Clinical Validity and Utility of Tumor-Infiltrating Lymphocytes in Routine Clinical Practice for Breast Cancer Patients: Current and Future Directions

Lironne Wein, Peter Savas, Stephen J Luen, Balaji Virassamy, Roberto Salgado, Sherene Loi, Lironne Wein, Peter Savas, Stephen J Luen, Balaji Virassamy, Roberto Salgado, Sherene Loi

Abstract

The interest in tumor-infiltrating lymphocytes (TILs) as a prognostic biomarker in breast cancer has grown in recent years. Biomarkers must undergo comprehensive evaluation in terms of analytical validity, clinical validity and clinical utility before they can be accepted as part of clinical practice. The International Immuno-Oncology Biomarker Working Group has developed a practice guideline on scoring TILs in breast cancer in order to standardize TIL assessment. The prognostic value of TILs as a biomarker in early-stage breast cancer has been established by assessing tumor samples in thousands of patients from large prospective clinical trials of adjuvant therapy. There is a strong linear relationship between increase in TILs and improved disease-free survival for triple-negative and HER2-positive disease. Higher levels of TILs have also been associated with increased rates of pathological complete response to neoadjuvant therapy. TILs have potential clinical utility in breast cancer in a number of areas. These include prediction of responders to immune checkpoint blockade, identification of primary HER2-positive and triple-negative patients who have excellent prognoses and may thus be appropriate for treatment de-escalation, and potentially incorporation into a neoadjuvant endpoint which may be a better surrogate maker for drug development.

Keywords: antitumor immunity; breast cancer; cancer biomarkers; checkpoint inhibitors; tumor-infiltrating lymphocytes.

Figures

Figure 1
Figure 1
Model to predict risk of distant recurrence at 5 years (%) by tumor-infiltrating lymphocytes (TILs) and nodal status by tumor size and age. The predicted rate of distant recurrence on the y axis as a continuous function of the level of stromal TILs in the primary tumor on the x axis is presented according to nodal status after adjuvant chemotherapy. This prognostic algorithm is for TNBC and assumes a mean age of 49.5 years and mean tumor size of 2 cm. Loi et al., San Antonio Breast Cancer Symposium 2015 (15).
Figure 2
Figure 2
Tumor-infiltrating lymphocyte (TIL) heterogeneity. Zone with high TILs on the left, zone with low TILs on the right. Magnification 100×.
Figure 3
Figure 3
Tumor-infiltrating lymphocytes (TILs): primary versus metastatic disease. Case study: breast primary with high number of TILs (left), pleural metastasis with no TILs (right). Magnification 100× (left), 200× (right).

