bluuebunny/crossref_metadata_2025 huggingface dataset:
Underuse of microsatellite instability testing and predictors of high microsatellite instability disease among young colorectal cancer patients.
Authors: Shaikh Talha , Handorf Elizabeth , Meyer Joshua E. , Hall Michael J. , Esnaola Nestor F.
Published: March 2017

534

Background: The purpose was to identify predictors of non-adherence to MSI testing in young CRC patients and identify factors associated with an increased risk of high microsatellite instability (MSI-H) disease. Methods: Patients 18-49 years old diagnosed with invasive colorectal adenocarcinoma between 2010-2012 and known MSI testing status were identified using the National Cancer Data Base. Multivariable logistic regression was used to identify independent predictors of receipt of MSI testing, as well as MSI-H status among those tested. Results: Among 17,218 patients identified, only 7,422 (43%) underwent MSI testing; the proportion of patients tested increased between 2010 (36%) and 2012 (48%; p < 0.001). Higher educational level, early stage disease, and number of regional lymph nodes examined > 12 were independently associated with MSI testing, whereas older age (40-49), Hispanic ethnicity, non-private insurance status, non-academic/research facility, facility location, rectosigmoid/rectal tumor location, non-mucinous histology, unknown grade, non-receipt of definitive surgery were associated with underuse. Among 6,358 tested patients with known MSI status, 531 (8%) patients had MSI-H disease. Lower income, previous cancer history, and stage II disease were independently associated with MSI-H status, whereas older age (40-49), female sex, advanced comorbidity, non-metropolitan facility status, facility location, distal tumor location, non-mucinous histology, unknown/lower tumor grade, and non-receipt of chemotherapy were inversely associated with MSI-H status. Conclusions: Despite national guidelines, significant underuse of routine MSI testing in young patients diagnosed with colorectal cancer persists. Interventions are warranted to improve adherence to guideline-based care in these patients, particularly among those at increased risk of MSI-H disease. [Table: see text]
What about the guys? An assessment of gender differences in hereditary colorectal cancer testing.
Authors: Espenschied Carin , Pepper Jonathan , McFarland Rachel E.
Published: March 2017

537

Background: Approximately 5-10% of colorectal cancer (CRC) is due to hereditary causes. Identification of an inherited cause may impact surgical and treatment decisions for CRC patients and may identify increased risks for other cancers that warrant increased screening and/or risk reduction measures. Men have testing for hereditary breast and ovarian cancer less often than women, even though these genes may also cause increased risk for cancer in men and men are as likely as women to carry mutations in these genes and pass them onto their children. We aimed to explore whether similar gender differences exist related to testing for hereditary CRC. Methods: We retrospectively reviewed clinical data and test results from consecutive CRC cases, who had a multi-gene panel with 13-49 genes at our laboratory, between March 2012 and June 2016. Statistical comparisons between males and females were conducted using Fisher’s exact test. Results: Of CRC cases (n = 7142), 61.1% were female and 12.8% were positive for mutation or likely pathogenic variant. Average age of CRC onset for men was 47.2, and for women was 49.5. Women with CRC before age 20 had the highest mutation rate (31.8%), but men were more likely to test positive than women overall (14.1% vs 12.0%, p = 1.1e-2). Mutations were most frequent in the same three genes for both men and women, but in different orders: MLH1, CHEK2, and MSH2 for males and CHEK2, MSH2, and MLH1 for females. The only genes with significant differences in mutation rates between men and women were MLH1 (3.2% vs 1.5%, p = 2.0e-6) and MSH6(1.7% vs 0.8%, p = 3.0e-3). Conclusions: Hereditary CRC is expected to affect men and women equally. In our cohort, however, the majority of individuals tested were women, while men were more likely to test positive. Possible explanations include smaller sample size and earlier age of onset in men, perceptions of referring clinicians, and different levels of interest in genetic counseling and testing between male and female patients. These data highlight an important opportunity for educating and identifying more men with hereditary CRC who may benefit from genetic information. Further studies are needed to confirm these results and explore reasons for the differences.
Changes in platelet/lymphocyte ratio after CRT to predict oncologic outcome in patients with rectal cancer.
Authors: Lee In Hee , Hwang Soyoon , Baek Dong Won , Lee Soo Jung , Kang Byung Woog , Chae Yee Soo , Kim Hye Jin , Kim Jong Gwang
Published: March 2017

539

Background: Previous studies have shown that the neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) are potential prognostic markers in many different cancers. However, the relationship between the changes of these ratios after concurrent chemoradiotherapy (CRT) and clinical outcome in rectal cancer patients was not reported yet. Accordingly, the aim of this study was to evaluate the prognostic relevance of the changes in NLR and PLR in patients with rectal cancer who treated with CRT followed by surgery. Methods: We enrolled 296 patients with histologically confirmed rectal adenocarcinoma who have received preoperative CRT at Kyungpook National University Medical Center (Daegu, Korea) between January 2006 and December 2015. We analyzed full hematological data both pre CRT (initial visit) and post CRT (before surgery) and oncologic outcomes including pathologic complete response (pCR), relapse-free survival (RFS), and overall survival (OS). An NLR≥5 and PLR ≥235 were considered to cut-off values according to previous studies. The ratio of change in NLR and PLR were calculated by following formula: ratio of change in NLR = (post NLR-pre NLR)/ pre NLR *100, ratio of change in PLR = (post PLR-pre PLR)/pre PLR *100. Significant cut-off value for ratio of change in NLR and PLR were calculated by simulation analysis (SAS Institute Japan, Tokyo, Japan). Results: Of the 296 patients, the majority were male (69.6%), with a median age of 59.1 years (range 25~88). Of these patients, 41 (13.9%) obtained pCR after CRT. Sixty-one patients (20.6%) had high PLR before CRT, which significantly correlated with pCR (p = 0.014) and RFS (p = 0.026), while high NLR was associated with pCR (p = 0.012) only. The optimal cut-off value for the ratio of change in PLR was 200 for RFS. The patients who had relatively higher ratio of change in PLR (ratio of change in PLR ≥ 200) showed better RFS compared to lower ratio of change (ratio of change in PLR < 200) (3-year RFS 90.9% vs. 69.7%, p = 0.05). Changes in NLR did not correlate with oncologic outcomes. Conclusions: Changes in platelet/lymphocyte ratio could also be a potential clinical biomarker in predicting oncologic outcome in rectal cancer patients treated with preoperative CRT.
Topographical incidence and survival analysis of gastrointestinal tract cancer in adolescent and young adults compared with older adults in the United States.
Authors: Levine Oren Hannun , Zbuk Kevin M. , Bleyer Archie
Published: March 2017

