Emerging immune gene signatures as prognostic or predictive biomarkers in breast cancer

  • Mi Jeong KwonEmail author


Several multigene assays have been developed to predict the risk of distant recurrence and response to adjuvant therapy in early breast cancer. However, the prognostic or predictive value of current proliferation gene signature-based assays are limited to hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) early breast cancer. Considerable discordance between the different assays in classifying patients into risk groups has also been reported, thus raising questions about the clinical utility of these assays for individual patients. Therefore, there still remains a need for better prognostic or predictive biomarkers for breast cancer. The role of immune cells comprising tumor microenvironment in tumor progression has been recognized. Accumulating evidences have shown that immune gene signatures and tumor-infiltrating lymphocytes (TILs) can be prognostic or predictive factors in breast cancer, particularly with regard to HER2+ and triple-negative breast cancer. In this review, I summarize current multigene assays for breast cancer and discuss recent progress in identifying novel breast cancer biomarkers, focusing on the emerging importance of immune gene signatures and TILs as prognostic or predictive biomarkers.


Breast cancer Prognostic biomarker Predictive biomarker Multigene assay Immune gene signatures Tumor-infiltrating lymphocytes 



This research was supported by the Basic Science Research Program through the National Research Foundation of a Korea (NRF) funded by the Ministry of Education (Grant Number: NRF-2018R1D1A1B07043031).

Compliance with ethical standards

Conflict of interest

The author declares no conflict of interest.


  1. (2019) Atezolizumab combo approved for PD-L1-positive TNBC. Cancer Discov 9:OF2.
  2. Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, Martino S, Wang M, Jones VE, Saphner TJ, Wolff AC, Wood WC, Davidson NE, Sledge GW, Sparano JA, Badve SS (2014) 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 32:2959–2966. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Adams S, Loi S, Toppmeyer D, Cescon DW, De Laurentiis M, Nanda R, Winer EP, Mukai H, Tamura K, Armstrong A, Liu MC, Iwata H, Ryvo L, Wimberger P, Rugo HS, Tan AR, Jia L, Ding Y, Karantza V, Schmid P (2019a) Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study. Ann Oncol 30:405–411. CrossRefPubMedGoogle Scholar
  4. Adams S, Schmid P, Rugo HS, Winer EP, Loirat D, Awada A, Cescon DW, Iwata H, Campone M, Nanda R, Hui R, Curigliano G, Toppmeyer D, O’Shaughnessy J, Loi S, Paluch-Shimon S, Tan AR, Card D, Zhao J, Karantza V, Cortes J (2019b) Pembrolizumab monotherapy for previously treated metastatic triple-negative breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol 30:397–404. CrossRefPubMedGoogle Scholar
  5. Albain KS, Barlow WE, Shak S, Hortobagyi GN, Livingston RB, Yeh IT, Ravdin P, Bugarini R, Baehner FL, Davidson NE, Sledge GW, Winer EP, Hudis C, Ingle JN, Perez EA, Pritchard KI, Shepherd L, Gralow JR, Yoshizawa C, Allred DC, Osborne CK, Hayes DF, Breast Cancer Intergroup of North America (2010) Prognostic and predictive value of the 21-gene recurrence score assay in postmenopausal women with node-positive, oestrogen-receptor-positive breast cancer on chemotherapy: a retrospective analysis of a randomised trial. Lancet Oncol 11:55–65. CrossRefPubMedGoogle Scholar
  6. Althobiti M, Aleskandarany MA, Joseph C, Toss M, Mongan N, Diez-Rodriguez M, Nolan CC, Ashankyty I, Ellis IO, Green AR, Rakha EA (2018) Heterogeneity of tumour-infiltrating lymphocytes in breast cancer and its prognostic significance. Histopathology 73:887–896. CrossRefPubMedGoogle Scholar
