J Korean Surg Soc.  2013 May;84(5):273-280.

Neoadjuvant human epidermal growth factor receptor-2 targeted therapy in patients with locally advanced breast cancer

• Cho DH
• Lee SK
• Kim S
• Choi MY
• Jung SP
• Lee J
• Kim J
• Koo MY
• Bae SY
• Kim JH
• Kim JS
• Ho KW
• Lee JE
• Nam SJ
• Yang JH

Abstract

PURPOSE
We analyzed the responses of patients with locally advanced breast cancer to neoadjuvant chemotherapy (NAC) and NAC combined with neoadjuvant human epidermal growth factor receptor-2 (HER2) targeted therapy (NCHTT).
METHODS
We retrospectively reviewed 59 patients with HER2 amplified locally advanced breast cancer among patients who were treated surgically after neoadjuvant therapy at Samsung Medical Center between 2005 and 2009. Thirty-one patients received conventional NAC and 28 patients received NCHTT. Pathologic responses were assessed according to response evaluation criteria in solid tumors (RECIST) guidelines.
RESULTS
Pathologic complete response (pCR) was achieved in 13 out of 28 patients treated with NCHTT and in 6 out of 31 patients treated with NAC alone (46.4% vs. 19.4%, respectively, P = 0.049). Breast conserving surgery (BCS) was more frequently performed in the NCHTT group than in the NAC only group (71.4% vs. 19.4%, P < 0.001). The 3-year recurrence-free survival (RFS) rate was 100% in the NCHTT group and 76.4% in the NAC group (P = 0.014). Together, NCHTT, type of operation (BCS vs. mastectomy) and pathologic nodal status were significant prognostic factors for RFS in univariate analysis.
CONCLUSION
We found that NCHTT produced higher pCR rates than NAC alone in locally advanced breast cancer.

Keyword

Breast neoplasms; Neoadjuvant therapy; ErbB-2; Response

MeSH Terms

Breast
Breast Neoplasms
Epidermal Growth Factor
Humans
Mastectomy, Segmental
Neoadjuvant Therapy
Polymerase Chain Reaction
Retrospective Studies
Epidermal Growth Factor

Figure

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  Fig. 1 Recurrence-free survival (RFS) curve for advanced breast cancer patients treated by neoadjuvant chemotherapy combined with neoadjuvant human epidermal growth factor receptor 2 targeted therapy (NCHTT) and neoadjuvant chemotherapy (NAC).

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  Fig. 2 Overall survival (OS) curve for advanced breast cancer patients treated by neoadjuvant chemotherapy combined with neoadjuvant human epidermal growth factor receptor 2 targeted therapy (NCHTT) and neoadjuvant chemotherapy (NAC).

Reference

1. Early Breast Cancer Trialists' Collaborative Group (EBCTCG).Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005. 365:1687–1717.

2. Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, et al. Cancer statistics, 2006. CA Cancer J Clin. 2006. 56:106–130.

3. De Lena M, Zucali R, Viganotti G, Valagussa P, Bonadonna G. Combined chemotherapy-radiotherapy approach in locally advanced (T3b-T4) breast cancer. Cancer Chemother Pharmacol. 1978. 1:53–59.

4. Rubens RD, Sexton S, Tong D, Winter PJ, Knight RK, Hayward JL. Combined chemotherapy and radiotherapy for locally advanced breast cancer. . Eur J Cancer. 1980. 16:351–356.

5. Kantarjian HM, Hortobagyi GN, Smith TL, Blumenschein GR, Montague E, Buzdar AU, et al. The management of locally advanced breast cancer: a combined modality approach. Eur J Cancer Clin Oncol. 1984. 20:1353–1361.

6. Lippman ME, Sorace RA, Bagley CS, Danforth DW Jr, Lichter A, Wesley MN. Treatment of locally advanced breast cancer using primary induction chemotherapy with hormonal synchronization followed by radiation therapy with or without debulking surgery. NCI Monogr. 1986. (1):153–159 .

7. Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998. 16:2672–2685.

8. Kim JW, Jung SK, Eum T, Koo BY, Kang HJ, Kim LS. Pathologic findings of residual tumor according to the response rate after neoadjuvant chemotherapy for breast cancer. J Korean Surg Soc. 2008. 75:1–8.

9. Press MF, Bernstein L, Thomas PA, Meisner LF, Zhou JY, Ma Y, et al. HER-2/neu gene amplification characterized by fluorescence in situ hybridization: poor prognosis in node-negative breast carcinomas. J Clin Oncol. 1997. 15:2894–2904.

10. Moy B, Goss PE. Lapatinib: current status and future directions in breast cancer. Oncologist. 2006. 11:1047–1057.

11. Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, et al. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005. 23:3676–3685.

12. Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010. 17:1471–1474.

13. Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008. 26:778–785.

14. Kuerer HM, Newman Smith, Ames FC, Hunt KK, Dhingra K, 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. 17:460–469.

15. Baselga J, Swain SM. anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009. 9:463–475.

16. Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TP, Leahy DJ, et al. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell. 2003. 12:541–552.

17. Nahta R, Esteva FJ. Herceptin: mechanisms of action and resistance. Cancer Lett. 2006. 232:123–138.

18. Longva KE, Pedersen NM, Haslekas C, Stang E, Madshus IH. Herceptin-induced inhibition of ErbB2 signaling involves reduced phosphorylation of Akt but not endocytic down-regulation of ErbB2. Int J Cancer. 2005. 116:359–367.

19. Pegram MD, Konecny GE, O'Callaghan C, Beryt M, Pietras R, Slamon DJ. Rational combinations of trastuzumab with chemotherapeutic drugs used in the treatment of breast cancer. J Natl Cancer Inst. 2004. 96:739–749.

20. Arnould L, Gelly M, Penault-Llorca F, Benoit L, Bonnetain F, Migeon C, et al. Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism? Br J Cancer. 2006. 94:259–267.

21. Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex . Cancer Cell. 2004. 5:317–328.

22. Mendoza N, Phillips GL, Silva J, Schwall R, Wickramasinghe D. Inhibition of ligand-mediated HER2 activation in androgen-independent prostate cancer. Cancer Res. 2002. 62:5485–5488.

23. Bouchalova K, Cizkova M, Cwiertka K, Trojanec R, Friedecky D, Hajduch M. Lapatinib in breast cancer - the predictive significance of HER1 (EGFR), HER2, PTEN and PIK3CA genes and lapatinib plasma level assessment. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010. 154:281–288.

24. Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, et al. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010. 375:377–384.

25. Untch M, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, et al. Neoadjuvant treatment with trastuzumab in HER2-positive breast cancer: results from the Gepar- Quattro study. J Clin Oncol. 2010. 28:2024–2031.