Risk Of Second Primary Tumors Research Articles

Impact of two nurse-led interventions targeting diet among breast cancer survivors: Results from a randomized controlled trial.

Breast cancer is the most common neoplasm among women worldwide. Improvements in early detection and treatment have resulted in improved survival rates; however, the continuation of unhealthy behaviours after diagnosis can increase the risk of second primary tumours. The aim of the study was to evaluate the effectiveness of two nurse-led health education interventions aiming at improving dietary behaviours among women diagnosed with breast cancer. Participants (n=492) were included in a double-blind randomized controlled trial with three arms: a control group received usual care; women in the first intervention group received a booklet containing dietary advice; women in the second intervention group received the same booklet plus a tailored telephone intervention delivered by a trained nurse. One year after the intervention, women in both intervention groups were more likely to adhere to the recommendation of decreasing the consumption of animal fats compared with the control group (OR:5.0; 95% CI:1.5-16.9 and OR:6.6; 95% CI:2.0-22.6, respectively). Moreover, compared with the control group, the adjusted probability of eating the recommended amount of fruit and vegetables was higher in the second intervention group (OR:2.7; 95% CI:1.4-5.3). In summary, the booklet containing dietary advice for breast cancer survivors, either alone or supplemented with a nurse-led telephone intervention, was effective in promoting adherence to diet recommendations.

340O - Risk of second primary tumors in patients with nasopharyngeal carcinoma following definitive intensity-modulated radiotherapy

340O - Risk of second primary tumors in patients with nasopharyngeal carcinoma following definitive intensity-modulated radiotherapy

Treating Nicotine Dependence and Preventing Smoking Relapse in Cancer Patients.

Despite the well-documented harmful effects of smoking, many cancer patients continue to smoke. Smoking cessation is critical to address in this population given the associated increase in treatment toxicity, risk of second primary tumors, decrease in treatment response and higher disease-specific and all-cause mortality with continued smoking following a cancer diagnosis. This review seeks to summarize the latest recommendations and guidelines on smoking cessation treatment for patients diagnosed with cancer, and the evidence behind those recommendations. We reviewed the latest evidence for smoking cessation treatments for cancer patients and the clinical guidelines and recommendation available for oncologists and health care providers. The unique aspects of nicotine dependence among patients diagnosed with cancer, and key challenges and barriers that cancer survivors and health care providers experience when considering smoking cessation treatments, and available clinical resources, are also discussed. Lastly, the authors summarize future directions in the field of smoking cessation treatment for cancer patients. While there are areas of improvement in research of smoking cessation treatment for cancer patients, critical under-explored areas remain. Nonetheless, providers should adhere to the NCCN guidelines and offer a brief counseling intervention to motivate patients to quit smoking when appropriate resources are not available.

The Molecular Genetics of Retinoblastoma

Retinoblastoma is a rare, malignant, childhood tumor that is primarily initiated by the inactivation of both alleles of the retinoblastoma tumor susceptibility gene, RB1, in a developing human retinal cell. A rare subset of retinoblastoma is initiated by somatic amplification of the MYCN oncogene in a predisposing retinal cell. Surprisingly the retinoblastoma protein (pRB), encoded by RB1, is an important transcription factor. Cell-cycle control by pRB is mainly accomplished by transcriptional repression of the genes required for cell-cycle progression. Control of differentiation by pRB is achieved by the activation of transcription. Through extensive post-translational modifications and interactions with other proteins, pRB and family members also influence senescence, chromosomal stability, and apoptosis. Almost every type of tumor has disruption in the retinoblastoma pathway associated with tumor progression, but germline mutation of the RB1 gene predisposes children to a 95% specific risk of developing retinoblastoma and a significantly increased risk of second primary tumors, such as osteosarcoma and melanoma. However, retinoblastoma is also characterized by other genomic changes subsequent to RB1 mutation. Keywords: aneuploidy; apoptosis; chromosome instability (CIN); E2F ; LOH ; MYCN ; proband; RB1 ; retinoblast; retinoma; SV40 ; TAg ; tumor suppressor

Orbital sarcomas in retinoblastoma patients: recommendations for screening and treatment guidelines.

