MutS homologue 2 and the long-term benefit of adjuvant chemotherapy in lung cancer.
OBJECTIVE
We sought to determine the long-term (median follow-up, 7.5 years) predictive power of human MutS homologue 2 (MSH2) immunohistochemical expression in patients who enrolled in the International Adjuvant Lung Trial.


METHODS
We tested the interaction between MSH2 and the allocated treatment (chemotherapy versus observation) in a Cox model adjusted on clinicopathologic variables. The significance level was set at 0.01.


RESULTS
MSH2 levels were low in 257 (38%) and high in 416 (62%) tumors. The benefit from chemotherapy was likely different according to MSH2 (interaction test, P = 0.06): there was a trend for chemotherapy to prolong overall survival when MSH2 was low [hazard ratio (HR), 0.76; 95% confidence interval (95% CI), 0.59-0.97; P = 0.03], but not when MSH2 was high (HR, 1.12; 95% CI, 0.81-1.55; P = 0.48). In the control arm, the HR was 0.66 (95% CI, 0.49-0.90; P = 0.01) when MSH2 was high. When combining MSH2 with excision repair cross-complementing group 1 (ERCC1) into four subgroups, the benefit of chemotherapy decreased with the number of markers expressed at high levels (P = 0.01). A similar decrease was noted when combining MSH2 and P27 (P = 0.01). Chemotherapy prolonged overall survival in the combined low MSH2/low ERCC1 subgroup (HR, 0.65; 95% CI, 0.47-0.91; P = 0.01) and in the combined low MSH2/low P27 subgroup (HR, 0.65; 95% CI, 0.46-0.93; P = 0.01).


CONCLUSIONS
MSH2 expression is a borderline significant predictor of a long-term benefit from adjuvant cisplatin-based chemotherapy in patients with completely resected lung cancer. MSH2 combined with ERCC1 or P27 may identify patients most likely to benefit durably from chemotherapy.
Department of Medicine, Biostatistics and Epidemiology Unit, Translational Research Laboratory, Paris-Sud University, Gustave-Roussy Institute, Villejuif, France.
Nermine S
NS
Kamal
Jean-Charles
JC
Soria
Jean
J
Mendiboure
David
D
Planchard
Ken A
KA
Olaussen
Vanessa
V
Rousseau
Helmut
H
Popper
Robert
R
Pirker
Pascale
P
Bertrand
Ariane
A
Dunant
Thierry
T
Le Chevalier
Martin
M
Filipits
Pierre
P
Fouret
D000368:Aged; D014408:Biomarkers, Tumor / Q000008:administration & dosage / Q000378:metabolism; D017024:Chemotherapy, Adjuvant; D004268:DNA-Binding Proteins / Q000819:agonists / Q000378:metabolism; D004720:Endonucleases / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000145:classification / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000378:metabolism*; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism
D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen; C071447:ERCC1 protein, human; D004720:Endonucleases; D051718:MutS Homolog 2 Protein