Prognostic and Predictive Factors

  • Sitki Tuzlali
  • Ekrem YavuzEmail author


A variety of pathological parameters are used to assess prognosis and predict therapeutic response for breast cancer patients. These parameters include tumor size, axillary lymph node status, histological features, hormone receptor status, HER2 status and the proliferative capacity of the tumor. Several gene expression profiling assays have been developed in an attempt to predict the survival and response to therapies of breast cancer patients. These assays are based on the identification of prognostic gene signatures by using microarrays. Many groups have attempted to develop genomic tests based on genomic profiling to improve the prediction of clinical outcome compared with standard pathological and clinical markers.


Prognostic factors Predictive factors Tumor size Grading Scarff-Bloom-Richardson grading Nottingham Grading System Tubule formation Lymphovascular invasion Hormone receptors In situ hybridization ISH FISH CISH SISH Ki67 Gene expression tests Luminal A Luminal B HER-2 enriched Basal-like Apocrine subtype Interferon subtype Claudin-low MammaPrint Oncotype DX PAM50 Prosigna Genomic grade index Breast cancer index EndoPredict test ASCO/CAP 


  1. 1.
    Schnitt SJ. Classification and prognosis of invasive breast cancer: from morphology to molecular taxonomy: Long Course Article. Mod Pathol. 2010;23:S60–4.CrossRefGoogle Scholar
  2. 2.
    Edge SB, Byrd DR, Carducci MA, Compton CC, editors. AJCC cancer staging manual. 7th ed. New York: Springer; 2009.Google Scholar
  3. 3.
    Elston CW, Gresham GA, Rao GS, Zebro T, Haybittle JL, et al. The cancer research campaign (Kings/Cambridge) trial for early breast cancer-pathological aspects. Brit J Cancer. 1982;45:655–69.CrossRefGoogle Scholar
  4. 4.
    Fisher ER, Sass R, Fisher B. Pathologic findings from the National Surgical Adjuvant Project for breast cancer (protocol no 4). Discrimination for tenth year treatment failure. Cancer. 1984;53:712–23.CrossRefGoogle Scholar
  5. 5.
    Carter GL, Allen C, Henson DE. Relation of tumour size, lymph node status, and survival in 24,740 breast cancer cases. Cancer. 1989;63:181–7.CrossRefGoogle Scholar
  6. 6.
    Neville AM, Bettelheim R, Gelber RD, Säve-Söderbergh J, Davis BW, Reed R, et al. Factors predicting treatment responsiveness and prognosis in node-negative breast cancer. J Clin Oncol. 1992;10:696–705.CrossRefGoogle Scholar
  7. 7.
    Lakhani S, Ellis IO, Tan PH, van de Vijver MJ, editors. World Health Organization classification of tumors, WHO classification of tumors of the breast. 2nd ed. Lyon: IARC; 2012.Google Scholar
  8. 8.
    Lester SC, Bose S, Chen YY, Connolly JL, de Baca ME, Fitzgibbons PL, et al. Members of the Cancer committee, College of American Pathologists. Protocol for the examination of specimens from patients with invasive carcinoma of the breast. Arch Pathol Lab Med. 2009;133(10):1515–38.PubMedGoogle Scholar
  9. 9.
    Zurrida S, Morabito A, Galimberti V, Luini A, Greco M, Bartoli C, et al. Importance of the level of axillary involvement in relation to traditional variables in the prognosis of breast cancer. Int J Oncol. 1999;15(3):475–80.PubMedGoogle Scholar
  10. 10.
    Giuliano AE, Hunt KK, Ballman KV, Beitsch PD, Whitworth PW, Blumencranz PW, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011;305(6):569–75.CrossRefGoogle Scholar
  11. 11.
    Elston CW, Ellis IO. 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. 1991;19:403–10.CrossRefGoogle Scholar
  12. 12.
    Rakha EA, El-Sayed ME, Lee AH, Elston CW, Grainge MJ, Hodi Z, et al. Prognostic significance of Nottingham histologic grade in invasive breast carcinoma. J Clin Oncol. 2008;26:3153–8.CrossRefGoogle Scholar
  13. 13.
    Rakha EA, Reis-Filho JS, Baehner F, Dabbs DJ, Decker D, et al. Breast cancer prognostic classification in the molecular era: the role of histological grade. Breast Cancer Res. 2010;12(4):207.CrossRefGoogle Scholar
  14. 14.
    Pathology reporting of breast disease: a joint document incorporating the third edition of the NHS Breast Screening Programmes guidelines for pathology reporting in breast cancer screening and the second edition of The Royal College of Pathologists’ minimum dataset for breast cancer histopathology. Sheffield; NHS Cancer Screening Programmes and The Royal College of Pathologists; 2005.Google Scholar
  15. 15.
    Ellis IO, Galea M, Broughton N, Locker A, Blamey RW, Elston CW. Pathological prognostic factors in breast cancer. II, histological type. Relationship with survival in a large study with long-term follow-up. Histopathology. 1992;20:479–89.CrossRefGoogle Scholar
