Immune infiltration in invasive lobular breast cancer

C. Desmedt, R. Salgado, M. Fornili, G. Pruneri, G. Van Den Eynden, G. Zoppoli, F. Rothe, L. Buisseret, S. Garaud, K. Willard-Gallo, D. Brown, Y. Bareche, G. Rouas, C. Galant, F. Bertucci, S. Loi, G. Viale, A. Di Leo, A.R. Green, I.O. Ellis & 4 others E.A. Rakha, D. Larsimont, E. Biganzoli, C. Sotiriou

Research output: Contribution to journalArticle

Abstract

Background: Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer after invasive ductal cancer (IDC). Here, we aimed at evaluating the prevalence, levels, and composition of tumor-infiltrating lymphocytes (TILs) and their association with clinico-pathological and outcome variables in ILC, and to compare them with IDC. Methods: We considered two patient series with TIL data: a multicentric retrospective series (n=614) and the BIG 02-98 study (n=149 ILC and 807 IDC). We compared immune subsets identified by immuno-histochemistry in the ILC (n=159) and IDC (n=468) patients from the Nottinghamseries, as well as the CIBERSORT immune profiling of the ILC (n=98) and IDC (n=388) METABRIC and The Cancer Genome Atlas patients. All ILC/IDC comparisons were done in estrogen receptor (ER)-positive/ human epidermal growth factor receptor 2 (HER2)-negative tumors. All statistical tests were two-sided. Results: TIL levels were statistically significantly lower in ILC compared with IDC (fold-change = 0.79, 95% confidence interval = 0.70 to 0.88, P <.001). In ILC, high TIL levels were associated with young age, lymph node involvement, and high proliferative tumors. In the univariate analysis, high TIL levels were associated with worse prognosis in the retrospective and BIG 02-98 lobular series, although they did not reach statistical significance in the latter. The Nottingham series revealed that the levels of intratumoral but not total CD8 were statistically significantly lower in ILC compared with IDC. Comparison of the CIBERSORT profiles highlighted statistically significant differences in terms of immune composition. Conclusions: This study shows differences between the immune infiltrates of ER-positive/HER2-negative ILC and IDC in terms of prevalence, levels, localization, composition, and clinical associations. © The Author(s) 2018.
Original languageEnglish
Pages (from-to)768-776
Number of pages9
JournalJournal of the National Cancer Institute
Volume110
Issue number7
DOIs
Publication statusPublished - 2018

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Breast Neoplasms
Tumor-Infiltrating Lymphocytes
Neoplasms
Estrogen Receptors
Atlases
Lymph Nodes
Genome
Confidence Intervals

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Desmedt, C., Salgado, R., Fornili, M., Pruneri, G., Van Den Eynden, G., Zoppoli, G., ... Sotiriou, C. (2018). Immune infiltration in invasive lobular breast cancer. Journal of the National Cancer Institute, 110(7), 768-776. https://doi.org/10.1093/jnci/djx268

Immune infiltration in invasive lobular breast cancer. / Desmedt, C.; Salgado, R.; Fornili, M.; Pruneri, G.; Van Den Eynden, G.; Zoppoli, G.; Rothe, F.; Buisseret, L.; Garaud, S.; Willard-Gallo, K.; Brown, D.; Bareche, Y.; Rouas, G.; Galant, C.; Bertucci, F.; Loi, S.; Viale, G.; Di Leo, A.; Green, A.R.; Ellis, I.O.; Rakha, E.A.; Larsimont, D.; Biganzoli, E.; Sotiriou, C.

In: Journal of the National Cancer Institute, Vol. 110, No. 7, 2018, p. 768-776.

