Mutagen Sensitivity as aPredictor of Tumor Recurrence in Patients With Cancer of the Upper Aerodigestive Tract

Spitz, Margaret R.; Lippman, Scott M.; Jiang, Hong; Lee, John; Khuri, Fadlo R.; Hsu, T. C.; Trizna, Zoltan; Schantz, Stimson P.; Benner, Steven E.; Hong, Waun Ki

doi:10.1093/jnci/90.3.243

Cited by 33 publications

(24 citation statements)

References 11 publications

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“…We have previously reported that bleomycin-induced mutagen sensitivity was a significant predictor of SPT or recurrence in a subset of the current study population (12,31). In this study, we confirmed this finding with substantially larger sample size and using SPT and recurrence as the combined outcome event.…”

Section: Discussionsupporting

confidence: 87%

“…Patients took 13 cRA or placebo for a total of 3 years followed by 4 years of follow-up. Follow-up information on SPTs and tumor recurrence was collected at 3,6,9,12,16,20,24,28, and 36 months after randomization with additional evaluations at 6-month intervals for 4 years. A SPT was defined using the criteria established by Warren and Gates (37).…”

Section: Methodsmentioning

confidence: 99%

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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

Gu²,

Dong

et al. 2006

Clinical Cancer Research

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Purpose: 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 SPTand recurrence. Experimental Design: 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 SPTand recurrence. Results: In the Cox proportional hazards model, patients with higher mutagen sensitivity (using a cutoff of z0.50 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.Head and neck cancer (including malignancies in the oral cavity, pharynx, and larynx) will occur with an estimated incidence of 40,500 new cases (22,040 in oral cavity, 8,950 in pharynx, and 9,510 in larynx) and cause f11,170 deaths in the United States in 2006 (1). Cigarette smoking and alcohol consumption are the predominant risk factors for head and neck cancer, estimated to be responsible for three fourths of all the cases (2). However, only a small fraction of smokers and drinkers develop these cancers, suggesting that variations in genetic susceptibility may play important roles in cancer etiology. There have been numerous studies supporting this concept, including evidence of increased risk of head and neck cancer ...

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Section: Discussionsupporting

confidence: 87%

Section: Methodsmentioning

confidence: 99%

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

Gu²,

Dong

et al. 2006

Clinical Cancer Research

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“…Spitz et al (47) reported that in vitro sensitivity to bleomycin could be a predictor of tumor recurrence in HNSCC patients. We also demonstrated that there was a joint effect between IGF-I and bleomycin-induced mutagen sensitivity in lung cancer risk (48).…”

Section: Discussionmentioning

confidence: 99%

Serum Levels of Insulin Growth Factor (IGF-I) and IGF-Binding Protein Predict Risk of Second Primary Tumors in Patients with Head and Neck Cancer

Wu¹,

Zhao²,

Anh³

et al. 2004

Clinical Cancer Research

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Purpose: Second primary tumors (SPTs) are a hallmark of head and neck squamous cell carcinomas (HNSCCs). Serum levels of insulin growth factors (IGFs) and their binding proteins (IGFBPs) have been associated with subsequent development of several epithelial cancers in prospective studies.Experimental Design: To examine the role of IGFs in SPT development, we conducted a nested case-control study within a randomized, placebo-controlled chemoprevention trial in patients with early-stage HNSCC. We compared prediagnostic serum IGF-I and IGFBP-3 levels in 80 patients who subsequently developed SPTs and 173 controls (patients without SPTs) matched to the cases on age (؎5 years), sex, ethnicity, year of randomization, and length of follow-up.Results: The cases exhibited significantly higher levels of IGF-I and IGFBP-3 than did the controls (P ‫؍‬ 0.001 and 0.019, respectively). Elevated IGF-I levels were associated with a 3.66-fold significantly increased risk of SPT. Lower and higher IGFBP-3 levels were associated with a 2.22-and 7.12-fold significant increased risk, respectively. The median SPT-free time was significantly shorter in patients with higher IGF-I levels than in patients with lower IGF-I levels (P < 0.0001). A similar trend was observed for IGFBP-3 (P ‫؍‬ 0.002). Moreover, in the Cox proportional hazards model, higher IGF-I levels were significantly associated with increased risk of SPT with a hazard ratio of 2.78. Patients with the lower and higher IGFBP-3 levels also exhibited significantly increased risks with hazard ratios of 1.65 and 2.17, respectively.Conclusions: This is the first study demonstrating that higher IGF-I levels, and lower and higher IGFBP-3 levels are risk factors for SPT development. Thus, measuring serum IGF-I and IGFBP-3 levels may be useful markers in assessing the risk of second tumors in patients successfully treated for their index cancer.

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“…195,199). Work by molecular epidemiology pioneer Spitz and colleagues and others in dopamine receptor genes (200) reflects an important advance in understanding genetic influences on tobacco dependence. In the 1970s, Peto predicted one billion avoidable deaths in the 20th century if then-current smoking patterns persisted and (with Doll) showed that half of all persistent smokers would eventually die of smoking, a risk that lessened with smoking cessation.…”

Section: Behavioral Preventionmentioning

confidence: 99%

Cancer Prevention Research: Back to the Future

Lippman

2009

Cancer Prevention Research

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Mutagen Sensitivity as aPredictor of Tumor Recurrence in Patients With Cancer of the Upper Aerodigestive Tract

Cited by 33 publications

References 11 publications

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

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

Serum Levels of Insulin Growth Factor (IGF-I) and IGF-Binding Protein Predict Risk of Second Primary Tumors in Patients with Head and Neck Cancer

Cancer Prevention Research: Back to the Future

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