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


CONCLUSIONS
CD40 signaling may play a role in determining response to trastuzumab-plus-T/FEC therapy in patients with HER-2-overexpressing breast cancer.
Esteva
Francisco J
FJ
Department of Breast Medical Oncology, Unit 1354, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. festeva@mdanderson.org
Wang
Jing
J
Lin
Feng
F
Mejia
Jaime A
JA
Yan
Kai
K
Altundag
Kadri
K
Valero
Vicente
V
Buzdar
Aman U
AU
Hortobagyi
Gabriel N
GN
Symmans
W Fraser
WF
Pusztai
Lajos
L
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D044963:Biopsy, Fine-Needle; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D019013:CD40 Antigens / Q000378:metabolism*; D003520:Cyclophosphamide / Q000008:administration & dosage; D015251:Epirubicin / Q000008:administration & dosage; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008408:Mastectomy / Q000379:methods; D015411:Mastectomy, Modified Radical; D015412:Mastectomy, Segmental; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D009367:Neoplasm Staging; D018365:Neoplasm, Residual; D017239:Paclitaxel / Q000008:administration & dosage; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D000068878:Trastuzumab; D016896:Treatment Outcome; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D019013:CD40 Antigens; D003520:Cyclophosphamide; D015251:Epirubicin; D005472:Fluorouracil; D017239:Paclitaxel; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human