Stacey A. Cohen

Timing of Aspirin and Other Nonsteroidal Anti-Inflammatory Drug Use Among Patients With Colorectal Cancer in Relation to Tumor Markers and Survival

Purpose Regular use of aspirin is associated with improved survival for patients with colorectal cancer (CRC). However, the timing of and the subtype of CRC that would benefit the most from using aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in relation to survival is unclear. Patients and Methods In all, 2,419 patients age 18 to 74 years with incident invasive CRC who were diagnosed from 1997 to 2008 were identified from population-based cancer registries in the United States, Canada, and Australia. Detailed epidemiologic questionnaires were administered at study enrollment and at 5-year follow-up. Survival outcomes were completed through linkage to national death registries. BRAF- and KRAS-mutation status, microsatellite instability, and CpG island methylator phenotype were also evaluated. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for overall survival (OS) and CRC-specific survival. Results After a median of 10.8 years of follow-up since diagnosis, 381 deaths (100 as a result of CRC) were observed. Compared with nonusers, postdiagnostic aspirin-only users had more favorable OS (HR, 0.75; 95% CI, 0.59 to 0.95) and CRC-specific survival (HR, 0.44; 95% CI, 0.25 to 0.71), especially among those who initiated aspirin use (OS: HR, 0.64; 95% CI, 0.47 to 0.86; CRC-specific survival: HR, 0.40; 95% CI, 0.20 to 0.80). The association between any NSAID use after diagnosis and OS differed significantly by KRAS-mutation status ( Pinteraction = .01). Use of any NSAID after diagnosis was associated with improved OS only among participants with KRAS wild-type tumors (HR, 0.60; 95% CI, 0.46 to 0.80) but not among those with KRAS-mutant tumors (HR, 1.24; 95% CI, 0.78 to 1.96). Conclusion Among long-term CRC survivors, regular use of NSAIDs after CRC diagnosis was significantly associated with improved survival in individuals with KRAS wild-type tumors.

Initiation of universal tumor screening for Lynch syndrome in colorectal cancer patients as a model for the implementation of genetic information into clinical oncology practice

Lynch syndrome confers a hereditary predisposition to colorectal and other cancers. Universal tumor screening (UTS) for Lynch syndrome is recommended by several professional societies, but the implementation can be complex. This article describes the evaluation, process development, and initiation of Lynch syndrome UTS at a tertiary referral cancer center.

Targeted therapy in gastroesophageal cancers: past, present and future

Gastroesophageal cancer is a significant global problem that frequently presents at an incurable stage and has very poor survival with standard chemotherapy approaches. This review will examine the epidemiology and molecular biology of gastroesophageal cancer and will focus on the key deregulated signaling pathways that have been targeted in the clinic. A comprehensive overview of clinical data highlighting successes and failures with targeted agents will be presented. Most notably, HER2-targeted therapy with the monoclonal antibody trastuzumab has proven beneficial in first-line therapy and has been incorporated into standard practice. Targeting the VEGF pathway has also proven beneficial, and the VEGFR-targeted monoclonal antibody ramucirumab is now approved for second-line therapy. In contrast to these positive results, agents targeting the EGFR and MET pathways have been evaluated extensively in gastroesophageal cancer but have repeatedly failed to show benefit. An increased understanding of the molecular predictors of response to targeted therapies is sorely needed. In the future, improved molecular pathology approaches should subdivide this heterogeneous disease entity to allow individualization of cancer therapy based on integrated and global identification of deregulated signaling pathways. Better patient selection, rational combinations of targeted therapies and incorporation of emerging immunotherapeutic approaches should further improve the treatment of this deadly disease.

Stage IV colorectal cancer primary site and patterns of distant metastasis

BACKGROUND Although colorectal cancer (CRC) usually metastasizes to the liver and/or lungs, factors influencing the anatomic pattern of metastases remain poorly understood. METHODS We assessed the relationship between primary CRC site and pattern of synchronous metastasis among 1202 individuals diagnosed with incident metastatic CRC between 2010 and 2014 and identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) registry. Polytomous logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between primary tumor site and synchronous metastatic pattern. RESULTS Compared to patients with proximal colon primaries, patients with rectal primaries were more likely to present with lungs-only or liver and lungs metastases versus liver-only metastases (ORlungs-onlyvs.liver-only: 2.39, 95% CI: 1.35-4.24, ORliver+lungsvs.liver-only: 2.20, 95% CI: 1.46-3.32). CONCLUSION These findings suggest that patients with rectal primaries are more likely than patients with colon primaries to present with synchronous lung metastases.

Cancer Treatment Delays in American Indians and Alaska Natives Enrolled in Medicare

To assess whether timing of initial post-diagnosis cancer care differs between American Indian and Alaska Native (AI/AN) and non-Hispanic White (NHW) patients, we accessed SEER-Medicare data for breast, colorectal, lung, and prostate cancers (2001-2007). Medicare claims data were examined for initiation of cancer-directed treatment. Overall, AI/ANs experienced longer median times to starting treatment than NHWs (45 and 39 days, p < .001) and lower rates of treatment initiation (HR[95%CI]: 0.86[0.79-0.93]). Differences were largest for prostate (HR: 0.80[0.71-0.89]) and smallest for breast cancer (HR: 0.96[0.83-1.11]). American Indians / Alaska Natives also had elevated odds of greater than 10 weeks between diagnosis and treatment compared with NHWs (OR[95% CI]: 1.37[1.16-1.63]), especially for prostate cancer (OR: 1.41[1.14-1.76]). Adjustment for comorbidity and socio-demographic factors attenuated associations except for prostate cancer. In this insured population, we observed evidence that AI/ANs start cancer therapy later than NHWs. The modest magnitude of delays suggests that they are unlikely to be a determinant of survival disparities.

Indian Health Service Care System and Cancer Stage in American Indians and Alaska Natives

Abstract:Purpose. We aimed to determine whether the association between late-stage cancer and American Indian/Alaska Native (AI/AN) race differed by enrollment in the Indian Health Service Care System (IHSCS). Methods. We used Surveillance, Epidemiology, and End Results (SEER) data linked to Medicare files to compare the odds of late-stage breast, colorectal, lung, or prostate cancer between non-Hispanic Whites (NHWs) (n=285,993) and AI/ANs with (n=581) and without (n=543) IHSCS enrollment. Results. For AI/ANs without IHSCS enrollment, the odds of late-stage disease were higher in AI/ANs compared with NHWs for breast (OR=3.17, 95%CI: 1.82–5.53) and for prostate (OR=2.59, 95%CI:1.55–4.32) cancer, but not for colorectal or lung cancers. Among AI/ANs with IHSCS enrollment, there was not a significant association between late-stage disease and AI/AN race for any of the four cancers evaluated. Conclusion. Our results suggest that enrollment in the IHSCS reduced the disparity between AI/ANs and NHWs with respect to late-stage cancer diagnoses.

Biomarker-driven and molecular targeted therapies for colorectal cancers

Improved clinical selection and identification of new molecules and innovative strategies have widened treatment options and increased overall survival in metastatic colorectal cancer patients in recent years. Biomarker-driven therapies represent an emerging issue in this field and new targeted treatments are under investigation and probably will be soon adopted into daily clinical practice. In the present review, the role RAS, BRAF mutations, Her2 amplification, microsatellite instability, and CpG island methylator phenotype are discussed according to their possible roles as prognostic, predictive markers, as well as possible biomarker-driven treatment options.

The CpG island methylator phenotype is concordant between primary colorectal carcinoma and matched distant metastases

BackgroundThe CpG island methylator phenotype (CIMP) in stage III colon cancer (CRC) has been associated with improved survival after treatment with adjuvant irinotecan-based chemotherapy. In this analysis, we determine whether CIMP status in the primary CRC is concordant with the CIMP status of matched metastases in order to determine if assessment of CIMP status in the primary tumor can be used to predict CIMP status of metastatic disease, which is relevant for patient management as well as for understanding the biology of CIMP CRCs.MethodsWe assessed the CIMP status of 70 pairs of primary CRC and matched metastases using a CRC-specific panel of five markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1) where CIMP positive was defined as 3/5 positive markers at a percent methylated reference threshold of ≥10%. Concordance was compared using the Fisher’s exact test and P < 0.05 was considered significant.ResultsSixty-nine of the pairs (98.6%) showed concordant CIMP status in the primary tumor and matched metastasis; five (7.0%) of the pairs were concordantly CIMP positive. Only one pair (1.4%) had divergent CIMP status, demonstrating CIMP positivity (4/5 markers positive) in the primary tumor, while the matched metastasis was CIMP negative (0 markers positive).ConclusionsCIMP status is generally concordant between primary CRCs and matched metastases. Thus, CIMP status in the primary tumor is maintained in matched metastases and can be used to inform CIMP-based therapy options for the metastases.

Abstract A28: Type 2 diabetes and risk of colorectal polyps in a colonoscopy-based study

Background: Type-2 diabetes mellitus (T2DM) and colorectal cancer (CRC) are both relatively common diseases among the adult population in the US; both diseases also share similar risk factors, including obesity, chronic inflammation, sedentary lifestyle, and selected dietary factors. Estimates suggest that 14% of CRC patients have T2DM as a comorbid condition at diagnosis. T2DM has also been identified as an independent risk factor for colorectal cancer. Most colorectal cancers arise from polyp precursor lesions, including advanced adenomas and a subset of serrated polyps, termed sessile serrated polyps. There is limited evidence regarding the association between T2DM and specific subtypes of colorectal polyps. We investigated the relationship between T2DM and the risk of subsets of colorectal polyps in a colonoscopy-based study in western Washington State. Methods: Study participants were a subset of 20-79 year-old enrollees at Group Health, a population-based integrated health care system in the greater Puget Sound area in Washington State, who underwent a colonoscopy for any indication from 1998-2007. Eligible study participants completed a structured questionnaire to collect risk factor information, including self-report of clinically-diagnosed diabetes, and whether it was treated with medications. Participants were diagnosed as having adenomas (n=633), serrated polyps (n=602), synchronous presence of both adenomas and serrated polyps (n= 244) or as polyp-free controls (n=1052) on the basis of a standardized pathology review. Multivariable polytomous logistic regression was used to compare case groups with polyp-free controls and other case groups. Odds ratios (OR) and 95% confidence intervals (CI) were estimated, overall and by subtype, adjusted for age, sex, race, educational status, body mass index, smoking, alcohol intake, aspirin and nonsteroidal anti-inflammatory drug use, physical activity, history of previous endoscopy, and diet (fruits, vegetables and red meat intake). Results: About 10% of the study population reported a history of clinically diagnosed T2DM, and 77% of those with T2DM took anti-diabetic medications. T2DM was not associated with the risk for colorectal polyps overall (adjusted OR 0.84; 95% CI 0.61-1.15). When evaluated by polyp subtype, T2DM diagnosis was not associated with the risk for adenomas (adjusted OR 1.02; 95% CI 0.70-1.48), but it was inversely associated with the risk for serrated polyps (adjusted OR 0.61, 95% CI 0.40-0.95). There was significant heterogeneity between adenomas and serrated polyps for their association with T2DM (P for heterogeneity=0.0001); however, the associations did not vary by lesion severity within each polyp subtype (advanced vs. non-advanced adenomas, sessile serrated vs. hyperplastic polyps). Also, associations did not differ statistically significantly between treated and non-treated diabetics for either adenomas or serrated polyps, but there was an increased risk for polyps overall among those not taking anti-diabetic medications (adjusted OR 1.26; 95% CI 0.63-2.53). This association was suggestive but did not reach statistical significance. Conclusions: We observed that the risk for serrated polyps was significantly lower among those with a history of diabetes, while there was no observed association between colorectal adenomas and T2DM. This differential association may possibly be due to a variable effect of anti-diabetic medications on serrated pathway lesions, as suggested by the increased risk for polyps among untreated diabetics. Further studies are needed to better understand the mechanistic processes through which diabetes and its treatment may be differentially associated with the development of adenomas and serrated polyps. Citation Format: Sheetal Hardikar, Andrea N. Burnett-Hartman, Stacey A. Cohen, Polly A. Newcomb. Type 2 diabetes and risk of colorectal polyps in a colonoscopy-based study. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr A28.

Abstract LB-360: Association between weight change after colorectal cancer diagnosis and long-term mortality differs by age

Previous studies evaluating the association of weight gain following colorectal cancer (CRC) diagnosis with mortality have been inconsistent. In this study, we evaluate whether this association differs by age at diagnosis. Incident, invasive CRC cases were identified from the Puget Sound Surveillance, Epidemiology and End Results (SEER) Registry from 1997-2008 and enrolled in the Seattle Colon Cancer Family Registry. A standardized interview (at mean 8 months after diagnosis) ascertained self-reported height and weight two years prior. A follow-up questionnaire was administered approximately 5 years after baseline, with 1,087 participants providing height and weight at both time points. Survival outcomes were assessed through linkage to the National Death Index. Delayed-entry Cox regression was used to estimate the association between change in weight (kg) and all-cause or CRC-specific mortality (Hazard Ratio (HR) and 95% Confidence Interval (95% CI)), with survival time beginning at the 5-year follow-up survey. Models adjusted for age at diagnosis, sex, smoking history (ever/never), cancer stage at diagnosis (I-IV, missing), days from diagnosis and baseline survey, and body mass index (kg/m2) at baseline. Analyses were stratified by age at diagnosis ( Over a median 4.7 years (range 0-9.0) of follow-up after the 5-year survey, 234 participants died (69 from CRC). At the 5-year follow-up, 579 (54%) participants had lost weight (median -5 kg), 114 (11%) reported the same weight, and 385 (36%) had gained weight (median 4 kg). Among those aged Citation Format: Jonathan M. Kocarnik, Xinwei Hua, Jamaica Robinson, Amanda I. Phipps, Stacey Cohen, Polly A. Newcomb. Association between weight change after colorectal cancer diagnosis and long-term mortality differs by age. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-360.