Predictive value of p53, mdm-2, p21, and mib-1 for chemotherapy response in advanced breast cancer.
p53 is a transcription factor that participates in cell cycle checkpoint processes and apoptosis. The protein product of the murine double minute gene 2 (mdm-2) plays a central role in the regulation of p53. In response to DNA-damaging agents, the wild-type p53-activated fragment 1 (WAF1 also known as p21) is an important downstream effector in the p53-specific growth arrest pathway. In breast cancer patients, it is unclear whether measuring p53, mdm-2, or p21 expression provides information on how patients will respond to chemotherapy. Mib-1 monoclonal antibody recognizes the proliferation-related antigen Ki-67. High tumor proliferation has previously been associated with response to chemotherapy. p53, mdm-2, p21, and mib-1 expression were assessed by immunohistochemical methods in primary tumors derived from 134 patients who took part in a randomized multicenter trial comparing docetaxel to sequential methotrexate and 5-fluorouracil (MF) in advanced breast cancer. Low mib-1 staining correlated with negative p53 staining (P = 0.001), and mdm-2 and p21 stainings correlated positively with each other (P < 0.001). p53, mdm-2, p21, and mib-1 expression were not significantly associated with response to chemotherapy, time to progression, or overall survival in the whole patient population or in the docetaxel group. However, in the MF group, a low mib expression (<25%) and a high mdm-2 expression (> or =10%) predicted a better response (P = 0.014 and P = 0.046, respectively) to treatment and a longer time to progression in both univariate and multivariate analyses. p53 staining status was not associated with response to treatment in either group. Interestingly, tumors with both negative mdm-2 and p21 expression, irrespective of p53 status, had a high response rate to docetaxel but no response to MF. Although highly preliminary, the findings suggest that different tumor biological factors may predict response to different chemotherapy regimens with distinct mechanisms of action. The results of our phenotype analysis also indicate that it is more likely that a panel of tumor biological factors instead of only one single factor may be needed for better prediction of chemotherapy response.
Sjöström
J
J
Department of Oncology, Helsinki University Central Hospital, Finland. johanna.sjostrom@hus.fi
Blomqvist
C
C
Heikkilä
P
P
Boguslawski
K V
KV
Räisänen-Sokolowski
A
A
Bengtsson
N O
NO
Mjaaland
I
I
Malmström
P
P
Ostenstadt
B
B
Bergh
J
J
Wist
E
E
Valvere
V
V
Saksela
E
E
D000293:Adolescent; D000328:Adult; D000368:Aged; D034961:Antigens, Nuclear; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D000077143:Docetaxel; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen; D008727:Methotrexate / Q000008:administration & dosage; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016612:Paraffin Embedding; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2; D016032:Randomized Controlled Trials as Topic; D043823:Taxoids; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
D034961:Antigens, Nuclear; D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D000077143:Docetaxel; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D017239:Paclitaxel; D005472:Fluorouracil; D008727:Methotrexate