Functional proteomics characterization of residual triple-negative breast cancer after standard neoadjuvant chemotherapy.
BACKGROUND
In this study, we used functional proteomics to determine the molecular characteristics of residual triple receptor-negative breast cancer (TNBC) patients after neoadjuvant systemic chemotherapy (NCT) and their relationship with patient outcomes in order to identify potential targets for therapy.


METHODS
Protein was extracted from 54 residual TNBCs, and 76 proteins related to breast cancer signaling were measured by reverse phase protein arrays (RPPAs). Univariable and multivariable Cox proportional hazard models were fitted for each protein. Survival outcomes were estimated by the Kaplan-Meier product limit method. Training and cross validation were carried out. The coefficients estimated from the multivariable Cox model were used to calculate a risk score (RS) for each sample.


RESULTS
Multivariable analysis using the top 25 proteins from univariable analysis at a false discovery rate (FDR) of 0.3 showed that AKT, IGFBP2, LKB1, S6 and Stathmin were predictors of recurrence-free survival (RFS). The cross-validation model was reproducible. The RS model calculated based on the multivariable analysis was -1.1086 × AKT + 0.2501 × IGFBP2 - 0.6745 × LKB1+1.0692 × S6 + 1.4086 × stathmin with a corresponding area under the curve, AUC = 0.856. The RS was an independent predictor of RFS (HR = 3.28, 95%CI = 2.07-5.20, P < 0.001).


CONCLUSIONS
We found a five-protein model that independently predicted RFS risk in patients with residual TNBC disease. The PI3 K pathway may represent potential therapeutic targets in this resistant disease.
Departments of Breast Medical Oncology.
J
J
Sohn
Biostatistics.
K A
KA
Do
Departments of Breast Medical Oncology.
S
S
Liu
Departments of Breast Medical Oncology.
H
H
Chen
Systems Biology.
G B
GB
Mills
Departments of Breast Medical Oncology.
G N
GN
Hortobagyi
Surgical Oncology (FMB), The University of Texas MD Anderson Cancer Center, Houston, USA.
F
F
Meric-Bernstam
Departments of Breast Medical Oncology; Systems Biology. Electronic address: agonzalez@mdanderson.org.
A M
AM
Gonzalez-Angulo
D000091162:AMP-Activated Protein Kinase Kinases; D000328:Adult; D000368:Aged; D018943:Anthracyclines / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D001952:Bridged-Ring Compounds / Q000627:therapeutic use; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D040901:Proteomics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction; D050777:Stathmin / Q000378:metabolism; D013534:Survival; D043823:Taxoids / Q000627:therapeutic use; D064726:Triple Negative Breast Neoplasms / Q000401:mortality* / Q000628:therapy*
D018943:Anthracyclines; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001952:Bridged-Ring Compounds; C577903:IGFBP2 protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D038601:Ribosomal Protein S6; D050777:Stathmin; D043823:Taxoids; C080625:taxane; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases
molecular characterization; neoadjuvant chemotherapy; residual disease; resistance; triple receptor-negative breast cancer