  7. Ascierto ML, Kmieciak M, Idowu MO, Manjili R, Zhao Y, Grimes M, Dumur C, Wang E, Ramakrishnan V, Wang XY, Bear HD, Marincola FM, Manjili MH (2012) A signature of immune function genes associated with recurrence-free survival in breast cancer patients. Breast Cancer Res Treat 131:871–880. CrossRefPubMedGoogle Scholar
  8. Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, Albright A, Cheng JD, Kang SP, Shankaran V, Piha-Paul SA, Yearley J, Seiwert TY, Ribas A, Mcclanahan TK (2017) IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 127:2930–2940. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Bartlett J, Canney P, Campbell A, Cameron D, Donovan J, Dunn J, Earl H, Francis A, Hall P, Harmer V, Higgins H, Hillier L, Hulme C, Hughes-Davies L, Makris A, Morgan A, Mccabe C, Pinder S, Poole C, Rea D, Stallard N, Stein R (2013) Selecting breast cancer patients for chemotherapy: the opening of the UK OPTIMA trial. Clin Oncol (R Coll Radiol) 25:109–116. CrossRefGoogle Scholar
  10. Bartlett JM, Bayani J, Marshall A, Dunn JA, Campbell A, Cunningham C, Sobol MS, Hall PS, Poole CJ, Cameron DA, Earl HM, Rea DW, Macpherson IR, Canney P, Francis A, Mccabe C, Pinder SE, Hughes-Davies L, Makris A, Stein RC, Optima TMG (2016) Comparing breast cancer multiparameter tests in the OPTIMA Prelim Trial: no test is more equal than the others. J Natl Cancer Inst. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Bianchini G, Qi Y, Alvarez RH, Iwamoto T, Coutant C, Ibrahim NK, Valero V, Cristofanilli M, Green MC, Radvanyi L, Hatzis C, Hortobagyi GN, Andre F, Gianni L, Symmans WF, Pusztai L (2010) Molecular anatomy of breast cancer stroma and its prognostic value in estrogen receptor-positive and -negative cancers. J Clin Oncol 28:4316–4323. CrossRefPubMedGoogle Scholar
  12. Buus R, Sestak I, Kronenwett R, Denkert C, Dubsky P, Krappmann K, Scheer M, Petry C, Cuzick J, Dowsett M (2016) Comparison of EndoPredict and EPclin with Oncotype DX Recurrence Score for prediction of risk of distant recurrence after endocrine therapy. J Natl Cancer Inst. CrossRefPubMedPubMedCentralGoogle Scholar
  13. Buyse M, Loi S, Van’t Veer L, Viale G, Delorenzi M, Glas AM, d’Assignies MS, Bergh J, Lidereau R, Ellis P, Harris A, Bogaerts J, Therasse P, Floore A, Amakrane M, Piette F, Rutgers E, Sotiriou C, Cardoso F, Piccart MJ, TRANSBIG Consortium (2006) Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. J Natl Cancer Inst 98:1183–1192. CrossRefPubMedGoogle Scholar
  14. Cardoso F, 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 (2016) 70-Gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med 375:717–729. CrossRefPubMedGoogle Scholar
  15. Chan TA, Yarchoan M, Jaffee E, Swanton C, Quezada SA, Stenzinger A, Peters S (2019) Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann Oncol 30:44–56. CrossRefPubMedGoogle Scholar
  16. Cheng Q, Chang JT, Gwin WR, Zhu J, Ambs S, Geradts J, Lyerly HK (2014) A signature of epithelial-mesenchymal plasticity and stromal activation in primary tumor modulates late recurrence in breast cancer independent of disease subtype. Breast Cancer Res 16:407. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Cianfrocca M, Goldstein LJ (2004) Prognostic and predictive factors in early-stage breast cancer. Oncologist 9:606–616. CrossRefPubMedGoogle Scholar
  18. Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, Thurlimann B, Senn HJ, Panel Members (2015) Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol 26:1533–1546. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Cui Y, Li B, Pollom EL, Horst KC, Li R (2018) Integrating radiosensitivity and immune gene signatures for predicting benefit of radiotherapy in breast cancer. Clin Cancer Res 24:4754–4762. CrossRefPubMedPubMedCentralGoogle Scholar
  20. Danaher P, Warren S, Lu R, Samayoa J, Sullivan A, Pekker I, Wallden B, Marincola FM, Cesano A (2018) Pan-cancer adaptive immune resistance as defined by the Tumor Inflammation Signature (TIS): results from The Cancer Genome Atlas (TCGA). J Immunother Cancer 6:63. CrossRefPubMedPubMedCentralGoogle Scholar