Research output: Contribution to journalArticle

Desmedt, C, Salgado, R, Fornili, M, Pruneri, G, Van Den Eynden, G, Zoppoli, G, Rothe, F, Buisseret, L, Garaud, S, Willard-Gallo, K, Brown, D, Bareche, Y, Rouas, G, Galant, C, Bertucci, F, Loi, S, Viale, G, Di Leo, A, Green, AR, Ellis, IO, Rakha, EA, Larsimont, D, Biganzoli, E & Sotiriou, C 2018, 'Immune infiltration in invasive lobular breast cancer', Journal of the National Cancer Institute, vol. 110, no. 7, pp. 768-776. https://doi.org/10.1093/jnci/djx268
Desmedt C, Salgado R, Fornili M, Pruneri G, Van Den Eynden G, Zoppoli G et al. Immune infiltration in invasive lobular breast cancer. Journal of the National Cancer Institute. 2018;110(7):768-776. https://doi.org/10.1093/jnci/djx268
Desmedt, C. ; Salgado, R. ; Fornili, M. ; Pruneri, G. ; Van Den Eynden, G. ; Zoppoli, G. ; Rothe, F. ; Buisseret, L. ; Garaud, S. ; Willard-Gallo, K. ; Brown, D. ; Bareche, Y. ; Rouas, G. ; Galant, C. ; Bertucci, F. ; Loi, S. ; Viale, G. ; Di Leo, A. ; Green, A.R. ; Ellis, I.O. ; Rakha, E.A. ; Larsimont, D. ; Biganzoli, E. ; Sotiriou, C. / Immune infiltration in invasive lobular breast cancer. In: Journal of the National Cancer Institute. 2018 ; Vol. 110, No. 7. pp. 768-776.
@article{fe12aec5f41b45358225f44a05406b71,
title = "Immune infiltration in invasive lobular breast cancer",
abstract = "Background: Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer after invasive ductal cancer (IDC). Here, we aimed at evaluating the prevalence, levels, and composition of tumor-infiltrating lymphocytes (TILs) and their association with clinico-pathological and outcome variables in ILC, and to compare them with IDC. Methods: We considered two patient series with TIL data: a multicentric retrospective series (n=614) and the BIG 02-98 study (n=149 ILC and 807 IDC). We compared immune subsets identified by immuno-histochemistry in the ILC (n=159) and IDC (n=468) patients from the Nottinghamseries, as well as the CIBERSORT immune profiling of the ILC (n=98) and IDC (n=388) METABRIC and The Cancer Genome Atlas patients. All ILC/IDC comparisons were done in estrogen receptor (ER)-positive/ human epidermal growth factor receptor 2 (HER2)-negative tumors. All statistical tests were two-sided. Results: TIL levels were statistically significantly lower in ILC compared with IDC (fold-change = 0.79, 95{\%} confidence interval = 0.70 to 0.88, P <.001). In ILC, high TIL levels were associated with young age, lymph node involvement, and high proliferative tumors. In the univariate analysis, high TIL levels were associated with worse prognosis in the retrospective and BIG 02-98 lobular series, although they did not reach statistical significance in the latter. The Nottingham series revealed that the levels of intratumoral but not total CD8 were statistically significantly lower in ILC compared with IDC. Comparison of the CIBERSORT profiles highlighted statistically significant differences in terms of immune composition. Conclusions: This study shows differences between the immune infiltrates of ER-positive/HER2-negative ILC and IDC in terms of prevalence, levels, localization, composition, and clinical associations. {\circledC} The Author(s) 2018.",
author = "C. Desmedt and R. Salgado and M. Fornili and G. Pruneri and {Van Den Eynden}, G. and G. Zoppoli and F. Rothe and L. Buisseret and S. Garaud and K. Willard-Gallo and D. Brown and Y. Bareche and G. Rouas and C. Galant and F. Bertucci and S. Loi and G. Viale and {Di Leo}, A. and A.R. Green and I.O. Ellis and E.A. Rakha and D. Larsimont and E. Biganzoli and C. Sotiriou",
note = "Cited By :4 Export Date: 5 February 2019 CODEN: JNCIA Correspondence Address: Sotiriou, C.; J.C. Heuson Breast Cancer Translational Research Laboratory, Institut Jules Bordet, 125 Boulevard de Waterloo, Belgium; email: christine.desmedt@bordet.be Funding details: Breast Cancer Research Foundation, BCRF Funding details: Associazione Italiana per la Ricerca sul Cancro, AIRC Funding details: Fondation Medic Funding details: Susan G. Komen for the Cure Funding details: Fonds De La Recherche Scientifique - FNRS, FNRS Funding details: Sanofi Funding text 1: This work was supported by Susan Komen for the Cure, Fondation MEDIC, Les Amis de Bordet (CD), Fonds National de Recherche Scientifique (DB and CS), the Cancer Council Victoria John Colebatch fellowship (SL), the Breast Cancer Research Foundation, the Italian Association for Leukemia and Lymphoma, and the Italian Association for Cancer Research. We thank the