Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research
Published in: Breast Cancer Research 6/2007

Open Access 01-12-2007 | Research article

CD40 signaling predicts response to preoperative trastuzumab and concomitant paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide in HER-2-overexpressing breast cancer

Authors: Francisco J Esteva, Jing Wang, Feng Lin, Jaime A Mejia, Kai Yan, Kadri Altundag, Vicente Valero, Aman U Buzdar, Gabriel N Hortobagyi, W Fraser Symmans, Lajos Pusztai

Published in: Breast Cancer Research | Issue 6/2007

Login to get access

Abstract

Introduction

We performed gene expression analysis to identify molecular predictors of resistance to preoperative concomitant trastuzumab and paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide (T/FEC).

Methods

Pretreatment fine-needle aspiration specimens from 45 patients with HER-2-overexpressing stage II to IIIA breast cancer were subjected to transcriptional profiling and examined for differential expression of various genes and gene sets. The primary endpoint for tumor response was pathologic complete response (pCR). Correlations between pCR and gene expression were sought.

Results

The overall pCR rate was 64%. Age, nuclear grade, tumor size, nodal status, quantitative expression of estrogen and HER-2 receptor mRNA, and HER-2 gene copy number showed no correlation with pCR. Results of gene set enrichment analysis suggested that the lower expression of genes involved with CD40 signaling is associated with a greater risk of residual cancer after the preoperative chemotherapy that includes trastuzumab.

