Breast Cancer Research and Treatment

, Volume 131, Issue 2, pp 413–424 | Cite as

Routine pathologic parameters can predict Oncotype DXTM recurrence scores in subsets of ER positive patients: who does not always need testing?

  • K. H. AllisonEmail author
  • P. L. Kandalaft
  • C. M. Sitlani
  • S. M. Dintzis
  • A. M. Gown
Preclinical study


Oncotype DXTM is an RT-PCR-based assay used to predict chemotherapy benefit in patients with estrogen receptor (ER) positive breast cancers. We were interested if routinely available pathologic parameters could predict Oncotype DXTM Recurrence Scores (RS) in subsets of patients. We identified 173 breast cancers with available RSs and used 104 of these as a test set and 69 cases as a validation set. Pathologic characteristics including size, histologic type, Nottingham grade, and lymphatic invasion were recorded. Test set cases were stained for ER, progesterone receptor (PR), HER2, Ki67, CyclinD1, BCL2, D2-40, and P53. Statistical correlations with RS and regression tree analysis were performed. The validation set was subjected to analysis on the basis of grade, PR, and Ki67. In the test set, grade, PR levels and Ki67 had the strongest correlation with RS (P = 0.0002–0.0007). Regression tree analysis showed grade and PR as factors that could segregate cases into RS categories, with Ki67 adding value in certain subsets. A subset of cancers with a high likelihood of having a low RS (0–18) was identified with the following characteristics: grade 1, strong PR expression (Allred score ≥5) and Ki67 ≤ 10%. No cases with these characteristics had a high RS (≥31) and 73% had a low RS. Cancers highly likely to have a high RS were grade 3, low to absent PR expression (Allred score <5) and Ki67 > 10%. 80% of cases with these characteristics had a high RS and no cases had a low RS. Our validation set had similar findings in these two subsets. In conclusion, When cost and time are a consideration and the added value of Oncotype DXTM testing is in question, it may be reasonable to assume the results of this test in two specific subsets of breast cancers: (1) grade 1, high PR, low Ki67 cancers (low RS), and (2) grade 3, low PR, high Ki67 cancers (high RS).


Oncotype DX 21 gene recurrence score assay Breast cancer Recurrence score Immunohistochemistry RT-PCR Estrogen receptor Progesterone receptor Nottingham grade Ki67 


  1. 1.
    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(27):2817–2826. doi: 10.1056/NEJMoa041588 PubMedCrossRefGoogle Scholar
  2. 2.
    Habel LA, Shak S, Jacobs MK, Capra A, Alexander C, Pho M, Baker J, Walker M, Watson D, Hackett J, Blick NT, Greenberg D, Fehrenbacher L, Langholz B, Quesenberry CP (2006) A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Breast Cancer Res 8 (3):R25Google Scholar
  3. 3.
    Esteva FJ, Sahin AA, Cristofanilli M, Coombes K, Lee SJ, Baker J, Cronin M, Walker M, Watson D, Shak S, Hortobagyi GN (2005) Prognostic role of a multigene reverse transcriptase-PCR assay in patients with node-negative breast cancer not receiving adjuvant systemic therapy. Clin Cancer Res 11(9):3315–3319PubMedCrossRefGoogle Scholar
  4. 4.
    Gianni L, Zambetti M, Clark K, Baker J, Cronin M, Wu J, Mariani G, Rodriguez J, Carcangiu M, Watson D, Valagussa P, Rouzier R, Symmans WF, Ross JS, Hortobagyi GN, Pusztai L, Shak S (2005) Original reports—Breast Cancer—gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol 23(29):7265PubMedCrossRefGoogle Scholar
  5. 5.
    Toi M, Iwata H, Yamanaka T, Masuda N, Ohno S, Nakamura S, Nakayama T, Kashiwaba M, Kamigaki S, Kuroi K (2010) Clinical significance of the 21-gene signature (Oncotype DX) in hormone receptor-positive early stage primary breast cancer in the Japanese population. Cancer 116(13):3112–3118. doi: 10.1002/cncr.25206 PubMedCrossRefGoogle Scholar
  6. 6.
    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(23):3726–3734. doi: 10.1200/JCO.2005.04.7985 PubMedCrossRefGoogle Scholar
  7. 7.
    Carlson RW, Allred DC, Anderson BO, Burstein HJ, Carter WB, Edge SB, Erban JK, Farrar WB, Goldstein LJ, Gradishar WJ, Hayes DF, Hudis CA, Jahanzeb M, Kiel K, Ljung BM, Marcom PK, Mayer IA, McCormick B, Nabell LM, Pierce LJ, Reed EC, Smith ML, Somlo G, Theriault RL, Topham NS, Ward JH, Winer EP, Wolff AC (2009) Breast cancer Clinical practice guidelines in oncology. J Natl Compr Cancer Netw 7(2):122–192Google Scholar
  8. 8.
    Harris L, Fritsche H, Mennel R, Norton L, Ravdin P, Taube S, Somerfield MR, Hayes DF, Bast RC Jr (2007) American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25(33):5287–5312. doi: 10.1200/JCO.2007.14.2364 PubMedCrossRefGoogle Scholar
  9. 9.
    Flanagan MB, Dabbs DJ, Brufsky AM, Beriwal S, Bhargava R (2008) Histopathologic variables predict Oncotype DX recurrence score. Mod Pathol 21(10):1255–1261. doi: 10.1038/modpathol.2008.54 PubMedCrossRefGoogle Scholar
  10. 10.
    Cuzick J, Dowsett M, Wale C, Salter J, Quinn E, Zabaglo L, Howell A, Buzdar A, Forbes JF (2009) Prognostic value of a combined ER, PgR, Ki67, HER2 immunohistochemical (IHC4) score and comparison with the GHI recurrence score—results from TransATAC. Cancer Res 69(24):74CrossRefGoogle Scholar
  11. 11.
    Auerbach J, Kim M, Fineberg S (2010) Can features evaluated in the routine pathologic assessment of lymph node—Negative Estrogen Receptor—positive stage I or II invasive breast cancer be used to predict the oncotype DX recurrence score? Arch Pathol Lab Med 134(11):1697–1701. doi: 10.1043/2009-0439-OAR.1 PubMedGoogle Scholar
  12. 12.
    Wolf I, Ben-Baruch N, Shapira-Frommer R, Rizel S, Goldberg H, Yaal-Hahoshen N, Klein B, Geffen DB, Kaufman B (2008) Association between standard clinical and pathologic characteristics and the 21-gene recurrence score in breast cancer patients: a population-based study. Cancer 112(4):731–736. doi: 10.1002/cncr.23225 PubMedCrossRefGoogle Scholar
  13. 13.
    Harvey JM, Clark GM, Osborne CK, Allred DC (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17(5):1474–1481PubMedGoogle Scholar
  14. 14.
    Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF (2007) American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med 131(1):18–43PubMedGoogle Scholar
  15. 15.
    Wolff AC, Hammond ME, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A, McShane LM, Paik S, Pegram MD, Perez EA, Press MF, Rhodes A, Sturgeon C, Taube SE, Tubbs R, Vance GH, van de Vijver M, Wheeler TM, Hayes DF (2007) 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 25(1):118–145. doi: 10.1200/JCO.2006.09.2775 PubMedCrossRefGoogle Scholar