Nottingham Health Science Biobank and Breast Cancer Now Tissue Bank, as well as the bio-banks from the Institut Jules Bordet, the European Institute of Oncology, the Sint Augustinus Hospital, the Cliniques Universitaires de Saint Luc, and the Institut Paoli-Calmettes for the provision of tissue samples. BIG 2-98 was conducted under the umbrella of the Breast International Group, with sponsorship and funding provided by Sanofi. References: Savas, P., Salgado, R., Denkert, C., Clinical relevance of host immunity in breast cancer: From TILs to the clinic (2015) Nat Rev Clin Oncol., 13 (4), pp. 228-241; Pruneri, G., Vingiani, A., Denkert, C., Tumor infiltrating lymphocytes in early breast cancer (2018) The Breast., 37, pp. 207-214; Stanton, S.E., Adams, S., Disis, M.L., Variation in the incidence and magnitude of tumor-infiltrating lymphocytes in breast cancer subtypes (2016) JAMA Oncol., 2 (10), pp. 1354-1360; Salgado, R., Denkert, C., Demaria, S., The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: Recommendations by an International TILs Working Group 2014 (2014) Ann Oncol., 26 (2), pp. 259-271; Buisseret, L., Desmedt, C., Garaud, S., Reliability of tumor-infiltrating lymphocyte and tertiary lymphoid structure assessment in human breast cancer (2017) Mod Pathol., 30 (9), pp. 1204-1212; Newman, A.M., Liu, C.L., Green, M.R., Robust enumeration of cell subsets from tissue expression profiles (2015) Nat Methods., 12 (5), pp. 453-457; Ali, H.R., Chlon, L., Pharoah, P.D.P., Markowetz, F., Caldas, C., Patterns of immune infiltration in breast cancer and their clinical implications: A gene-expressionbased retrospective study (2016) PLoS Med., pp. 1-24; Bense, R.D., Sotiriou, C., Piccart-Gebhart, M.J., Relevance of tumorinfiltrating immune cell composition and functionality for disease outcome in breast cancer (2017) J Natl Cancer Inst., 109 (1), p. djw192; Guiu, S., Wolfer, A., Jacot, W., Invasive lobular breast cancer and its variants: How special are they for systemic therapy decisions (2014) Crit Rev Oncol Hematol., 92 (3), pp. 235-257; Pestalozzi, B.C., Zahrieh, D., Mallon, E., Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: Combined results of 15 International Breast Cancer Study Group clinical trials (2008) J Clin Oncol., 26 (18), pp. 3006-3014; Ciriello, G., Gatza, M.L., Beck, A.H., Comprehensive molecular portraits of invasive lobular breast cancer (2015) Cell., 163 (2), pp. 506-519; Michaut, M., Chin, S.F., Majewski, I., Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer (2016) Sci Rep., 6, p. 18517; Desmedt, C., Zoppoli, G., Gundem, G., Genomic characterization of primary invasive lobular breast cancer (2016) J Clin Oncol., 34 (16), pp. 1872-1881; Pereira, B., Chin, S.F., Rueda, O.M., The somatic mutation profiles of 2, 433 breast cancers refines their genomic and transcriptomic landscapes (2016) Nat Commun., 7, p. 11479; Loi, S., Sirtaine, N., Piette, F., Prognostic and predictive value of tumorinfiltrating 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) J Clin Oncol., 31 (7), pp. 860-867; Mahmoud, S.M., Lee, A.H., Paish, E.C., Macmillan, R.D., Ellis, I.O., Green, A.R., The prognostic significance of B lymphocytes in invasive carcinoma of the breast (2011) Breast Cancer Res Treat., 132 (2), pp. 545-553; Mahmoud, S.M., Lee, A.H., Paish, E.C., Macmillan, R.D., Ellis, I.O., Green, A.R., Tumourinfiltrating macrophages and clinical outcome in breast cancer (2011) J Clin Pathol., 65 (2), pp. 159-163; Mahmoud, S.M., Paish, E.C., Powe, D.G., An evaluation of the clinical significance of FOXP3 infiltrating cells in human breast cancer (2011) Breast Cancer Res Treat., 127 (1), pp. 99-108; Curtis, C., Shah, S.P., Chin, S.F., The genomic and transcriptomic architecture of 2, 000 breast tumours reveals novel subgroups (2012) Nature., 486 (7403), pp. 346-352; Sonnenblick, A., Francis, P.A., Azim, H.A., Jr., Final 10-year results of the Breast International Group 2-98 phase III trial and the role of Ki67 in predicting benefit of adjuvant docetaxel in patients with oestrogen receptor positive breast cancer (2015) Eur J Cancer., 51 (12), pp. 1481-1489; Intraclass correlations: Uses in assessing rater reliability (1979) Psychol Bull., 86 (2), pp. 420-428. , Shrout PE FJL; A new biometrical procedure for testing the equality of measurements from two different analytical methods/ Application of linear regression procedures for method comparison studies in clinical chemistry, part i (1983) J Clin Chem Clin Biochem., 21 (11), pp. 