Conclusion

CD40 signaling may play a role in determining response to trastuzumab-plus-T/FEC therapy in patients with HER-2-overexpressing breast cancer.
Appendix
Available only for authorised users
Literature
1.
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL: Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987, 235: 177-182. 10.1126/science.3798106.CrossRefPubMed
2.
3.
Press MF, Slamon DJ, Flom KJ, Park J, Zhou JY, Bernstein L: Evaluation of HER-2/neu gene amplification and overexpression: comparison of frequently used assay methods in a molecularly characterized cohort of breast cancer specimens. J Clin Oncol. 2002, 20: 3095-3105.CrossRefPubMed
4.
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001, 344: 783-792. 10.1056/NEJM200103153441101.CrossRefPubMed
5.
Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Anton A, Lluch A, et al: Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005, 23: 4265-4274. 10.1200/JCO.2005.04.173.CrossRefPubMed
6.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005, 353: 1659-1672. 10.1056/NEJMoa052306.CrossRefPubMed
7.
Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005, 353: 1673-1684. 10.1056/NEJMoa052122.CrossRefPubMed
8.
Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ: Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat Clin Pract Oncol. 2006, 3: 269-280. 10.1038/ncponc0509.CrossRefPubMed
9.
Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, Murphy M, Novotny WF, Burchmore M, et al: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002, 20: 719-726. 10.1200/JCO.20.3.719.CrossRefPubMed
10.
Pusztai L, Esteva FJ: Continued use of trastuzumab (herceptin) after progression on prior trastuzumab therapy in HER-2-positive metastatic breast cancer. Cancer Invest. 2006, 24: 187-191. 10.1080/07357900500524629.CrossRefPubMed
11.
Esteva FJ, Valero V, Booser D, Guerra LT, Murray JL, Pusztai L, Cristofanilli M, Arun B, Esmaeli B, Fritsche HA, et al: Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2002, 20: 1800-1808. 10.1200/JCO.2002.07.058.CrossRefPubMed
12.
Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, 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. 10.1200/JCO.2005.07.032.CrossRefPubMed
13.
Kuerer HM, Newman LA, Smith TL, Ames FC, Hunt KK, Dhingra K, Theriault RL, Singh G, Binkley SM, Sneige N, 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.CrossRefPubMed
14.
Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, et al: 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. 2003, 21: 4165-4174. 10.1200/JCO.2003.12.005.CrossRefPubMed
15.
Buzdar AU, Valero V, Ibrahim NK, Francis D, Broglio KR, Theriault RL, Pusztai L, Green MC, Singletary SE, Hunt KK, et al: Neoadjuvant therapy with paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide chemotherapy and concurrent trastuzumab in human epidermal growth factor receptor 2-positive operable breast cancer: an update of the initial randomized study population and data of additional patients treated with the same regimen. Clin Cancer Res. 2007, 13: 228-233. 10.1158/1078-0432.CCR-06-1345.CrossRefPubMed
16.
Mazouni C, Peintinger F, Wan-Kau S, Andre F, Gonzalez-Angulo AM, Symmans WF, Meric-Bernstam F, Valero V, Hortobagyi GN, Pusztai L: 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: 2650-2655. 10.1200/JCO.2006.08.2271.CrossRefPubMed
17.
Hess KR, Anderson K, Symmans WF, Valero V, Ibrahim N, Mejia JA, Booser D, Theriault RL, Buzdar AU, Dempsey PJ, et al: Pharmacogenomic predictor of sensitivity to preoperative chemotherapy with paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide in breast cancer. J Clin Oncol. 2006, 24: 4236-4244. 10.1200/JCO.2006.05.6861.CrossRefPubMed
18.
19.
Gong Y, Yan K, Lin F, Anderson K, Sotiriou C, Andre F, Holmes FA, Valero V, Booser D, Pippen JE, et al: Determination of oestrogen-receptor status and ERBB2 status of breast carcinoma: a gene-expression profiling study. Lancet Oncol. 2007, 8: 203-211. 10.1016/S1470-2045(07)70042-6.CrossRefPubMed
20.
Pounds S, Morris SW: Estimating the occurrence of false positives and false negatives in microarray studies by approximating and partitioning the empirical distribution of p values. Bioinformatics. 2003, 19: 1236-1242. 10.1093/bioinformatics/btg148.CrossRefPubMed
21.
22.
Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES, et al: Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005, 102: 15545-15550. 10.1073/pnas.0506580102.CrossRefPubMedPubMedCentral
23.
Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, Livasy C, Carey LA, Reynolds E, Dressler L, et al: The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics. 2006, 7: 96-10.1186/1471-2164-7-96.CrossRefPubMedPubMedCentral
24.
