Tumour-infiltrating lymphocytes and response to neoadjuvant letrozole in patients with early oestrogen receptor-positive breast cancer: analysis from a nationwide phase II DBCG trial

Signe Korsgaard Skriver, Maj-Britt Jensen, Ann Soegaard Knoop, Bent Ejlertsen, Anne-Vibeke Laenkholm, Signe Korsgaard Skriver, Maj-Britt Jensen, Ann Soegaard Knoop, Bent Ejlertsen, Anne-Vibeke Laenkholm

Abstract

Background: The presence of tumour-infiltrating lymphocytes (TILs) is associated with response to neoadjuvant chemotherapy among patients with triple-negative and HER2-positive breast cancer. However, the significance of TILs is less clear in luminal breast cancer. Here, we in postmenopausal patients with primary oestrogen receptor-positive (ER+), HER2 normal, operable breast cancer assessed the importance of inducing TILs during 4 months of letrozole on response in a neoadjuvant phase II study.

Methods: Participants were postmenopausal women with ER+, HER2 normal operable breast cancer assigned to 4 months of neoadjuvant letrozole. Pretreatment core biopsies and surgical specimens were assessed centrally for the percentage of TILs on haematoxylin and eosin-stained slides according to the International Immuno-Oncology Biomarker Working Group on Breast Cancer guidelines. Pathological response was assessed by the Residual Cancer Burden (RCB) index and a modified Miller-Payne grading system and was analysed according to change in TILs.

Results: Tumour specimens were available from 106 of the 112 patients treated per protocol. TIL concentration increased with mean 6.8 percentage point (p < 0.0001) during treatment (range - 39 to 60). An increase in TILs was significantly associated with pathological response with OR = 0.71 (95% CI 0.53-0.96; p = 0.02) per 10% absolute increase for pathological response and correspondingly OR = 0.56 (95% CI 0.40-0.78; p = 0.0007) for lower RCB index per 10% increase.

Conclusion: Increasing TILs during letrozole was significantly associated with a poor treatment response. An increase in TILs during endocrine therapy might imply immunogenicity, and these patients could be targetable by immunotherapy.

Trial registration: ClinicalTrials.govNCT00908531, registered 27 May 2009.

Keywords: Breast neoplasms; Endocrine therapy; Letrozole; Neoadjuvant; TILs.

Conflict of interest statement

SKS: none. MBJ: Nanostring Technologies, Inc. (grant: institutional) and Oncology venture (grant: institutional). ASK: Roche (grant: institutional). Ad Board: Novartis, Astra Zeneca, MDS, Roche, Pfizer, and ELI LILLY DANMARK A/S. BE: Nanostring Technologies, Inc. (grant: institutional), Novartis (grant: institutional), and Roche (grant: institutional). AVL: Nanostring Technologies, Inc. (grant) and Roche (grant).

Figures

Fig. 1
Fig. 1
Bean plot illustrating distributions of TILs before and after neoadjuvant endocrine treatment in patients with no pathological response and in patients with pathological response (complete or partial). Pre- and posttreatment distribution differs significantly in patients with no pathological response (p ≤ 0.0001), but not in patients with response (p = 0.1)

