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Prognostication of a 13-immune-related-gene signature in patients with early triple-negative breast cancer

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Abstract

Purpose

We investigated the expression profiles of immune genes in patients with triple-negative breast cancer (TNBC) to identify the prognostic value of immune genes and their clinical implications.

Methods

NanoString nCounter Analysis of 770 immune-related genes was used to measure immune gene expression in patients with TNBC who underwent curative surgery followed by adjuvant chemotherapy at Samsung Medical Center between 2000 and 2004. Statistical analyses were conducted to identify the associations between gene expression and distant recurrence-free survival (DRFS).

Results

Of 1189 patients who underwent curative BC surgery, 200 TNBC patients were included and stage was the only clinical factor predictive of DRFS. In terms of immune genes, 155 of 770 genes were associated with DRFS (p < 0.01). Further multivariate analysis revealed that 13 genes, CD1B, CD53, CT45A1, GTF3C1, IL11RA, IL1RN, LRRN3, MAPK1, NEFL, PRKCE, PTPRC, SPACA3 and TNFSF11, were associated with patient prognosis (p < 0.05). The prognostic value of stage and expression levels of 13 immune genes was analyzed and the area under the receiver operating characteristic curve (AUC) was 0.923. Based on the AUC, we divided patients into three genetic risk groups and DRFS rate was significantly different according to genetic risk groups, even in the same stage (p < 0.001).

Conclusions

In this study, a 13-gene expression profile in combination with stage precisely predicted distant recurrence of early TNBC. Therefore, this 13-immune-gene signature could help predict TNBC prognosis and provide guidance for treatment as well as the opportunity to develop new targets for immunotherapy in TNBC patients.

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References

  1. Bonotto M, Gerratana L, Poletto E, Driol P, Giangreco M, Russo S, Minisini AM, Andreetta C, Mansutti M, Pisa FE, Fasola G, Puglisi F (2014) Measures of outcome in metastatic breast cancer: insights from a real-world scenario. Oncologist 19:608–615. https://doi.org/10.1634/theoncologist.2014-0002

    Article  PubMed  Google Scholar 

  2. den Brok WD, Speers CH, Gondara L, Baxter E, Tyldesley SK, Lohrisch CA (2017) Survival with metastatic breast cancer based on initial presentation, de novo versus relapsed. Breast Cancer Res Treat 161:549–556. https://doi.org/10.1007/s10549-016-4080-9

    Article  Google Scholar 

  3. (2019) National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology — breast cancer. V1. 2019

  4. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121:2750–2767. https://doi.org/10.1172/JCI45014

    Article  CAS  PubMed  Google Scholar 

  5. Burstein MD, Tsimelzon A, Poage GM, Covington KR, Contreras A, Fuqua SA, Savage MI, Osborne CK, Hilsenbeck SG, Chang JC, Mills GB, Lau CC, Brown PH (2015) Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res 21:1688–1698. https://doi.org/10.1158/1078-0432.CCR-14-0432

    Article  CAS  PubMed  Google Scholar 

  6. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366:2443–2454. https://doi.org/10.1056/NEJMoa1200690

    Article  CAS  PubMed  Google Scholar 

  7. 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 366:2455–2465. https://doi.org/10.1056/NEJMoa1200694

    Article  CAS  PubMed  Google Scholar 

  8. Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A, investigators K (2015) Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 372:2521–2532. https://doi.org/10.1056/NEJMoa1503093

    Article  CAS  PubMed  Google Scholar 

  9. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L, Investigators K (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372:2018–2028. https://doi.org/10.1056/NEJMoa1501824

    Article  PubMed  Google Scholar 

  10. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF, Investigators K (2017) Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 376:1015–1026. https://doi.org/10.1056/NEJMoa1613683

    Article  CAS  PubMed  Google Scholar 

  11. 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 2:361–370. https://doi.org/10.1158/2326-6066.CIR-13-0127

    Article  CAS  PubMed  Google Scholar 

  12. 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 20:2773–2782. https://doi.org/10.1158/1078-0432.CCR-13-2702

    Article  CAS  PubMed  Google Scholar 

  13. Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Dieras V, Hegg R, Im SA, Shaw Wright G, Henschel V, Molinero L, Chui SY, Funke R, Husain A, Winer EP, Loi S, Emens LA, Investigators IMT (2018) Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer. N Engl J Med 379:2108–2121. https://doi.org/10.1056/NEJMoa1809615

    Article  CAS  PubMed  Google Scholar 

  14. Schmid P, Cortes J, Pusztai L, McArthur H, Kummel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O'Shaughnessy J, Investigators K (2020) Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med 382:810–821. https://doi.org/10.1056/NEJMoa1910549

    Article  CAS  PubMed  Google Scholar 

  15. Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, Karantza V, Buisseret L (2016) Pembrolizumab in Patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J Clin Oncol 34:2460–2467. https://doi.org/10.1200/JCO.2015.64.8931

    Article  CAS  PubMed  Google Scholar 

  16. Katz H, Alsharedi M (2017) Immunotherapy in triple-negative breast cancer. Med Oncol 35:13. https://doi.org/10.1007/s12032-017-1071-6

