Gene expression profile associated with response to doxorubicin-based therapy in breast cancer.
OBJECTIVE
This study was designed to identify genes that could predict response to doxorubicin-based primary chemotherapy in breast cancer patients.


METHODS
Biopsy samples were obtained before primary treatment with doxorubicin and cyclophosphamide. RNA was extracted and amplified and gene expression was analyzed using cDNA microarrays.


RESULTS
Response to chemotherapy was evaluated in 51 patients, and based on Response Evaluation Criteria in Solid Tumors guidelines, 42 patients, who presented at least a partial response (> or =30% reduction in tumor dimension), were classified as responsive. Gene profile of samples, divided into training set (n = 38) and independent validation set (n = 13), were at first analyzed against a cDNA microarray platform containing 692 genes. Unsupervised clustering could not separate responders from nonresponders. A classifier was identified comprising EMILIN1, FAM14B, and PBEF, which however could not correctly classify samples included in the validation set. Our next step was to analyze gene profile in a more comprehensive cDNA microarray platform, containing 4,608 open reading frame expressed sequence tags. Seven samples of the initial training set (all responder patients) could not be analyzed. Unsupervised clustering could correctly group all the resistant samples as well as at least 85% of the sensitive samples. Additionally, a classifier, including PRSS11, MTSS1, and CLPTM1, could correctly distinguish 95.4% of the 44 samples analyzed, with only two misclassifications, one sensitive sample and one resistant tumor. The robustness of this classifier is 2.5 greater than the first one.


CONCLUSIONS
A trio of genes might potentially distinguish doxorubicin-responsive from nonresponsive tumors, but further validation by a larger number of samples is still needed.
Folgueira
Maria Aparecida Azevedo Koike
MA
Disciplina de Oncologia do Departamento de Radiologia da Faculdade de Medicina da Universidade de São Paulo, Brazil.
Carraro
Dirce Maria
DM
Brentani
Helena
H
Patrão
Diogo Ferreira da Costa
DF
Barbosa
Edson Mantovani
EM
Netto
Mário Mourão
MM
Caldeira
José Roberto Fígaro
JR
Katayama
Maria Lucia Hirata
ML
Soares
Fernando Augusto
FA
Oliveira
Célia Tosello
CT
Reis
Luiz Fernando Lima
LF
Kaiano
Jane Haruko Lima
JH
Camargo
Luiz Paulo
LP
Vêncio
Ricardo Zorzetto Nicoliello
RZ
Snitcovsky
Igor Moysés Longo
IM
Makdissi
Fabiana Baroni Alves
FB
e Silva
Paulo José da Silva
PJ
Góes
João Carlos Guedes Sampaio
JC
Brentani
Maria Mitzi
MM
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016000:Cluster Analysis; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
D004317:Doxorubicin; D003520:Cyclophosphamide