  21. Denkert C, Von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, Budczies J, Huober J, Klauschen F, Furlanetto J, Schmitt WD, Blohmer JU, Karn T, Pfitzner BM, Kummel S, Engels K, Schneeweiss A, Hartmann A, Noske A, Fasching PA, Jackisch C, Van Mackelenbergh M, Sinn P, Schem C, Hanusch C, Untch M, Loibl S (2018) Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol 19:40–50. CrossRefPubMedGoogle Scholar
  22. Desmedt C, Haibe-Kains B, Wirapati P, Buyse M, Larsimont D, Bontempi G, Delorenzi M, Piccart M, Sotiriou C (2008) Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes. Clin Cancer Res 14:5158–5165. CrossRefPubMedGoogle Scholar
  23. Dieci MV, Radosevic-Robin N, Fineberg S, Van Den Eynden G, Ternes N, Penault-Llorca F, Pruneri G, D’Alfonso TM, Demaria S, Castaneda C, Sanchez J, Badve S, Michiels S, Bossuyt V, Rojo F, Singh B, Nielsen T, Viale G, Kim SR, Hewitt S, Wienert S, Loibl S, Rimm D, Symmans F, Denkert C, Adams S, Loi S, Salgado R, International Immuno-Oncology Biomarker Working Group on Breast Cancer (2018) 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 52:16–25. CrossRefPubMedGoogle Scholar
  24. Dirix LY, Takacs I, Jerusalem G, Nikolinakos P, Arkenau HT, Forero-Torres A, Boccia R, Lippman ME, Somer R, Smakal M, Emens LA, Hrinczenko B, Edenfield W, Gurtler J, Von Heydebreck A, Grote HJ, Chin K, Hamilton EP (2018) Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat 167:671–686. CrossRefPubMedGoogle Scholar
  25. Donegan WL (1997) Tumor-related prognostic factors for breast cancer. CA Cancer J Clin 47:28–51. CrossRefPubMedGoogle Scholar
  26. Dowsett M, Cuzick J, Wale C, Forbes J, Mallon EA, Salter J, Quinn E, Dunbier A, Baum M, Buzdar A, Howell A, Bugarini R, Baehner FL, Shak S (2010) Prediction of risk of distant recurrence using the 21-gene recurrence score in node-negative and node-positive postmenopausal patients with breast cancer treated with anastrozole or tamoxifen: a TransATAC study. J Clin Oncol 28:1829–1834. CrossRefPubMedGoogle Scholar
  27. Dowsett M, Sestak I, Lopez-Knowles E, Sidhu K, Dunbier AK, Cowens JW, Ferree S, Storhoff J, Schaper C, Cuzick J (2013) Comparison of PAM50 risk of recurrence score with oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol 31:2783–2790. CrossRefPubMedGoogle Scholar
  28. Esteva FJ, Hubbard-Lucey VM, Tang J, Pusztai L (2019) Immunotherapy and targeted therapy combinations in metastatic breast cancer. Lancet Oncol 20:e175–e186. CrossRefPubMedGoogle Scholar
  29. Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P, Becette V, Andre S, Piccart M, Campone M, Brain E, Macgrogan G, Petit T, Jassem J, Bibeau F, Blot E, Bogaerts J, Aguet M, Bergh J, Iggo R, Delorenzi M (2009) A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med 15:68–74. CrossRefPubMedGoogle Scholar
  30. Filipits M, Rudas M, Jakesz R, Dubsky P, Fitzal F, Singer CF, Dietze O, Greil R, Jelen A, Sevelda P, Freibauer C, Muller V, Janicke F, Schmidt M, Kolbl H, Rody A, Kaufmann M, Schroth W, Brauch H, Schwab M, Fritz P, Weber KE, Feder IS, Hennig G, Kronenwett R, Gehrmann M, Gnant M (2011) A new molecular predictor of distant recurrence in ER-positive, HER2-negative breast cancer adds independent information to conventional clinical risk factors. Clin Cancer Res 17:6012–6020. CrossRefPubMedGoogle Scholar
  31. Finak G, Bertos N, Pepin F, Sadekova S, Souleimanova M, Zhao H, Chen H, Omeroglu G, Meterissian S, Omeroglu A, Hallett M, Park M (2008) Stromal gene expression predicts clinical outcome in breast cancer. Nat Med 14:518–527. CrossRefPubMedGoogle Scholar
  32. Fitzal F, Filipits M, Rudas M, Greil R, Dietze O, Samonigg H, Lax S, Herz W, Dubsky P, Bartsch R, Kronenwett R, Gnant M (2015) The genomic expression test EndoPredict is a prognostic tool for identifying risk of local recurrence in postmenopausal endocrine receptor-positive, her2neu-negative breast cancer patients randomised within the prospective ABCSG 8 trial. Br J Cancer 112:1405–1410. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12:298–306. CrossRefPubMedGoogle Scholar