Retinoblastoma is the most common primary ocular malignancy in children. Although currently retinoblastoma has an excellent survival rate in developed countries, hereditary retinoblastoma survivors as well as those with a history of radiation therapy as children are at an increased risk for second primary tumors (SPTs), and specifically, for orbital sarcomas. Despite the known increased risk for SPTs in retinoblastoma survivors and the associated morbidity and mortality, no screening or treatment guidelines exist. Understanding of retinoblastoma tumorigenesis and genomic expression has expanded significantly, and treatment has evolved with a shift away from radiotherapy. Until the last two decades, however, radiation was the therapy of choice for patients with bilateral disease. Because both hereditary retinoblastoma and radiation are independent risk factors for the development of SPTs such as sarcomas and these SPTs are often fatal, appropriate surveillance for retinoblastoma survivors is crucial. As a result of the excellent survival rates for retinoblastoma patients, it is important to: recognize the risk of sarcoma, particularly in patients with hereditary retinoblastoma and/or prior radiation therapy; establish a screening protocol, such as the one proposed, to maximize early detection; and discuss and develop treatment guidelines for high-risk patients. Future directions of research for these patients will involve the development of molecularly targeted agents and the use of proton radiotherapy.

Second Primary Tumours in Head and Neck Cancer

Introduction and objectivesHead and neck cancer patients have a higher risk of second primary tumours than the general population. The most frequent locations are head and neck, lung and oesophagus, decreasing long-term survival.The aim of this work was to analyse the incidence, location according to index tumour and stage, chronology, patient age, and survival after diagnosis. MethodRetrospective study on 579 patients with head and neck squamous cell carcinoma, treated with curative intent, with a minimum 24-month follow-up. Early stages (I/II) were 42.4%, and 57.6% were stages III and IV. ResultsSecond primary tumour incidence was 15% (87/579), with 9.2% (8/97) developing a third tumour. The most frequent locations of the second tumours were head and neck, 37.9% (33/87); lung, 36.8% (32/87); oesophagus, 5.7% (5/87); and colon, 5.7% (5/87). Five- and 10-year survival in patients without a second tumour was 65.1% and 52.7%, respectively, versus 58.7% and 40.2% in those who developed one. ConclusionsThe incidence of second primary tumours increased in the last decade, having a negative effect on survival. Since no specific early diagnosis tool is available, alcohol and tobacco avoidance along with scheduled follow-up are suggested procedures to reduce its incidence.

Second Primary Neoplasms in Patients With Uveal Melanoma: A SEER Database Analysis

To determine the risk of second primary neoplasms (SPNs) in subjects previously diagnosed with uveal melanoma (UM), including an analysis on whether radiotherapy is a risk factor to develop these SPNs. Retrospective cohort study. Using the Surveillance, Epidemiology, and End Results (SEER) 9 database, we identified patients diagnosed with UM as their first malignancy between 1973 and 2011 (n= 3976). We obtained standardized incidence ratios (SIR) and excess absolute risks of SPNs on patients with UM compared to a reference population. Multivariate Cox regression models were used to evaluate the effect of radiotherapy in SPN risk. Sixteen percent (n= 641) of the patients developed SPNs during a median follow-up of 83months (range, 1-463months). This represented an 11% excess risk compared to the reference population, mainly owing to a significantly increased risk of skin melanomas (SIR= 2.93, 95% CI: 2.23-3.78) and kidney tumors (SIR= 1.91, 95% CI: 1.27-2.76), primarily in those diagnosed between 30 and 59 years of age. The occurrence of second UM was also increased (SIR= 16.90, 95% CI: 9.00-28.90), which likely includes recurrences misclassified as a second cancer. Radiotherapy was performed in 39% (n= 1538) of the patients. Multivariate analysis revealed that this treatment was not an independent risk factor for SPNs (hazard ratio= 1.06, 95% CI: 0.88-1.26, P= .54). Patients with UM presented an 11% higher risk of SPNs compared to the reference population. Radiotherapy does not seem to be a risk factor. SPNs should be considered in the surveillance of UM.

