bluuebunny/crossref_metadata_2025 huggingface dataset:
Burden of high-risk HPV infection in women in the United States and implications for anal cancer screening: NHANES (1999-2012).
Authors: Dunn Erin , Moore Kevin J. , Koru-Sengul Tulay
Published: February 2017

532

Background: High-risk Human Papilloma Virus (HPV) infections put women at risk for cervical, anal, vaginal, and vulvar cancers. HPV can spread from the genital region to the anus even in absence of sexual intercourse. As anal cancer is more prevalent in women, it is important to consider HPV transmission from the vagina to the anus. National surveys provide estimates of population-specific prevalence to identify the burden of high-risk HPV infection in women. Appreciating high-risk HPV infection in women and the potential for HPV spread from the genitals to the anus is crucial for cancer screening efforts. Methods: We calculated prevalence of HPV infections in women in the United States from 1999-2012 National Health and Nutrition Examination Survey (NHANES) to obtain a representative sample of the U.S. non-institutionalized civilian population. NHANES performs in-person interviews and physical examinations and collects biological samples at homes and mobile examination centers. We provided epidemiology of HPV infection and its types for women. Analysis was performed by SAS v9.3. Results: DNA-measured HPV from vaginal swabs showed 42.9% of women were HPV positive. We calculated odds ratios across demographic groups for high-risk HPV types (16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 73, 82). Non-Hispanic White (NHW) women had the highest prevalence of high-risk HPV (62.5%). Other Hispanic women had lower odds of having high-risk HPV compared to NHW (OR=0.65; 95% CI=0.49, 0.88). Never married women had greater odds of high-risk infection than married women (1.61; 1.26, 2.06). Current smokers had greater odds than never smokers of high-risk infection (1.26; 1.00, 1.59). Conclusions: Our results show the burden and demographic disparities of high-risk HPV infection in women. Understanding the burden of potentially oncogenic HPV infections in the female genital region is important for cervical cancer screening and highlights a potential importance for anal cancer screenings in HPV positive women. Recognizing demographic disparities could lead research into risk factors and risk conditions that guide the preponderance of HPV infection and anal cancer in specific female populations.
KRAS tests utilizations, biologics uptakes, and disparities in access by demographic groups among metastatic colon cancer patients.
Authors: Goto Daisuke , Mullins C. Daniel , Bikov Kaloyan A. , Seal Brian S. , Hanna Nader
Published: February 2017

533

Background: Mutant KRAS oncogenes are observed in approximately 35%-45% of colorectal cancer patients. Cetuximab (CET) and panitumumab (PAN) are epidermal growth factor receptor (EGFR) inhibitors that are used in the treatment of metastatic colon cancer (mCC). KRAS mutations decrease the treatment response of these biologic agents. Reports of this decreased treatment response in CET and PAN surfaced in 2006. In 2009, the FDA changed the label on CET and PAN to state that these agents were “not recommended” for the treatment of colon cancer in patients with KRAS mutations. This label change encouraged prescribers to perform KRAS tests. The objective of this study is to examine the utilization of KRAS tests for mCC treatment in real-world practice. Methods: We examined 6,044 mCC patients in the SEER-Medicare database who were diagnosed between 2006 and 2009 (their median age at diagnosis was 78). Using recorded procedure codes, we identified whether each patient received a KRAS test or not and whether CET and/or PAN were given. We further identified demographic characteristics of patients. Results: Among the 6,044 patients, 15% patients were tested for KRAS mutations. This frequency increased from 7% for those diagnosed in 2006 to 24% for those diagnosed in 2009. Following KRAS testing, CET or PAN were administered to 29% of patients. On average for 2006-2009, 5% of patients who were not tested received CET or PAN (or 15% if patients who did not receive any treatment are excluded). This frequency dropped from 7% for those diagnosed in 2006 to 2% for those diagnosed in 2009 (19% and 7% respectively if patients without any treatment are excluded). We found disparities in receipt of KRAS testing: the test was administered to 12% of black patients, 16% of white patients, 17% of males, and 14% of females. These differences were found statistically significant (p < 0.05). Conclusions: KRAS testing rates increased over time. Moreover, as time passed fewer patients were administered CET and/or PAN without being tested for KRAS mutations. Black patients and women were less likely to receive a KRAS test, which could impact access to treatment.
Second primary malignancies in anal carcinoma.
Authors: Shah Binay Kumar , Budhathoki Nibash
Published: February 2017

