Pathological Assessment Following Pre-operative Systemic Therapy

Translational Research (Vered Stearns, Section Editor)


There are several specialized pathological evaluation algorithms available to sub-classify response to chemotherapy ranging from simple to complex that provide prognostic survival information. Currently, pathological complete response (pCR) is used as a surrogate marker of overall survival and overall disease-free survival, but pCR does not uniformly predict excellent overall survival. We would like to move away from a binary system of evaluating pathological response to a drug regimen of pCR versus non-pCR so that we identify subtle but potentially significant differences between drug regimens. Following treatment, hormone receptor status and HER2/neu status can change, and repeat hormone receptor studies should be performed on residual disease because changes will impact patient treatment and survival. The traditional prognostic factors of tumor grade and hormone receptor status pre-treatment also contribute to overall survival and disease-free survival in patients with and without a pCR.


Breast carcinoma Neoadjuvant chemotherapy Pre-operative systemic therapy Miller-Payne Residual Cancer Burden Hormone receptor Neoadjuvant response index Estrogen receptor HER2/neu AJCC 


Papers of particular interest, published recently, have been highlighted as: •Of importance

  1. 1.
    NCCN. Clinical practice guidelines in oncology. Breast cancer V.I: National comprehensive cancer network. (2009).
  2. 2.
    Fisher B, Bryant J, Wolmark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672–85.PubMedGoogle Scholar
  3. 3.
    Kuerer HM, Newman LA, Smith TL, et al. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy. J Clin Oncol. 1999;17(2):460–9.PubMedGoogle Scholar
  4. 4.
    Symmans WF, Peintinger F, Hatzis C, et al. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007;25:4414–22.PubMedCrossRefGoogle Scholar
  5. 5.
    • von Minckwitz G, Kaufmann M, Kümmel S, et al. Definition and impact of pathological complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. Results from the German neoadjuvant meta-analysis. [abst 1028]. Presented at ASCO Annual Meeting 2011, Chicago Illinois June 3rd–7th 2011. This reference illustrates that all pCR are not equal for predicting overall survival and disease-free survival and that the hormone receptor status and tumor grade impact the prognostic strength of a pCR.Google Scholar
  6. 6.
    Rouzier R, Extra JM, Klijanienko J, et al. Incidence and prognostic significance of complete axillary downstaging after primary chemotherapy in breast cancer patients with T1 to T3 tumors and cytologically proven axillary metastatic lymph nodes. J Clin Oncol. 2002;20(5):1304–10.PubMedCrossRefGoogle Scholar
  7. 7.
    Hennessy BT, Hortobagyi GN, Rouzier R, et al. Outcome after pathologic complete eradication of cytologically proven breast cancer axillary node metastases following primary chemotherapy. J Clin Oncol. 2005;23(36):9304–11.PubMedCrossRefGoogle Scholar
  8. 8.
    Thomas E, Holmes FA, Smith TL, et al. The use of alternate non-cross resistant adjuvant chemotherapy on the bases of pathological response to a neoadjuvant doxorubicin-based regimen in women with operable breast cancer: long-term results from a prospective randomized trial. J Clin Oncol. 2004;22:2294–302.PubMedCrossRefGoogle Scholar
  9. 9.
    Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, et al. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997;15(7):2483–93.PubMedGoogle Scholar
  10. 10.
    Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27. J Clin Oncol. 2008;26(5):778–85.PubMedCrossRefGoogle Scholar
  11. 11.
    Gianni L, Baselga J, Eiermann W, et al. Feasibility and tolerability of sequential Doxorubicin/Paclitaxel followed by cyclophosphamide, methotrexate, and fluorouracil and its effects on tumor response as preoperative therapy. Clin Can Res. 2005;11:8715–21.CrossRefGoogle Scholar
  12. 12.
    Von Minckwitz G, Costa SD, Raab G, et al. Dose-dense doxorubicin and docetaxel with or without tamoxifen a spreoperative therapy in patients with operable carcinoma of the breast: a randomized, controlled, open phase IIb study. J Clin Oncol. 2001;19:3506–15.Google Scholar
  13. 13.
    Jackisch C, von Minckwitz G, Eidtmann H, et al. Dose-dense biweekly (8 weeks) versus sequential (24 weeks) neoadjuvant chemotherapy with doxorubicin–cyclophosphamide and docetaxel in operable breast cancer–2nd Interim Analysis of the GABG GEPAR-DUO Trial. Clin Breast Cancer. 2002;3:276–80.PubMedCrossRefGoogle Scholar
  14. 14.