Segundos tumores primarios en cáncer de cabeza y cuello

Introduction and objectivesHead and neck cancer patients have a higher risk of second primary tumours than the general population. The most frequent locations are head and neck, lung and oesophagus, decreasing long-term survival.The aim of this work was to analyse the incidence, location according to index tumour and stage, chronology, patient age, and survival after diagnosis. MethodRetrospective study on 579 patients with head and neck squamous cell carcinoma, treated with curative intent, with a minimum 24-month follow-up. Early stages (I/II) were 42.4%, and 57.6% were stages III and IV. ResultsSecond primary tumour incidence was 15% (87/579), with 9.2% (8/97) developing a third tumour. The most frequent locations of the second tumours were head and neck, 37.9% (33/87); lung, 36.8% (32/87); oesophagus, 5.7% (5/87); and colon, 5.7% (5/87). Five- and 10-year survival in patients without a second tumour was 65.1% and 52.7% respectively, versus 58.7% and 40.2% in those who developed one. ConclusionsThe incidence of second primary tumours increased in the last decade, having a negative effect on survival. Since no specific early diagnosis tool is available, alcohol and tobacco avoidance along with scheduled follow-up are suggested procedures to reduce its incidence.

Abstract 3056: Mitochondrial DNA copy number and risk of second primary tumors in long-term breast cancer survivors

Abstract Background. Mitochondria is constantly exposed to reactive oxygen species (ROS), an important factor in carcinogenesis. Altered mitochondrial DNA (mtDNA) copy number in peripheral blood has been associated with increased risks of several cancers, including breast cancer. However, the association of mtDNA copy number with clinical outcomes of breast cancer has not been reported. This study aimed to assess the association of mtDNA copy number with second primary tumors (SPT) in long-term breast cancer survivors. Methods. We measured mtDNA by quantitative PCR in patients in 68 long-term breast cancer survivors with SPT, 100 long-term breast cancer survivors without SPT and 97 newly diagnosed breast cancer cases. Cases with and without SPT were matched by years since diagnosis, age at time of sample collection and race. Differences between mtDNA copy number among groups were analyzed using the Wilcoxon rank sum test. Results. MtDNA copy number was significantly higher in long-term breast cancer survivors (either with SPT or not SPT) compared with newly diagnosed breast cancer patients (Mean (SD), 1.03 ± 0.25 vs 0.95 ± 0.27; p = 0.005). We did not observe significant differences of mtDNA copy number between long-term survivors with SPT and without SPT. However, in stratified analyses by epidemiological and clinical variables, we observed lower mtDNA copy number in HER2-positive long-term survivors with SPT than those without SPT (0.84 ± 0.13 vs 1.27 ± 0.44; p = 0.010) and in pre-menopause long-term survivors with SPT than those without SPT (0.95 ± 0.20 vs 1.06 ± 0.22; p = 0.034). A borderline significance of mtDNA copy number between SPT and non-SPT ER-negative long-term survivors was also noted (0.90 ± 0.17 vs 1.18 ± 0.41, p = 0.056). Conclusion. Higher mtDNA copy number was found in long-term breast cancer survivors compared to newly diagnosed cases. There were significant associations between lower mtDNA copy number and SPT in long-term breast cancer survivors who are HER2+ or are pre-menopause. These results indicate a role of mtDNA copy number in long-term breast cancer survivorship. Citation Format: Miguel Santibanez, Alma Rodriguez, Michelle A. Hildebrandt, David W. Chang, Xifeng Wu. Mitochondrial DNA copy number and risk of second primary tumors in long-term breast cancer survivors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3056. doi:10.1158/1538-7445.AM2015-3056

Risk of Second Primary Tumors After Childhood and Adolescent Ovarian Malignancies: A SEER Analysis (1973–2011)