  16. 16.
    Gown AM, Goldstein LC, Barry TS, Kussick SJ, Kandalaft PL, Kim PM, Tse CC (2008) High concordance between immunohistochemistry and fluorescence in situ hybridization testing for HER2 status in breast cancer requires a normalized IHC scoring system. Mod Pathol 21(10):1271–1277PubMedCrossRefGoogle Scholar
  17. 17.
    Alkushi ALP, Coldman A, Huntsman D, Miller D, Gilks CB (2004) Interpretation of p53 immunoreactivity in endometrial carcinoma: establishing a clinically relevant cut-off level. Int J Gynecol Pathol 23(2):129–137PubMedCrossRefGoogle Scholar
  18. 18.
    Breiman L (1984) Classification and regression trees. The Wadsworth statistics/probability series. Wadsworth International Group, Belmont, CAGoogle Scholar
  19. 19.
    Kelly CM, Krishnamurthy S, Bianchini G, Litton JK, Gonzalez-Angulo AM, Hortobagyi GN, Pusztai L (2010) Utility of oncotype DX risk estimates in clinically intermediate risk hormone receptor-positive, HER2-normal, grade II, lymph node-negative breast cancers. Cancer 116(22):5161–5167. doi: 10.1002/cncr.25269 PubMedCrossRefGoogle Scholar
  20. 20.
    Gwin K, Pinto M, Tavassoli FA (2009) Complementary value of the Ki-67 proliferation index to the oncotype DX recurrence score. Int J Surg Pathol 17(4):303–310. doi: 10.1177/1066896909340274 PubMedCrossRefGoogle Scholar
  21. 21.
    Geradts J, Bean SM, Bentley RC, Barry WT (2010) The oncotype DX recurrence score is correlated with a composite index including routinely reported pathobiologic features. Cancer Invest 28(9):969–977. doi: 10.3109/07357907.2010.512600 PubMedCrossRefGoogle Scholar
  22. 22.
    Stendahl M, Ryden L, Nordenskjold B, Jonsson PE, Landberg G, Jirstrom K (2006) High progesterone receptor expression correlates to the effect of adjuvant tamoxifen in premenopausal breast cancer patients. Clin Cancer Res 12(15):4614–4618. doi: 10.1158/1078-0432.CCR-06-0248 PubMedCrossRefGoogle Scholar
  23. 23.
    Arpino G, Weiss H, Lee AV, Schiff R, De Placido S, Osborne CK, Elledge RM (2005) Estrogen receptor-positive, progesterone receptor-negative breast cancer: association with growth factor receptor expression and tamoxifen resistance. J Natl Cancer Inst 97(17):1254–1261. doi: 10.1093/jnci/dji249 PubMedCrossRefGoogle Scholar
  24. 24.
    Liu S, Chia SK, Mehl E, Leung S, Rajput A, Cheang MC, Nielsen TO (2009) Progesterone receptor is a significant factor associated with clinical outcomes and effect of adjuvant tamoxifen therapy in breast cancer patients. Breast Cancer Res Treat 119(1):53–61. doi: 10.1007/s10549-009-0318-0 PubMedCrossRefGoogle Scholar
  25. 25.
    Tang P, Wang J, Hicks DG, Wang X, Schiffhauer L, McMahon L, Yang Q, Shayne M, Huston A, Skinner KA, Griggs J, Lyman G (2010) A lower Allred score for progesterone receptor is strongly associated with a higher recurrence score of 21-gene assay in breast cancer. Cancer Invest 28(9):978–982. doi: 10.3109/07357907.2010.496754 PubMedCrossRefGoogle Scholar
  26. 26.
    Goldstein LJ, Gray R, Badve S, Childs BH, Yoshizawa C, Rowley S, Shak S, Baehner FL, Ravdin PM, Davidson NE, Sledge GW Jr, Perez EA, Shulman LN, Martino S, Sparano JA (2008) Prognostic utility of the 21-gene assay in hormone receptor-positive operable breast cancer compared with classical clinicopathologic features. J Clin Oncol 26(25):4063–4071. doi: 10.1200/JCO.2007.14.4501 PubMedCrossRefGoogle Scholar
  27. 27.
    Baehner FQC, Pomeroy C, Cherbavaz C, Shak S (2009) Biopsy cavities in breast cancer specimens: their impact on quantitative RT-PCR gene expression profiles and recurrence risk assessment. Mod Pathol 22(1s):4A–11A. doi: 10.1038/modpathol.2008.208 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2011

Authors and Affiliations

  • K. H. Allison
    • 1
    Email author
  • P. L. Kandalaft
    • 2
  • C. M. Sitlani
    • 1
  • S. M. Dintzis
    • 1
  • A. M. Gown
    • 2
  1. 1.University of Washington Medical CenterSeattleUSA
  2. 2.PhenoPath LaboratoriesSeattleUSA

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