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Issues in the assessment of the pathologic effect of primary systemic therapy for breast cancer

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Abstract

Background

Emerging evidence suggests that induction of pathologic complete response (pCR) after primary systemic therapy (PST) is, at least to some extent, predictive of survival. However, standards for processing surgical specimens and for histopathologic evaluation of the pathologic response to therapy appear to be lacking.

Methods

To perform a systematic review of representative articles on this topic, a computerized (MEDLINE) search was undertaken followed by a manual search based on the reference lists of the publications identified.

Results

Several classification systems have been used to assess pathologic response to PST, the term pCR has not been applied in a consistent standardized manner, and only limited information is available about the reliability and validity of these classification systems. However, definitions of pCR can be summarized as follows: near pCR, only focal invasive tumor residues in the removed breast; quasi pCR, total or near total disappearance of invasive tumor in the removed breast; pCRinv, only in situ tumor residual in the removed breast; comprehensive pCR, no evidence of residual invasive tumor in the removed breast; strict pCR, disappearance of all tumor cells in the removed breast; comprehensive pCRbr+n, no evidence of residual invasive tumor in the breast and axillary nodes; strict pCRbr+n, no malignant tumor cells in the removed breast and axillary nodes. Comparison of the use of the term “pCR” in various trials reveals that it is not applied equivalently in these studies.

Conclusion

Assessment of pCR needs to be standardized, with verification for reliability and validity. For now, the non-equivalency in the definition of pCR should be taken into account when comparing the results of PST.

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Abbreviations

BCT:

Breast conserving therapy

DFS:

Disease-free survival

NSABP:

National surgical Adjuvant Breast and Bowel Project

PST:

Primary systemic therapy

OS:

Overall survival

pCR:

Pathologic complete response

References

  1. Kaufmann M, von Minckwitz G, Smith R, Valero V, Gianni L, Eiermann W, Howell A, Costa SD, Beuzeboc P, Untch M, Blohmer JU, Sinn HP, Sittek R, Souchon R, Tulusan AH, Volm T, Senn HJ: International expert panel on the use of primary (preoperative) systemic treatment of operable breast cancer: review and recommendations.J Clin Oncol 21:2600–2608, 2003.

    Article  PubMed  Google Scholar 

  2. Schwartz GF, Hortobagyi GN: Proceedings of the consensus conference on neoadjuvant chemotherapy in carcinoma of the breast, April 26–28, 2003, Philadelphia, Pennsylvania.Cancer 100: 2512–2532, 2004.

    Article  PubMed  Google Scholar 

  3. Estevez LG, Gradishar WJ: Evidence-based use of neoadjuvant taxane in operable and inoperable breast cancer.Clin Cancer Res 10: 3249–3261, 2004.

    Article  PubMed  CAS  Google Scholar 

  4. Shannon C, Smith I: Is there still a role for neoadjuvant therapy in breast cancer?Crit Rev Oncol Hematol 45: 77–90, 2003.

    Article  PubMed  Google Scholar 

  5. Esserman L: Neoadjuvant chemotherapy for primary breast cancer: lessons learned and opportunities to optimize therapy.Ann Surg Oncol 11: 3S-8S, 2004.

    Article  PubMed  Google Scholar 

  6. Iwata H, Nakamura S, Toi M, Shin E, Masuda N, Ohno S, Takatsuka Y, Hisamatsu K, Yamazaki K, Kusama M, Kaise H, Sato Y, Kuroi K, Akiyama F, Tsuda H, Kurosumi M: Interim analysis of a phase II trial of cyclophosphamide, epirubicin, 5-fluorouracil (CEF) followed by docetaxel as preoperative chemotherapy for early stage breast carcinoma.Breast Cancer (in print), 2005.

  7. Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A, Margolese RG, Cruz AB, Jr., Hoehn JL, Lees AW, Dimitrov NV, Bear HD: Effect of preoperative chemotherapy on the outcome of women with operable breast cancer.J Clin Oncol 16: 2672–2685, 1998.

    PubMed  CAS  Google Scholar 

  8. Kuerer HM, Newman LA, Buzdar AU, Hunt KK, Dhingra K, Buchholz TA, Binkley SM, Ames FC, Feig BW, Ross MI, Hortobagyi GN, Singletary SE: Residual metastatic axillary lymph nodes following neoadjuvant chemotherapy predict disease-free survival in patients with locally advanced breast cancer.Am J Surg 176: 502–509, 1998.