709-720. , Passing H, Bablok; An analysis of transformations (1964) J R Stat Soc ser B., pp. 211-252. , Box GE CD; Harrell, F.E., (2001) Regression Modeling Strategies: With Applications to Linear Models, Logistic and Ordinal Regression, and Survival Analysis, , Heidelberg, Germany: Springer; Benjamini Yosef, Y.H., Controlling the false discovery rate: A practical and powerful approach to multiple testing (1995) J R Stat Soc ser B., 57 (1), pp. 289-300; (2017) R: A Language and Environment for Statistical Computing, , http://www.R-project.org/, R Found Stat Comput Vienna, Austria. R Core Team; Desmedt, C., Fumagalli, D., Pietri, E., Uncovering the genomic heterogeneity of multifocal breast cancer (2015) J Pathol., 236 (4), pp. 457-466; Desmedt, C., Haibe-Kains, B., Wirapati, P., Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes (2008) Clin Cancer Res., 14 (16), pp. 5158-5165; Teschendorff, A.E., Miremadi, A., Pinder, S.E., Ellis, I.O., Caldas, C., An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer (2007) Genome Biol., 8 (8), p. R157; Bild, A.H., Yao, G., Chang, J.T., Oncogenic pathway signatures in human cancers as a guide to targeted therapies (2006) Nature., 439 (7074), pp. 353-357; Saal, L.H., Johansson, P., Holm, K., Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity (2007) Proc Natl Acad Sci U S A., 104 (18), pp. 7564-7569; Majumder, P.K., Febbo, P.G., Bikoff, R., MTOR inhibition reverses Aktdependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways (2004) Nat Med., 10 (6), pp. 594-601; Creighton, C.J., Hilger, A.M., Murthy, S., Rae, J.M., Chinnaiyan, A.M., El-Ashry, D., Activation of mitogen-activated protein kinase in estrogen receptor alpha-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor alpha-negative human breast tumors (2006) Cancer Res., 66 (7), pp. 3903-3911; Creighton, C.J., A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors (2007) Oncogene., 26 (32), pp. 4648-4655; Der, S.D., Zhou, A., Williams, B.R.G., Silverman, R.H., Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays (1998) Proc Natl Acad Sci U S A., 95 (26), pp. 15623-15628; Gu-Trantien, C., Loi, S., Garaud, S., CD4() follicular helper T cell infiltration predicts breast cancer survival (2013) J Clin Invest., 123 (7), pp. 2873-2892; Alexe, G., Dalgin, G.S., Scanfeld, D., High expression of lymphocyteassociated genes in node-negative HER2 breast cancers correlates with lower recurrence rates (2007) Cancer Res., 67 (22), pp. 10669-10676; Ali, H.R., Provenzano, E., Dawson, S.J., Association between CD8 T-cell infiltration and breast cancer survival in 12, 439 patients (2014) Ann Oncol., 25 (8), pp. 1536-1543; Yamaguchi, R., Tanaka, M., Yano, A., Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer (2012) Hum Pathol., 43 (10), pp. 1688-1694; Droeser, R., Zlobec, I., Kilic, E., Differential pattern and prognostic significance of CD4, FOXP3 and IL-17 tumor infiltrating lymphocytes in ductal and lobular breast cancers (2012) BMC Cancer., 12, p. 134; Ali, H.R., Provenzano, E., Dawson, S.J., Association between CD8 T-cell infiltration and breast cancer survival in 12 439 patients (2014) Ann Oncol., 25 (8), pp. 1536-1543; Fang, J.Z., Li, C., Liu, X.Y., Hu, T.T., Fan, Z.S., Han, Z.G., Hepatocyte-specific arid1a deficiency initiates mouse steatohepatitis and hepatocellular carcinoma (2015) PLoS One., 10 (11), p. e0143042; Mlecnik, B., Angell, H.K., Maby, P., Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability (2016) Cell., 44 (3), pp. 698-711; Bane, A.L., Beck, J.C., Bleiweiss, I., BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays (2007) Am J Surg Pathol., 31 (1), pp. 121-128; Shah, C.A., Allison, K.H., Garcia, R.L., Gray, H.J., Goff, B.A., Swisher, E.M., Intratumoral T cells, tumor-associated macrophages, and regulatory T cells: Association with p53 mutations, circulating tumor DNA and survival in women with ovarian cancer (2008) Gynecol Oncol., 109 (2), pp. 215-219; Quigley, D., Silwal-Pandit, L., Dannenfelser, R., Lymphocyte invasion in IC10/basal-like breast tumors is associated with wild-type TP53 (2015) Mol Cancer Res., 13 (3), pp. 493-501; Dunbier, A.K., Ghazoui, Z., Anderson, H., Molecular profiling of aromatase inhibitor-treated postmenopausal breast tumors identifies immune-related correlates of resistance (2013) Clin Cancer Res., 19 (10), pp. 2775-2786",
year = "2018",
doi = "10.1093/jnci/djx268",
language = "English",
volume = "110",
pages = "768--776",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "7",

