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01-02-2017 | Preclinical study

PD-L1 expression and tumor infiltrating PD-1+ lymphocytes associated with outcome in HER2+ breast cancer patients

Authors: Julia Y. S. Tsang, Wai-Ling Au, Kwan-Yin Lo, Yun-Bi Ni, Thazin Hlaing, Jintao Hu, Siu-Ki Chan, Kui-Fat Chan, Sai-Yin Cheung, Gary M. Tse

Published in: Breast Cancer Research and Treatment | Issue 1/2017

Abstract

Purpose

Clinical trials showing programmed death (PD)-1–PD-ligand 1 (L1) axis as a promising therapeutic target in melanoma and non-small cell lung cancers have made the pathway a focus of recent attention. However, the data regarding PD-L1/PD-1 in breast cancer are inconsistent. Given the heterogeneity of breast cancers, the clinical relevance of PD-L1 and PD-1 tumor infiltrating lymphocytes (TIL) may vary according to subtypes of breast cancer. We aim to investigate PD-L1 expression in a large cohort of breast cancers and analyze its clinico-pathological as well as outcome relationship according to molecular subtypes. Also, we evaluate the relationship of PD-1 TIL and PD-L1 expression with patients’ survival, particularly for breast cancers with high TIL.

Methods and results

Immunohistochemical analysis of PD-L1 on tissue arrays for 1091 breast cancer patients and PD-1 TIL on 97 whole sections was performed. Associations of PD-L1 with luminal cancers (p < 0.001) and features associated with that subtype [lower histologic grade, absence of necrosis, ER, PR, and AR expression (p < 0.001)] were observed. However, in HER2+ breast cancers, PD-L1 was an independent poor prognostic indicator (DFS: HR = 1.866, p = 0.001; OS: HR = 1.517, p = 0.036). Interestingly, HER2+ cancers showed a lower PD-1 TIL level compared to the other high TIL cases (p = 0.011). Cases with low PD-TIL but high PD-L1 expression showed the worst survival. This could be indicative of an active immune suppression by PD-L1 expression.

Conclusions

Our data showed the relevance of PD-L1 expression in HER2+ breast cancer. A combined evaluation of PD-L1 and PD-1 TIL in the prognosis of breast cancer might also be of value in treatment prediction.

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Zou W, Wolchok JD, Chen L (2016) PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci Transl Med 8(328):328rv324. doi:10.1126/scitranslmed.aad7118 CrossRef

Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465. doi:10.1056/NEJMoa1200694 CrossRefPubMedPubMedCentral

Topalian SL, Drake CG, Pardoll DM (2012) Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr Opin Immunol 24(2):207–212. doi:10.1016/j.coi.2011.12.009 CrossRefPubMedPubMedCentral

Patel SP, Kurzrock R (2015) PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther 14(4):847–856. doi:10.1158/1535-7163.MCT-14-0983 CrossRefPubMed

He J, Hu Y, Hu M, Li B (2015) Development of PD-1/PD-L1 pathway in tumor immune microenvironment and treatment for non-small cell lung cancer. Sci Rep 5:13110. doi:10.1038/srep13110 CrossRefPubMedPubMedCentral

Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, Beck A, Miller A, Tsuji T, Eppolito C, Qian F, Lele S, Shrikant P, Old LJ, Odunsi K (2010) Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl Acad Sci USA 107(17):7875–7880. doi:10.1073/pnas.1003345107 CrossRefPubMedPubMedCentral

Park IH, Kong SY, Ro JY, Kwon Y, Kang JH, Mo HJ, Jung SY, Lee S, Lee KS, Kang HS, Lee E, Joo J, Ro J (2016) Prognostic implications of tumor-infiltrating lymphocytes in association with programmed death ligand 1 expression in early-stage breast cancer. Clin Breast Cancer 16(1):51–58. doi:10.1016/j.clbc.2015.07.006 CrossRefPubMed