  16. 16.
    Pinder S, Ellis IO, Galea M, O'Rouke S, Blamey RW, Elston CW. Pathological prognostic factors in breast cancer—vascular invasion: relationship with recurrence and survival in a large series with long-term followup. Histopathology. 1994;24(1):41–7.CrossRefGoogle Scholar
  17. 17.
    Rakha EA, Martin S, Lee AH, Morgan D, Pharoah PD, Hodi Z, et al. The prognostic significance of lymphovascular invasion in invasive breast carcinoma. Cancer. 2012;118(15):3670–80.CrossRefGoogle Scholar
  18. 18.
    Bardou VJ, Arpino G, Elledge RM, Osborne CK, Clark GM. Progesterone receptor status significantly improves outcome prediction over estrogen receptor status alone for adjuvant endocrine therapy in two large breast cancer databases. J Clin Oncol. 2003;21(10):1973–9.CrossRefGoogle Scholar
  19. 19.
    Rakha E, Ellis IO. Modern classification of breast cancer: should we stick with morphology or convert to molecular profile characteristics. Adv Anat Pathol. 2011;18(4):255–67.CrossRefGoogle Scholar
  20. 20.
    Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28(16):2784–95.CrossRefGoogle Scholar
  21. 21.
    Goldstein NS, Ferkowicz M, Odish E, Mani A, Hastah F. Minimum formalin fixation time for consistent estrogen receptor immunohistochemical staining of invasive breast carcinoma. Am J Clin Pathol. 2003;120:86–92.CrossRefGoogle Scholar
  22. 22.
    Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, et al. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008;26:1642–9.CrossRefGoogle Scholar
  23. 23.
    Perez EA, Suman VJ, Davidson NE, Martino S, Kaufman PA, Lingle WL, et al. HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial. J Clin Oncol. 2006;24(19):3032–8.CrossRefGoogle Scholar
  24. 24.
    Dowsett M, Hanna WM, Kockx M, Penault-Llorca F, Rüschoff J, Gutjahr T, et al. Standardization of HER2 testing: results of an international proficiency-testing ring study. Mod Pathol. 2007;20(5):584–91.CrossRefGoogle Scholar
  25. 25.
    Tuzlali S, Yavuz E, Canda T, Güray M, Geçer MO, Süllü Y, et al. In situ hybridization analysis of invasive breast carcinomas with immunohistochemically negative Her-2 status (a national multicenter study). Turk J Pathol. 2014;30(2):87–93.CrossRefGoogle Scholar
  26. 26.
    Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25:118–45.CrossRefGoogle Scholar
  27. 27.
    Middleton LP, Price KM, Puig P, Heydon LJ, Tarco E, Sneige N, et al. Implementation of American Society of Clinical Oncology/College of American Pathologists HER2 Guideline Recommendations in a tertiary care facility increases HER2 immunohistochemistry and fluorescence in situ hybridization concordance and decreases the number of inconclusive cases. Arch Pathol Lab Med. 2009;133:775–80.PubMedGoogle Scholar
  28. 28.
    Liu YH, Xu FP, Rao JY, Zhuang HG, Luo XL, Li L, et al. Justification of the change from 10% to 30% for the immunohistochemical HER2 scoring criterion in breast cancer. Am J Clin Pathol. 2009;132:74–9.CrossRefGoogle Scholar
  29. 29.
    Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997–4013.CrossRefGoogle Scholar
  30. 30.
    Wolff AC, Hammond ME, Hicks DG. American Society of Clinical Oncology/College of American Pathologists clinical practice guideline upcoming modifications. Proof thet clinical practice guidelines are living documents. Arch Pathol Lab Med. 2015;139(8):970–1.CrossRefGoogle Scholar
  31. 31.
    Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update. J Clin Oncol. 2018;36(20):2105–22. Scholar
  32. 32.
    Kos Z, Dabbs DJ. Biomarker assessment and molecular testing for prognostication in breast cancer. Histopathology. 2016;68:70–85.CrossRefGoogle Scholar
  33. 33.
    Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thürlimann B, et al. 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. 2013;24:2206–23.CrossRefGoogle Scholar
  34. 34.
    Cheang MCU, Chia SK, Voduc D, Gao D, Leung S, Snider J, et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009;101:736–50.CrossRefGoogle Scholar
  35. 35.
    Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al. 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. 2015;26:1533–46.CrossRefGoogle Scholar
  36. 36.
    Dowsett M, Nielsen TO, A’Hern R, Bartlett J, Coombes RC, Cuzick J, et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst. 2011;103(22):1656–64.CrossRefGoogle Scholar
  37. 37.
    Zabaglo L, Salter J, Anderson H, Quinn E, Hills M, Detre S, et al. Comparative validation of the SP6 antibody to Ki67 in breast cancer. J Clin Pathol. 2010;63(9):800–4.CrossRefGoogle Scholar
  38. 38.