534

Background: Survival of cancer patients is increasing. Therefore, there is a need to evaluate long term complications in cancer survivors. There is no data on second primary malignancies in anal cancer. This study was conducted to evaluate second primary malignancies in patients with anal carcinoma. Methods: We selected adult patients diagnosed with anal cancer from National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) 13 database We calculated the risk of second primary malignancies in the anal cancer patients using multiple primary standardized incidence ratio (MP-SIR) session of SEER*stat software. Results: Among 7,661 patients with anal carcinoma, 3,196 were men and 4,465 were women. Median follow up duration was 87 months (range: 7-239 months). Median age at the time of diagnosis of SPM was 69.33 yrs (range: 34-103 yrs). Median latency for SPM was 52 months (range: 6-219 months). A total of 675 patients (9.07%) developed 747 second primary malignancies, with an observed/expected (O/E) ratio of 1.41 (95% confidence interval =1.32-1.52, p<0.001), and an absolute excess risk of 55.36 per 10,000 populations. Significant excess risks were observed for oral cavity and pharyngeal tumor, rectal and anal canal tumor, laryngeal tumor, lung and bronchial cancer, Kaposi sarcoma, hematologic malignancies, ovarian, vaginal, and vulval tumors. Conclusions: The risk of second primary malignancies in adult patients with anal cancer is significantly increased compared to general population.
Evaluation of two-dimensional response to predict overall survival in patients with metastatic colorectal cancer treated with the first-line bevacizumab-based chemotherapy.
Authors: Nakayama Goro , Takano Nao , Tanaka Chie , Kobayashi Daisuke , Koike Masahiko , Fujiwara Michitaka , Kodera Yasuhiro
Published: February 2017

539

Background: The evaluation of the quantitative analyses for tumor response, such as early tumor shrinkage (EST) or depth of response (DpR), could be useful to serve the surrogate for survival benefits in chemotherapies for patients with mCRC. However, these analyses might be insufficient to explain an individual-level surrogacy of long-term survival outcomes in anti-angiogenic agents, because patient tumor dynamics might be highly diverse. In this study, we defined ‘2-DR’ by both tumor shrinkage and time factors as a new efficacy outcome measure to explain the impact of chemotherapy with BEV on long-term survival outcome. Methods: All patients included in this analysis had participated in phase II clinical trial (CCOG-0801, UMIN000006818). Forty-seven patients with previously untreated mCRC were treated with mFOLFOX6 plus BEV, followed by FOLFIRI plus BEV. The median PFS and OS were 7.3 and 30.8 months, respectively. ETS and DpR are defined as the ratio of tumor shrinkage observed at 8 week after initiation of treatment and the nadir to baseline. 2-DR, that is the area enclosed by the coordinate points including ETS, DpR and 20% increase over nadir at progression disease, is calculated as follows: 2-DR (week×%) = (0.5 TR+1.1 TP-4)×DpR+0.5 TR×ETS–10 TP, where TR is the time duration from the date of initiation of therapy to maximum tumor shrinkage and TP is the time duration from the date of observation of maximum tumor shrinkage to 20% increase over nadir. Results: Median ETS, DpR and 2-DR were 23% (range, -33 to 72), 31% (range, -33 to 100) and 10.3 (week×%) (range, -4.4 to 92.6), respectively. The Spearman rank correlation coefficients were 0.27 between ETS and OS, 0.28 between DpR and OS, and 0.46 between 2-DR and OS, respectively. There was strong relationship between 2-DR and OS (p<0.01). Median OS in the higher and lower 2-DR groups was 21.5 months (95% CI, 20.4 to 29.8) and 32.9 months (95% CI, 24.5 to 41.3), respectively (p<0.01). A Cox regression model revealed that 2-DR was the only independent prognostic factors for OS (HR 0.26, p<0.01). Conclusions: 2-DR could be a new surrogate marker of OS in the BEV-based first-line chemotherapy for mCRC.
Delay to colectomy and survival for patients diagnosed with colon cancer.
Authors: Bagaria Sanjay Prakash , Heckman Michael , Diehl Nancy N. , Parker Alexander S. , Wasif Nabil
Published: February 2017