Baptista MZ, Sarian LO, Derchain SF, Pinto GA, Vassallo J (2016) Prognostic significance of PD-L1 and PD-L2 in breast cancer. Hum Pathol 47(1):78–84. doi:10.1016/j.humpath.2015.09.006 CrossRefPubMed

Cimino-Mathews A, Thompson E, Taube JM, Ye X, Lu Y, Meeker A, Xu H, Sharma R, Lecksell K, Cornish TC, Cuka N, Argani P, Emens LA (2016) PD-L1 (B7-H1) expression and the immune tumor microenvironment in primary and metastatic breast carcinomas. Hum Pathol 47(1):52–63. doi:10.1016/j.humpath.2015.09.003 CrossRefPubMed

10.

Qin T, Zeng YD, Qin G, Xu F, Lu JB, Fang WF, Xue C, Zhan JH, Zhang XK, Zheng QF, Peng RJ, Yuan ZY, Zhang L, Wang SS (2015) High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer. Oncotarget 6(32):33972–33981. doi:10.18632/oncotarget.5583 PubMedPubMedCentral

11.

Ali HR, Glont SE, Blows FM, Provenzano E, Dawson SJ, Liu B, Hiller L, Dunn J, Poole CJ, Bowden S, Earl HM, Pharoah PD, Caldas C (2015) PD-L1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes. Ann Oncol 26(7):1488–1493. doi:10.1093/annonc/mdv192 PubMed

12.

Sabatier R, Finetti P, Mamessier E, Adelaide J, Chaffanet M, Ali HR, Viens P, Caldas C, Birnbaum D, Bertucci F (2015) Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget 6(7):5449–5464. doi:10.18632/oncotarget.3216 CrossRefPubMed

13.

Muenst S, Schaerli AR, Gao F, Daster S, Trella E, Droeser RA, Muraro MG, Zajac P, Zanetti R, Gillanders WE, Weber WP, Soysal SD (2014) Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 146(1):15–24. doi:10.1007/s10549-014-2988-5 CrossRefPubMedPubMedCentral

14.

Ghebeh H, Mohammed S, Al-Omair A, Qattan A, Lehe C, Al-Qudaihi G, Elkum N, Alshabanah M, Bin Amer S, Tulbah A, Ajarim D, Al-Tweigeri T, Dermime S (2006) The B7-H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia 8(3):190–198. doi:10.1593/neo.05733 CrossRefPubMedPubMedCentral

15.

Gatalica Z, Snyder C, Maney T, Ghazalpour A, Holterman DA, Xiao N, Overberg P, Rose I, Basu GD, Vranic S, Lynch HT, Von Hoff DD, Hamid O (2014) Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer Epidemiol Biomarkers Prev 23(12):2965–2970. doi:10.1158/1055-9965.EPI-14-0654 CrossRefPubMed

16.

Schalper KA, Velcheti V, Carvajal D, Wimberly H, Brown J, Pusztai L, Rimm DL (2014) In situ tumor PD-L1 mRNA expression is associated with increased TILs and better outcome in breast carcinomas. Clin Cancer Res 20(10):2773–2782. doi:10.1158/1078-0432.CCR-13-2702 CrossRefPubMed

17.

Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, Wienert S, Van den Eynden G, Baehner FL, Penault-Llorca F, Perez EA, Thompson EA, Symmans WF, Richardson AL, Brock J, Criscitiello C, Bailey H, Ignatiadis M, Floris G, Sparano J, Kos Z, Nielsen T, Rimm DL, Allison KH, Reis-Filho JS, Loibl S, Sotiriou C, Viale G, Badve S, Adams S, Willard-Gallo K, Loi S (2015) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26(2):259–271. doi:10.1093/annonc/mdu450 CrossRefPubMed

18.