    Polley MY, Leung SC, McShane LM, Gao D, Hugh JC, Mastropasqua MG, et al. International Ki67 in Breast Cancer Working Group of the Breast International Group and North American Breast Cancer Group. An international Ki67 reproducibility study. J Natl Cancer Inst. 2013;105(24):1897–906.CrossRefGoogle Scholar
  39. 39.
    Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52.CrossRefGoogle Scholar
  40. 40.
    Weigelt B, Geyer FC, Jorge S, Reis-Filho JS. Histological types of breast cancer: how special are they? Mol Oncol. 2010;4:192–208.CrossRefGoogle Scholar
  41. 41.
    Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N Engl J Med. 2010;363:1938–48.CrossRefGoogle Scholar
  42. 42.
    Dabbs DJ, Klein ME, Mohsin SK, Tubbs RR, Shuai Y, Bhargava R. High false-negative rate of HER2 quantitative reverse transcription polymerase chain reaction of the oncotype DX test: an independent quality assurance study. J Clin Oncol. 2011;29:4279–85.CrossRefGoogle Scholar
  43. 43.
    van’t Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530–6.CrossRefGoogle Scholar
  44. 44.
    Bueno-de-Mesquita JM, Linn SC, Keijzer R, Wesseling J, Nuyten DS, van Krimpen C, et al. Validation of 70-gene prognosis signature in node-negative breast cancer. Breast Cancer Res Treat. 2009;117:483–95.CrossRefGoogle Scholar
  45. 45.
    Mook S, Schmidt MK, Weigelt B, Kreike B, Eekhout I, van de Vijver MJ, et al. The 70-gene prognosis signature predicts early metastasis in breast cancer patients between 55 and 70 years of age. Ann Oncol. 2010;21:717–22.CrossRefGoogle Scholar
  46. 46.
    Mook S, Schmidt MK, Viale G, Pruneri G, Eekhout I, Floore A, et al. The 70-gene prognosis signature predicts disease outcome in breast cancer patients with 1–3 positive lymph nodes in an independent validation study. Breast Cancer Res Treat. 2009;116:295–302.CrossRefGoogle Scholar
  47. 47.
    Drukker CA, Bueno-De-Mesquita JM, Retel VP, van Harten WH, van Tinteren H, Wesseling J, et al. A prospective evaluation of a breast cancer prognosis signature in the observational RASTER study. Int J Cancer. 2013;133:929–36.CrossRefGoogle Scholar
  48. 48.
    Rutgers E, Piccart-Gebhart MJ, Bogaerts J, Delaloge S, Veer LV, Rubio IT, et al. The EORTC 10041/BIG 03-04 MINDACT trial is feasible: results of the pilot phase. Eur J Cancer. 2011;47:2742–9.CrossRefGoogle Scholar
  49. 49.
    Viale G, de Snoo FA, Slaets L, Bogaerts J, van’t Veer L, Rutgers EJ, et al. MINDACT investigators. Immunohistochemical versus molecular (BluePrint and MammaPrint) subtyping of breast carcinoma. Outcome results from the EORTC 10041/BIG 3-04 MINDACT trial. Breast Cancer Res Treat. 2018;167(1):123–31.CrossRefGoogle Scholar
  50. 50.
    Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351(27):2817–26.CrossRefGoogle Scholar
  51. 51.
    Sparano JA, Gray RJ, Makowe DF, Pritchard KI, Albain KS, Hayes DF, et al. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med. 2015;373:2005–14.CrossRefGoogle Scholar
  52. 52.
    Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27:1160–7.CrossRefGoogle Scholar
  53. 53.
    Nielsen TO, Parker JS, Leung S, Voduc D, Ebbert M, Vickery T, et al. A comparison of PAM50 intrinsic subtyping with immunohistochemistry and clinical prognostic factors in tamoxifen-treated estrogen receptor-positive breast cancer. Clin Cancer Res. 2010;16:5222–32.CrossRefGoogle Scholar
  54. 54.
    Nielsen T, Wallden B, Schaper C, Ferree S, Liu S, Gao D, et al. 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. 2014;14:177.CrossRefGoogle Scholar
  55. 55.
    Dowsett M, Sestak I, Lopez-Knowles E, Sidhu K, Dunbier AK, Cowens JW, et al. Comparison of PAM50 risk of recurrence score with Oncotype DX and IHC4 for predicting risk of distant recurrence after endocrine therapy. J Clin Oncol. 2013;31:2783–90.CrossRefGoogle Scholar
  56. 56.
    Gnant M, Filipits M, Greil R, Stoeger H, Rudas M, Bago-Horvath Z, et al. 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. 2014;25:339–45.CrossRefGoogle Scholar
  57. 57.
    Bartlett JM, Bayani J, Marshall A, Dunn JA, Campbell A, Cunningham C, et al. OPTIMA TMG. Comparing breast cancer multiparameter tests in the OPTIMA Prelim Trial: no test is more equal than the others. J Natl Cancer Inst. 2016;108(9):djw050. Scholar
  58. 58.
    Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, et al. Breast Cancer-major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(4):290–303.CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Tuzlali Private Pathology LaboratoryIstanbulTurkey
  2. 2.Istanbul University, Istanbul Medical Faculty, Department of PathologyIstanbulTurkey

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