  34. Gibney GT, Weiner LM, Atkins MB (2016) Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol 17:e542–e551. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Gingras I, Desmedt C, Ignatiadis M, Sotiriou C (2015) CCR 20th Anniversary Commentary: gene-expression signature in breast cancer-where did it start and where are we now? Clin Cancer Res 21:4743–4746. CrossRefPubMedGoogle Scholar
  36. Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, Weaver DL, Winchester DJ, Hortobagyi GN (2017) Breast cancer—major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 67:290–303. CrossRefPubMedGoogle Scholar
  37. Gnant M, Filipits M, Greil R, Stoeger H, Rudas M, Bago-Horvath Z, Mlineritsch B, Kwasny W, Knauer M, Singer C, Jakesz R, Dubsky P, Fitzal F, Bartsch R, Steger G, Balic M, Ressler S, Cowens JW, Storhoff J, Ferree S, Schaper C, Liu S, Fesl C, Nielsen TO, Austrian Breast and Colorectal Cancer Study Group (2014) Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. Ann Oncol 25:339–345. CrossRefPubMedGoogle Scholar
  38. Gong G, Kwon MJ, Han J, Lee HJ, Lee SK, Lee JE, Lee SH, Park S, Choi JS, Cho SY, Ahn SH, Lee JW, Cho SR, Moon Y, Nam BH, Nam SJ, Choi YL, Shin YK (2017) A new molecular prognostic score for predicting the risk of distant metastasis in patients with HR+/HER2− early breast cancer. Sci Rep 7:45554. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Han J, Choi YL, Kim H, Choi JY, Lee SK, Lee JE, Choi JS, Park S, Choi JS, Kim YD, Nam SJ, Nam BH, Kwon MJ, Shin YK (2017) MMP11 and CD2 as novel prognostic factors in hormone receptor-negative, HER2-positive breast cancer. Breast Cancer Res Treat 164:41–56. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. CrossRefPubMedGoogle Scholar
  41. Harris LN, Ismaila N, Mcshane LM, Andre F, Collyar DE, Gonzalez-Angulo AM, Hammond EH, Kuderer NM, Liu MC, Mennel RG, Van Poznak C, Bast RC, Hayes DF, American Society of Clinical Oncology (2016) 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 34:1134–1150. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Havel JJ, Chowell D, Chan TA (2019) The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer 19:133–150. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Hida AI, Sagara Y, Yotsumoto D, Kanemitsu S, Kawano J, Baba S, Rai Y, Oshiro Y, Aogi K, Ohi Y (2016) Prognostic and predictive impacts of tumor-infiltrating lymphocytes differ between Triple-negative and HER2-positive breast cancers treated with standard systemic therapies. Breast Cancer Res Treat 158:1–9. CrossRefPubMedPubMedCentralGoogle Scholar
  44. Ignatiadis M, Dawson SJ (2014) Circulating tumor cells and circulating tumor DNA for precision medicine: dream or reality? Ann Oncol 25:2304–2313. CrossRefPubMedGoogle Scholar
  45. Ingold Heppner B, Untch M, Denkert C, Pfitzner BM, Lederer B, Schmitt W, Eidtmann H, Fasching PA, Tesch H, Solbach C, Rezai M, Zahm DM, Holms F, Glados M, Krabisch P, Heck E, Ober A, Lorenz P, Diebold K, Habeck JO, Loibl S (2016) Tumor-infiltrating lymphocytes: a predictive and prognostic biomarker in neoadjuvant-treated HER2-positive breast cancer. Clin Cancer Res 22:5747–5754. CrossRefPubMedGoogle Scholar
  46. Jensen MB, Laenkholm AV, Nielsen TO, Eriksen JO, Wehn P, Hood T, Ram N, Buckingham W, Ferree S, Ejlertsen B (2018) The Prosigna gene expression assay and responsiveness to adjuvant cyclophosphamide-based chemotherapy in premenopausal high-risk patients with breast cancer. Breast Cancer Res 20:79. CrossRefPubMedPubMedCentralGoogle Scholar
  47. Joyce JA (2005) Therapeutic targeting of the tumor microenvironment. Cancer Cell 7:513–520. CrossRefPubMedGoogle Scholar