References

    1. Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018;19(1):40–50. doi: 10.1016/S1470-2045(17)30904-X.
    1. Loi S, Drubay D, Adams S, Pruneri G, Francis PA, Lacroix-Triki M, et al. Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers. J Clin Oncol. 2019;37(7):559–569. doi: 10.1200/JCO.18.01010.
    1. Salgado R, Denkert C, Campbell C, Savas P, Nuciforo P, Aura C, 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. JAMA Oncol. 2015;1(4):448–454. doi: 10.1001/jamaoncol.2015.0830.
    1. Dunbier AK, Ghazoui Z, Anderson H, Salter J, Nerurkar A, Osin P, et al. Molecular profiling of aromatase inhibitor-treated postmenopausal breast tumors identifies immune-related correlates of resistance. Clin Cancer Res Off J Am Assoc Cancer Res. 2013;19(10):2775–2786. doi: 10.1158/1078-0432.CCR-12-1000.
    1. Solinas C, Carbognin L, De Silva P, Criscitiello C, Lambertini M. Tumor-infiltrating lymphocytes in breast cancer according to tumor subtype: current state of the art. Breast. 2017;35:142–150. doi: 10.1016/j.breast.2017.07.005.
    1. Denkert C, Loibl S, Noske A, Roller M, Müller BM, Komor M, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2009;28(1):105–113. doi: 10.1200/JCO.2009.23.7370.
    1. Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R, 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. 2014;33(9):983–991. doi: 10.1200/JCO.2014.58.1967.
    1. Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, et al. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast Edinb Scotl. 2003;12(5):320–327. doi: 10.1016/S0960-9776(03)00106-1.
    1. Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol Off J Am Soc Clin Oncol. 2007;25(28):4414–4422. doi: 10.1200/JCO.2007.10.6823.
    1. Bossuyt V, Provenzano E, Symmans WF, Boughey JC, Coles C, Curigliano G, et al. Recommendations for standardized pathological characterization of residual disease for neoadjuvant clinical trials of breast cancer by the BIG-NABCG collaboration. Ann Oncol. 2015;26(7):1280–1291. doi: 10.1093/annonc/mdv161.
    1. Ellis MJ, Tao Y, Luo J, A’Hern R, Evans DB, Bhatnagar AS, et al. Outcome prediction for estrogen receptor–positive breast cancer based on postneoadjuvant endocrine therapy tumor characteristics. JNCI J Natl Cancer Inst. 2008;100(19):1380–1388. doi: 10.1093/jnci/djn309.
    1. Polley M-YC, Leung SCY, McShane LM, Gao D, Hugh JC, Mastropasqua MG, et al. An international Ki67 reproducibility study. JNCI J Natl Cancer Inst. 2013;105(24):1897–1906. doi: 10.1093/jnci/djt306.
    1. Skriver SK, Laenkholm A-V, Rasmussen BB, Handler J, Grundtmann B, Tvedskov TF, et al. Neoadjuvant letrozole for postmenopausal estrogen receptor-positive, HER2-negative breast cancer patients, a study from the Danish Breast Cancer Cooperative Group (DBCG) Acta Oncol. 2018;57(1):31–37. doi: 10.1080/0284186X.2017.1401228.
    1. Hammond MEH, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28(16):2784–2795. doi: 10.1200/JCO.2009.25.6529.
    1. Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, 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. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(31):3997–4013. doi: 10.1200/JCO.2013.50.9984.
    1. Dowsett M, Nielsen TO. A’Hern R, Bartlett J, Coombes RC, Cuzick J, et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer Working Group. JNCI J Natl Cancer Inst. 2011;103(22):1656–1664. doi: 10.1093/jnci/djr393.
    1. Dieci MV, Radosevic-Robin N, Fineberg S, van den Eynden G, Ternes N, Penault-Llorca F, et al. Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: a report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer. Semin Cancer Biol. 2018;52:16–25. doi: 10.1016/j.semcancer.2017.10.003.
    1. Residual Cancer Burden Calculator [Internet]. MD Anderson Cancer Center. [cited 2019 Oct 7]. Available from: .