Gros A, Robbins PF, Yao X, Li YF, Turcotte S, Tran E, Wunderlich JR, Mixon A, Farid S, Dudley ME, Hanada K, Almeida JR, Darko S, Douek DC, Yang JC, Rosenberg SA (2014) PD-1 identifies the patient-specific CD8(+) tumor-reactive repertoire infiltrating human tumors. J Clin Invest 124(5):2246–2259. doi:10.1172/JCI73639 CrossRefPubMedPubMedCentral

19.

Ma W, Gilligan BM, Yuan J, Li T (2016) Current status and perspectives in translational biomarker research for PD-1/PD-L1 immune checkpoint blockade therapy. J Hematol Oncol 9(1):47. doi:10.1186/s13045-016-0277-y CrossRefPubMedPubMedCentral

20.

Ghebeh H, Barhoush E, Tulbah A, Elkum N, Al-Tweigeri T, Dermime S (2008) FOXP3+ tregs and B7-H1 +/PD-1+ T lymphocytes co-infiltrate the tumor tissues of high-risk breast cancer patients: implication for immunotherapy. BMC Cancer 8:57. doi:10.1186/1471-2407-8-57 CrossRefPubMedPubMedCentral

21.

Sun S, Fei X, Mao Y, Wang X, Garfield DH, Huang O, Wang J, Yuan F, Sun L, Yu Q, Jin X, Shen K (2014) PD-1(+) immune cell infiltration inversely correlates with survival of operable breast cancer patients. Cancer Immunol Immunother 63(4):395–406. doi:10.1007/s00262-014-1519-x CrossRefPubMed

22.

Muenst S, Soysal SD, Gao F, Obermann EC, Oertli D, Gillanders WE (2013) The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat 139(3):667–676. doi:10.1007/s10549-013-2581-3 CrossRefPubMed

23.

Elston CW, Ellis IO (1991) 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. Histopathology 19(5):403–410CrossRefPubMed

24.

Lakhani SR, Ellis IO, Schnitee SJ, Tan PH, van de Vijver MJ (eds) (2012) World Health Organisation classification of tumors of the breast, 4th edn. IARC Press, Lyon

25.

Ni YB, Tsang JY, Chan SK, Tse GM (2014) A novel morphologic-molecular recurrence predictive model refines traditional prognostic tools for invasive breast carcinoma. Ann Surg Oncol 21(9):2928–2933. doi:10.1245/s10434-014-3691-9 CrossRefPubMed

26.

McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100(2):229–235. doi:10.1007/s10549-006-9242-8 CrossRefPubMed

27.

Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thurlimann B, Senn HJ (2013) 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. Ann Oncol 24(9):2206–2223. doi:10.1093/annonc/mdt303 CrossRefPubMedPubMedCentral

28.

Ilie M, Hofman V, Dietel M, Soria JC, Hofman P (2016) Assessment of the PD-L1 status by immunohistochemistry: challenges and perspectives for therapeutic strategies in lung cancer patients. Virchows Arch. doi:10.1007/s00428-016-1910-4 PubMed

29.

Dong H, Zhu G, Tamada K, Chen L (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5(12):1365–1369. doi:10.1038/70932 CrossRefPubMed

30.

Shukuya T, Carbone DP (2016) Predictive markers for the efficacy of anti-PD-1/PD-L1 antibodies in lung cancer. J Thorac Oncol. doi:10.1016/j.jtho.2016.02.015

31.

Muenst S, Tzankov A, Gillanders WE, Soysal SD (2014) Author’s response to “letter to the editor: unvalidated antibodies and misleading results”. Breast Cancer Res Treat 147(2):459–462. doi:10.1007/s10549-014-3064-x CrossRefPubMed

32.

Schalper KA (2014) PD-L1 expression and tumor-infiltrating lymphocytes: revisiting the antitumor immune response potential in breast cancer. Oncoimmunology 3:e29288. doi:10.4161/onci.29288 CrossRefPubMedPubMedCentral

33.

