Cell cycle regulators and outcome of adjuvant cisplatin-based chemotherapy in completely resected non-small-cell lung cancer: the International Adjuvant Lung Cancer Trial Biologic Program.
OBJECTIVE
The International Adjuvant Lung Cancer Trial (IALT) demonstrated that adjuvant cisplatin-based chemotherapy improves the survival of patients with completely resected non-small-cell lung cancer (NSCLC). The purpose of our study was to determine whether cell cycle regulators are of prognostic and/or predictive value in patients who were enrolled onto the IALT.


METHODS
Expression of p27Kip1, p16INK4A, cyclin D1, cyclin D3, cyclin E, and Ki-67 was immunohistochemically assessed in tumor specimens obtained from 778 IALT patients. Prognostic and predictive analyses were based on Cox models adjusted for clinical and pathologic parameters.


RESULTS
There was a relationship between p27Kip1 status and benefit of cisplatin-based chemotherapy (test for interaction, P = .02). Among patients with p27Kip1-negative tumors, cisplatin-based chemotherapy resulted in longer overall survival compared with controls (adjusted hazard ratio [HR] for death = 0.66; 95% CI, 0.50 to 0.88; P = .006). In patients with p27Kip1-positive tumors, overall survival was not different between patients treated with cisplatin-based chemotherapy and controls (adjusted HR for death = 1.09; 95% CI, 0.82 to 1.45; P = .54). The other cell cycle regulators and Ki-67 did not predict benefit of adjuvant cisplatin-based chemotherapy. None of these biomarkers was significantly associated with overall survival of the patients in the total study population.


CONCLUSIONS
NSCLC patients with p27Kip1-negative tumors benefit from adjuvant cisplatin-based chemotherapy after complete tumor resection. Before establishing p27Kip1 as a routine marker for selection of patients for adjuvant chemotherapy, the predictive value of p27Kip1 has to be confirmed in patients from other trials.
Filipits
Martin
M
Department of Medicine I, Medical University of Vienna, Vienna, Austria. martin.filipits@meduniwien.ac.at
Pirker
Robert
R
Dunant
Ariane
A
Lantuejoul
Sylvie
S
Schmid
Katharina
K
Huynh
Anh
A
Haddad
Vincent
V
André
Fabrice
F
Stahel
Rolf
R
Pignon
Jean-Pierre
JP
Soria
Jean-Charles
JC
Popper
Helmut H
HH
Le Chevalier
Thierry
T
Brambilla
Elisabeth
E
D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000601:surgery*; D002453:Cell Cycle; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000627:therapeutic use*; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000601:surgery*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002945:Cisplatin