541

Background: A long wait-time for colectomy for colon cancer should theoretically affect survival but, to date, the association between delay to colectomy and survival remains unresolved. Methods: We studied 4,692 patients who underwent colectomy for colon cancer between 1990 and 2012. Wait-time was defined as the number of days between diagnosis and colectomy. Cox regression models were used to estimate all-cause mortality across wait-time categories. Multivariable analyses were controlled for clinicopathologic variables and Charlson comorbidity index. Results: The number of patients in the wait-time group of 1-28 days was 3,950 (84.2%), 29-84 days was 681 (22.7%), and >84 days was 61 (1.3%). A wait-time of 29-84 days was not associated with an increased risk of death (HR=1.13; p=0.056) when compared to a wait-time of 1-28 days. Though a wait-time >84 days represented a small group, it was associated with an increased risk of death (HR=1.60; p=0.013). For patients with stage I and II disease, wait-times of 29-84 days (HR =1.44; p=0.0001) and >84 days (adjusted HR=2.24; p=0.0007) were associated with an increased risk of mortality. Conclusions: A wait-time for colon cancer surgery of up to 12 weeks is likely safe for most patients. However, those suspected to have early-stage colon cancer may benefit from less of delay. These data provide a framework to address concerns over prolonged wait-times and can direct efforts for timely surgical intervention in patients with colon cancer. [Table: see text]
A prospective study to evaluate the usefulness of the clanging tuning fork test and the nerve conduction velocity test for oxaliplatin-induced peripheral neuropathy.
Authors: Hirashima Yoshinori , Hanaoka Takuya , Watanabe Koichiro , Nagashina Kengo , Inagaki Takashi , Nishikawa Kazuo , Hisamatsu Yasushi , Morinaga Ryotaro , Otsu Satoshi , Kumamoto Toshihide , Shirao Kuniaki
Published: February 2017

544

Background: Neurotoxicity is the most frequent dose-limiting toxicity of oxaliplatin. Cumulative sensory peripheral neurotoxicity results in discontinuation of chemotherapy for cancer and impairs neurological function irreversibly. To develop new strategies to continue chemotherapy according to the treatment plan without more severe neurotoxicity, objective assessment tools for oxaliplatin-induced peripheral neuropathy (OIPN) are needed. The clanging tuning fork test (CTFT) and the nerve conduction velocity test (NCVT) are widely used forbenign neuropathies. However, little is known about their clinical usefulness for OIPN. Methods: Colorectal cancer patients were prospectively monitored at baseline and during chemotherapy with modified FOLFOX6. The incidence and severity of OIPN were recorded using NCI-CTC grading (ver. 4.0). CTFT was conducted every 2 weeks and NCVT every 8 weeks. A generalized estimating equation model was used to examine the correlations between NCI-CTC grade and CTFT/NCVT. The accuracy of the assessment was evaluated using receiver operating characteristic (ROC) curve analysis. Results: Twenty-one patients without peripheral sensory neuropathy (PSN) were enrolled. Mean CTFT values were 13.4 ± 0.7 sec at baseline, 14.1 ± 0.4 sec with grade 0 PSN, 14.0 ± 0.4 sec with grade 1 PSN, 12.5 ± 0.7 sec with grade 2 PSN, and 7.5 ± 0.9 sec with grade 3 PSN. The mean CTFT value with grade 3 PSN was significantly shorter than with the other grades (p<.001, all). ROC curve analysis showed that variation in CTFT provides a high-accuracy assessment of grade 3 PSN (AUC=0.898, 95% CI: 0.764-1.000, p=.004), and its optimal cut-off value was -3.5 sec (sensitivity and specificity for grade 3 PSN were 86% and 79%, respectively). Unlike CTFT, NCVT showed little association with OIPN. Conclusions: CTFT was found to be very effective for assessing grade 3 OIPN. The present results suggest that CTFT, a simple, quick, and non-invasive examination, is a promising assessment tool for OIPN. Clinical trial information: 000004305.
Awareness of KRAS testing by oncologists and panitumumab use in colorectal cancer patients: A European survey.
Authors: Trojan Jorg , Taylor Aliki , Terwey Jan-Henrik , Downey Gerry , Kafatos George , Garcia Alfonso Pilar , Tomasek Jiri , Mineur Laurent , van Krieken Han , Aprile Giuseppe
Published: February 2017