Straub M, Drecoll E, Pfarr N, Weichert W, Langer R, Hapfelmeier A, Gotz C, Wolff KD, Kolk A, Specht K (2016) CD274/PD-L1 gene amplification and PD-L1 protein expression are common events in squamous cell carcinoma of the oral cavity. Oncotarget. doi:10.18632/oncotarget.7593

34.

Ikeda S, Okamoto T, Okano S, Umemoto Y, Tagawa T, Morodomi Y, Kohno M, Shimamatsu S, Kitahara H, Suzuki Y, Fujishita T, Maehara Y (2016) PD-L1 is upregulated by simultaneous amplification of the PD-L1 and JAK2 genes in non-small cell lung cancer. J Thorac Oncol 11(1):62–71. doi:10.1016/j.jtho.2015.09.010 CrossRefPubMed

35.

Mittendorf EA, Philips AV, Meric-Bernstam F, Qiao N, Wu Y, Harrington S, Su X, Wang Y, Gonzalez-Angulo AM, Akcakanat A, Chawla A, Curran M, Hwu P, Sharma P, Litton JK, Molldrem JJ, Alatrash G (2014) PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2(4):361–370. doi:10.1158/2326-6066.CIR-13-0127 CrossRefPubMedPubMedCentral

36.

Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, Mischel PS, Stokoe D, Pieper RO (2007) Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 13(1):84–88. doi:10.1038/nm1517 CrossRefPubMed

37.

Ng CK, Schultheis AM, Bidard FC, Weigelt B, Reis-Filho JS (2015) Breast cancer genomics from microarrays to massively parallel sequencing: paradigms and new insights. J Natl Cancer Inst. doi:10.1093/jnci/djv015

38.

Meyer DS, Brinkhaus H, Muller U, Muller M, Cardiff RD, Bentires-Alj M (2011) Luminal expression of PIK3CA mutant H1047R in the mammary gland induces heterogeneous tumors. Cancer Res 71(13):4344–4351. doi:10.1158/0008-5472.CAN-10-3827 CrossRefPubMed

39.

Meyer DS, Koren S, Leroy C, Brinkhaus H, Muller U, Klebba I, Muller M, Cardiff RD, Bentires-Alj M (2013) Expression of PIK3CA mutant E545K in the mammary gland induces heterogeneous tumors but is less potent than mutant H1047R. Oncogenesis 2:e74. doi:10.1038/oncsis.2013.38 CrossRefPubMedPubMedCentral

40.

Taube JM, Klein A, Brahmer JR, Xu H, Pan X, Kim JH, Chen L, Pardoll DM, Topalian SL, Anders RA (2014) Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin Cancer Res 20(19):5064–5074. doi:10.1158/1078-0432.CCR-13-3271 CrossRefPubMedPubMedCentral

41.

Tsang JY, Hui SW, Ni YB, Chan SK, Yamaguchi R, Kwong A, Law BK, Tse GM (2014) Lymphocytic infiltrate is associated with favorable biomarkers profile in HER2-overexpressing breast cancers and adverse biomarker profile in ER-positive breast cancers. Breast Cancer Res Treat 143(1):1–9. doi:10.1007/s10549-013-2781-x CrossRefPubMed

42.

Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 104(9):3360–3365. doi:10.1073/pnas.0611533104 CrossRefPubMedPubMedCentral

43.

Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M (2004) B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res 10(15):5094–5100. doi:10.1158/1078-0432.CCR-04-0428 CrossRefPubMed

Title: PD-L1 expression and tumor infiltrating PD-1+ lymphocytes associated with outcome in HER2+ breast cancer patients
Authors: Julia Y. S. Tsang
Wai-Ling Au
Kwan-Yin Lo
Yun-Bi Ni
Thazin Hlaing
Jintao Hu
Siu-Ki Chan
Kui-Fat Chan
Sai-Yin Cheung
Gary M. Tse
Publication date: 01-02-2017
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2017
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-016-4095-2

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