Study ObjectiveTo calculate the incidence of second primary tumors (SPTs) in patients previously diagnosed with malignant ovarian tumors in childhood and adolescence. This is an area of interest given the high survival rate and, thus, the long disease-free period that these patients face. Design and ParticipantsWe conducted a retrospective study following a cohort of patients between 1973 and 2011. Using the National Cancer Institute's Surveillance, Epidemiology and End-Result (SEER) database, we identified patients with an ovarian malignant tumor diagnosed at 19 years of age or younger. ResultsOf the 806 patients included in our study, 28 patients developed an SPT after the diagnosis of malignant ovarian tumor. This cohort had higher risk of solid tumors (standardized incidence ratio [SIR] 1.85, 95% CI 1.15 to 2.83) and lymphohematologic malignancies (SIR 5.28, 95% CI 2.12 to 10.88) compared with the general population. There is a higher incidence of lymphoma (SIR 4.25, 95% CI 1.16 to 10.89) and acute nonlymphocytic leukemia (SIR 19.65, 95% CI 4.05 to 57.42), following initial diagnosis of ovarian malignancy during childhood or adolescence. ConclusionThe association between ovarian malignancy during childhood or adolescence and lymphoma has not been previously described. Increased incidence of acute nonlymphocytic leukemia supports previous data, underlying the need for long-term follow-up and surveillance of these patients.

Risk of second primary tumors in men diagnosed with prostate cancer: a population-based cohort study.

The survival of men diagnosed with prostate cancer has improved over time, and the current 10-year relative survival rate is 99.7%. The long survival of patients with this common cancer raises questions about the risk of a second primary cancer and the need for continued surveillance. A population-based cohort of 441,504 men who were diagnosed with prostate cancer between 1992 and 2010 was identified from Surveillance, Epidemiology and End Results Program (SEER) data (SEER13). The standardized incidence ratio (SIR) was calculated as an estimate of the risk of a second primary malignancy based on the incidence in the general population. Prostate cancer survivors had a lower risk of being diagnosed with another cancer overall compared with the US population (SIR = 0.60; 95% confidence interval, 0.60-0.61). The risks of leukemia and cancers of the oral cavity and pharynx, esophagus, stomach, colon and rectum, liver, gallbladder, pancreas, lung and bronchus, and larynx were significantly lower. Conversely, these patients had a greater risk of bladder, kidney, and endocrine and soft tissue cancers. Men who received treatment with radiation therapy (external-beam radiation therapy) had long-term increases in their risk of bladder cancer (SIR = 1.42) and rectal cancer (SIR = 1.70) risk compared with who did not receive radiation (SIRbladder = 0.76; SIRrectal = 0.74). There were significant racial differences in the risk of being diagnosed with a second primary cancer, and the magnitude and direction of these risks depended on tumor type. Prostate cancer survivors remain at risk of subsequent malignancies, and race and treatment choice important determinants of long-term risk.

Second primary tumors and myeloperoxidase expression in buccal mucosal squamous cell carcinoma

The present study investigated the relationship between the expression of manganese superoxide dismutase (MnSOD), catalase, glutathione peroxidase (GPx), and myeloperoxidase (MPO) in buccal mucosal squamous cell carcinoma (SCC), and the risk of second primary tumors (SPTs). Immunohistochemistry was performed to examine the expression of MnSOD, GPx, catalase, and MPO in tissue microarray slides of 173 male patients with buccal mucosal SCC who had undergone potentially curative resections. Forty-five (26.01%) patients developed SPTs. The prevalent subsites of SPTs were buccal mucosa (48.89%), tongue (13.33%), and lip (11.11%). High expression level of MPO was correlated with an increased risk of SPTs, even after adjustment for development of clinicopathologic parameters (high vs. low expression, adjusted hazard ratio=3.89; 95% confidence interval, 1.33-11.41; P=.013). SPTs are common in male buccal mucosal SCC patients. Higher MPO expression in buccal mucosal SCC is a risk factor for SPTs.