547

Background: Panitumumab (Pmab) is licensed for treatment in metastatic colorectal cancer (mCRC) patients with wild type KRAS mutation status (US) and wild type RAS (KRAS and NRAS) mutation status (most other countries). To resolve uncertainties about KRAS testing, a survey and medical records review (MRR) are being carried out in Europe in three rounds: the first two rounds (2012-2013) evaluated KRAS testing and round 3 is evaluating RAS testing. These studies are specific obligations in Europe for the conditional marketing authorization for Pmab. Here we present results of rounds 1 and 2. Methods: Eligible oncologists were contacted by telephone in nine European countries (France, Germany, Italy, Spain, Czech Republic, Netherlands, Belgium, Denmark, and Sweden). To be eligible, the physician was required to be a practicing oncologist and have prescribed Pmab to mCRC patients. Results: 299 of 301 (99.3%) oncologists participating in the survey were aware of the need to perform KRAS testing prior to first dose of Pmab and 294 (97.7%) were aware of patients’ KRAS mutation status prior to first dose. 283 of 301 (94.0%) did not prescribe Pmab to mCRC patients with mutant or unknown KRAS status. 164 physicians administered Pmab simultaneously with oxaliplatin-containing chemotherapy to patients and 10 (6.1%) to patients with mutant or unknown KRAS status. 306 patients from 79 participating oncologists were included in the MRR. 302 of 306 mCRC patients (98.7%) were tested for KRAS tumor status, known by the oncologist before first dose of Pmab. 299 of 302 patients (99.0%) had wild-type KRAS tumor status. 83 of 85 patients (97.6%) treated with Pmab and oxaliplatin-containing chemotherapy had wild-type KRAS tumor status. 55 of 56 linked pathology laboratories (98.2%) participated in a Quality Assurance scheme; all used a CE marked or otherwise validated KRAS detection method. Conclusions: Results from both studies show a high level of knowledge among oncologists of the need for KRAS testing in mCRC patients prior to treatment with Pmab and the contraindication with oxaliplatin-containing chemotherapy with mutant or unknown KRAS tumour status. The final round of this study evaluating RAS testing in Europe is currently underway.
Improving the prediction of colon cancer survival after curative resection.
Authors: Pabani Aliyah , Cheung Winson Y. , Mazurek Matthew , Spratlin Jennifer L. , Mulder Karen E. , Ghosh Sunita , Price Hiller Julie A. , Standeven Leah Jean , Ho Maria Yi
Published: February 2017

