Weiss, Noel S

ImportanceThe fecal immunochemical test (FIT) is widely used for colorectal cancer (CRC) screening, but evidence of its effectiveness is limited.ObjectiveTo evaluate whether FIT screening is associated with a lower risk of dying from CRC overall, according to cancer location, and within demographic groups.Design, Setting, and ParticipantsThis nested case-control study in a cohort of screening-eligible people was conducted in 2 large, integrated health systems of racially, ethnically, and socioeconomically diverse members with long-term programs of mailed FIT screening outreach. Eligible participants included people aged 52 to 85 years who died from colorectal adenocarcinoma between 2011 and 2017 (cases); cases were matched in a 1:8 ratio based on age, sex, health-plan membership duration, and geographic area to randomly selected persons who were alive and CRC-free on case’s diagnosis date (controls). Data analysis was conducted from January 2002 to December 2017.ExposuresCompleting 1 or more FIT screenings in the 5-year period prior to the CRC diagnosis date among cases or the corresponding date among controls; in secondary analyses, 2- to 10-year intervals were evaluated.Main Outcomes and MeasuresThe primary study outcome was CRC death overall and by tumor location. Secondary analyses were performed to assess CRC death by race and ethnicity.ResultsFrom a cohort of 2 127 128 people, a total of 10 711 participants (3529 aged 60-69 years [32.9%]; 5587 male [52.1%] and 5124 female [47.8%]; 1254 non-Hispanic Asian [11.7%]; 973 non-Hispanic Black [9.1%]; 1929 Hispanic or Latino [18.0%]; 6345 non-Hispanic White [59.2%]) was identified, including 1103 cases and 9608 controls. Among controls during the 10-year period prior to the reference date, 6101 (63.5%) completed 1 or more FITs with a cumulative 12.6% positivity rate (768 controls), of whom 610 (79.4%) had a colonoscopy within 1 year. During the 5-year period, 494 cases (44.8%) and 5345 controls (55.6%) completed 1 or more FITs. In regression analysis, completing 1 or more FIT screening was associated with a 33% lower risk of death from CRC (adjusted odds ratio [aOR], 0.67; 95% CI, 0.59-0.76) and 42% lower risk in the left colon and rectum (aOR, 0.58; 95% CI, 0.48-0.71). There was no association with right colon cancers (aOR, 0.83; 95% CI, 0.69-1.01) but the difference in the estimates between the right colon and left colon or rectum was statistically significant (P = .01). FIT screening was associated with lower CRC mortality risk among non-Hispanic Asian (aOR, 0.37; 95% CI, 0.23-0.59), non-Hispanic Black (aOR, 0.58; 95% CI, 0.39-0.85) and non-Hispanic White individuals (aOR, 0.70; 95% CI, 0.57-0.86) (P for homogeneity = .04 for homogeneity).Conclusions and RelevanceIn this nested case-control study, completing FIT was associated with a lower risk of overall death from CRC, particularly in the left colon, and the associations were observed across racial and ethnic groups. These findings support the use of FIT in population-based screening strategies.

Objective To examine whether receiving a fecal occult blood test after a negative sigmoidoscopy reduced mortality from colorectal cancer. Methods We used a nested case–control design with incidence-density matching in historical cohorts of 1,877,740 50–90-year-old persons during 2006–2012, in an integrated health-system setting. We selected 1758 average risk patients who died from colorectal cancer and 3503 matched colorectal cancer-free persons. Colorectal cancer-specific death was ascertained from cancer and mortality registries. Screening histories were determined from electronic and chart–audit clinical data in the 5- to 10-year period prior to the reference date. We evaluated receipt of subsequent fecal occult blood test within five years of the reference date among patients with negative sigmoidoscopy two to six years before the reference date. Results Of the 5261 patients, 831 patients (204 colorectal cancer deaths/627 controls) had either negative sigmoidoscopy only ( n = 592) or negative sigmoidoscopy with subsequent screening fecal occult blood test ( n = 239). Fifty-six (27.5%) of the 204 patients dying of colorectal cancer and 183 (29.2%) of the 627 colorectal cancer-free patients received fecal occult blood test following a negative sigmoidoscopy. Conditional regressions found no significant association between fecal occult blood test receipt and colorectal cancer death risk, overall (adjusted odds ratio = 0.93, confidence interval: 0.65–1.33), or for right (odds ratio = 1.02, confidence interval: 0.65–1.60) or left-colon/rectum (odds ratio = 0.77, confidence interval: 0.39–1.52) cancers. Similar results were obtained in sensitivity analyses with alternative exposure ascertainment windows or timing of fecal occult blood test. Conclusions Our results suggest that receipt of at least one fecal occult blood test during the several years after a negative sigmoidoscopy did not substantially reduce mortality from colorectal cancer.