Tobacco Smoking and Increased Risk of Death and Progression for Patients With p16-Positive and p16-Negative Oropharyngeal Cancer

Tobacco smoking is associated with oropharynx cancer survival, but to what extent cancer progression or death increases with increasing tobacco exposure is unknown. Patients with oropharynx cancer enrolled onto a phase III trial of radiotherapy from 1991 to 1997 (Radiation Therapy Oncology Group [RTOG] 9003) or of chemoradiotherapy from 2002 to 2005 (RTOG 0129) were evaluated for tumor human papillomavirus status by a surrogate, p16 immunohistochemistry, and for tobacco exposure by a standardized questionnaire. Associations between tobacco exposure and overall survival (OS) and progression-free survival (PFS) were estimated by Cox proportional hazards models. Prevalence of p16-positive cancer was 39.5% among patients in RTOG 9003 and 68.0% in RTOG 0129. Median pack-years of tobacco smoking were lower among p16-positive than p16-negative patients in both trials (RTOG 9003: 29 v 45.9 pack-years; P = .02; RTOG 0129: 10 v 40 pack-years; P < .001). After adjustment for p16 and other factors, risk of progression (PFS) or death (OS) increased by 1% per pack-year (for both, hazard ratio [HR], 1.01; 95% CI, 1.00 to 1.01; P = .002) or 2% per year of smoking (for both, HR, 1.02; 95% CI, 1.01 to 1.03; P < .001) in both trials. In RTOG 9003, risk of death doubled (HR, 2.19; 95% CI, 1.46 to 3.28) among those who smoked during radiotherapy after accounting for pack-years and other factors, and risk of second primary tumors increased by 1.5% per pack-year (HR, 1.015; 95% CI, 1.005 to 1.026). Risk of oropharyngeal cancer progression and death increases directly as a function of tobacco exposure at diagnosis and during therapy and is independent of tumor p16 status and treatment.

Risk Factors for Multiple Malignancies in Head and Neck

Objective: Our aim was to assess the prognostic role of several epidemiological, clinical andbiological factors, related to a higher risk for multiple malignancies in head and neck cancer (HNC) patients. Method: In 76 consecutive patients treated with curative radiotherapy, p53 gene status, microsatellite instability (MSI) of the index tumor, and inherited chromosome fragility (CF), with epidemiological and clinical characters, were analyzed and correlated with the risk for second primary tumor (SPT). The follow-up was 77 months in mean (2-180 months). Results: SPT was observed in 22 patients (28.9%). p53 mutation was detected in 36 (47.3%) out of 76 first primary HNC analyzed. MSI was documented in the first primary HNC from 22 out of 63 (34.9%). Susceptibility to bleomycin-induced chromatid breaks (CF+) was found in 26 out of 54 (48.1%). Statistical analysis suggests that MSI, CF and smoking persistence after index tumor treatment were significantly correlated with an increased risk of developing multiple malignancies ( P = .05, P &lt; .01 and P = .02). Conclusion: A genetic susceptibility to DNA damage may play a central role in development of multiple malignancies in HNC patients. Testing for MSI phenotype and CF at the time of the original cancer diagnosis could identify high risk patients.

Role of panendoscopy to identify synchronous second primary malignancies in patients with oral cavity and oropharyngeal squamous cell carcinoma

Tobacco use increases the risk for squamous cell carcinoma (SCC) of the upper aerodigestive tract. The reported incidence of synchronous second primary tumors in head and neck cancer is approximately 10%. Therefore, patients with oral cancer have routinely undergone "panendoscopy" consisting of direct laryngoscopy, bronchoscopy, and esophagoscopy. Recent studies indicate increasing numbers of upper aerodigestive tumors occurring in nonsmoking populations who may have a lesser risk for second primary tumors. The purpose of this study was to evaluate the utility of performing "panendoscopy" to identify second primary tumors in these patient populations. A retrospective study of 64 consecutive patients at a university head and neck surgery practice was performed. A cohort of patients with oral cavity or oropharyngeal SCC with no tobacco history who underwent diagnostic panendoscopy were compared with similarly staged patients with a current or past history of tobacco use. Operative reports were examined for synchronous primaries, and epidemiologic data were collected. Subgroup analysis of incidence of synchronous primaries with regard to smoking status, age, sex, T classification, N classification, and location of primary tumor was also carried out. Student's t test statistical analysis was used to ascertain significance. No synchronous second primary malignancies were discovered in the nonsmoking patients. In all, 12.1% of smoking patients were diagnosed with synchronous primary cancers on panendoscopy, and this difference was significant (p = .0392). Routine panendoscopy of the upper aerodigestive tract in patients who have never smoked is unlikely to result in identification of synchronous second primary tumors.