    Article  PubMed  CAS  Google Scholar 

  9. Kuerer HM, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K, Theriault RL, Singh G, Binkley SM, Sneige N, Buchholz TA, Ross MI, McNeese MD, Buzdar AU, Hortobagyi GN, Singletary SE: Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadjuvant chemotherapy.J Clin Oncol 17: 460–469, 1999.

    PubMed  CAS  Google Scholar 

  10. Smith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, Ah-See AK, Eremin O, Walker LG, Sarkar TK, Eggleton SP, Ogston KN: Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel.J Clin Oncol 20: 1456–1466, 2002.

    Article  PubMed  CAS  Google Scholar 

  11. Tomczykowski J, Szubstarski F, Kurylcio L, Stanislawek A, Barycki J, Baranowski W: Does the degree of cell lesion in breast cancer after inductive chemotherapy have any prognostic value?Acta Oncol 38: 949–953, 1999.

    Article  PubMed  CAS  Google Scholar 

  12. Dieras V, Fumoleau P, Romieu G, Tubiana-Hulin M, Namer M, Mauriac L, Guastalla JP, Pujade-Lauraine E, Kerbrat P, Maillart P, Penault-Llorca F, Buyse M, Pouillart P: Randomized parallel study of doxorubicin plus paclitaxel and doxorubicin plus cyclophosphamide as neoadjuvant treatment of patients with breast cancer.J Clin Oncol 22: 4958–4965, 2004.

    Article  PubMed  CAS  Google Scholar 

  13. Sharkey FE, Addington SL, Fowler LJ, Page CP, Cruz AB: Effects of preoperative chemotherapy on the morphology of resectable breast carcinoma.Mod Pathol 9: 893–900, 1996.

    PubMed  CAS  Google Scholar 

  14. Aktepe F, Kapucuoglu N, Pak I: The effects of chemotherapy on breast cancer tissue in locally advanced breast cancer.Histopathology 29: 63–67, 1996.

    Article  PubMed  CAS  Google Scholar 

  15. Smith IC, Miller ID: Issues involved in research into the neoadjuvant treatment of breast cancer.Anticancer Drugs 12 Suppl 1: S25–29, 2001.

    Google Scholar 

  16. 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 95: 681–695, 2002.

    Article  PubMed  Google Scholar 

  17. Kennedy S, Merino MJ, Swain SM, Lippman ME: The effects of hormonal and chemotherapy on tumoral and nonneoplastic breast tissue.Hum Pathol 21: 192–198, 1990.

    Article  PubMed  CAS  Google Scholar 

  18. Moll UM, Chumas J: Morphologic effects of neoadjuvant chemotherapy in locally advanced breast cancer.Pathol Res Pract 193: 187–196, 1997.

    PubMed  CAS  Google Scholar 

  19. Rajan R, Poniecka A, Smith TL, Yang Y, Frye D, Pusztai L, Fiterman DJ, Gal-Gombos E, Whitman G, Rouzier R, Green M, Kuerer H, Buzdar AU, Hortobagyi GN, Symmans WF: Change in tumor cellularity of breast carcinoma after neoadjuvant chemotherapy as a variable in the pathologic assessment of response.Cancer 100:1365–1373, 2004.

    Article  PubMed  Google Scholar 

  20. Rajan R, Esteva FJ, Symmans WF: Pathologic changes in breast cancer following neoadjuvant chemotherapy: implications for the assessment of response.Clin Breast Cancer 5: 235–238, 2004.

    Article  PubMed  Google Scholar 

  21. Wu W, Kamma H, Ueno E, Fujiwara M, Satoh H, Hara H, Yashiro T, Aiyoshi Y: The intraductal component of breast cancer is poorly responsive to neo-adjuvant chemotherapy.Oncol Rep 9: 1027–1031, 2002.

    PubMed  Google Scholar 

  22. Sinn HP, Schmid H, Junkermann H, Huober J, Leppien G, Kaufmann M, Bastert G, Otto HF: Histologic regression of breast cancer after primary (neoadjuvant) chemotherapy.Geburtshilfe Frauenheilkd 54: 552–558, 1994.