  48. Kandoth C, Mclellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, Mcmichael JF, Wyczalkowski MA, Leiserson MDM, Miller CA, Welch JS, Walter MJ, Wendl MC, Ley TJ, Wilson RK, Raphael BJ, Ding L (2013) Mutational landscape and significance across 12 major cancer types. Nature 502:333–339. CrossRefPubMedPubMedCentralGoogle Scholar
  49. Kwon MJ, Lee SB, Han J, Lee JE, Lee JW, Gong G, Beitsch PD, Nam SJ, Ahn SH, Nam BH, Shin YK (2018) BCT score predicts chemotherapy benefit in Asian patients with hormone receptor-positive, HER2-negative, lymph node-negative breast cancer. PLoS ONE 13:e0207155. CrossRefPubMedPubMedCentralGoogle Scholar
  50. Laenkholm AV, Jensen MB, Eriksen JO, Rasmussen BB, Knoop AS, Buckingham W, Ferree S, Schaper C, Nielsen TO, Haffner T, Kibol T, Moller Talman ML, Bak Jylling AM, Tabor TP, Ejlertsen B (2018) PAM50 risk of recurrence score predicts 10-year distant recurrence in a comprehensive Danish Cohort of postmenopausal women allocated to 5 years of endocrine therapy for hormone receptor-positive early breast cancer. J Clin Oncol 36:735–740. CrossRefPubMedGoogle Scholar
  51. Lee HJ, Lee JJ, Song IH, Park IA, Kang J, Yu JH, Ahn JH, Gong G (2015) Prognostic and predictive value of NanoString-based immune-related gene signatures in a neoadjuvant setting of triple-negative breast cancer: relationship to tumor-infiltrating lymphocytes. Breast Cancer Res Treat 151:619–627. CrossRefPubMedGoogle Scholar
  52. Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, De Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C (2013) 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 31:860–867. CrossRefPubMedGoogle Scholar
  53. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, Kellokumpu-Lehtinen PL, Bono P, Kataja V, Desmedt C, Piccart MJ, Loibl S, Denkert C, Smyth MJ, Joensuu H, Sotiriou C (2014) 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 25:1544–1550. CrossRefPubMedGoogle Scholar
  54. Loibl S, Weber K, Huober J, Krappmann K, Marme F, Schem C, Engels K, Pfitzner BM, Kummel S, Furlanetto J, Hartmann A, Darb-Esfahani S, Muller V, Staebler A, Von Minckwitz G, Kronenwett R, Denkert C (2018) Risk assessment after neoadjuvant chemotherapy in luminal breast cancer using a clinicomolecular predictor. Clin Cancer Res 24:3358–3365. CrossRefPubMedGoogle Scholar
  55. Luen SJ, Savas P, Fox SB, Salgado R, Loi S (2017) Tumour-infiltrating lymphocytes and the emerging role of immunotherapy in breast cancer. Pathology 49:141–155. CrossRefPubMedGoogle Scholar
  56. Ma XJ, Salunga R, Dahiya S, Wang W, Carney E, Durbecq V, Harris A, Goss P, Sotiriou C, Erlander M, Sgroi D (2008) A five-gene molecular grade index and HOXB13:IL17BR are complementary prognostic factors in early stage breast cancer. Clin Cancer Res 14:2601–2608. CrossRefPubMedGoogle Scholar
  57. Mamounas EP, Liu Q, Paik S, Baehner FL, Tang G, Jeong JH, Kim SR, Butler SM, Jamshidian F, Cherbavaz DB, Sing AP, Shak S, Julian TB, Lembersky BC, Wickerham DL, Costantino JP, Wolmark N (2017) 21-Gene recurrence score and locoregional recurrence in node-positive/ER-positive breast cancer treated with chemo-endocrine therapy. J Natl Cancer Inst. CrossRefPubMedPubMedCentralGoogle Scholar
  58. Mao Y, Keller ET, Garfield DH, Shen K, Wang J (2013) Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev 32:303–315. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Martin M, Brase JC, Calvo L, Krappmann K, Ruiz-Borrego M, Fisch K, Ruiz A, Weber KE, Munarriz B, Petry C, Rodriguez CA, Kronenwett R, Crespo C, Alba E, Carrasco E, Casas M, Caballero R, Rodriguez-Lescure A (2014) Clinical validation of the EndoPredict test in node-positive, chemotherapy-treated ER+/HER2− breast cancer patients: results from the GEICAM 9906 trial. Breast Cancer Res 16:R38. CrossRefPubMedPubMedCentralGoogle Scholar
  60. Miglietta F, Griguolo G, Guarneri V, Dieci MV (2019) Programmed cell death ligand 1 in breast cancer: technical aspects, prognostic implications, and predictive value. Oncologist. CrossRefPubMedGoogle Scholar
