Joint effect of mutagen sensitivity and insulin-like growth factors in predicting the risk of developing secondary primary tumors and tumor recurrence in patients with head and neck cancer.
OBJECTIVE
Early-stage head and neck cancer patients are at high risks for tumor recurrence and secondary primary tumor (SPT) development. We hypothesized that latent genetic instability and proliferation potential may be associated with elevated risks of SPT and recurrence.


METHODS
We conducted a nested case-control study within a randomized, placebo-controlled chemoprevention trial in patients with early-stage head and neck cancer. We compared prediagnostic bleomycin-induced chromatid breaks in peripheral blood lymphocyte cultures (as an indicator of latent genetic instability) between 298 cases (patients with SPT/recurrence) and 693 controls (patients without SPT/recurrence). We also determined the joint effects of latent genetic instability and elevated proliferation potential [indicated by serum insulin-like growth factor (IGF) level] in modulating the risk of SPT and recurrence.


RESULTS
In the Cox proportional hazards model, patients with higher mutagen sensitivity (using a cutoff of > or =0.50 breaks per cell) exhibited a significantly increased risk of developing SPT/recurrence [hazard ratio, 1.38; 95% confidence interval (95% CI), 1.02-1.86]. Cases also exhibited significantly higher levels of IGF-I and IGF-binding protein-3 than controls (P = 0.022 and 0.042, respectively). Moreover, there were joint effects between mutagen sensitivity and IGFs in modulating SPT/recurrence risk. Using patients with low IGF-I level and low mutagen sensitivity profile as the reference group, the odds ratios of developing SPT/recurrence for patients with high IGF-I level alone, high mutagen sensitivity alone, and both high IGF-I level and high mutagen sensitivity were 2.85 (95% CI, 0.92-8.82), 3.92 (95% CI, 1.28-11.97), and 6.16 (95% CI, 2.03-18.71), respectively. A similar joint effect was observed for mutagen sensitivity and IGF-binding protein-3 level.


CONCLUSIONS
This is the largest prospective study to evaluate mutagen sensitivity as a prognosis marker in head and neck cancer because mutagen sensitivity data were derived from baseline samples drawn before the development of SPT or tumor recurrence. The results also show for the first time that latent genetic instability and elevated proliferation potential jointly elevate the risk of second tumors in early-stage head and neck cancers.
Wu
Xifeng
X
Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. xwu@mdanderson.org
Gu
Jian
J
Dong
Qiong
Q
Huang
Maosheng
M
Do
Kim-Anh
KA
Hong
Waun Ki
WK
Spitz
Margaret R
MR
D001761:Bleomycin / Q000494:pharmacology*; D016022:Case-Control Studies; D002842:Chromatids / Q000187:drug effects; D005260:Female; D005500:Follow-Up Studies; D006258:Head and Neck Neoplasms / Q000175:diagnosis* / Q000556:secondary* / Q000628:therapy; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000032:analysis*; D015474:Isotretinoin / Q000627:therapeutic use; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009153:Mutagens / Q000494:pharmacology*; D009367:Neoplasm Staging; D010919:Placebos; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D016896:Treatment Outcome
C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018969:Insulin-Like Growth Factor Binding Proteins; D009153:Mutagens; D010919:Placebos; D001761:Bleomycin; D007334:Insulin-Like Growth Factor I; D015474:Isotretinoin