Post-treatment tumor gene expression signatures are more predictive of treatment outcomes than baseline signatures in breast cancer.
OBJECTIVE
Tumor gene expression signatures have been used to classify, prognosticate, and predict chemotherapy sensitivity in breast cancer, although almost all efforts have been focused on the unchallenged baseline tumor. Most cancer patients receive systemic therapy, and exposure to drug may modify the tumor's short-term and long-term outcomes. Drug-induced tumor gene signatures may thus be more predictive of treatment outcomes than the unperturbed tumor gene signatures.


METHODS
Using a set of 47 breast cancer patients, we obtained paired prechemotherapy and postchemotherapy tumor biopsies and developed gene panels of baseline tumor (T1), postchemotherapy tumor (T2), and chemotherapy-induced relative change signatures (TDelta) to predict pathological response and progression-free survival (PFS). The signatures were validated in two independent test sets with paired prechemotherapy and postchemotherapy tumor samples, comprising of 18-20 patients each.


RESULTS
T2 and TDelta were superior to T1 signatures in predicting for PFS (area under the curve of receiver operating characteristic 0.770 and 0.660 vs. 0.530) and pathological response (area under the curve of receiver operating characteristic 0.631 and 0.462 vs. 0.446) in the validation sets. In multivariate analysis for PFS with other clinical predictors, T2, but not T1, signatures remained as significant independent predictors.


CONCLUSIONS
Postchemotherapy tumor gene signatures outperformed baseline signatures and clinical predictors in predicting for pathological response and PFS, independent of clinical and pathological response to chemotherapy. Drug-induced tumor gene signatures may be more informative than unchallenged signatures in predicting treatment outcomes. These findings challenge the current practice of relying only on the baseline tumor to predict outcome, which overlooks the contributions of therapeutic interventions.
Lee
Soo-Chin
SC
Department of Haematology-Oncology, National University Hospital, Singapore, Singapore. Soo_Chin_Lee@nuh.com.sg
Xu
Xin
X
Chng
Wee-Joo
WJ
Watson
Mark
M
Lim
Yi-Wan
YW
Wong
Chiung-Ing
CI
Iau
Philip
P
Sukri
Norita
N
Lim
Siew-Eng
SE
Yap
Hui-Ling
HL
Buhari
Shaik Ahmad
SA
Tan
Patrick
P
Guo
Jiayi
J
Chuah
Benjamin
B
McLeod
Howard L
HL
Goh
Boon-Cher
BC
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D018572:Disease-Free Survival; D000077143:Docetaxel; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D015999:Multivariate Analysis; D015203:Reproducibility of Results; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin