carsten Denkert,et al.  Prospective Validation of Immunological Infiltrate for Prediction of Response to Neoadjuvant Chemotherapy in HER2-Negative Breast Cancer – A Substudy of the Neoadjuvant GeparQuinto Trial , 2013, PloS one.

[14]  Carsten Denkert,et al.  Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[15]  D. Fearon,et al.  T cell exclusion, immune privilege, and the tumor microenvironment , 2015, Science.

[16]  C. Horak,et al.  Nivolumab plus ipilimumab in advanced melanoma. , 2013, The New England journal of medicine.

[17]  S. Paik,et al.  Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): an open-label, randomised phase 3 trial. , 2013, The Lancet. Oncology.

[18]  Stefan Michiels,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. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  Nina Daschil,et al.  Lapatinib and doxorubicin enhance the Stat1‐dependent antitumor immune response , 2013, European journal of immunology.

[20]  L. Presta,et al.  Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets , 2000, Nature Medicine.

[21]  Carsten Denkert,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. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  Carsten Denkert,et al.  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. , 2015, JAMA oncology.

[23]  W. Sauerbrei,et al.  Reporting recommendations for tumor marker prognostic studies (REMARK). , 2005, Journal of the National Cancer Institute.

[24]  C. Hudis Trastuzumab--mechanism of action and use in clinical practice. , 2007, The New England journal of medicine.

[25]  John M S Bartlett,et al.  Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. , 2014, Archives of pathology & laboratory medicine.

[26]  L. Gianni,et al.  The immune system and response to HER2-targeted treatment in breast cancer. , 2014, The Lancet. Oncology.

[27]  D Tripathy,et al.  Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  T. Nielsen,et al.  The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. , 2015, Annals of oncology : official journal of the European Society for Medical Oncology.

[29]  J. Ross,et al.  The HER-2 receptor and breast cancer: ten years of targeted anti-HER-2 therapy and personalized medicine. , 2009, The oncologist.

[30]  Carsten Denkert,et al.  Clinical relevance of host immunity in breast cancer: from TILs to the clinic , 2016, Nature Reviews Clinical Oncology.

[31]  Peter A Fasching,et al.  Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the GeparQuattro study. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  Molin Wang,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. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.