    1. Creighton CJ. The molecular profile of luminal B breast cancer. Biol Targets Ther. 2012;6:289–297. doi: 10.2147/BTT.S29923.
    1. Fujimoto Y, Watanabe T, Hida AI, Higuchi T, Miyagawa Y, Ozawa H, et al. Prognostic significance of tumor-infiltrating lymphocytes may differ depending on Ki67 expression levels in estrogen receptor-positive/HER2-negative operated breast cancers. Breast Cancer. 2019;26(6):738–747. doi: 10.1007/s12282-019-00977-0.
    1. Loibl S, Volz C, Mau C, Blohmer J-U, Costa SD, Eidtmann H, et al. Response and prognosis after neoadjuvant chemotherapy in 1,051 patients with infiltrating lobular breast carcinoma. Breast Cancer Res Treat. 2014;144(1):153–162. doi: 10.1007/s10549-014-2861-6.
    1. Delpech Y, Coutant C, Hsu L, Barranger E, Iwamoto T, Barcenas CH, et al. Clinical benefit from neoadjuvant chemotherapy in oestrogen receptor-positive invasive ductal and lobular carcinomas. Br J Cancer. 2013;108(2):285–291. doi: 10.1038/bjc.2012.557.
    1. Liang X, Briaux A, Becette V, Benoist C, Boulai A, Chemlali W, et al. Molecular profiling of hormone receptor-positive, HER2-negative breast cancers from patients treated with neoadjuvant endocrine therapy in the CARMINA 02 trial (UCBG-0609) J Hematol OncolJ Hematol Oncol. 2018;11(1):124. doi: 10.1186/s13045-018-0670-9.
    1. Stanton SE, Adams S, Disis ML. Variation in the incidence and magnitude of tumor-infiltrating lymphocytes in breast cancer subtypes: a systematic review. JAMA Oncol. 2016;2(10):1354–1360. doi: 10.1001/jamaoncol.2016.1061.
    1. Jensen M-B, Laenkholm A-V, Offersen BV, Christiansen P, Kroman N, Mouridsen HT, et al. The clinical database and implementation of treatment guidelines by the Danish Breast Cancer Cooperative Group in 2007-2016. Acta Oncol Stockh Swed. 2018;57(1):13–18. doi: 10.1080/0284186X.2017.1404638.
    1. Savas P, Salgado R, Denkert C, Sotiriou C, Darcy PK, Smyth MJ, et al. Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat Rev Clin Oncol. 2016;13(4):228–241. doi: 10.1038/nrclinonc.2015.215.
    1. Jiang X, Ellison SJ, Alarid ET, Shapiro DJ. Interplay between the levels of estrogen and estrogen receptor controls the level of the granzyme inhibitor, proteinase inhibitor 9 and susceptibility to immune surveillance by natural killer cells. Oncogene. 2007;26(28):4106–4114. doi: 10.1038/sj.onc.1210197.
    1. Lønning PE, Geisler J. Evaluation of plasma and tissue estrogen suppression with third-generation aromatase inhibitors: of relevance to clinical understanding? J Steroid Biochem Mol Biol. 2010;118(4–5):288–293. doi: 10.1016/j.jsbmb.2009.09.013.
    1. Chan MS, Wang L, Felizola SJ, Ueno T, Toi M, Loo W, et al. Changes of tumor infiltrating lymphocyte subtypes before and after neoadjuvant endocrine therapy in estrogen receptor-positive breast cancer patients – an immunohistochemical study of cd8+ and foxp3+ using double immunostaining with correlation to the pathobiological response of the patients. Int J Biol Markers. 2012;27(4):295–304. doi: 10.5301/JBM.2012.10439.
    1. Pernas S, Tolaney SM, Winer EP, Goel S. CDK4/6 inhibition in breast cancer: current practice and future directions. Ther Adv Med Oncol. 2018;10:1758835918786451. doi: 10.1177/1758835918786451.
    1. Goel S, DeCristo MJ, Watt AC, BrinJones H, Sceneay J, Li BB, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548(7668):471–475. doi: 10.1038/nature23465.
    1. Skriver SK, Jensen M-B, Knoop AS, Ejlertsen B, Laenkholm A-V. P4–10-18. Changes in tumour infiltrating lymphocytes during neoadjuvant endocrine therapy and possible clinical implications for guiding therapy [Internet]. Poster presented at: San Antonio Breast Cancer Symposium; 2019; San Antonio, TX. [cited 2020 Jan 29]. Available from: .

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