Gene expression patterns for doxorubicin (Adriamycin) and cyclophosphamide (cytoxan) (AC) response and resistance.
BACKGROUND
Doxorubicin and cyclophosphamide (Adriamycin/cytoxan, AC) is a standard chemotherapy regimen for breast cancer, but de novo resistance is frequent. We hypothesized that gene expression profiles predictive of AC response may be different from our previously published patterns with docetaxel.


METHODS
Core biopsies from 40 patients were obtained before treatment with AC (6 cycles, 60/600 mg/m2q3 weeks), and clinical responses recorded after treatment. Gene expression patterns were analyzed using Affymetrix U133A chips which comprise approximately 22,200 genes.


RESULTS
Clinical complete responses (cCR) were observed in 22, partial responses in 7, stable disease in 11 patients. Differential expression between sensitive cCR and resistant tumors with a low false discovery rate (< 5%) was obtained. Of these 253 differentially expressed genes, pathways up-regulated in sensitive tumors included cell cycle (BUB3, CDKN1B), survival (BCL2, BAG1, BIRC1, STK39), stress response (CYP2B6, MAPK14), and estrogen-related pathways (ER, IRS1). Resistant tumors expressed gene promoting transcription (GTF3C1, ILF3), differentiation (ST14, CTNNBIP1), signal transduction (EIF1AX, EIF4EBP1), and amino acid metabolism (SRM, PLOD1, PLOD3). With leave-one-out cross validation, 67% of the samples were correctly classified, with a permutation p-value of 0.4. The previously published 92-gene molecular portrait for docetaxel sensitivity could not discriminate AC sensitivity and resistance.


CONCLUSIONS
This preliminary study supports that molecular profiles for AC response are likely to exist, with unique expression patterns for individual chemotherapy regimens. Larger validation studies are necessary to define and refine patterns for different agents.
Cleator
Susan
S
Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, United Kingdom.
Tsimelzon
Anna
A
Ashworth
Alan
A
Dowsett
Mitch
M
Dexter
Timothy
T
Powles
Trevor
T
Hilsenbeck
Susan
S
Wong
Helen
H
Osborne
C Kent
CK
O'Connell
Peter
P
Chang
Jenny C
JC
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D004317:Doxorubicin; D003520:Cyclophosphamide