MicroRNA-related genetic variations as predictors for risk of second primary tumor and/or recurrence in patients with early-stage head and neck cancer

Second primary tumor (SPT) and/or recurrence negatively impact the prognosis of patients with curatively treated early-stage head and neck cancer. MicroRNAs (miRNAs) play important roles in cancer development. We explored whether the variations of miRNA-related pathway were associated with the risk of SPT/recurrence in patients with early-stage head and neck cancer. This study includes 150 early-stage head and neck cancer patients with SPT/recurrence and 300 patients without SPT/recurrence. Two hundred and thirty-five tagging and potentially functional single-nucleotide polymorphisms (SNPs) were genotyped from eight miRNA biogenesis pathway genes and 135 miRNA-targeted genes. Eighteen miRNA-related SNPs were significantly associated with the risk of SPT/recurrence. The most significant SNP was rs3747238, a miRNA-binding site SNP in SMC1B. The variant homozygous genotype of this SNP was associated with a 1.74-fold increased risk [95% confidence interval (CI) 1.19-2.54; P = 0.004]. Cumulative effect analysis showed joint effects for the number of unfavorable genotype in patients. Survival tree analysis further identified the high-order gene-gene interactions and categorized the study subjects into low-, medium- and high-risk groups. Patients in the high-risk group had a 4.84-fold increased risk (95% CI: 3.11-7.51; P = 2.45 × 10(-12)) and a shorter event-free median survival time of 37.9 months (log rank P = 2.28 × 10(-13)). Our results suggested that miRNA-related genetic polymorphisms may be used individually and jointly to predict the risk of SPT/recurrence of early-stage head and neck cancer patients.

Skin cancer increases risk of second primary tumour

Skin cancer increases risk of second primary tumour

A phase III, intergroup, randomized, double-blind, chemoprevention trial of selenium (Se) supplementation in resected stage I non-small cell lung cancer (NSCLC).

CRA7004 Background: Selenium was reported to have possible lung cancer chemopreventive benefits based on a large skin cancer trial secondary observation. (JAMA 1996; 276: 1957-1963). Since that time, research continued to suggest that Se could decrease risk of second primary tumor (SPT) in persons with resected NSCLC. In 2007, a publication from another group suggested an increased association of Se with type 2 diabetes (Annals Int Med 147:217-223). Methods: From Oct 2000-Nov 2009, 6 groups, led by ECOG, carried out a double blind, placebo controlled trial using selenized yeast 200 micrograms daily in a 2:1 randomization vs. placebo for 48 mo in completely resected stage I NSCLC. Participation was 6–36 mo post-op and required a negative mediastinal node biopsy, no excessive vitamin intake, normal liver function, a negative chest x-ray, and no other evidence of recurrence. Planned size of 1,960 participants had been designed to detect a 40% decrease in SPTs with 80% power. Methylation studies of sputum and blood (S. Belinsky) add important biologic correlates to this project. Results: Interim analysis occurred in Oct 2009 after 1,561/1,772 pts reached step 2 (completion of the 4 week (step 1) run-in period requiring at least 75% of the study drug to be taken). Endpoints included SPTs, recurrence, and toxicity. A total of 216 SPTs developed of which 84 (38.9%) were lung cancer. SPT (lung/overall) incidence was 1.36/3.66 per 100 person yrs for placebo vs. 1.91/4.11 for Se (p=.150). 5 yr progression free survival was 78% for placebo vs. 72% for Se. Study was stopped according to futility analysis. Grade 1 or 2 toxicity occurred in 38% of placebo and 39% Se. Grade 3 toxicity was 3% placebo vs. &lt;1% Se. Compliance was excellent (&gt;95% at 2 yrs). Conclusions: No increase in diabetes mellitus or skin cancer was detected. Se was safe but conferred no benefit over placebo. Methylation studies are continuing. [Table: see text]

A phase III, intergroup, randomized, double-blind, chemoprevention trial of selenium (Se) supplementation in resected stage I non-small cell lung cancer (NSCLC).

CRA7004 Background: Selenium was reported to have possible lung cancer chemopreventive benefits based on a large skin cancer trial secondary observation. (JAMA 1996; 276: 1957-1963). Since that time, research continued to suggest that Se could decrease risk of second primary tumor (SPT) in persons with resected NSCLC. In 2007, a publication from another group suggested an increased association of Se with type 2 diabetes (Annals Int Med 147:217-223). Methods: From Oct 2000-Nov 2009, 6 groups, led by ECOG, carried out a double blind, placebo controlled trial using selenized yeast 200 micrograms daily in a 2:1 randomization vs. placebo for 48 mo in completely resected stage I NSCLC. Participation was 6–36 mo post-op and required a negative mediastinal node biopsy, no excessive vitamin intake, normal liver function, a negative chest x-ray, and no other evidence of recurrence. Planned size of 1,960 participants had been designed to detect a 40% decrease in SPTs with 80% power. Methylation studies of sputum and blood (S. Belinsky) add important biologic correlates to this project. Results: Interim analysis occurred in Oct 2009 after 1,561/1,772 pts reached step 2 (completion of the 4 week (step 1) run-in period requiring at least 75% of the study drug to be taken). Endpoints included SPTs, recurrence, and toxicity. A total of 216 SPTs developed of which 84 (38.9%) were lung cancer. SPT (lung/overall) incidence was 1.36/3.66 per 100 person yrs for placebo vs. 1.91/4.11 for Se (p=.150). 5 yr progression free survival was 78% for placebo vs. 72% for Se. Study was stopped according to futility analysis. Grade 1 or 2 toxicity occurred in 38% of placebo and 39% Se. Grade 3 toxicity was 3% placebo vs. <1% Se. Compliance was excellent (>95% at 2 yrs). Conclusions: No increase in diabetes mellitus or skin cancer was detected. Se was safe but conferred no benefit over placebo. Methylation studies are continuing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer

Genetic variants in the telomere maintenance pathway as predictors of second primary tumors and recurrence of early-stage head and neck cancer.

1504 Background: Telomere is critical for chromosome stability. Telomere shortening has been associated with cancer development. In this study, we evaluated genetic variants in the telomere maintenance pathway as predictors for the risk of second primary tumor (SPT) or recurrence in early-stage head and neck squamous cell carcinoma (HNSCC) patients. Methods: We genotyped 427 single nucleotide polymorphisms (SNP) from 41 telomere maintenance pathway genes in a nested 1:2 case-control study of 150 early stage HNSCC patients with SPT/recurrence and 300 patients without. Individual and cumulative effects and interactions of these SNPs on SPT/recurrence were assessed. Results: In the Cox proportional hazards model, patients carrying the variant genotypes of rs9562605, located in the BRCA2 gene, were associated with a 0.5-fold (95% CI 0.4- 0.8) reduced risk of SPT/recurrence, and longer median SPT/recurrence-free survival time (MST) (> 93 months) than those with wild-type genotype (81.6 months) (p = 2.4 × 10-3). A cumulative effect analysis was performed by combining the unfavorable genotypes of the 53 significant SNPs with p < 0.05. A progressively increasing SPT/recurrence risk was observed as the number of unfavorable genotypes increased (p for trend < 0.0001). Specifically, compared to the subjects with fewer than 19 unfavorable genotypes, subjects with more than 30 unfavorable genotypes had 19.7-fold (95% CI 9.6-40.4) increased risk and significantly shorter MST (28.2 months vs. > 93 months, log-rank p = 2.0 × 10-24). From survival tree analysis, rs10849605 was the first split with the smallest p-value (2.5 × 10-3). Node 18 ranked the highest risk group (HR > 3.7, 95% CI 9.6-568.4, MST = 13.4 months) as compared to the reference node, node 1 (MST > 93 months) (log-rank p = 1.1 × 10-23). Conclusions: The study identified several promising SNPs and further demonstrated that the combination of multiple SNPs and their interactions may be useful to predict clinical outcome of early-stage head and neck cancer. No significant financial relationships to disclose.