Abstract Purpose: DNA topoisomerase inhibitors are commonly used for treating small-cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) repairs DNA damage caused by this class of drugs and may therefore influence treatment outcome. In this study, we investigated whether common TDP1 single-nucleotide polymorphisms (SNP) are associated with overall survival among SCLC patients. Experimental Design: Two TDP1 SNPs (rs942190 and rs2401863) were analyzed in 890 patients from 10 studies in the International Lung Cancer Consortium (ILCCO). The Kaplan–Meier method and Cox regression analyses were used to evaluate genotype associations with overall mortality at 36 months postdiagnosis, adjusting for age, sex, race, and tumor stage. Results: Patients homozygous for the minor allele (GG) of rs942190 had poorer survival compared with those carrying AA alleles, with a HR of 1.36 [95% confidence interval (CI): 1.08–1.72, P = 0.01), but no association with survival was observed for patients carrying the AG genotype (HR = 1.04, 95% CI, 0.84–1.29, P = 0.72). For rs2401863, patients homozygous for the minor allele (CC) tended to have better survival than patients carrying AA alleles (HR = 0.79; 95% CI, 0.61–1.02, P = 0.07). Results from the Genotype Tissue Expression (GTEx) Project, the Encyclopedia of DNA Elements (ENCODE), and the ePOSSUM web application support the potential function of rs942190. Conclusions: We found the rs942190 GG genotype to be associated with relatively poor survival among SCLC patients. Further investigation is needed to confirm the result and to determine whether this genotype may be a predictive marker for treatment efficacy of DNA topoisomerase inhibitors. Clin Cancer Res; 23(24); 7550–7. ©2017 AACR.

Abstract Introduction: DNA topoisomerase inhibitors (e.g. etoposide, irinotecan, teniposide, topotecan) are commonly used for treating small cell lung cancer (SCLC). Tyrosyl-DNA phosphodiesterase (TDP1) plays a role in repairing DNA damage caused by DNA topoisomerase inhibitors and it is believed to be responsible for resistance to this class of drugs. The purpose of this study was to determine whether common TDP1 polymorphisms are associated with overall survival among SCLC patients. Method: Two common TDP1 SNPs (rs942190 and rs2401863, r2(European)=0.63 and r2(East Asian)=0.26) were analyzed in 898 patients from 10 studies in the International Lung Cancer Consortium, conducted in the U.S., Canada, Japan, Italy, Spain and the United Kingdom. Genotype data were obtained from either the OncoArray Consortium or other existing genome-wide association studies. Cox proportional hazard regression models with robust standard error were used to evaluate genotype associations for overall survival at 36 months post-diagnosis, adjusting for age, sex, race and tumor stage. Results: Patients homozygous for the minor allele (GG) of TDP1 SNP rs942190 were associated with poorer survival compared to those carrying both major alleles (AA), with a hazard ratio (HR) of 1.36 (95% confidence interval (CI): 1.07-1.72, p-value=0.01), but there was no association with survival for patients with the heterozygous genotype (HR=1.02, 95% CI: 0.83-1.27, p-value=0.83). For rs2401863, patients carrying both minor alleles (CC) tended to have better survival than patients carrying AA alleles, but this was within the limits of chance given no significant association (HR=0.79, 95% CI: 0.61-1.02, p-value=0.07). In addition, multi-tissue expression quantitative trait loci (eQTL) analyses from the Genotype-Tissue Expression Project indicated a potential effect of rs942190 on lung tissue, with higher TDP1 gene expression for the GG than AG or AA genotypes. Conclusion: We found that among SCLC patients the TDP1 rs942190 GG genotype was associated with poor overall survival. Further study could determine if this genotype can serve as a predictive marker for the treatment efficacy of DNA topoisomerase inhibitors in SCLC. Citation Format: Pawadee Lohavanichbutr, Lori C. Sakoda, Christopher I. Amos, Susanne M. Arnold, David C. Christiani, Michael P. Davies, John K. Field, Eric B. Haura, Rayjean J. Hung, Takashi Kohno, Maria Teresa Landi, Geoffrey Liu, Yi Liu, Michael W. Marcus, Grainne M. O'Kane, Matthew B. Schabath, Kouya Shiraishi, Stacey A. Slone, Adonina Tardón, Ping Yang, Kazushi Yoshida, Ruyang Zhang, Xuchen Zong, Noel S. Weiss, Chu Chen. Common TDP1 polymorphisms in relation to survival among small cell lung cancer patients in a multicenter study from the International Lung Cancer Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2248. doi:10.1158/1538-7445.AM2017-2248