}

TY - JOUR

T1 - Immune infiltration in invasive lobular breast cancer

AU - Desmedt, C.

AU - Salgado, R.

AU - Fornili, M.

AU - Pruneri, G.

AU - Van Den Eynden, G.

AU - Zoppoli, G.

AU - Rothe, F.

AU - Buisseret, L.

AU - Garaud, S.

AU - Willard-Gallo, K.

AU - Brown, D.

AU - Bareche, Y.

AU - Rouas, G.

AU - Galant, C.

AU - Bertucci, F.

AU - Loi, S.

AU - Viale, G.

AU - Di Leo, A.

AU - Green, A.R.

AU - Ellis, I.O.

AU - Rakha, E.A.

AU - Larsimont, D.

AU - Biganzoli, E.

AU - Sotiriou, C.

N1 - Cited By :4 Export Date: 5 February 2019 CODEN: JNCIA Correspondence Address: Sotiriou, C.; J.C. Heuson Breast Cancer Translational Research Laboratory, Institut Jules Bordet, 125 Boulevard de Waterloo, Belgium; email: christine.desmedt@bordet.be Funding details: Breast Cancer Research Foundation, BCRF Funding details: Associazione Italiana per la Ricerca sul Cancro, AIRC Funding details: Fondation Medic Funding details: Susan G. Komen for the Cure Funding details: Fonds De La Recherche Scientifique - FNRS, FNRS Funding details: Sanofi Funding text 1: This work was supported by Susan Komen for the Cure, Fondation MEDIC, Les Amis de Bordet (CD), Fonds National de Recherche Scientifique (DB and CS), the Cancer Council Victoria John Colebatch fellowship (SL), the Breast Cancer Research Foundation, the Italian Association for Leukemia and Lymphoma, and the Italian Association for Cancer Research. We thank the Nottingham Health Science Biobank and Breast Cancer Now Tissue Bank, as well as the bio-banks from the Institut Jules Bordet, the European Institute of Oncology, the Sint Augustinus Hospital, the Cliniques Universitaires de Saint Luc, and the Institut Paoli-Calmettes for the provision of tissue samples. BIG 2-98 was conducted under the umbrella of the Breast International Group, with sponsorship and funding provided by Sanofi. References: Savas, P., Salgado, R., Denkert, C., Clinical relevance of host immunity in breast cancer: From TILs to the clinic (2015) Nat Rev Clin Oncol., 13 (4), pp. 228-241; Pruneri, G., Vingiani, A., Denkert, C., Tumor infiltrating lymphocytes in early breast cancer (2018) The Breast., 37, pp. 207-214; Stanton, S.E., Adams, S., Disis, M.L., Variation in the incidence and magnitude of tumor-infiltrating lymphocytes in breast cancer subtypes (2016) JAMA Oncol., 2 (10), pp. 1354-1360; Salgado, R., Denkert, C., Demaria, S., The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: Recommendations by an International TILs Working Group 2014 (2014) Ann Oncol., 26 (2), pp. 259-271; Buisseret, L., Desmedt, C., Garaud, S., Reliability of tumor-infiltrating lymphocyte and tertiary lymphoid structure assessment in human breast cancer (2017) Mod Pathol., 30 (9), pp. 1204-1212; Newman, A.M., Liu, C.L., Green, M.R., Robust enumeration of cell subsets from tissue expression profiles (2015) Nat Methods., 12 (5), pp. 453-457; Ali, H.R., Chlon, L., Pharoah, P.D.P., Markowetz, F., Caldas, C., Patterns of immune infiltration in breast cancer and their clinical implications: A gene-expressionbased retrospective study (2016) PLoS Med., pp. 1-24; Bense, R.D., Sotiriou, C., Piccart-Gebhart, M.J., Relevance of tumorinfiltrating immune cell composition and functionality for disease outcome in breast cancer (2017) J Natl Cancer Inst., 109 (1), p. djw192; Guiu, S., Wolfer, A., Jacot, W., Invasive lobular breast cancer and its variants: How special are they for systemic therapy decisions (2014) Crit Rev Oncol Hematol., 92 (3), pp. 