545

Background: Adolescent and young adults (AYAs) who develop gastrointestinal (GI) cancer are rare and have unique needs. There is limited literature defining the epidemiology of malignant disease across the entire GI tract in this age group. The objective of this study was to explore incidence and survival trends in the United States for all types of GI cancers in AYAs compared to older adults. Methods: We analyzed all incident cases of GI tract cancers in AYAs aged 15 to 39 and older adults aged 40 to 64 in the National Cancer Institute Surveillance, Epidemiology and End Results (SEER) program 2000-2013 database. For each age group and sex, we determined incidence rates, temporal changes in incidence, overall prognosis and stage-based prognosis for all primary tumor sites throughout the GI tract. Results: The incidence of colorectal cancer (CRC) distal to the splenic flexure has increased in AYAs whereas all CRC has decreased in older adults. We found that compared to older adults, AYAs have experienced better survival for most cancers arising at or proximal to the cecum regardless of stage. Conversely, more distal tumors were associated with worse prognosis in AYAs for regional or distant-stage disease. For distal CRC, the greatest age-based discrepancy in survival occurred for regional disease. Despite decreasing incidence of anal cancer in AYAs, young females have experienced worse survival with this disease compared to AYA males and older adults. Conclusions: We have identified age and gender-based disparities in survival relating to GI cancers. Rising rates of distal CRC in AYAs highlight the need for further exploration of molecular mechanisms and potential therapeutic targets for these malignancies which are also associated with worse survival in the younger population.
Vitamin D levels and its relationship with successful completion of adjuvant chemotherapy and improved survival in early stage colorectal cancer patients.
Authors: Tariq Khurram Bilal , Gopal Aaron , Nayak-Kapoor Asha
Published: March 2017

549

Background: Vitamin D deficiency is associated with increased colorectal cancer (CRC) risk and decreased colorectal cancer survival. The purpose of this study was to determine the effect of colorectal cancer adjuvant treatment on the vitamin D status in CRC. Methods: 102 patients at the GCC with Stage I-III CRC were selected between 2009 -2011. A retrospective analyses of baseline vitamin D in these patients was made to determine if vitamin D level predicts survival. Those patients who have received neoadjuvant treatment were excluded. Only patients who had a baseline vitamin D level drawn at baseline were included. Vitamin D sufficiency was defined as serum level of 30ng/ml or greater, insufficiency as 20 to 29ng/ml and deficiency as less than 20ng/ml. Results: Mean age of the patients was 76.4 years. 45 % were Stage I , 35% comprised Stage II and 25% were Stage III. 25OHD Level was insufficient in 85% and deficient in 10% and sufficient in only 5% of the patients. In the patients who received chemotherapy (45% ), those with sufficient vitamin D levels had a statistically longer survival than those with deficient levels (p<0.002). Also the patients with sufficient levels, they were more likely to complete the 6 months of chemotherapy than those with deficient levels (p<0.006). The median Vitamin D level for all 102 patients was 22.8ng/ml. Patients with sufficient vitamin D levels were more likely to have lower body mass index (p<0.01). There was no correlation between race and level of vitamin D. Patients with a sufficient vitamin D Level (25 patients), had a survival which was significantly more than those with deficient levels (p<0.001). Patients with sufficient vitamin D levels were more likely to have stage I and II disease than stage III ( p <0.04). For each stage of CRC, patients with sufficient vitaminD levels had a better overall survival than those with deficient vitamin D level(p<0.01). Conclusions: Patients with sufficient levels of vitamin D are associated with better overall survival in early stage CRC. Whether aggressive vitamin D repletion would improve the outcome in vitamin D deficient CRC patients remains unknown.
Association of PIK3CA H1047R and STK11 F354L mutations with response to neoadjuvant chemoradiotherapy and survival in esophageal cancer.
Authors: Hsu Po Kuei , Chou Teh-Ying ,   Lihpao Life Science Corp.
Published: March 2017

55

Background: Neoadjuvant chemoradiotherapy is the standard treatment for locally advanced esophageal cancer. However, its efficacy is limited in non-responders and there is no reliable clinical parameter in predicting treatment response. We aim to identify chemoradiation-resistant cancers and avoid unnecessary treatments in non-responders with mutation analysis. Methods: Genomic DNA was extracted from diagnostic biopsy specimens of 20 patients (10 with good and 10 with poor response) with esophageal squamous cell carcinoma after neoadjuvant chemoradiotherapy and esophagectomy. Using next-generation sequencing, we screened mutation hotspots in 46 cancer-related genes (Ion AmpliSeq Cancer Panel). Potential predictive genetic variations were validated in another cohort of patients. Chemoradiotherapy response was based on pathological evaluation of surgically resected specimens. The prognostic significance of genetic variations was evaluated with Cox regression survival analysis. Results: In the first cohort, we discovered PIK3CA H1047R and STK11 F354L as potential targets to predict chemoradiation resistance. Next, we investigate these genetic variations in another 54 patients. Altogether, 18.9% (14/74) and 6.8% (5/74) of patients had PIK3CA H1047R and STK11 F354L, respectively. In patients with poor response to chemoradiotherapy, 45.8% (11/24) had either PIK3CA H1047R or STK11 F354L; compared to 12.0% (6/50) in patients with good response ( p = 0.001). In other words, 64.7% of patients with either one genetic variation responded poorly to chemoradiotherapy. In survival analysis, the 5-yr survival rates were 7.7% and 43.7% in patients with either one genetic variation and those without, respectively ( p = 0.003). In multivariable analysis, the presence of either one genetic variation was a significant prognostic factor for overall survival (Hazard ratio: 2.43, 95% confidence interval: 1.195-4.944, p= 0.014). Conclusions: PIK3CA H1047R and STK11 F354L mutations are associated with poor response to neoadjuvant chemoradiotherapy and worse prognosis in esophageal cancer. It may potentially be biomarkers to guide treatment decisions.
Cardiotoxicity in Chinese cancer patients treated with 5-fluorouracil or capecitabine: A multicenter prospective observational study.
Authors: Chen Gong , Peng Jianjun , Dong Chao , Qiu Meng , Wang Chang , Li Hua wei , Yu Hao , Zhang Min , Zhao Qun , Zhu Bo , Zhang Jun , Li Wenliang , Wang Fenghua , Wu Qiong , Yuan Ying , Zhou Wen-hao
Published: March 2017

553

Background: Although the cardiotoxicity associated with 5-Fluorouracil (5-FU) or capecitabine administration has been well addressed in literature, there is still a lack of data from prospective clinical trials in Chinese population. The aim of this study was to evaluate the incidence, manifestations and predisposing factors for the cardiotoxicity in Chinese cancer patients treated 5-FU or capecitabine. Methods: A multicenter prospective observational study was performed in 527 patients with various solid tumors from 12 cancer centers in china . Of these patients, 196 received 5-FU-based and 331 received oral capecitabine-based chemotherapy as either first-line or adjuvant therapy. Outcome measures including electrocardiogram(ECG), myocardial enzymes, cardiac troponin(cTn), BNP and echocardio- graphy(UCG) etc. Univariate analysis and the logistic regression were performed for subgroup analysis and identification of the significant independent variables that are associated with cardiotoxicity of both agents. Results: In total, 161 of 527 patients (30.55%) experienced cardiotoxicity. The incidence of cardiotoxicity was 33.84% (112 out of 331) in the capecitabine-treated population, significantly higher than 25 %( 49 out of 196) in the 5-FU treated population (P = 0.0042). 110 out of 527 patients (20.87%) suffered arrhythmia, 105/527 (19.92%) developed ischemic changes, while 20/527(3.80%) heart failure and 6/527 (1.14%) myocardial infarction only. Among the factors evaluated with univariate analysis and the logistic regression, a history of cardiac disease, chemotherapy agent, duration of treatment and hypertension were significant with cardiotoxicity occurrence. The odds ratio were 15.447(with a history of cardiac history vs without), 2.118 (Capecitabine group vs 5-FU group), 1.079(5-8 vs 1-4 cycles) and 1.698 (with hypertension vs without) respectively. Conclusions: Cardiotoxicity induced by fluoropyrimidines in Chinese population may be underestimated in clinical practice.Possible risk factors are duration of treatment, chemotherapy agents, preexisting cardiac disease and hypertension.
The efficacy of aprepitant for the patients receiving FOLFOXIRI and FOLFIRINOX: A phase II study.
Authors: Hiroki Yukami , Terazawa Tetsuji , Miyamoto Takahiro , Asaishi Ken , Shimamoto Fukutaro , Kuwakado Shin , Nishitani Hitoshi , Kii Takayuki , Goto Masahiro , Higuchi Kazuhide , Sanomura Makoto
Published: March 2017

560

Background: Aprepitant (APR) showed the efficacy for the prevention of chemotherapy-induced nausea and vomiting (CINV) with highly emetogenic chemotherapy. The combination chemotherapies of moderately emetoegnic agents of oxaliplatin and irinotecan are classified as moderately emetogenic risk according to ASCO guideline, but showed severe vomiting and nausea. Methods: This phase II trial evaluated the efficacy of APR (day1;125mg, day2-3; 80mg) in patients receiving mFOLFOXIRI(oxaliplatin; 85 mg/m2, irinotecan; 150 mg/m2, leucovorin; 200 mg/m2, 5-FU infusional; 2400 mg/m2/46hour, every 2 weeks) and FOLFIRINOX (oxaliplatin; 85 mg/m2, irinotecan; 180 mg/m2, leucovorin;200 mg/m2, 5-FU bolus; 400 mg/m2, 5-FU infusional; 2400 mg/m2/46hour, every 2weeks). The primary objective was the complete vomiting inhibitation rate (CVIR) during first cycle. The null hypothesis and expectation of CVIR were 30% and 60% (one-sided α = 0.05, β = 1.0), so 23 patients were needed. CVIR was assessed according to MAT (MASCC Antiemesis Tool). Results: 25 patients were enrolled. The characteristics were as follows; median age (range), 65 (39-71); male/ female, 16/9; PS0/ 1, 11/ 14; mFOLFOXIRI/ FOLFIRINOX, 20/ 5; BMI < 22/ 22 or more, 14/ 11; history of alcohol yes/ no, 11/ 14. The CVIR was 92% (95%CI: 74-99) and complete response (no vomiting and no rescue medication use) rate was 72% (95%CI: 51-88%). The toxicities (all grade/ grade 3 or 4) were as follows; nausea, 17/ 2; vomiting, 3/ 0; fatigue, 16/ 2; constipation, 6/ 0. Conclusions: APR was effective for CVIR. Further prevention of nausea is expected.
The role of early postoperative PET-CT in patients with pathological stage III colon cancer: Results from a large single institution study.
Authors: Moore Assaf , Ben-Aharon Irit , Purim Ofer , Perl Gali , Ulitsky Olga , Amit Limor , Kundel Yulia , Lewin Ron , Wasserberg Nir , Asman Yael , Kashtan Hanoch , Brenner Baruch
Published: March 2017

562

Background: Current staging of patients (pts) with pathological stage III colon cancer is suboptimal; many pts still recur despite unremarkable preoperative staging work-up. We previously reported that early postoperative PET-CT can alter the stage and management of pts with high risk stage III colon cancer in up to 19% of patients. The aim of the current study was to expand the previous one to a larger cohort and to determine the role of early postoperative PET-CT in the general population of stage III colon cancer pts, regardless of their individual risk. Methods: A retrospective chart review of all consecutive pts with stage III colon cancer who underwent early postoperative PET-CT between 2007 and 2016. Demographic and clinicopathological data were collected. Results: 247 pts, 124 (50%) males, with a median age of 66 years (range, 30-92), were included. Pathological stage was IIIA, IIIB and IIIC in 18 (7.3%), 161 (65.1%) and 72 (29.1%) pts, respectively. The median number of lymph nodes retrieved was 15 (range, 6-64) and that of positive lymph nodes was 2 (range, 0-21). High FDG-uptake was observed in 52 (21.0%) pts, including 6 (2.4%) who had clear postoperative changes, 10 (4.0%) who had a false positive abnormal uptake of whom 6 underwent invasive diagnostic procedures. The PET-CT results modified the management of 36 pts (14.5%) who were found to have true positive findings: 30 (12.1%) were proven to have overt metastatic disease and in 6 (2.4%) a second primary was discovered. With the median follow-up of 39.0 months (range 7.2-98.4 months), of the 30 pts found to be metastatic, 10 (33.3%) underwent curative treatments and are currently with no evidence of disease (NED). Updated data, on more patients and a longer follow-up, will be presented at the meeting. Conclusions: Early postoperative PET-CT changed the staging and treatment of 14.5% of resected stage III pts, and has the potential for early detection of curable metastatic disease. We currently evaluate this strategy and its actual impact in a prospective trial.
Investigations of a novel diagnostic technology for colorectal cancer.
Authors: Tao Hongmei , Du Xuedong , Ding Shijin , Tang Xing , Lou Da , Lin Yue , Yu Chris Chang
Published: March 2017

564

Background: Currently endoscopy examination takes an important role in the diagnosis of colorectal cancer, and there are no other clinically viable non-invasive diagnostic methods. In this investigation, a newly developed, novel IVD cancer diagnostic technology named Cancer Differentiation Analysis (CDA) Technology was investigated for colorectal cancer diagnosis. CDA is a new technology using multi-level and multi-parameter information which measures information relating to both protein fragments and cellular signals in blood samples in one single test. Methods: Peripheral blood was drawn in EDTA tubes for CDA tests. Intravenous blood samples from individuals with colorectal cancer (n = 193), as well as control samples (n = 705) were collected. Cancer group has been clinically diagnosed, and individuals in control group have been confirmed by physical examinations free of cancer. All blood samples were tested using a CDA device, and collected data were analyzed in the SPSS Packages. Results: Data analysis (using T test) showed a significant statistical difference with P value < 0.05 between colorectal cancer group and control group. Details of CDA test results were given in Table 1. Based on initial data, the area under curve (AUC), sensitivity and specificity of CDA technology for colorectal cancer were determined to be 0.861, 76.7% and 76.7% (cut-off value was set at a level at which sensitivity and specificity are comparable), respectively. Conclusions: CDA technology is able to statistically distinguish control group from colorectal cancer group with reasonably high sensitivity and specificity (both above 75%). As a non-invasive and potentially cost effective method capable of large population screening, CDA technology could be a very promising approach for the screening and diagnosis of colorectal cancer. [Table: see text]
Inequality trends in proximal and distal colon cancers.
Authors: Bodek Daniel David , Patel Pavan
Published: March 2017

565

Background: Recently, the USPHTF released new colon cancer screening guidelines. No priority was given to any screening method. Given studies showing that Blacks had a greater proportion of proximal cancers, we sought to better highlight the inequalities in outcomes in order to consider the appropriateness of sigmoidoscopies versus colonoscopies. Methods: The SEER database was utilized to pull incidence and 5 year relative survival data (1992-2013). Patients aged 50-84 were divided by race and percentage of a county’s population below the poverty line ( < or > 15%). Adenocarcinomas were divided between distal cancer in the sigmoid, rectum, and anus versus cancer in the remainder of the colon. This data was analyzed using HDCalc, modelling rate difference, rate ratio, and the Index of Disparity. The Joinpoint regression program was then used to model Average Annual Percent Change (AAPC). Results: The AAPC in distal cancer incidence among Whites (-3.2%, [95% CI = -3.5%, -2.8%], p < 0.05) was greater than in Hispanics (-1.6%, [95% Cl = -2.1%, -1.1%], p < 0.05), or Blacks (-2.3%, [95% CI = -2.9%, -1.8%], p < 0.05). This resulted in a decline in the Index of Disparity (AAPC: -6.6, [95% Cl: -9.1, -4.0], p < 0.05) largely due to Whites' greater gains relative to Hispanics (Rate Ratio AAPC: -1.6%, [95% Cl: -1.9%, -1.3%], p < 0.05). Less impressive were AAPC trends in proximal cancers, which were significant in Whites (-1.8%, [95% CI: -2.2%, -1.5%], p < 0.05) and Blacks (-1.3%, [95% Cl: -1.8%, -0.8%], p < 0.05). Additionally, the AAPC for proximal cancer’s Index of Disparity was also lower (-3.1%, [95% Cl: -3.8%, -2.4%], p < 0.05). In terms of survival, only distal cancer’s AAPC for its Index of Disparity was significant (-3%, (95% Cl: -5%, -1.1%), p < 0.05). Poorer counties performed worse in incidence reduction across races but similarly in survival improvements. Conclusions: While it is encouraging to see improvements in distal colon cancer outcomes, it is troubling to see that measures in proximal cancers are lagging behind. The slower improvements among the Black population and higher baseline mortality and incidence of such cancers would seem to indicate a need to further study the comparative value of more aggressive screening, particularly in this group.
Validation of diagnosis codes to identify side of colon in an electronic health record registry.
Authors: Luhn Patricia , Kuk Deborah , Carrigan Gillis , Nussbaum Nathan , Sorg Rachael , Rohrer Rebecca , Tucker Melisa , Arnieri Brandon , Taylor Michael , Abernethy Amy Pickar
Published: March 2017

568

Background: The anatomical side of the colon from which a tumor arises is prognostic. Real-world evidence (RWE) studies in colon cancer should include this information. Can International Classification of Diseases (ICD) codes be reliably used to determine side of tumor, and, if so, when? Should electronic health records (EHR) be reviewed to supplement? Methods: Flatiron Health maintains an EHR-derived registry for metastatic colon cancer patients (current N = 9403). A random sample of 100 patients was included in this study. Data about tumor site was compared using ICD codes versus data abstracted from unstructured documents in the EHR (e.g., surgical notes). Concordance was determined via observed agreement and Cohen’s kappa coefficient (𝜿). Accuracy of ICD codes was determined by calculating the sensitivity, specificity, and positive predictive values, and corresponding 95% confidence intervals (CI), using abstracted data as the gold standard. Results: Sampled patients had similar side of colon distribution compared with the full registry: left colon (32% vs. 30%, respectively), right (17% vs. 25%), transverse (7% vs. 5%), unspecified side (39% vs. 37%), and rectum (5% vs. 2%). ICD codes can be general, or specific to the side of tumor. The observed agreement between the ICD codes and abstracted data for tumor site for all sampled patients was 0.57 (𝜿 = 0.42). When restricting to the 56% of patients with a side-specific ICD code, the observed agreement was 0.91 (𝜿 = 0.85). See table for all accuracy estimates. Conclusions: RWE offers growing opportunities for oncology research. Before meaningful RWE analyses can take place, data must be carefully characterized. Here, we describe tumor side EHR data in colon cancer and find that ICD codes specifying tumor side are available over half of the time. When these ICD codes are available, the accuracy of tumor side information in ICD codes is high. When not available, the dataset can be supplemented by chart abstraction. [Table: see text]
Clinicopathological associations and prognostic implications of KRAS mutation in metastatic colorectal cancer (CRC) population over 9 years at a single institute.
Authors: Melinamani Shruthi , Buckingham Lela , Hill Marisa E. , Leslie William T.
Published: March 2017

573

Background: Mutations in Kirstin RAS (KRAS) oncogene play a significant role in the constitutive activation of RAS/RAF/MEK/ERK pathway in CRC. Our objective was to evaluate the association of KRAS mutation status with the clinicopathological characteristics of the tumor and analyze prognostic implications of KRAS mutation in CRC patients. Methods: A total of 154 CRC patients diagnosed between 2007 and 2016 were included in this study. Formalin-fixed paraffin-embedded tissue from CRC patients who had metastatic disease were analyzed for KRAS mutations by allele-specific PCR. Baseline clinicopathological features and survival times were retrieved from electronic medical records. χ2, Fisher’s exact tests and Pearson’s correlation were used for association and binomial logistic regression to calculate the odds ratio. Kaplan Meier analysis and log rank test were used to compare survival outcomes. Results: KRAS mutations were identified in 61(39.6%) patients, 29(47.5%) were Caucasians, 22(36.1%) African Americans, 5(8.2%) Asians & 5(8.2%) other ethnic groups. The median age was 65 years with 31(44.9%) male and 30(35.3%) female patients. The majority of KRAS mutations were G12D (27 cases, 44.26%) and G12V (17 cases, 27.86%). KRAS mutations were most frequent in CRC adenocarcinomas (50 cases, 86.2%; P = 0.011) with poorly differentiated histology (p < 0.001) and current/former smokers (60.7% vs. 41.4%; P  = 0.03). Advancing age (OR = 1.150; 95% CI = 1.049 to 1.261; P = 0.003), increasing body weight (OR = 1.799; 95% CI = 1.118 to 1.954; P = 0.034) and increasing BMI (OR = 1.131; 95% CI = 1.05 to 1.204; P = 0.002) were associated with increasing likelihood of KRAS mutation. Patients with KRAS mutation had a tendency to shorter median overall survival than those with wild-type KRAS (30.9 vs. 33.1 months; P = 0.951). Subgroup analysis demonstrated that the patients with KRAS mutations showed worse survival in the group with poorly differentiated histology (median, 5.7 vs. 21.6 months; P = 0.04). Conclusions: CRC patients harboring KRAS mutation constitute a heterogeneous group with distinct tumor characteristics and clinicopathological associations.
Long-standing Crohn’s disease and its implication on anal squamous cell cancer management.
Authors: Moncrief Sara , Mathis Kellie L. , Lightner Amy
Published: March 2017

576

Background: Anal squamous cell carcinoma (ASCC) is rare, accounting for 1% of gastrointestinal malignancies, but the incidence is rising. Risk factors for the development of ASCC in patients with Crohn’s disease (CD) include immunotherapy, increased duration of disease, and chronic fistulizing perianal disease. We sought to understand management strategies for ASCC in the setting of CD. Methods: A retrospective review from 2001-2016 was conducted for ICD-9/10 codes pertaining to Crohn’s disease (CD) (555.9/ K50) and ASCC (154.3/C44.520). Adult patients with a diagnosis of CD at the time of ASCC diagnosis were included. Results: A total of 7 patients (5 female) were included with a median age of 50 years. The majority presented with perianal pain (4) and bleeding (3). The mean duration of CD was 20 years, and all patients had perianal disease for > 10 years. Five patients had perianal fistulizing disease at the time of ASCC presentation. Clinical stage at diagnosis of ASCC was stage 0 (n = 1), I (n = 1), II (n = 1), III (n = 2), IV (n = 1), and unknown (n = 1). All patients were treated with Nigro protocol which included radiation (50-55Gy), 5-fluorouracil, and mitomycin; 1 patient received cisplatin due to concurrent Non-Hodgkin’s Lymphoma. Three patients required fecal diversion during radiation due to significant perianal disease. Two patients experienced complications related to radiation including anal and vaginal stenosis and an anovaginal fistula. One additional patient required an APR with rectus abdominis myocutaneous flap for uncontrolled CD after treatment. During follow-up, 3 of the 7 patients undergoing definitive chemoradiation developed residual or recurrent disease and required salvage APR. All patients were alive at last follow-up, 2 with metastatic disease. 5-year disease free survival was 56%. Conclusions: Patients with ASCC in the setting of CD may be managed with the standard Nigro protocol, but complications from radiation are common in this setting. Three of seven patients required salvage surgery for residual or recurrent disease, and an additional patient required APR for palliation of CD symptoms. Given the aggressive nature of ASCC in this population, surveillance guidelines are necessary.
Multivariate analysis of determinant factors in adjuvant chemotherapy (AC) utilization in patients with stage II colon cancer (CC): Analysis of the National Cancer Database (NCDB).
Authors: Huynh Donny V. , Mukkamalla Shiva Kumar Reddy , Somasundar Ponnandai Sadasivan , Rathore Ritesh
Published: March 2017

577

Background: Evidence from randomized controlled trials does not support routine use of AC for patients with stage II CC. Clinical guidelines recommend discussion of AC in patients with high-risk disease. In our study, we analyzed NCDB data to determine factors favoring the use of AC in this setting. Methods: NCDB data was extracted on a total of 45,098 patients from 2004 to 2009 with stage II CC. Descriptive characteristics were analyzed using Chi-square test and odds ratios were calculated using multiple logistic regression. Results: Frequency of AC was significantly different among patients belonging to different age groups, tumor laterality, grade, pathologic tumor status (pT), and clinical nodal status (cN) (Chi-square test; p < 0.0001). Age distribution analysis revealed higher frequency of AC administration among patients of 18-64 years compared to those of 65-74 years and older, irrespective of single-agent or multi-agent regimens (p < 0.0001). Multivariate analysis was performed using multiple logistic regression technique. The odds of AC administration increased with increasing pT status, worsening tumor grade, and inadequate lymph node dissection ( < 12 lymph nodes evaluated) (p < 0.0001). AC administration was also more likely with left sided primary tumors (p < 0.0001). Conclusions: Using NCDB data, our analysis reveals conventional factors which are associated with AC administration in patients with resected stage II CC. Use of single-agent vs. multi-agent regimens did not differ, though elderly patients and those without left sided tumors were less likely to receive AC. Oncologists should be able to utilize these findings in discussions with stage II CC patients regarding the use of AC. [Table: see text]
The relationship between the degree of aberrant methylation in colorectal cancer tissue and appearance of tumor-derived DNA in blood.
Authors: Symonds Erin L , Pedersen Susanne Kartin , Baker Rohan , Mansfield Scott , Bastin Dawn , Young Graeme P
Published: March 2017

579

Background: We have developed a blood test for colorectal cancer (CRC) detecting circulating tumor DNA (ctDNA) by measuring the presence of methylated BCAT1 and IKZF1. This study aimed to compare the levels of methylated BCAT1/IKZF1 in tissue from patients with colorectal cancer to those in blood before and after tumor resection. Methods: 80 people with invasive CRC had blood collected prior to resection. Tumor and adjacent non-tumor colorectal tissue was collected at surgery. Five patients had tissue collected from secondary cancers in the liver. Additional blood samples were collected within a year of surgery from 45 of these patients. DNA was extracted from all samples and assayed for methylated BCAT1 and IKZF1 DNA. Results: The median % BCAT1 and IKZF1 methylation in colorectal tissues were 45.7% and 59.9% (tumor), and 4.8% and 0% (non-tumor), p < 0.001. Median methylation levels in secondary tumors of the liver were 4.9% for BCAT1 and 29.5% for IKZF1, compared to 0% for both biomarkers in non-tumor liver tissue (p < 0.01). The methylation levels did not differ across CRC stages (p > 0.05), whereas the detection of ctDNA in the blood was significantly associated with tumor staging (p < 0.01). Of the 21 ctDNA positive CRC patients, 18 (86%) tested negative post resection. Of the 3 that remained blood positive post resection, further cancers were confirmed in two (one with recurrence in the lung, one with thyroid cancer). Conclusions: Aberrant BCAT1 and IKZF1 methylation is an early event in CRC development and is localised to the tumor tissue. Methylated BCAT1 and IKZF1 in blood are dependent on tumor stage and measuring minimal residual disease by detecting ctDNA based on methylated BCAT1 and IKZF1 may inform completeness of tumor resection.
Evaluation of meaningful change in bowel move frequency for patients with carcinoid syndrome.
Authors: Hudgens Stacie , Gable Jonathon , Kulke Matthew H. , Bergsland Emily , Anthony Lowell Brian , Caplin Martyn E. , Oberg Kjell E. , Pavel Marianne E. , Banks Phillip , Yang Qi Melissa , Lapuerta Pablo
Published: March 2017

583

Background: Telotristat ethyl is a tryptophan hydroxylase inhibitor in development for the treatment of carcinoid syndrome (CS) in patients who receive somatostatin analog (SSA) therapy. In TELESTAR, a pivotal Phase 3 study, telotristat ethyl significantly reduced bowel movement (BM) frequency compared to placebo. Objective: The objective of this study was to psychometrically assess meaningful change in BM frequency using data collected within the TELESTAR study. Methods: An anchor-based approach consisted of mapping change from baseline in BM frequency to other patient reported assessments of change. These included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire - Core Questionnaire (EORTC QLQ-C30) Diarrhea Symptom responders, the EORTC GI.NET21 GI Symptom responders, and patient reported adequate relief at Week 12 (responders had a ≥ 10-point decrease in scores from Day 1 to Week 12). Parameters included within group mean change from baseline to Week 12, t-tests of the change (Wilcoxon Rank Sum for adequate relief), effect size (ES: calculated as the difference between mean on-treatment and baseline BM frequency, divided by the standard deviation of the baseline), and related confidence intervals. Results: There were 135 patients with CS, with a mean age of 63.6 years and mean baseline BM frequency of 5.7 BM/day. Anchor-based analyses indicated significant differences in BM frequency between adequate relief groups at Week 12 (ES: -1.58 vs. -0.79; p = 0.014), responders and non-responders on the EORTC QLQ-C30 Diarrhea Symptoms domain (ES: -1.24 vs. -0.59; p < 0.0001), and responders and non-responders on the EORTC GI.NET21 GI Symptoms Domain (ES: -1.49 vs. -0.75; p = 0.0053). These corresponded to BM frequency reductions of 1.7-1.9 BM/day, or ≥ 30%. Conclusions: Results of this study indicated that patients with CS experienced clinically meaningful reductions in BM frequency of ≥ 30% over the course of 12 weeks.
SMAD4 loss in colorectal cancer: Correlation with recurrence, chemoresistance, and immune infiltrate.
Authors: Wasserman Isaac , Lee Lik Hang , Shia Jinru , Wu Chao , Chen Xi , Guillem Jose G. , Paty Philip , Weiser Martin R. , Nash Garrett Michael , Temple Larissa K. F. , Saltz Leonard , Yaeger Rona D. , Barlas Afsar , Manova-Todorova Katia O , Vakiani Efsevia , Elghouayel Arthur E , Kemeny Nancy E. , Garcia-Aguilar Julio , Sawyers Charles L. , Smith Jesse Joshua
Published: March 2017

587

Background: Few markers reliably identify colorectal cancer (CRC) patients at risk of recurrence and death. SMAD4 loss occurs in 10-20% of cases and has shown promise in identifying high-risk stage II/III patients. We examined SMAD4 status and association with clinical/pathologic features in 446 stage I-IV CRC patients at Memorial Sloan Kettering (MSK). Methods: Patients undergoing curative resection were included (1981-2010). Familial polyposis syndrome patients and those with inadequate tissue were excluded. Tissue microarrays were constructed (n=364). Immunohistochemistry for SMAD4 and mismatch repair (MMR) proteins was completed. SMAD4 nuclear stain intensity was scored (scale=0-3; 0=loss). On whole sections, MMR proteins (present or absent), tumor-infiltrating lymphocytes (TILs) and peritumoral lymphocyte aggregates (PLAs) were scored (scale=0-3). Associations between clinical/pathologic features and SMAD4 loss vs. retention were analyzed. Kaplan-Meier estimates and log-rank test were used for recurrence-free and overall survival analyses (RFS and OS). Results: SMAD4 loss was noted in 13%. Median age at diagnosis was 53 years, and 51% were male. The cohort consisted of 61% hindgut tumors and 62% stage II/III patients. With up to 33 years of follow-up, the mean was 6 years. SMAD4 loss correlated with higher tumor and nodal stage, adjuvant therapy use, and lower TIL and PLA scores (p<0.04 for all). Unlike prior studies, no significant differences in OS based on SMAD4 status across the entire cohort were noted; however, older patients (>median) were noted to have worse OS with SMAD4 loss (p<0.01). SMAD4 loss did correlate with worse RFS (p=0.02), persisting even when excluding MMR-deficient patients. Additionally, SMAD4 loss was associated with worse RFS in both the adjuvant chemotherapy group (median RFS=3.8 vs. 13 years; p=0.06) and the resection-only group (median RFS=4.2 years vs. not yet reached; p< 0.01). Conclusions: SMAD4 loss correlates with worse RFS and resistance to adjuvant therapy. SMAD4 loss also correlates with lower TIL and PLA scores. Future work will address chemoresistance mechanisms, relevance to adjuvant therapy use, and loss of immune infiltrate in SMAD4-null tumors.
Methylomic classifiers of anal cancer outcomes: An NRG Oncology / RTOG 98-11 tissue study.
Authors: Siegel Erin M. , Eschrich Steven A. , Berglund Anders E. , Ajidahun Abidemi O. , Magliocco Anthony Martin , Putney Ryan , Riggs Bridget , Moughan Jennifer , Hoffe Sarah E. , Simko Jeff , Ajani Jaffer A. , Guha Chandan , Okawara Gordon S. , Clouse John W. , Becker Mark J. , Pizzolato Joseph F. , Crane Christopher H. , Shibata David
Published: March 2017

588

Background: Genome-wide epigenetic events appear to play a role in the development and behavior of HPV+ cancers. The value of adjuvant therapy following chemoradiation for localized anal cancer (AC) remains unclear. Molecular prognostication to identify patients (pts) who may be at higher risk for recurrence would be valuable. The goal was to define methylomic profiles predictive of disease-free (DFS) and overall (OS) survival in pts with AC. Methods: Genomic DNA was extracted, processed and methylation status at ~450,000 CpG loci examined (Illumina HumanMethylation450 Array). A multistep bioinformatics methodology was applied to develop a prognostic methylomic classifier for OS and DFS: (1) feature selection for methylated regions (β-value interquartile range ≥ 0.2, ≥ 2 adjacent significant probes within a CpG Island and p < 0.05 by univariate Cox proportional hazards) (2) selected features were entered into a supervised principal component analysis (PCA) and 3 components (PC1, PC2, PC3) were derived (3) classifier was built using forward selection multivariate regression models [PC1, PC2, PC3 alone and in combination with clinical features (size: > T2 vs. ≤ T2, nodal status: N0 vs N+)] using a 10-fold cross-validation (4) final model prediction risk score was generated, dichotomized and evaluated for prognostic values in Cox regression analysis. Results: 121 AC specimens from RTOG 98-11 were examined. The methylomic-only classifier model trended towards statistical significance (log-rank p = 0.05; HR = 1.96; 95% CI 0.99-3.88) in DFS (PC1, PC3 selected). In the combined model with clinical features, the final classifier included T status and epigenetic features (PC1, PC3) and was strongly predictive for DFS (p < 0.0001, HR = 4.45; 2.02-9.76). Final OS classifier models [methylomic-only (p = 0.28 HR = 1.55; 0.70-3.44) or combined (p = 0.013 HR = 2.88; 1.20-6.89)] were not as accurate. Conclusions: Methylomic and clinical features synergize to predict DFS in AC. Multivariate modeling reveal independent contributions from clinical and methylomic variables. Epigenomic profiling may contribute to identification of high-risk pts who may benefit from adjuvant strategies. Support: U10CA180822, U10CA180868, U24CA196067
Quantitative proteomic analysis of TUBB3 to identify gastric cancer patients who may benefit from docetaxel: A reevaluation of the ITACA-S trial.
Authors: Cecchi Fabiola , Catenacci Daniel V.T. , Tian Yuan , Miceli Rosalba , Pietrantonio Filippo , Pellegrinelli Alessandro , Martinetti Antonia , Di Bartolomeo Maria , Hembrough Todd A.
Published: March 2017

59

Background: Chemotherapy (CTX) becomes targeted therapy when biomarkers can predict a patient’s response. A relationship between resistance to taxanes and overexpression of class III b-tubulin (TUBB3) has been suggested by small clinical studies, but not confirmed in randomized trials. The Intergroup Trial of Adjuvant CTX in Adenocarcinoma of the Stomach (ITACA-S) evaluated the survival advantage of postoperative sequential CTX with FOLFIRI followed by docetaxel plus cisplatin in comparison to monotherapy with 5-FU/LV in patients with radically resected gastric cancer (N = 1106). The results showed no difference in survival between the two CTX arms. In a random subset of patients (N = 247) from the ITACA-S trial, we applied mass spectrometry-based proteomics to assess the role of TUBB3 as a predictive biomarker for response to taxane-containing therapy. Methods: Archived tumor tissues were microdissected and solubilized for proteomic analysis. TUBB3 and 44 other protein biomarkers were quantified using a mass spectrometry-based selected reaction monitoring assay. A predetermined TUBB3 cutoff of 700 amol/µg was based on the assay’s limit of detection. The Mantel-Cox log-rank test was used for survival comparisons. Results: Among patients treated with taxane-containing CTX (n = 125), those with TUBB3 levels below the cutoff had nearly twice the median overall survival (OS) as patients with TUBB3 levels above the cutoff (1566 vs. 801 days, p = 0.0282). TUBB3 levels made no statistical difference in survival among patients who did not receive taxane. Of note, among patients with high TUBB3 levels ( > 700 amol), those treated without taxane-containing CTX survived far longer than patients in the taxane arm (OS = 1991 vs 801 days, p = 0.048). Conclusions: Quantitative proteomic analysis of TUBB3 expression identified a subset of gastric cancer patients who benefitted from the addition of docetaxel to adjuvant CTX. Patients with high TUBB3 expression levels had worse outcomes on a taxane-containing regimen than on CTX without taxane. Personalized CTX based on the TUBB3 biomarker is promising and warrants further validation. Clinical trial information: NCT01989858.