  61. Mittempergher L, De Ronde JJ, Nieuwland M, Kerkhoven RM, Simon I, Rutgers EJ, Wessels LF, Van’t Veer LJ (2011) Gene expression profiles from formalin fixed paraffin embedded breast cancer tissue are largely comparable to fresh frozen matched tissue. PLoS ONE 6:e17163. CrossRefPubMedPubMedCentralGoogle Scholar
  62. Mittempergher L, Saghatchian M, Wolf DM, Michiels S, Canisius S, Dessen P, Delaloge S, Lazar V, Benz SC, Tursz T, Bernards R, Van’t Veer LJ (2013) A gene signature for late distant metastasis in breast cancer identifies a potential mechanism of late recurrences. Mol Oncol 7:987–999. CrossRefPubMedPubMedCentralGoogle Scholar
  63. Nicolini A, Ferrari P, Duffy MJ (2018) Prognostic and predictive biomarkers in breast cancer: past, present and future. Semin Cancer Biol 52:56–73. CrossRefPubMedGoogle Scholar
  64. Nielsen T, Wallden B, Schaper C, Ferree S, Liu S, Gao D, Barry G, Dowidar N, Maysuria M, Storhoff J (2014) Analytical validation of the PAM50-based Prosigna Breast Cancer Prognostic Gene Signature Assay and nCounter Analysis System using formalin-fixed paraffin-embedded breast tumor specimens. BMC Cancer 14:177. CrossRefPubMedPubMedCentralGoogle Scholar
  65. Oh E, Choi YL, Park T, Lee S, Nam SJ, Shin YK (2012) A prognostic model for lymph node-negative breast cancer patients based on the integration of proliferation and immunity. Breast Cancer Res Treat 132:499–509. CrossRefPubMedGoogle Scholar
  66. Ono M, Tsuda H, Shimizu C, Yamamoto S, Shibata T, Yamamoto H, Hirata T, Yonemori K, Ando M, Tamura K, Katsumata N, Kinoshita T, Takiguchi Y, Tanzawa H, Fujiwara Y (2012) Tumor-infiltrating lymphocytes are correlated with response to neoadjuvant chemotherapy in triple-negative breast cancer. Breast Cancer Res Treat 132:793–805. CrossRefPubMedGoogle Scholar
  67. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, Baehner FL, Walker MG, Watson D, Park T, Hiller W, Fisher ER, Wickerham DL, Bryant J, Wolmark N (2004) A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 351:2817–2826. CrossRefPubMedGoogle Scholar
  68. Paik S, Tang G, Shak S, Kim C, Baker J, Kim W, Cronin M, Baehner FL, Watson D, Bryant J, Costantino JP, Geyer CE Jr, Wickerham DL, Wolmark N (2006) Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol 24:3726–3734. CrossRefPubMedGoogle Scholar
  69. Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, Davies S, Fauron C, He X, Hu Z, Quackenbush JF, Stijleman IJ, Palazzo J, Marron JS, Nobel AB, Mardis E, Nielsen TO, Ellis MJ, Perou CM, Bernard PS (2009) Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 27:1160–1167. CrossRefPubMedPubMedCentralGoogle Scholar
  70. Partridge AH, Carey LA (2017) Unmet needs in clinical research in breast cancer: where do we need to go? Clin Cancer Res 23:2611–2616. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Prat A, Galvan P, Jimenez B, Buckingham W, Jeiranian HA, Schaper C, Vidal M, Alvarez M, Diaz S, Ellis C, Nuciforo P, Ferree S, Ribelles N, Adamo B, Ramon YCS, Peg V, Alba E (2016) Prediction of response to neoadjuvant chemotherapy using core needle biopsy samples with the Prosigna Assay. Clin Cancer Res 22:560–566. CrossRefPubMedGoogle Scholar
  72. Rody A, Holtrich U, Pusztai L, Liedtke C, Gaetje R, Ruckhaeberle E, Solbach C, Hanker L, Ahr A, Metzler D, Engels K, Karn T, Kaufmann M (2009) T-cell metagene predicts a favorable prognosis in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res 11:R15. CrossRefPubMedPubMedCentralGoogle Scholar
  73. Rody A, Karn T, Liedtke C, Pusztai L, Ruckhaeberle E, Hanker L, Gaetje R, Solbach C, Ahr A, Metzler D, Schmidt M, Muller V, Holtrich U, Kaufmann M (2011) A clinically relevant gene signature in triple negative and basal-like breast cancer. Breast Cancer Res 13:R97. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Ross JS, Hatzis C, Symmans WF, Pusztai L, Hortobagyi GN (2008) Commercialized multigene predictors of clinical outcome for breast cancer. Oncologist 13:477–493. CrossRefPubMedGoogle Scholar