235-257; Pestalozzi, B.C., Zahrieh, D., Mallon, E., Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: Combined results of 15 International Breast Cancer Study Group clinical trials (2008) J Clin Oncol., 26 (18), pp. 3006-3014; Ciriello, G., Gatza, M.L., Beck, A.H., Comprehensive molecular portraits of invasive lobular breast cancer (2015) Cell., 163 (2), pp. 506-519; Michaut, M., Chin, S.F., Majewski, I., Integration of genomic, transcriptomic and proteomic data identifies two biologically distinct subtypes of invasive lobular breast cancer (2016) Sci Rep., 6, p. 18517; Desmedt, C., Zoppoli, G., Gundem, G., Genomic characterization of primary invasive lobular breast cancer (2016) J Clin Oncol., 34 (16), pp. 1872-1881; Pereira, B., Chin, S.F., Rueda, O.M., The somatic mutation profiles of 2, 433 breast cancers refines their genomic and transcriptomic landscapes (2016) Nat Commun., 7, p. 11479; Loi, S., Sirtaine, N., Piette, F., Prognostic and predictive value of tumorinfiltrating 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) J Clin Oncol., 31 (7), pp. 860-867; Mahmoud, S.M., Lee, A.H., Paish, E.C., Macmillan, R.D., Ellis, I.O., Green, A.R., The prognostic significance of B lymphocytes in invasive carcinoma of the breast (2011) Breast Cancer Res Treat., 132 (2), pp. 545-553; Mahmoud, S.M., Lee, A.H., Paish, E.C., Macmillan, R.D., Ellis, I.O., Green, A.R., Tumourinfiltrating macrophages and clinical outcome in breast cancer (2011) J Clin Pathol., 65 (2), pp. 159-163; Mahmoud, S.M., Paish, E.C., Powe, D.G., An evaluation of the clinical significance of FOXP3 infiltrating cells in human breast cancer (2011) Breast Cancer Res Treat., 127 (1), pp. 99-108; Curtis, C., Shah, S.P., Chin, S.F., The genomic and transcriptomic architecture of 2, 000 breast tumours reveals novel subgroups (2012) Nature., 486 (7403), pp. 346-352; Sonnenblick, A., Francis, P.A., Azim, H.A., Jr., Final 10-year results of the Breast International Group 2-98 phase III trial and the role of Ki67 in predicting benefit of adjuvant docetaxel in patients with oestrogen receptor positive breast cancer (2015) Eur J Cancer., 51 (12), pp. 1481-1489; Intraclass correlations: Uses in assessing rater reliability (1979) Psychol Bull., 86 (2), pp. 420-428. , Shrout PE FJL; A new biometrical procedure for testing the equality of measurements from two different analytical methods/ Application of linear regression procedures for method comparison studies in clinical chemistry, part i (1983) J Clin Chem Clin Biochem., 21 (11), pp. 709-720. , Passing H, Bablok; An analysis of transformations (1964) J R Stat Soc ser B., pp. 211-252. , Box GE CD; Harrell, F.E., (2001) Regression Modeling Strategies: With Applications to Linear Models, Logistic and Ordinal Regression, and Survival Analysis, , Heidelberg, Germany: Springer; Benjamini Yosef, Y.H., Controlling the false discovery rate: A practical and powerful approach to multiple testing (1995) J R Stat Soc ser B., 57 (1), pp. 289-300; (2017) R: A Language and Environment for Statistical Computing, , http://www.R-project.org/, R Found Stat Comput Vienna, Austria. R Core Team; Desmedt, C., Fumagalli, D., Pietri, E., Uncovering the genomic heterogeneity of multifocal breast cancer (2015) J Pathol., 236 (4), pp. 457-466; Desmedt, C., Haibe-Kains, B., Wirapati, P., Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes (2008) Clin Cancer Res., 14 (16), pp. 5158-5165; Teschendorff, A.E., Miremadi, A., Pinder, S.E., Ellis, I.O., Caldas, C., An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer (2007) Genome Biol., 8 (8), p. R157; Bild, A.H., Yao, G., Chang, J.T., Oncogenic pathway signatures in human cancers as a guide to targeted therapies (2006) Nature., 439 (7074), pp. 353-357; Saal, L.H., Johansson, P., Holm, K., Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity (2007) Proc Natl Acad Sci U S A., 104 (18), pp. 7564-7569; Majumder, P.K., Febbo, P.G., Bikoff, R., MTOR inhibition reverses Aktdependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways (2004) Nat Med., 10 (6), pp. 594-601; Creighton, C.J., Hilger, A.M., Murthy, S., Rae, J.M., Chinnaiyan, A.M., El-Ashry, D., Activation of mitogen-activated protein kinase in estrogen receptor alpha-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor alpha-negative human breast tumors (2006) Cancer Res., 66 (7), pp. 3903-3911; Creighton, C.J., A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors (2007) Oncogene., 26 (32), pp. 4648-4655; Der, S.D., Zhou, A., Williams, B.R.G., Silverman, R.H., Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays (1998) Proc Natl Acad Sci U S A., 95 (26), pp. 15623-15628; Gu-Trantien, C., Loi, S., Garaud, S., CD4() follicular helper T cell infiltration predicts breast cancer survival (2013) J Clin Invest., 123 (7), pp. 2873-2892; Alexe, G., Dalgin, G.S., Scanfeld, D., High expression of lymphocyteassociated genes in node-negative HER2 breast cancers correlates with lower recurrence rates (2007) Cancer Res., 67 (22), pp. 10669-10676; Ali, H.R., Provenzano, E., Dawson, S.J., Association between CD8 T-cell infiltration and breast cancer survival in 12, 439 patients (2014) Ann Oncol., 25 (8), pp. 1536-1543; Yamaguchi, R., Tanaka, M., Yano, A., Tumor-infiltrating lymphocytes are important pathologic predictors for neoadjuvant chemotherapy in patients with breast cancer (2012) Hum Pathol., 43 (10), pp. 1688-1694; Droeser, R., Zlobec, I., Kilic, E., Differential pattern and prognostic significance of CD4, FOXP3 and IL-17 tumor infiltrating lymphocytes in ductal and lobular breast cancers (2012) BMC Cancer., 12, p. 134; Ali, H.R., Provenzano, E., Dawson, S.J., Association between CD8 T-cell infiltration and breast cancer survival in 12 439 patients (2014) Ann Oncol., 25 (8), pp. 1536-1543; Fang, J.Z., Li, C., Liu, X.Y., Hu, T.T., Fan, Z.S., Han, Z.G., Hepatocyte-specific arid1a deficiency initiates mouse steatohepatitis and hepatocellular carcinoma (2015) PLoS One., 10 (11), p. e0143042; Mlecnik, B., Angell, H.K., Maby, P., Integrative analyses of colorectal cancer show immunoscore is a stronger predictor of patient survival than microsatellite instability (2016) Cell., 44 (3), pp. 698-711; Bane, A.L., Beck, J.C., Bleiweiss, I., BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays (2007) Am J Surg Pathol., 31 (1), pp. 121-128; Shah, C.A., Allison, K.H., Garcia, R.L., Gray, H.J., Goff, B.A., Swisher, E.M., Intratumoral T cells, tumor-associated macrophages, and regulatory T cells: Association with p53 mutations, circulating tumor DNA and survival in women with ovarian cancer (2008) Gynecol Oncol., 109 (2), pp. 215-219; Quigley, D., Silwal-Pandit, L., Dannenfelser, R., Lymphocyte invasion in IC10/basal-like breast tumors is associated with wild-type TP53 (2015) Mol Cancer Res., 13 (3), pp. 493-501; Dunbier, A.K., Ghazoui, Z., Anderson, H., Molecular profiling of aromatase inhibitor-treated postmenopausal breast tumors identifies immune-related correlates of resistance (2013) Clin Cancer Res., 19 (10), pp. 2775-2786