    Von Minckwitz G, Blohmer JU, Raab G, Lohr A, Gerber B, Heinrich G, et al. In vivo chemosensitivity-adapted preoperative chemotherapy in patients with early-stage breast cancer: the GEPARTRIO pilot study. Ann Oncol. 2005;16:56–63.CrossRefGoogle Scholar
  15. 15.
    Jones RL, Lakhani SR, Ring AE, et al. Pathological complete response and residual DCIS following neoadjuvant chemotherapy for breast carcinoma. Br J Canc. 2006;94:358–62.CrossRefGoogle Scholar
  16. 16.
    Marzouni C, Peintinger F, Wan-Kau S, et al. Residual ductal carcinoma in situ in patients with complete eradication of invasive breast cancer after neoadjuvant chemotherapy does not adversely affect patient outcome. J Clin Oncol. 2007;25:2650–5.CrossRefGoogle Scholar
  17. 17.
    Carey LA, Metzger R, Dees EC, et al. American joint committee on cancer tumor-node-metastasis stage after neoadjuvant chemotherapy and breast cancer outcome. J Natl Cancer Inst. 2005;97:1137–42.PubMedCrossRefGoogle Scholar
  18. 18.
    Ogston KN, Miller ID, Payne S, et al. A new histological grading system to assess response of breast carcinomas to primary chemotherapy: prognostic significance and survival. Breast. 2003;12:320–7.PubMedCrossRefGoogle Scholar
  19. 19.
    AJCC Cancer staging manual by the American Joint Committee on Cancer (Seventh edition): Edge SB, Byrd DR, Compton CC et al., editors. Springer-Verlag New York NY; 2010. ISBN 978-0-387-88440-0Google Scholar
  20. 20.
    Klauber-DeMore N, Ollila DW, Moore DT, et al. Size of residual lymph node metastasis after neoadjuvant chemotherapy in locally advanced breast cancer patients is prognostic. Ann Surg Oncol. 2006;13:685–91.PubMedCrossRefGoogle Scholar
  21. 21.
    Fisher ER, Wang J, Bryant J, Fisher B, Mamounas E, Wolmark N. Pathobiology of preoperative chemotherapy: findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer. 2002;95(4):681–95.PubMedCrossRefGoogle Scholar
  22. 22.
    Cote R, Giuliano AE, Hawes D, et al. ACOSOG ZOO10: a multicenter prognostic study of sentinel node (SN) and bone marrow (BM) micrometastases in women with clinical T1/T2 N0 M0 breast cancer. J Clin Oncol. 2010;28(Suppl):18–8.Google Scholar
  23. 23.
    • Weaver DL, Ashikaga T, Krag D et al. Effect of occult metastases on survival in node-negative breast cancer. N Engl J Med. 2011;364:412–421. This publication is the largest cohort available that reports the pre-treatment significance of isolated tumor cells and micrometastases on overall survival compared with truly node-negative patients.PubMedCrossRefGoogle Scholar
  24. 24.
    • Sakakibara M, Nagashima T, Kadowaki M et al. Clinical Significance of Axillary Microresiduals After Neoadjuvant Chemotherapy in Breast Cancer Patients with Cytologically Proven Metastases. Ann Surg Oncol. 2009;16(9):2470–2478. This study, although small, suggests that survival in the setting of isolated tumor cells in lymph nodes post-treatment may cluster with truly node-negative patients rather than with micrometastases that are equivalent to macrometastases pre-treatment.PubMedCrossRefGoogle Scholar
  25. 25.
    • Rodenhuis S, Mandjes IAM, Wesseling J, et al. A simple system for grading the response of breast cancer to neoadjuvant chemotherapy. Annals of Oncology 2010 21: 481–487. This article describes a method of estimating response to chemotherapy using standard pathological AJCC classification and data typically available in the patient’s medical record.Google Scholar
  26. 26.
    Sataloff DM, Mason BA, Prestipino AJ, et al. Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J Am Coll Surg. 1995;180:297–306.PubMedGoogle Scholar
  27. 27.
    Chevallier B, Roche H, Olivier JP, Chollet P, Hurteloup P. Inflammatory breast cancer: pilot study of intensive induction chemotherapy (FEC-HD) results in a high histologic response rate. Am J Clin Oncol. 1993;16:223–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Hirata T, Shimizu C, Yonemori K, et al. Change in the hormone receptor status following administration of neoadjuvant chemotherapy and its impact on the long-term outcome in patients with primary breast cancer. Br J Canc. 2009;101(9):1529–36.CrossRefGoogle Scholar
  29. 29.
    Neubauer H, Gall C, Vogel U, et al. Changes in tumour biological markers during primary systemic chemotherapy (PST). Anticancer Res. 2008;28:1797–804.PubMedGoogle Scholar
  30. 30.
    Kumaki N, Umemura S, Tang X, et al. Alteration of immunohistochemical biomarkers between pre- and post-chemotherapy: hormone receptors, HER2 and Ki67. Breast Canc. 2011;18:98–102.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Pathology, Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  2. 2.Department of Cancer Biology, Dana Farber Cancer InstituteHarvard Medical SchoolBostonUSA

Personalised recommendations