Identification of markers of taxane sensitivity using proteomic and genomic analyses of breast tumors from patients receiving neoadjuvant paclitaxel and radiation.
OBJECTIVE
To identify molecular markers of pathologic response to neoadjuvant paclitaxel/radiation treatment, protein and gene expression profiling were done on pretreatment biopsies.


METHODS
Patients with high-risk, operable breast cancer were treated with three cycles of paclitaxel followed by concurrent paclitaxel/radiation. Tumor tissue from pretreatment biopsies was obtained from 19 of the 38 patients enrolled in the study. Protein and gene expression profiling were done on serial sections of the biopsies from patients that achieved a pathologic complete response (pCR) and compared to those with residual disease, non-pCR (NR).


RESULTS
Proteomic and validation immunohistochemical analyses revealed that alpha-defensins (DEFA) were overexpressed in tumors from patients with a pCR. Gene expression analysis revealed that MAP2, a microtubule-associated protein, had significantly higher levels of expression in patients achieving a pCR. Elevation of MAP2 in breast cancer cell lines led to increased paclitaxel sensitivity. Furthermore, expression of genes that are associated with the basal-like, triple-negative phenotype were enriched in tumors from patients with a pCR. Analysis of a larger panel of tumors from patients receiving presurgical taxane-based treatment showed that DEFA and MAP2 expression as well as histologic features of inflammation were all statistically associated with response to therapy at the time of surgery.


CONCLUSIONS
We show the utility of molecular profiling of pretreatment biopsies to discover markers of response. Our results suggest the potential use of immune signaling molecules such as DEFA as well as MAP2, a microtubule-associated protein, as tumor markers that associate with response to neoadjuvant taxane-based therapy.
Bauer
Joshua A
JA
Departments of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Chakravarthy
A Bapsi
AB
Rosenbluth
Jennifer M
JM
Mi
Deming
D
Seeley
Erin H
EH
De Matos Granja-Ingram
Nara
N
Olivares
Maria G
MG
Kelley
Mark C
MC
Mayer
Ingrid A
IA
Meszoely
Ingrid M
IM
Means-Powell
Julie A
JA
Johnson
Kimberly N
KN
Tsai
Chiaojung Jillian
CJ
Ayers
Gregory D
GD
Sanders
Melinda E
ME
Schneider
Robert J
RJ
Formenti
Silvia C
SC
Caprioli
Richard M
RM
Pietenpol
Jennifer A
JA
D054316:Biomarkers, Pharmacological / Q000032:analysis* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000532:radiotherapy; D002277:Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000532:radiotherapy; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D023281:Genomics; D006801:Humans; D055442:Metabolome / Q000187:drug effects; D020360:Neoadjuvant Therapy; D020411:Oligonucleotide Array Sequence Analysis; D017239:Paclitaxel / Q000627:therapeutic use*; D040901:Proteomics; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
D054316:Biomarkers, Pharmacological; D043823:Taxoids; D017239:Paclitaxel