PY - 2018

Y1 - 2018

N2 - Background: Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer after invasive ductal cancer (IDC). Here, we aimed at evaluating the prevalence, levels, and composition of tumor-infiltrating lymphocytes (TILs) and their association with clinico-pathological and outcome variables in ILC, and to compare them with IDC. Methods: We considered two patient series with TIL data: a multicentric retrospective series (n=614) and the BIG 02-98 study (n=149 ILC and 807 IDC). We compared immune subsets identified by immuno-histochemistry in the ILC (n=159) and IDC (n=468) patients from the Nottinghamseries, as well as the CIBERSORT immune profiling of the ILC (n=98) and IDC (n=388) METABRIC and The Cancer Genome Atlas patients. All ILC/IDC comparisons were done in estrogen receptor (ER)-positive/ human epidermal growth factor receptor 2 (HER2)-negative tumors. All statistical tests were two-sided. Results: TIL levels were statistically significantly lower in ILC compared with IDC (fold-change = 0.79, 95% confidence interval = 0.70 to 0.88, P <.001). In ILC, high TIL levels were associated with young age, lymph node involvement, and high proliferative tumors. In the univariate analysis, high TIL levels were associated with worse prognosis in the retrospective and BIG 02-98 lobular series, although they did not reach statistical significance in the latter. The Nottingham series revealed that the levels of intratumoral but not total CD8 were statistically significantly lower in ILC compared with IDC. Comparison of the CIBERSORT profiles highlighted statistically significant differences in terms of immune composition. Conclusions: This study shows differences between the immune infiltrates of ER-positive/HER2-negative ILC and IDC in terms of prevalence, levels, localization, composition, and clinical associations. © The Author(s) 2018.

AB - Background: Invasive lobular breast cancer (ILC) is the second most common histological subtype of breast cancer after invasive ductal cancer (IDC). Here, we aimed at evaluating the prevalence, levels, and composition of tumor-infiltrating lymphocytes (TILs) and their association with clinico-pathological and outcome variables in ILC, and to compare them with IDC. Methods: We considered two patient series with TIL data: a multicentric retrospective series (n=614) and the BIG 02-98 study (n=149 ILC and 807 IDC). We compared immune subsets identified by immuno-histochemistry in the ILC (n=159) and IDC (n=468) patients from the Nottinghamseries, as well as the CIBERSORT immune profiling of the ILC (n=98) and IDC (n=388) METABRIC and The Cancer Genome Atlas patients. All ILC/IDC comparisons were done in estrogen receptor (ER)-positive/ human epidermal growth factor receptor 2 (HER2)-negative tumors. All statistical tests were two-sided. Results: TIL levels were statistically significantly lower in ILC compared with IDC (fold-change = 0.79, 95% confidence interval = 0.70 to 0.88, P <.001). In ILC, high TIL levels were associated with young age, lymph node involvement, and high proliferative tumors. In the univariate analysis, high TIL levels were associated with worse prognosis in the retrospective and BIG 02-98 lobular series, although they did not reach statistical significance in the latter. The Nottingham series revealed that the levels of intratumoral but not total CD8 were statistically significantly lower in ILC compared with IDC. Comparison of the CIBERSORT profiles highlighted statistically significant differences in terms of immune composition. Conclusions: This study shows differences between the immune infiltrates of ER-positive/HER2-negative ILC and IDC in terms of prevalence, levels, localization, composition, and clinical associations. © The Author(s) 2018.

U2 - 10.1093/jnci/djx268

DO - 10.1093/jnci/djx268

M3 - Article

VL - 110

SP - 768

EP - 776

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

SN - 0027-8874

IS - 7

ER -