References

    1. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol (2002) 3(11):991–8.10.1038/ni1102-991
    1. Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases – elimination, equilibrium and escape. Curr Opin Immunol (2014) 27:16–25.10.1016/j.coi.2014.01.004
    1. Ravelli A, Roviello G, Cretella D, Cavazzoni A, Biondi A, Cappelletti MR, et al. Tumor-infiltrating lymphocytes and breast cancer: beyond the prognostic and predictive utility. Tumour Biol (2017) 39(4).10.1177/1010428317695023
    1. Ingold Heppner B, Loibl S, Denkert C. Tumor-infiltrating lymphocytes: a promising biomarker in breast cancer. Breast Care (Basel) (2016) 11(2):96–100.10.1159/000444357
    1. Dushyanthen S, Beavis PA, Savas P, Teo ZL, Zhou C, Mansour M, et al. Relevance of tumor-infiltrating lymphocytes in breast cancer. BMC Med (2015) 13:202.10.1186/s12916-015-0431-3
    1. Yamaguchi R, Tanaka M, Yano A, Tse GM, Yamaguchi M, Koura K, et al. Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer. Hum Pathol (2012) 43:1688–94.10.1016/j.humpath.2011.12.013
    1. Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo 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 (2013) 31(7):860–7.10.1200/JCO.2011.41.0902
    1. Ali HR, Provenzano E, Dawson SJ, Blows FM, Liu B, Shah M, et al. Association between CD8+ T–cell infiltration and breast cancer survival in 12 439 patients. Ann Oncol (2014) 25:1536–43.10.1093/annonc/mdu191
    1. Ingold Heppner B, Untch M, Denkert C, Pfitzner BM, Lederer B, Schmitt W, et al. Tumor-infiltrating lymphocytes: a predictive and prognostic biomarker in neoadjuvant-treated HER2-positive breast cancer. Clin Cancer Res (2016) 22(23):5747–54.10.1158/1078-0432.CCR-15-2338
    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):228–41.10.1038/nrclinonc.2015.215
    1. Azim HA, Jr, Michiels S, Zagouri F, Delaloge S, Filipits M, Namer M, et al. Utility of prognostic genomic tests in breast cancer practice: the IMPAKT 2012 Working Group Consensus Statement. Ann Oncol (2013) 24(3):647–54.10.1093/annonc/mds645
    1. Harris LN, Ismaila N, McShane LM, Andre F, Collyar DE, Gonzalez-Angulo AM, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol (2016) 34(10):1134–50.10.1200/JCO.2015.65.2289
    1. Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol (2015) 26(2):259–71.10.1093/annonc/mdu450
    1. Leung SCY, Nielsen TO, Zabaglo L, Arun I, Badve SS, Bane AL, et al. Analytical validation of a standardized scoring protocol for Ki67: phase 3 of an international multicenter collaboration. NPJ Breast Cancer (2016) 2:16014.10.1038/npjbcancer.2016.14
    1. Loi S, Drubay D, Adams S, Francis PA, Joensuu H, Dieci MV, et al. Pooled individual patient data analysis of tumor infiltrating lymphocytes (TILs) in primary triple negative breast cancer (TNBC) treated with anthracycline-based chemotherapy. San Antonio Breast Cancer Symposium. (2015). Publication Number: S1-03.
    1. Brown M, Wittwer C. Flow cytometry: principles and clinical applications in hematology. Clin Chem (2000) 46:1221–9.
    1. Stack EC, Wang C, Roman KA, Hoyt CC. Multiplexed immunohistochemistry, imaging, and quantitation: a review, with an assessment of Tyramide signal amplification, multispectral imaging and multiplex analysis. Methods (2014) 70:46–58.10.1016/j.ymeth.2014.08.016
    1. Desmedt C, Haibe-Kains B, Wirapati P, Buyse M, Larsimont D, Bontempi G, et al. Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin Cancer Res (2008) 14(16):5158–65.10.1158/1078-0432.CCR-07-4756
    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 (2015) 33(9):983–91.10.1200/JCO.2014.58.1967
    1. Denkert C, Wienert S, Poterie A, Loibl S, Budczies J, Badve S, 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 (2016) 29(10):1155–64.10.1038/modpathol.2016.109
    1. Swisher SK, Wu Y, Castaneda CA, Lyons GR, Yang F, Tapia C, et al. Interobserver agreement between pathologists assessing tumor-infiltrating lymphocytes (TILs) in breast cancer using methodology proposed by the International TILs Working Group. Ann Surg Oncol (2016) 23(7):2242–8.10.1245/s10434-016-5173-8
