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

Abstract

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 ...

Novel Susceptibility Loci for Second Primary Tumors/Recurrence in Head and Neck Cancer Patients: Large-Scale Evaluation of Genetic Variants

“…Standard criteria for diagnosis of an SPT were applied. (15) The major sites of SPT in this population were lung (29.8%), head and neck (28.0%), prostate (14.2%), and bladder (5.1%). Local recurrence was defined as any tumor of similar histology appearing within 2 cm or within 3 years of the primary tumor.…”

Inter-individual variation in DNA repair capacity: A need for multi-pathway functional assays to promote translational DNA repair research

“…This has been borne out in patients with cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma of the head and neck, plus patients with lung, breast and bladder cancers (51). Of particular interest, a prospective study found that higher bleomycin sensitivity of lymphocytes (>0.5 chromatid breaks per cell) from patients with head and neck cancer was associated with an elevated risk (hazard ratio of 1.38) of developing second, unrelated primary tumors as well as recurrence of the original cancer (52); importantly the blood cells were drawn before development of second primary or recurrent tumors. A second prospective study found a significant association between bleomycin sensitivity in lymphoblastoid cell lines and combined risk of prostate, lung, colorectal and ovarian cancers in the patients from whom the cells were derived (53).…”

“…(i) Excepting a small number of prospective studies (52, 53, 198), virtually all studies associating DRC defects with cancer susceptibility have been retrospective, raising concerns that the observed DRC differences may reflect changes subsequent to cancer diagnosis, or to cancer treatment. Similar levels of DNA damage have been observed in lymphoblastoid cell lines derived before versus after cancer diagnosis (198), suggesting that cancer development may not alter DRC.…”

DNA Repair: From Genome Maintenance to Biomarker and Therapeutic Target

“…These studies had multiple limitations including suffering from 'reverse causation biases due to their retrospective nature. A limited number of prospective studies have examined the possible association between cancer risk and a reduced DNA repair capacity prospectively (31;62;63). The largest prospective trial was reported recently as part of the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial.…”