  75. Salgado R, Denkert C, Campbell C, Savas P, Nuciforo P, Aura C, De Azambuja E, Eidtmann H, Ellis CE, Baselga J, Piccart-Gebhart MJ, Michiels S, Bradbury I, Sotiriou C, Loi S (2015a) 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 1:448–454. CrossRefPubMedPubMedCentralGoogle Scholar
  76. 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, International TILs Working Group (2015b) The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol 26:259–271. CrossRefGoogle Scholar
  77. Savas P, Salgado R, Denkert C, Sotiriou C, Darcy PK, Smyth MJ, Loi S (2016) Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nat Rev Clin Oncol 13:228–241. CrossRefPubMedGoogle Scholar
  78. 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. CrossRefGoogle Scholar
  79. Schmidt M, Bohm D, Von Torne C, Steiner E, Puhl A, Pilch H, Lehr HA, Hengstler JG, Kolbl H, Gehrmann M (2008) The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res 68:5405–5413. CrossRefPubMedGoogle Scholar
  80. Sestak I, Cuzick J, Dowsett M, Lopez-Knowles E, Filipits M, Dubsky P, Cowens JW, Ferree S, Schaper C, Fesl C, Gnant M (2015) Prediction of late distant recurrence after 5 years of endocrine treatment: a combined analysis of patients from the Austrian breast and colorectal cancer study group 8 and arimidex, tamoxifen alone or in combination randomized trials using the PAM50 risk of recurrence score. J Clin Oncol 33:916–922. CrossRefPubMedGoogle Scholar
  81. Sestak I, Buus R, Cuzick J, Dubsky P, Kronenwett R, Denkert C, Ferree S, Sgroi D, Schnabel C, Baehner FL, Mallon E, Dowsett M (2018) Comparison of the performance of 6 prognostic signatures for estrogen receptor-positive breast cancer: a secondary analysis of a Randomized Clinical Trial. JAMA Oncol 4:545–553. CrossRefPubMedPubMedCentralGoogle Scholar
  82. Sgroi DC, Sestak I, Cuzick J, Zhang Y, Schnabel CA, Schroeder B, Erlander MG, Dunbier A, Sidhu K, Lopez-Knowles E, Goss PE, Dowsett M (2013) Prediction of late distant recurrence in patients with oestrogen-receptor-positive breast cancer: a prospective comparison of the breast-cancer index (BCI) assay, 21-gene recurrence score, and IHC4 in the TransATAC study population. Lancet Oncol 14:1067–1076. CrossRefPubMedPubMedCentralGoogle Scholar
  83. Sgroi DC, Chapman JA, Badovinac-Crnjevic T, Zarella E, Binns S, Zhang Y, Schnabel CA, Erlander MG, Pritchard KI, Han L, Shepherd LE, Goss PE, Pollak M (2016) Assessment of the prognostic and predictive utility of the Breast Cancer Index (BCI): an NCIC CTG MA.14 study. Breast Cancer Res 18:1. CrossRefPubMedPubMedCentralGoogle Scholar
  84. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Perez EA, Olson JA Jr, Zujewski J, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin P, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Atkins JN, Berenberg JL, Sledge GW (2015) Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med 373:2005–2014. CrossRefPubMedPubMedCentralGoogle Scholar
  85. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  86. Sparano JA, Gray RJ, Ravdin PM, 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, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr (2019) Clinical and genomic risk to guide the use of adjuvant therapy for breast cancer. N Engl J Med 380:2395–2405. CrossRefPubMedGoogle Scholar
  87. Teschendorff AE, Caldas C (2008) A robust classifier of high predictive value to identify good prognosis patients in ER-negative breast cancer. Breast Cancer Res 10:R73. CrossRefPubMedPubMedCentralGoogle Scholar
  88. Teschendorff AE, Miremadi A, Pinder SE, Ellis IO, Caldas C (2007) An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol 8:R157. CrossRefPubMedPubMedCentralGoogle Scholar
  89. Tian S, Roepman P, Van’t Veer LJ, Bernards R, De Snoo F, Glas AM (2010) Biological functions of the genes in the mammaprint breast cancer profile reflect the hallmarks of cancer. Biomark Insights 5:129–138. CrossRefPubMedPubMedCentralGoogle Scholar
  90. Tsai M, Lo S, Audeh W, Qamar R, Budway R, Levine E, Whitworth P, Mavromatis B, Zon R, Oldham D, Untch S, Treece T, Blumencranz L, Soliman H (2018) Association of 70-gene signature assay findings with physicians’ treatment guidance for patients with early breast cancer classified as intermediate risk by the 21-gene assay. JAMA Oncol 4:e173470. CrossRefPubMedGoogle Scholar
  91. 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 143:1–9. CrossRefPubMedGoogle Scholar
  92. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, Chmielowski B, Spasic M, Henry G, Ciobanu V, West AN, Carmona M, Kivork C, Seja E, Cherry G, Gutierrez AJ, Grogan TR, Mateus C, Tomasic G, Glaspy JA, Emerson RO, Robins H, Pierce RH, Elashoff DA, Robert C, Ribas A (2014) PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515:568–571. CrossRefPubMedPubMedCentralGoogle Scholar
  93. Van ‘t Veer LJ, Dai H, Van De Vijver MJ, He YD, Hart AA, Mao M, Peterse HL, Van Der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH (2002) Gene expression profiling predicts clinical outcome of breast cancer. Nature 415:530–536. CrossRefPubMedGoogle Scholar
  94. Varga Z, Sinn P, Seidman AD (2019) Summary of head-to-head comparisons of patient risk classifications by the 21-gene Recurrence Score(R) (RS) assay and other genomic assays for early breast cancer. Int J Cancer 145:882–893. CrossRefPubMedGoogle Scholar
  95. Vonderheide RH, Domchek SM, Clark AS (2017) Immunotherapy for breast cancer: what are we missing? Clin Cancer Res 23:2640–2646. CrossRefPubMedPubMedCentralGoogle Scholar
  96. Wallden B, Storhoff J, Nielsen T, Dowidar N, Schaper C, Ferree S, Liu S, Leung S, Geiss G, Snider J, Vickery T, Davies SR, Mardis ER, Gnant M, Sestak I, Ellis MJ, Perou CM, Bernard PS, Parker JS (2015) Development and verification of the PAM50-based Prosigna breast cancer gene signature assay. BMC Med Genomics 8:54. CrossRefPubMedPubMedCentralGoogle Scholar
  97. Winslow S, Lindquist KE, Edsjo A, Larsson C (2016) The expression pattern of matrix-producing tumor stroma is of prognostic importance in breast cancer. BMC Cancer 16:841. CrossRefPubMedPubMedCentralGoogle Scholar
  98. Yang B, Chou J, Tao Y, Wu D, Wu X, Li X, Li Y, Chu Y, Tang F, Shi Y, Ma L, Zhou T, Kaufmann W, Carey LA, Wu J, Hu Z (2018) An assessment of prognostic immunity markers in breast cancer. NPJ Breast Cancer 4:35. CrossRefPubMedPubMedCentralGoogle Scholar
  99. Yarchoan M, Albacker LA, Hopkins AC, Montesion M, Murugesan K, Vithayathil TT, Zaidi N, Azad NS, Laheru DA, Frampton GM, Jaffee EM (2019) PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight. CrossRefPubMedPubMedCentralGoogle Scholar
  100. Yau C, Esserman L, Moore DH, Waldman F, Sninsky J, Benz CC (2010) A multigene predictor of metastatic outcome in early stage hormone receptor-negative and triple-negative breast cancer. Breast Cancer Res 12:R85. CrossRefPubMedPubMedCentralGoogle Scholar
  101. Yau C, Sninsky J, Kwok S, Wang A, Degnim A, Ingle JN, Gillett C, Tutt A, Waldman F, Moore D, Esserman L, Benz CC (2013) An optimized five-gene multi-platform predictor of hormone receptor negative and triple negative breast cancer metastatic risk. Breast Cancer Res 15:R103. CrossRefPubMedPubMedCentralGoogle Scholar
  102. Zhang Y, Schnabel CA, Schroeder BE, Jerevall PL, Jankowitz RC, Fornander T, Stal O, Brufsky AM, Sgroi D, Erlander MG (2013) Breast cancer index identifies early-stage estrogen receptor-positive breast cancer patients at risk for early- and late-distant recurrence. Clin Cancer Res 19:4196–4205. CrossRefPubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  1. 1.Department of Pharmacy, College of PharmacyKyungpook National UniversityDaeguRepublic of Korea
  2. 2.Research Institute of Pharmaceutical SciencesKyungpook National UniversityDaeguRepublic of Korea

Personalised recommendations