    1. Nawaz S, Heindl A, Koelble K, Yuan Y. Beyond immune density: critical role of spatial heterogeneity in estrogen receptor-negative breast cancer. Mod Pathol (2015) 28(6):766–77.10.1038/modpathol.2015.37
    1. Sobottka B, Pestalozzi B, Fink D, Moch H, Varga Z. Similar lymphocytic infiltration pattern in primary breast cancer and their corresponding distant metastases. Oncoimmunology (2016) 5(6):e1153208.10.1080/2162402X.2016.1153208
    1. Cimino-Mathews A, Ye X, Meeker A, Argani P, Emens LA. Metastatic triple-negative breast cancers at first relapse have fewer tumor-infiltrating lymphocytes than their matched primary breast tumors: a pilot study. Hum Pathol (2013) 44(10):2055–63.10.1016/j.humpath.2013.03.010
    1. Ogiya R, Niikura N, Kumaki N, Bianchini G, Kitano S, Iwamoto T, et al. Comparison of tumor-infiltrating lymphocytes between primary and metastatic tumors in breast cancer patients. Cancer Sci (2016) 107(12):1730–5.10.1111/cas.13101
    1. Mansfield AS, Aubry MC, Moser JC, Harrington SM, Dronca RS, Park SS, et al. Temporal and spatial discordance of programmed cell death-ligand 1 expression and lymphocyte tumor infiltration between paired primary lesions and brain metastases in lung cancer. Ann Oncol (2016) 27(10):1953–8.10.1093/annonc/mdw289
    1. Baine MK, Turcu G, Zito CR, Adeniran AJ, Camp RL, Chen L, et al. Characterization of tumor infiltrating lymphocytes in paired primary and metastatic renal cell carcinoma specimens. Oncotarget (2015) 6(28):24990–5002.10.18632/oncotarget.4572
    1. Luen SJ, Salgado R, Fox S, Savas P, Eng-Wong J, Clark E, et al. Tumour-infiltrating lymphocytes in advanced HER2-positive breast cancer treated with pertuzumab or placebo in addition to trastuzumab and docetaxel: a retrospective analysis of the CLEOPATRA study. Lancet Oncol (2017) 18(1):52–62.10.1016/S1470-2045(16)30631-3
    1. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, 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 (2014) 25(8):1544–50.10.1093/annonc/mdu112
    1. Kim SR, Gavin PG, Pogue-Geile KL, Song N, Finnigan M, Bandos H, et al. A surrogate gene expression signature of tumor infiltrating lymphocytes (TILs) predicts degree of benefit from trastuzumab added to standard adjuvant chemotherapy in NSABP (NRG) trial B-31 for HER2+ breast cancer. AACR. (2015). abstract number 2837.
    1. Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, 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 (2014) 32(27):2959–66.10.1200/JCO.2013.55.0491
    1. Pruneri G, Gray KP, Vingiani A, Viale G, Curigliano G, Criscitiello C, et al. Tumor-infiltrating lymphocytes (TILs) are a powerful prognostic marker in patients with triple-negative breast cancer enrolled in the IBCSG phase III randomized clinical trial 22-00. Breast Cancer Res Treat (2016) 158(2):323–31.10.1007/s10549-016-3863-3
    1. Loi S, Drubay D, Adams S, Francis PA, Joensuu H, Dieci MV, et al. Pooled individual patient data analysis of stromal tumor infiltrating lymphocytes in primary triple negative breast cancer treated with anthracycline-based chemotherapy. San Antonio Breast Cancer Symposium, San Antonio: (2015). p. S1–03.
    1. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, et al. The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin (2017) 67(2):93–9.10.3322/caac.21388
    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 (2010) 28(1):105–13.10.1200/JCO.2009.23.7370
    1. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes (TILs) indicate trastuzumab benefit in early-stage HER2-positive breast cancer (HER2+ BC). Cancer Res (2013) 73:aS1–05.10.1158/0008-5472.SABCS13-S1-05
    1. Dieci M, Bisagni G, Cagossi K, Bottinin A, Sarti S, Placentini F, et al. Tumor infiltrating lymphocytes and correlation with outcome in the Cher-LOB study. Cancer Res (2015) 75:aD1e1.10.1158/1538-7445.SABCS14-PD1-1
    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: a secondary analysis of the NeoALTTO trial. JAMA Oncol (2015) 1(4):448–54.10.1001/jamaoncol.2015.0830
    1. Issa-Nummer Y, Darb-Esfahani S, Loibl S, Kunz G, Nekljudova V, Schrader I, 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. PLoS One (2013) 8(12):e79775.10.1371/journal.pone.0079775