    Article  CAS  PubMed  Google Scholar 

  17. Liu L, Wang Y, Miao L, Liu Q, Musetti S, Li J, Huang L (2018) Combination Immunotherapy of MUC1 mRNA Nano-vaccine and CTLA-4 Blockade Effectively Inhibits Growth of Triple Negative Breast Cancer. Mol Ther 26:45–55. https://doi.org/10.1016/j.ymthe.2017.10.020

    Article  CAS  PubMed  Google Scholar 

  18. Bloom HJ, Richardson WW (1957) Histological grading and prognosis in breast cancer; a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer 11:359–377

    Article  CAS  PubMed  Google Scholar 

  19. McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCIEWGoCD (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23:9067–9072. https://doi.org/10.1200/JCO.2004.01.0454

    Article  PubMed  Google Scholar 

  20. Emens LA, Cruz C, Eder JP, Braiteh F, Chung C, Tolaney SM, Kuter I, Nanda R, Cassier PA, Delord JP, Gordon MS, ElGabry E, Chang CW, Sarkar I, Grossman W, O'Hear C, Fasso M, Molinero L, Schmid P (2019) Long-term Clinical Outcomes and Biomarker Analyses of Atezolizumab Therapy for Patients With Metastatic Triple-Negative Breast Cancer: A Phase 1 Study. JAMA Oncol 5:74–82. https://doi.org/10.1001/jamaoncol.2018.4224

    Article  Google Scholar 

  21. Adams S, Diamond JR, Hamilton E, Pohlmann PR, Tolaney SM, Chang CW, Zhang W, Iizuka K, Foster PG, Molinero L, Funke R, Powderly J (2018) Atezolizumab Plus nab-Paclitaxel in the Treatment of Metastatic Triple-Negative Breast Cancer With 2-Year Survival Follow-up: A Phase 1b Clinical Trial. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2018.5152

    Article  PubMed  Google Scholar 

  22. Mori H, Kubo M, Yamaguchi R, Nishimura R, Osako T, Arima N, Okumura Y, Okido M, Yamada M, Kai M, Kishimoto J, Oda Y, Nakamura M (2017) The combination of PD-L1 expression and decreased tumor-infiltrating lymphocytes is associated with a poor prognosis in triple-negative breast cancer. Oncotarget 8:15584–15592. https://doi.org/10.18632/oncotarget.14698

    Article  PubMed  Google Scholar 

  23. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Audigier-Valette C, Minenza E, Linardou H, Burgers S, Salman P, Borghaei H, Ramalingam SS, Brahmer J, Reck M, O'Byrne KJ, Geese WJ, Green G, Chang H, Szustakowski J, Bhagavatheeswaran P, Healey D, Fu Y, Nathan F, Paz-Ares L (2018) Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med 378:2093–2104. https://doi.org/10.1056/NEJMoa1801946

    Article  CAS  PubMed  Google Scholar 

  24. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, Skora AD, Luber BS, Azad NS, Laheru D, Biedrzycki B, Donehower RC, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Duffy SM, Goldberg RM, de la Chapelle A, Koshiji M, Bhaijee F, Huebner T, Hruban RH, Wood LD, Cuka N, Pardoll DM, Papadopoulos N, Kinzler KW, Zhou S, Cornish TC, Taube JM, Anders RA, Eshleman JR, Vogelstein B, Diaz LA Jr (2015) PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med 372:2509–2520. https://doi.org/10.1056/NEJMoa1500596

    Article  CAS  PubMed  Google Scholar 

  25. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, Lee W, Yuan J, Wong P, Ho TS, Miller ML, Rekhtman N, Moreira AL, Ibrahim F, Bruggeman C, Gasmi B, Zappasodi R, Maeda Y, Sander C, Garon EB, Merghoub T, Wolchok JD, Schumacher TN, Chan TA (2015) Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348:124–128. https://doi.org/10.1126/science.aaa1348

    Article  CAS  PubMed  Google Scholar 

  26. 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 146:15–24. https://doi.org/10.1007/s10549-014-2988-5

    Article  CAS  PubMed  Google Scholar 

  27. Botti G, Collina F, Scognamiglio G, Rao F, Peluso V, De Cecio R, Piezzo M, Landi G, De Laurentiis M, Cantile M, Di Bonito M (2017) Programmed Death Ligand 1 (PD-L1) Tumor Expression Is Associated with a Better Prognosis and Diabetic Disease in Triple Negative Breast Cancer Patients. Int J Mol Sci. https://doi.org/10.3390/ijms18020459

    Article  PubMed  Google Scholar 

  28. Cheng WY, Ou Yang TH, Anastassiou D (2013) Development of a prognostic model for breast cancer survival in an open challenge environment. Sci Transl Med. https://doi.org/10.1126/scitranslmed.3005974

    Article  PubMed  Google Scholar 

  29. Cheng WY, Ou Yang TH, Anastassiou D (2013) Biomolecular events in cancer revealed by attractor metagenes. PLoS Comput Biol 9:e1002920. https://doi.org/10.1371/journal.pcbi.1002920

    Article  CAS  PubMed  Google Scholar 

  30. Cheng ML, Fong L (2014) Effects of RANKL-Targeted Therapy in Immunity and Cancer. Front Oncol 3:329. https://doi.org/10.3389/fonc.2013.00329

    Article  PubMed  Google Scholar 

  31. Stopeck AT, Lipton A, Body JJ, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A (2010) Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 28:5132–5139. https://doi.org/10.1200/JCO.2010.29.7101

    Article  CAS  PubMed  Google Scholar 

  32. Tan W, Zhang W, Strasner A, Grivennikov S, Cheng JQ, Hoffman RM, Karin M (2011) Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470:548–553. https://doi.org/10.1038/nature09707

    Article  CAS  PubMed  Google Scholar 

  33. Reyes ME, Fujii T, Branstetter D, Krishnamurthy S, Masuda H, Wang X, Reuben JM, Woodward WA, Edwards BJ, Hortobagyi GN, Tripathy D, Dougall WC, Eckhardt BL, Ueno NT (2017) Poor prognosis of patients with triple-negative breast cancer can be stratified by RANK and RANKL dual expression. Breast Cancer Res Treat 164:57–67. https://doi.org/10.1007/s10549-017-4233-5

    Article  CAS  PubMed  Google Scholar 

  34. Shang B, Gao A, Pan Y, Zhang G, Tu J, Zhou Y, Yang P, Cao Z, Wei Q, Ding Y, Zhang J, Zhao Y, Zhou Q (2014) CT45A1 acts as a new proto-oncogene to trigger tumorigenesis and cancer metastasis. Cell Death Dis 5:e1285. https://doi.org/10.1038/cddis.2014.244

    Article  CAS  PubMed  Google Scholar 

  35. Ahmad DA, Negm OH, Alabdullah ML, Mirza S, Hamed MR, Band V, Green AR, Ellis IO, Rakha EA (2016) Clinicopathological and prognostic significance of mitogen-activated protein kinases (MAPK) in breast cancers. Breast Cancer Res Treat 159:457–467. https://doi.org/10.1007/s10549-016-3967-9

    Article  CAS  PubMed  Google Scholar 

  36. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr (2018) Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med 379:111–121. https://doi.org/10.1056/NEJMoa1804710

    Article  CAS  PubMed  Google Scholar 

  37. F Cardoso van't Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, Pierga JY, Brain E, Causeret S, DeLorenzi M, Glas AM, Golfinopoulos V, Goulioti T, Knox S, Matos E, Meulemans B, Neijenhuis PA, Nitz U, Passalacqua R, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Sotiriou C, Stork L, Straehle C, Thomas G, Thompson AM, van der Hoeven JM, Vuylsteke P, Bernards R, Tryfonidis K, Rutgers E, Piccart M, Investigators M, 2016 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer N Engl J Med 375 717 729 10.1056/NEJMoa1602253

  38. Kim J-Y JH, Lim JE, Cho EY, Lee SK, Yu JH, Lee JE, Kim SW, Nam SJ, Park YH, Ahn JS, Im Y-H (2018) Prognostication of immune related gene expression in patients with triple negative breast cancer [abstract].In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4–8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4–08–30. Doi: 10.1158/1538-7445.SABCS18-P4-08-30

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Funding

This work was supported by grants from the National Research Foundation of Korea (NRF-2017R1D1A1B03028446, NRF-2018R1D1A1B07047723) and supported by Institute for Information &communications Technology Promotion (IITP) grant funded by the Korea government (MSIT) (2018–0-00861, Intelligent SW Technology Development for Medical Data Analysis), and supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR20C0025).

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Author notes

  1. Ji-Yeon Kim, Hae Hyun Jung have contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea

    Ji-Yeon Kim, Yeon Hee Park, Jin Seok Ahn & Young-Hyuck Im

  2. Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea

    Ji-Yeon Kim, Hae Hyun Jung, Yeon Hee Park & Young-Hyuck Im

  3. Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea

    Hae Hyun Jung, Yeon Hee Park & Young-Hyuck Im

  4. Statistics and Data Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea

    Insuk Sohn, Sook Young Woo & Hyun Cho

  5. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea

    Eun Yoon Cho

  6. Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, 06351, Korea

    Jeong Eon Lee, Seok Won Kim & Seok Jin Nam

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  1. Ji-Yeon Kim
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Contributions

Conception: JK, HHJ, YI; Data collection: JK, JEL, EYC, SKL, JHY, JEL, SWK, SJN, YHP, JSA, YI; Data analyses: JK, HHJ, IS, SYW, HC, JEL; Manuscript preparation: JK, YI; Manuscript review: all authors.

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Correspondence to Young-Hyuck Im.

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The institutional review board of Samsung Medical Center, Seoul, Korea approved this study protocol and waived the need for informed consent because this study used archival tissues and retrospective clinical data (IRB no: 2012–08-065).

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Kim, JY., Jung, H.H., Sohn, I. et al. Prognostication of a 13-immune-related-gene signature in patients with early triple-negative breast cancer. Breast Cancer Res Treat 184, 325–334 (2020). https://doi.org/10.1007/s10549-020-05874-1

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