    Article  PubMed  CAS  Google Scholar 

  23. Honkoop AH, van Diest PJ, de Jong JS, Linn SC, Giaccone G, Hoekman K, Wagstaff J, Pinedo HM: Prognostic role of clinical, pathological and biological characteristics in patients with locally advanced breast cancer.Br J Cancer 77: 621–626, 1998.

    PubMed  CAS  Google Scholar 

  24. 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 16: 223–228, 1993.

    Article  PubMed  CAS  Google Scholar 

  25. Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z: Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome.J Am Coll Surg 180: 297–306, 1995.

    PubMed  CAS  Google Scholar 

  26. Kurosumi M: Significance of histopathological evaluation in primary therapy for breast cancer-recent trends in primary modality with pathological complete response (pCR) as endpoint.Breast Cancer 11: 139–147, 2004.

    Article  PubMed  Google Scholar 

  27. Kurosumi M, Akiyama F, Iwase T, Motomura K, Okazaki M, Tsuda H: Histopathological criteria for assessment of therapeutic response in breast cancer.Breast Cancer 8: 1–2, 2001.

    Article  PubMed  CAS  Google Scholar 

  28. Kuroi K, Toi M, Tsuda H, Kurosumi M, Akiyama F: Unargued issues on the pathological assessment of response in primary systemic therapy for breast cancer.Biomed Pharmacother in submission: 2005.

  29. Brain E, Garrino C, Misset JL, Carbonero IG, Itzhaki M, Cvitkovic E, Goldschmidt E, Burki F, Regensberg C, Pappo E, Hagipantelli R, Musset M: Long-term prognostic and predictive factors in 107 stage II/III breast cancer patients treated with anthracycline-based neoadjuvant chemotherapy.Br J Cancer 75: 1360–1367, 1997.

    PubMed  CAS  Google Scholar 

  30. Matsuo K, Fukutomi T, Watanabe T, Hasegawa T, Tsuda H, Akashi-Tanaka S: Concordance in pathological response to neoadjuvant chemotherapy between invasive and noninvasive components of primary breast carcinomas.Breast Cancer 9: 75–81, 2002.

    Article  PubMed  Google Scholar 

  31. Semiglazov VF, Topuzov EE, Bavli JL, Moiseyenko VM, Ivanova OA, Seleznev IK, Orlov AA, Barash NY, Golubeva OM, Chepic OF: Primary (neoadjuvant) chemotherapy and radiotherapy compared with primary radiotherapy alone in stage IIb-IIIa breast cancer.Ann Oncol 5: 591–595, 1994.

    PubMed  CAS  Google Scholar 

  32. Ikeda T, Jinno H, Matsu A, Masamura S, Kitajima M: The role of neoadjuvant chemotherapy for breast cancer treatment.Breast Cancer 9: 8–14, 2002.

    Article  PubMed  Google Scholar 

  33. Nakamura S, Kenjo H, Nishio T, Kazama T, Doi O, Suzuki K: Efficacy of 3D-MR mammography for breast conserving surgery after neoadjuvant chemotherapy.Breast Cancer 9: 15–19, 2002.

    Article  PubMed  Google Scholar 

  34. Nakamura S: Present role and future perspectives of the evaluation of the efffect of primary chemotherapy by breast imaging.Breast cancer 11: 134–138, 2004.

    Article  PubMed  Google Scholar 

  35. Marshall C, Eremin J, El-Sheemy M, Eremin O, Griffiths PA: Monitoring the response of large (>3 cm) and locally advanced (T3-4, NO-2) breast cancer to neoadjuvant chemotherapy using 99mTc-Sestamibi uptake.Nucl Med Commun 26: 9–15, 2005.

    Article  PubMed  CAS  Google Scholar 

  36. Morrell LE, Lee YJ, Hurley J, Arias M, Mies C, Richman SP, Fernandez H, Donofrio KA, Raub WA, Jr., Cassileth PA: A Phase II trial of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin in the treatment of patients with locally advanced breast carcinoma.Cancer 82: 503–511, 1998.

    Article  PubMed  CAS  Google Scholar 

  37. Ganem G, Tubiana-Hulin M, Fumoleau P, Combe M, Misset JL, Vannetzel JM, Bachelot T, De Ybarlucea LR, Lotz V, Bendahmane B, Dieras V: Phase II trial combining docetaxel and doxorubicin as neoadjuvant chemotherapy in patients with operable breast cancer.Ann Oncol 14: 1623–1628, 2003.

    Article  PubMed  CAS  Google Scholar 

  38. Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N: The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27.J Clin Oncol 21: 4165–4174, 2003.

    Article  PubMed  CAS  Google Scholar 

  39. Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB, Jr., Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV: 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 15: 2483–2493, 1997.

    PubMed  CAS  Google Scholar 

  40. Dalton LW, Pinder SE, Elston CE, Ellis IO, Page DL, Dupont WD, Blarney RW: Histologic grading of breast cancer: linkage of patient outcome with level of pathologist agreement.Mod Pathol 13: 730–735, 2000.

    Article  PubMed  CAS  Google Scholar 

  41. Roberti NE: The role of histologic grading in the prognosis of patients with carcinoma of the breast: is this a neglected opportunity?Cancer 80: 1708–1716, 1997.

    Article  PubMed  CAS  Google Scholar 

  42. McCready DR, Hortobagyi GN, Kau SW, Smith TL, Buzdar AU, Balch CM: The prognostic significance of lymph node metastases after preoperative chemotherapy for locally advanced breast cancer.Arch Surg 124: 21–25, 1989.

    PubMed  CAS  Google Scholar 

  43. Machiavelli MR, Romero AO, Perez JE, Lacava JA, Dominguez ME, Rodriguez R, Barbieri MR, Romero Acuna LA, Romero Acuna JM, Langhi MJ, Amato S, Ortiz EH, Vallejo CT, Leone BA: Prognostic significance of pathological response of primary tumor and metastatic axillary lymph nodes after neoadjuvant chemotherapy for locally advanced breast carcinoma.Cancer J Sci Am 4: 125–131, 1998.

    PubMed  CAS  Google Scholar 

  44. Rouzier R, Extra JM, Klijanienko J, Falcou MC, Asselain B, Vincent-Salomon A, Vielh P, Bourstyn E: 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 20: 1304–1310, 2002.

    Article  PubMed  Google Scholar 

  45. Newman LA, Buzdar AU, Singletary SE, Kuerer HM, Buchholz T, Ames FC, Ross MI, Hunt KK: A prospective trial of preoperative chemotherapy in resectable breast cancer: predictors of breast-conservation therapy feasibility.Ann Surg Oncol 9: 228–234, 2002.

    Article  PubMed  Google Scholar 

  46. Amat S, Bougnoux P, Penault-Llorca F, Fetissof F, Cure H, Kwiatkowski F, Achard JL, Body G, Dauplat J, Chollet P: Neoadjuvant docetaxel for operable breast cancer induces a high pathological response and breast-conservation rate.Br J Cancer 88:1339–1345, 2003.

    Article  PubMed  CAS  Google Scholar 

  47. Buchholz TA, Hunt KK, Whitman GJ, Sahin AA, Hortobagyi GN: Neoadjuvant chemotherapy for breast carcinoma: multidisciplinary considerations of benefits and risks.Cancer 98: 1150–1160, 2003.

    Article  PubMed  Google Scholar 

  48. Makris A, Powles TJ, Ashley SE, Chang J, Hickish T, Tidy VA, Nash AG, Ford HT: A reduction in the requirements for mastectomy in a randomized trial of neoadjuvant chemoendocrine therapy in primary breast cancer.Ann Oncol 9: 1179–1184, 1998.

    Article  PubMed  CAS  Google Scholar 

  49. Hage van der JA, Velde van de CJ, Julien JP, Tubiana-Hulin M, Vandervelden C, Duchateau L: Preoperative chemotherapy in primary operable breast cancer: results from the European Organization for Research and Treatment of Cancer trial 10902.J Clin Oncol 19: 4224–4237, 2001.

    PubMed  Google Scholar 

  50. Buzdar AU, Singletary SE, Theriault RL, Booser DJ, Valero V, Ibrahim N, Smith TL, Asmar L, Frye D, Manuel N, Kau SW, McNeese M, Strom E, Hunt K, Ames F, Hortobagyi GN: Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer.J Clin Oncol 17: 3412–3417, 1999.

    PubMed  CAS  Google Scholar 

  51. Minckwitz von G, Costa SD, Raab G, Blohmer JU, Eidtmann H, Hilfrich J, Merkle E, Jackisch C, Gademann G, Tulusan AH, Eiermann W, Graf E, Kaufmann M: Dose-dense doxorubicin, docetaxel, and granulocyte colony-stimulating factor support with or without tamoxifen as preoperative therapy in patients with operable carcinoma of the breast: a randomized, controlled, open phase IIb study.J Clin Oncol 19: 3506–3515, 2001.

    Google Scholar 

  52. Jackisch C, Minckwitz von G, Eidtmann H, Costa SD, Raab G, Blohmer JU, Schutte M, Gerber B, Merkle E, Gademann G, Lampe D, Hilfrich J, Tulusan AH, Caputo A, Kaufmann M: Dose-dense biweekly doxorubicin/docetaxel versus sequential neoadjuvant chemotherapy with doxorubicin/cyclophosphamide/ docetaxel in operable breast cancer: second interim analysis.Clin Breast Cancer 3: 276–280, 2002.

    Article  PubMed  CAS  Google Scholar 

  53. Schwartz GF, Birchansky CA, Komarnicky LT, Mansfield CM, Cantor RI, Biermann WA, Fellin FM, McFarlane J: Induction chemotherapy followed by breast conservation for locally advanced carcinoma of the breast.Cancer 73: 362–369, 1994.

    Article  PubMed  CAS  Google Scholar 

  54. Bonadonna G, Valagussa P, Brambilla C, Ferrari L, Moliterni A, Terenziani M, Zambetti M: Primary chemotherapy in operable breast cancer: eight-year experience at the Milan Cancer Institute.J Clin Oncol 16: 93–100, 1998.

    PubMed  CAS  Google Scholar 

  55. Kuerer HM, Newman LA, Buzdar AU, Dhingra K, Hunt KK, Buchholz TA, Binkley SM, Strom EA, Ames FC, Ross MI, Feig BW, McNeese MD, Hortobagyi GN, Singletary SE: Pathologic tumor response in the breast following neoadjuvant chemotherapy predicts axillary lymph node status.Cancer J Set Am 4: 230–236, 1998.

    CAS  Google Scholar 

  56. Barni S, Piazza E, Frontini L, Visini M, Ardizzoia A, Grassi MM, Nosenzo MA, Mandala M, Biasioli R, Freddi E, Lucani L, Recalcati A, Pravettoni A, Sala R, Rezzani C, Villa S, Trabucchi E: Single-agent epiru-bicin as primary chemotherapy in T2-T3, N0-N2, M0 breast carcinoma: 6-year follow-up.Oncology 67: 40–47, 2004.

    Article  PubMed  CAS  Google Scholar 

  57. Ezzat AA, Ibrahim EM, Ajarim DS, Rahal MM, Raja MA, Tulbah AM, Al-Malik OA, Al-Shabanah M, Sorbris R: Phase II study of neoadjuvant paclitaxel and cisplatin for operable and locally advanced breast cancer: analysis of 126 patients.Br J Cancer 90: 968–974, 2004.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Showa University Toyosu Hospital, 4-1-18 Toyosu, Koutou-ku, 135-8577, Tokyo, Japan

    Katsumasa Kuroi, Masakazu Toi, Hitoshi Tsuda, Masafumi Kurosumi & Futoshi Akiyama

  2. Department of Surgery, Showa University Toyosu Hospital, Japan

    Katsumasa Kuroi

  3. Division of Clinical Trial and Research, Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Japan

    Masakazu Toi

  4. Department of Pathology II, National Defense Medical College, Japan

    Hitoshi Tsuda

  5. Department of Pathology, Saitama Cancer Center, Japan

    Masafumi Kurosumi

  6. Department of Breast Pathology, Cancer Institute, Japan

    Futoshi Akiyama

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  1. Katsumasa Kuroi
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  2. Masakazu Toi
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  3. Hitoshi Tsuda
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  4. Masafumi Kurosumi
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  5. Futoshi Akiyama
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Correspondence to Katsumasa Kuroi.

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Kuroi, K., Toi, M., Tsuda, H. et al. Issues in the assessment of the pathologic effect of primary systemic therapy for breast cancer. Breast Cancer 13, 38–48 (2006). https://doi.org/10.2325/jbcs.13.38

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