Pusztai L, Anderson K, Hess KR: Pharmacogenomic predictor discovery in phase II clinical trials for breast cancer. Clin Cancer Res. 2007, 13: 6080-6086. 10.1158/1078-0432.CCR-07-0809.CrossRefPubMed
25.
Baxendale AJ, Dawson CW, Stewart SE, Mudaliar V, Reynolds G, Gordon J, Murray PG, Young LS, Eliopoulos AG: Constitutive activation of the CD40 pathway promotes cell transformation and neoplastic growth. Oncogene. 2005, 24: 7913-7923. 10.1038/sj.onc.1208929.CrossRefPubMed
26.
Hirano A, Longo DL, Taub DD, Ferris DK, Young LS, Eliopoulos AG, Agathanggelou A, Cullen N, Macartney J, Fanslow WC, et al: Inhibition of human breast carcinoma growth by a soluble recombinant human CD40 ligand. Blood. 1999, 93: 2999-3007.PubMed
27.
Alexandroff AB, Jackson AM, Paterson T, Haley JL, Ross JA, Longo DL, Murphy WJ, James K, Taub DD: Role for CD40-CD40 ligand interactions in the immune response to solid tumours. Mol Immunol. 2000, 37: 515-526. 10.1016/S0161-5890(00)00079-1.CrossRefPubMed
28.
Wingett DG, Vestal RE, Forcier K, Hadjokas N, Nielson CP: CD40 is functionally expressed on human breast carcinomas: variable inducibility by cytokines and enhancement of Fas-mediated apoptosis. Breast Cancer Res Treat. 1998, 50: 27-36. 10.1023/A:1006012607452.CrossRefPubMed
29.
Tong AW, Papayoti MH, Netto G, Armstrong DT, Ordonez G, Lawson JM, Stone MJ: Growth-inhibitory effects of CD40 ligand (CD154) and its endogenous expression in human breast cancer. Clin Cancer Res. 2001, 7: 691-703.PubMed
30.
Pedersen AE, Thorn M, Gad M, Walter MR, Johnsen HE, Gaarsdal E, Nikolajsen K, Buus S, Claesson MH, Svane IM: Phenotypic and functional characterization of clinical grade dendritic cells generated from patients with advanced breast cancer for therapeutic vaccination. Scand J Immunol. 2005, 61: 147-156. 10.1111/j.0300-9475.2005.01531.x.CrossRefPubMed
31.
Pinzon-Charry A, Schmidt CW, López JA: The key role of CD40 ligand in overcoming tumor-induced dendritic cell dysfunction. Breast Cancer Res. 2006, 8: 402-10.1186/bcr1386.CrossRefPubMedPubMedCentral
32.
Pinzon-Charry A, Maxwell T, McGuckin MA, Schmidt C, Furnival C, López JA: Spontaneous apoptosis of blood dendritic cells in patients with breast cancer. Breast Cancer Res. 2006, 8: R5-10.1186/bcr1361.CrossRefPubMed
33.
Stumm S, Meyer A, Lindner M, Bastert G, Wallwiener D, Guckel B: Paclitaxel Treatment of Breast Cancer Cell Lines Modulates Fas/Fas Ligand Expression and Induces Apoptosis Which Can Be Inhibited Through the CD40 Receptor. Oncology. 2004, 66: 101-111. 10.1159/000077435.CrossRefPubMed
34.
Voorzanger-Rousselot N, Alberti L, Blay JY: CD40L induces multidrug resistance to apoptosis in breast carcinoma and lymphoma cells through caspase independent and dependent pathways. BMC Cancer. 2006, 6: 75-10.1186/1471-2407-6-75.CrossRefPubMedPubMedCentral
35.
Nahta R, Esteva FJ: Herceptin: mechanisms of action and resistance. Cancer Lett. 2006, 232: 123-138. 10.1016/j.canlet.2005.01.041.CrossRefPubMed
36.
Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, et al: PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004, 6: 117-127. 10.1016/j.ccr.2004.06.022.CrossRefPubMed
37.
Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ: Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005, 65: 11118-11128. 10.1158/0008-5472.CAN-04-3841.CrossRefPubMed
38.
Nahta R, Takahashi T, Ueno NT, Hung MC, Esteva FJ: P27(kip1) down-regulation is associated with trastuzumab resistance in breast cancer cells. Cancer Res. 2004, 64: 3981-3986. 10.1158/0008-5472.CAN-03-3900.CrossRefPubMed
Metadata
Title
CD40 signaling predicts response to preoperative trastuzumab and concomitant paclitaxel followed by 5-fluorouracil, epirubicin, and cyclophosphamide in HER-2-overexpressing breast cancer
Authors
Francisco J Esteva
Jing Wang
Feng Lin
Jaime A Mejia
Kai Yan
Kadri Altundag
Vicente Valero
Aman U Buzdar
Gabriel N Hortobagyi
W Fraser Symmans
Lajos Pusztai
Publication date
01-12-2007
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 6/2007
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr1836

Other articles of this Issue 6/2007

Breast Cancer Research 6/2007 Go to the issue

Research article

Vitamin D receptor polymorphisms and breast cancer risk in a large population-based case-control study of Caucasian and African-American women

Review

Breast tumour angiogenesis

Research article

Decursin and decursinol angelate inhibit estrogen-stimulated and estrogen-independent growth and survival of breast cancer cells

Commentary

Adjuvant endocrine therapy for premenopausal women with early breast cancer

Research article

Serum epidermal growth factor receptor and HER2 expression in primary and metastatic breast cancer patients

Letter

Are triple-negative tumours and basal-like breast cancer synonymous?
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits