Originally published as JCO Early Release 10.1200/JCO.2005.00.661 on February 14 2005
Journal of Clinical Oncology, Vol 23, No 11 (April 10), 2005: pp. 2460-2468
© 2005 American Society of Clinical Oncology.
Neoadjuvant Trastuzumab Induces Apoptosis in Primary Breast Cancers
Syed K. Mohsin,
Heidi L. Weiss,
M. Carolina Gutierrez,
Gary C. Chamness,
Rachel Schiff,
Michael P. DiGiovanna,
Chun-Xia Wang,
Susan G. Hilsenbeck,
C. Kent Osborne,
D. Craig Allred,
Richard Elledge,
Jenny C. Chang
From the Breast Center at Baylor College of Medicine/The Methodist Hospital; Department of Pathology, Baylor College of Medicine, Houston, TX; and Department of Internal Medicine, Yale Cancer Center, New Haven, CT
Address reprint requests to Jenny C. Chang, MD, Breast Center at Baylor College of Medicine/The Methodist Hospital, 1 Baylor Plaza, MS 600, Houston, TX 77030; e-mail: jcchang{at}breastcenter.tmc.edu.
PURPOSE: Greater understanding of the cellular response in trastuzumab-treated patients will provide insight into the clinical management of patients.
PATIENTS AND METHODS: We performed a neoadjuvant trial in 35 patients with locally advanced HER-2/neu overexpressing breast cancers who received weekly trastuzumab given as a single agent for the first 3 weeks, followed by a combination of trastuzumab and docetaxel for 12 weeks before surgery. Sequential core biopsies were taken at baseline and within weeks 1 and 3 after the first dose of trastuzumab. Clinical response to trastuzumab was assessed by tumor measurements on day 22 before chemotherapy. Core biopsies were assessed by immunohistochemistry for cell cycle and proliferation (Ki67, p27, phosphorylated [p] -MAPK), apoptosis and survival (apoptotic index, p-Akt), epidermal growth factor receptor, and total and p-HER-2.
RESULTS: There was early tumor regression with a median decrease of –20.0% (range. 0% to 60.4%) after only 3 weeks of trastuzumab, and eight patients (23%) had a partial response. Consistent with the clinical regressions, apoptosis was significantly induced (median increase from 3.5% to 4.7%; P = .006) within week 1, a 35% increase above baseline. No significant change in epidermal growth factor receptor score was observed in week 1, without changes in total or p-HER-2 expression. Tumors with high baseline Ki67 were less likely to respond (P = .02).
CONCLUSION: In primary breast cancers, trastuzumab substantially induces apoptosis, providing a molecular explanation for both its therapeutic efficacy and its successful combination with cytotoxic chemotherapy.
Supported in part by the R21 CA 87649-01 from the National Cancer Institute, a Grant-in-Aid from Genentech, Inc., the Emma Jacobs Clinical Breast Cancer Fund, the Breast Cancer Research Foundation, and the Breast Cancer SPORE, P50 CA50183 from the National Cancer Institute.
Terms in blue are defined in the glossary, found at the end of this issue and online at www.jco.org.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
This article has been cited by other articles:
|
|
|
|
 
F. Peintinger, A. U. Buzdar, H. M. Kuerer, J. A. Mejia, C. Hatzis, A. M. Gonzalez-Angulo, L. Pusztai, F. J. Esteva, S. S. Dawood, M. C. Green, et al.
Hormone receptor status and pathologic response of HER2-positive breast cancer treated with neoadjuvant chemotherapy and trastuzumab
Ann. Onc.,
July 29, 2008;
(2008)
mdn427v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Li, M. T. Lewis, J. Huang, C. Gutierrez, C. K. Osborne, M.-F. Wu, S. G. Hilsenbeck, A. Pavlick, X. Zhang, G. C. Chamness, et al.
Intrinsic Resistance of Tumorigenic Breast Cancer Cells to Chemotherapy
J Natl Cancer Inst,
May 7, 2008;
100(9):
672 - 679.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. E Hynes
ErbB Receptors in Cancer: HER2/ErbB2 as a Therapeutic Target
Am. Assoc. Cancer Res. Educ. Book,
April 12, 2008;
2008(1):
123 - 130.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Guix, N. de Matos Granja, I. Meszoely, T. B. Adkins, B. M. Wieman, K. E. Frierson, V. Sanchez, M. E. Sanders, A. M. Grau, I. A. Mayer, et al.
Short Preoperative Treatment With Erlotinib Inhibits Tumor Cell Proliferation in Hormone Receptor-Positive Breast Cancers
J. Clin. Oncol.,
February 20, 2008;
26(6):
897 - 906.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. R. Gralow, J. A. Zujewski, and E. Winer
Preoperative Therapy in Invasive Breast Cancer: Reviewing the State of the Science and Exploring New Research Directions
J. Clin. Oncol.,
February 10, 2008;
26(5):
696 - 697.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Varchetta, N. Gibelli, B. Oliviero, E. Nardini, R. Gennari, G. Gatti, L. S. Silva, L. Villani, E. Tagliabue, S. Menard, et al.