    1. West NR, Milne K, Truong PT, Macpherson N, Nelson BH, Watson PH. Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res (2011) 13(6):R126.10.1186/bcr3072
    1. Miyashita M, Sasano H, Tamaki K, Hirakawa H, Takahashi Y, Nakagawa S. Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: a retrospective multicenter study. Breast Cancer Res (2015) 17:124.10.1186/s13058-015-0632-x
    1. Dieci MV, Criscitiello C, Goubar A, Viale G, Conte P, Guarneri V, et al. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann Oncol (2014) 25(3):611–8.10.1093/annonc/mdt556
    1. Loi S, Dushyanthen S, Beavis PA, Salgado R, Denkert C, Savas P, et al. RAS/MAPK activation is associated with reduced tumor-infiltrating lymphocytes in triple-negative breast cancer: therapeutic cooperation between MEK and PD-1/PD-L1 immune checkpoint inhibitors. Clin Cancer Res (2016) 22(6):1499–509.10.1158/1078-0432.CCR-15-1125
    1. Arnedos M, Filleron T, Dieci MV, Adam J, Robbins PB, Loi S, et al. Genomic and immune characterization of metastatic breast cancer (MBC): and ancillary studies of the SAFIR01 & M overall survival CATO trials. Ann Oncol (2014) 25(Suppl 4):iv116(abstr3510).10.1093/annonc/mdu329.1
    1. Kashiwagi S, Asano Y, Goto W, Takada K, Takahashi K, Noda S, et al. Use of Tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer. PLoS One (2017) 12(2):e0170634.10.1371/journal.pone.0170634
    1. Bogunovic D, O’Neill DW, Belitskaya-Levy I, Vacic V, Yu YL, Adams S, et al. Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival. Proc Natl Acad Sci U S A (2009) 106(48):20429–34.10.1073/pnas.0905139106
    1. Kwak Y, Koh J, Kim DW, Kang SB, Kim WH, Lee HS. Immunoscore encompassing CD3+ and CD8+ T cell densities in distant metastasis is a robust prognostic marker for advanced colorectal cancer. Oncotarget (2016) 7(49):81778–90.10.18632/oncotarget.13207
    1. Schmid P, Cruz C, Braiteh FS, Eder JP, Tolaney S, Kuter I, et al. Atezolizumab in Metastatic Triple-Negative Breast Cancer: Long-Term Clinical Outcomes and Biomarker Analyses. American Association for Cancer Research; (2017).
    1. Luen SJ, Savas P, Fox SB, Salgado R, Loi S. Tumour-infiltrating lymphocytes and the emerging role of immunotherapy in breast cancer. Pathology (2017) 49(2):141–55.10.1016/j.pathol.2016.10.010
    1. Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol (2016) 17(6):791–800.10.1016/S1470-2045(16)00163-7
    1. Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet (2012) 379(9816):633–40.10.1016/S0140-6736(11)61847-3
    1. Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III adjuvant lapatinib and/or trastuzumab treatment optimization trial. J Clin Oncol (2016) 34(10):1034–42.10.1200/JCO.2015.62.1797
    1. Symmans WF, Wei C, Gould R, Yu X, Zhang Y, Liu M, et al. Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol (2017) 35(10):1049–60.10.1200/JCO.2015.63.1010
    1. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med (2000) 6(4):443–6.10.1038/74704
    1. Kroemer G, Senovilla L, Galluzzi L, Andre F, Zitvogel L. Natural and therapy induced immunosurveillance in breast cancer. Nat Med (2015) 21(10):1128e38.10.1038/nm.3944
    1. Musolino A, Naldi N, Bortesi B, Pezzuolo D, Capelletti M, Missale G, et al. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer. J Clin Oncol (2008) 26(11):1789e96.10.1200/JCO.2007.14.8957
    1. Tamura K, Shimizu C, Hojo T, Akashi-Tanaka S, Kinoshita T, Yonemori K, et al. FcgammaR2A and 3A polymorphisms predict clinical outcome of trastuzumab in both neoadjuvant and metastatic settings in patients with HER2-positive breast cancer. Ann Oncol (2011) 22(6):1302e7.10.1093/annonc/mdq585
    1. Norton N, Olson RM, Pegram M, Tenner K, Ballman KV, Clynes R, et al. Association studies of Fcgamma receptor polymorphisms with outcome in HER2+ breast cancer patients treated with trastuzumab in NCCTG (Alliance) Trial N9831. Cancer Immunol Res (2014) 2(10):962e9.10.1158/2326-6066.CIR-14-0059
    1. Park S, Jiang Z, Mortenson ED, Deng L, Radkevich-Brown O, Yang X, et al. The therapeutic effect of anti-HER2/neu antibody depends on both innate and adaptive immunity. Cancer Cell (2010) 18(2):160e70.10.1016/j.ccr.2010.06.014

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir