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.
Kamal
Nermine S
NS
Department of Medicine, Biostatistics and Epidemiology Unit, Translational Research Laboratory, Paris-Sud University, Gustave-Roussy Institute, Villejuif, France.
Soria
Jean-Charles
JC
Mendiboure
Jean
J
Planchard
David
D
Olaussen
Ken A
KA
Rousseau
Vanessa
V
Popper
Helmut
H
Pirker
Robert
R
Bertrand
Pascale
P
Dunant
Ariane
A
Le Chevalier
Thierry
T
Filipits
Martin
M
Fouret
Pierre
P
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