Elements Related to Heterogeneity of Antibody-Dependent Cell Cytotoxicity in Patients Under Trastuzumab Therapy for Primary Operable Breast Cancer Overexpressing Her2
Cancer Res.,
December 15, 2007;
67(24):
11991 - 11999.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. A. Ritter, M. Perez-Torres, C. Rinehart, M. Guix, T. Dugger, J. A. Engelman, and C. L. Arteaga
Human Breast Cancer Cells Selected for Resistance to Trastuzumab In vivo Overexpress Epidermal Growth Factor Receptor and ErbB Ligands and Remain Dependent on the ErbB Receptor Network
Clin. Cancer Res.,
August 15, 2007;
13(16):
4909 - 4919.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Arpino, C. Gutierrez, H. Weiss, M. Rimawi, S. Massarweh, L. Bharwani, S. De Placido, C. K. Osborne, and R. Schiff
Treatment of Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer Xenografts With Multiagent HER-Targeted Therapy
J Natl Cancer Inst,
May 2, 2007;
99(9):
694 - 705.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Perez, M. V. Karamouzis, D. V. Skarlos, A. Ardavanis, N. N. Sotiriadou, E. G. Iliopoulou, M. L. Salagianni, G. Orphanos, C. N. Baxevanis, G. Rigatos, et al.
CD4+CD25+ Regulatory T-Cell Frequency in HER-2/neu (HER)-Positive and HER-Negative Advanced-Stage Breast Cancer Patients
Clin. Cancer Res.,
May 1, 2007;
13(9):
2714 - 2721.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. K. Pansegrau, D. R. Grant, B. Norris, and K. A. Gelmon
Trastuzumab-Associated Peripheral Vascular Toxicity
J. Clin. Oncol.,
April 10, 2007;
25(11):
1438 - 1440.
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Suzuki, R. Niwa, S. Saji, M. Muta, M. Hirose, S. Iida, Y. Shiotsu, M. Satoh, K. Shitara, M. Kondo, et al.
A Nonfucosylated Anti-HER2 Antibody Augments Antibody-Dependent Cellular Cytotoxicity in Breast Cancer Patients
Clin. Cancer Res.,
March 15, 2007;
13(6):
1875 - 1882.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. L. Arteaga
Will Single-Time Tumor Profiling and a "Guilt by Association" Approach Allow Us to Outsmart HER2-Positive Breast Cancer?
Clin. Cancer Res.,
February 15, 2007;
13(4):
1071 - 1073.
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Shimizu, M. Ando, T. Kouno, N. Katsumata, and Y. Fujiwara
Current Trends and Controversies over Pre-operative Chemotherapy for Women with Operable Breast Cancer
Jpn. J. Clin. Oncol.,
January 3, 2007;
(2007)
hyl122v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. Chang
HER2 Inhibition: From Discovery to Clinical Practice
Clin. Cancer Res.,
January 1, 2007;
13(1):
1 - 3.
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Hurley, P. Doliny, I. Reis, O. Silva, C. Gomez-Fernandez, P. Velez, G. Pauletti, J. E. Powell, M. D. Pegram, and D. J. Slamon
Docetaxel, Cisplatin, and Trastuzumab As Primary Systemic Therapy for Human Epidermal Growth Factor Receptor 2-Positive Locally Advanced Breast Cancer
J. Clin. Oncol.,
April 20, 2006;
24(12):
1831 - 1838.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Z. T. Schafer, A. B. Parrish, K. M. Wright, S. S. Margolis, J. R. Marks, M. Deshmukh, and S. Kornbluth
Enhanced Sensitivity to Cytochrome c-Induced Apoptosis Mediated by PHAPI in Breast Cancer Cells
Cancer Res.,
February 15, 2006;
66(4):
2210 - 2218.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. B. Wedam, J. A. Low, S. X. Yang, C. K. Chow, P. Choyke, D. Danforth, S. M. Hewitt, A. Berman, S. M. Steinberg, D. J. Liewehr, et al.
Antiangiogenic and Antitumor Effects of Bevacizumab in Patients With Inflammatory and Locally Advanced Breast Cancer
J. Clin. Oncol.,
February 10, 2006;
24(5):
769 - 777.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Delord, C. Allal, M. Canal, E. Mery, P. Rochaix, I. Hennebelle, A. Pradines, E. Chatelut, R. Bugat, S. Guichard, et al.
Selective inhibition of HER2 inhibits AKT signal transduction and prolongs disease-free survival in a micrometastasis model of ovarian carcinoma
Ann. Onc.,
December 1, 2005;
16(12):
1889 - 1897.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Menard, S. M. Pupa, M. Campiglio, E. Taglibue, A. Balsari, F. Fagnoni, and A. Costa
Apoptosis Induction by Trastuzumab: Possible Role of the Core Biopsy Intervention
J. Clin. Oncol.,
October 1, 2005;
23(28):
7238 - 7240.
[Full Text]
[PDF]
|
|
|
|