552

Background: Cancer staging systems convey valuable prognostic information to both clinicians and patients. Currently, colon cancer is staged according to the American Joint Committee on Cancer (AJCC) TNM classification system. However, survival estimates for patients with the same stage of colon cancer may vary considerably due to other factors including age, sex, grade, and number of lymph nodes sampled. The objectives of this study are to 1) assess the accuracy of the seventh edition of the TNM classification system in predicting survival of patients with primary colon cancer after curative-intent surgery, and 2) evaluate the utility of incorporating additional demographic and tumor variables beyond TNM staging in improving prognostic accuracy. Methods: Patients with curative-intent resection of a first primary adenocarcinoma of the colon at the time of referral to the Cross Cancer Institute between 2004 and 2007 were identified from the Alberta Cancer Registry. We constructed three multivariate Cox’s proportional hazard models to explore the effect of supplementing TNM staging with additional demographic and tumor variables in predicting overall survival (OS). Results: 559 consecutive patients with complete chart records were identified. 52 % (n=290) were male; median age was 74. In the first model based only on T and N elements, N2 disease was correlated with increased mortality (hazard ratio [HR], 2.546; p<0.0001). When the number of lymph nodes examined (HR, 0.980; p=0.034) and number of metastatic lymph nodes detected (HR, 1.094; p<0.0001) were substituted for the N-staging element, both variables correlated positively and negatively with outcome, respectively. Finally, when tumor grade, sex and age were incorporated into the model, number of examined lymph nodes (HR, 0.980; p=0.029) and those containing tumor (HR, 1.093; p<0.0001) remained independent predictors of OS. Conclusions: Incorporating readily available demographic and tumor variables, such as age, sex and number of lymph nodes examined, can enhance the current TNM staging system and improve prognostication in early stage colon cancer.
RacGAP1 expression, increasing tumor malignant potential, as a predictive biomarker for lymph node metastasis and poor prognosis in colorectal cancer.
Authors: Imaoka Hiroki , Toiyama Yuji , Saigusa Susumu , Mori Koichiro , Noguchi Tomofumi , Ide Shozo , Uratani Ryo , Oki Satoshi , Fujikawa Hiroyuki , Hiro Junichiro , Kobayashi Minako , Tanaka Koji , Ohi Masaki , Araki Toshimitsu , Inoue Yasuhiro , Mohri Yasuhiko , Kusunoki Masato
Published: February 2017

555

Background: Rac GTPase activating protein (RacGAP) 1 plays a key role in controlling various cellular phenomena including cytokinesis, transformation and migration. Recently, the clinical significance of RacGAP1 expression has been reported in several malignancies. However, direct association between the RacGAP1 expression and colorectal cancer (CRC) has not been fully investigated. The aim of this study is to elucidate the function and clinical significance of RacGAP1 expression in CRC. Methods: The intrinsic functions of RacGAP1 in CRC cells were analyzed using small interfering RNA (siRNA). We analyzed RacGAP1 mRNA expression in surgical specimens from 193 CRC patients (Cohort 1) by real-time polymerase chain reaction. Then, we validated RacGAP1 protein expression using formalin-fixed paraffin-embedded samples from 298 CRC patients (Cohort 2) by immunohistochemistry. Finally, we evaluated the association between RacGAP1 mRNA and protein expression and clinicopathological data. Results: Reduced RacGAP1 expression by siRNA in CRC cell lines showed significantly decreased cellular proliferation, migration, and invasion. In Cohort 1, RacGAP1 expression in CRC was significantly higher than in adjacent normal mucosa, and increased according to TNM stage progression. High RacGAP1 expression in tumors was significantly associated with progression and prognosis. In Cohort 2, RacGAP1 protein was overexpressed mainly in the nuclei of CRC cells; however, its expression was scarcely observed in normal colorectal mucosa. RacGAP1 protein expression was significantly higher in CRC patients with higher T stage, vessel invasion, and lymph node and distant metastasis. Increased expression of RacGAP1 protein was significantly associated with poor disease-free and overall survival. Multivariate analyses revealed that high RacGAP1 expression was an independent predictive marker for lymph node metastasis, recurrence, and poor prognosis in CRC. Conclusions: Our data provide novel evidence for the biological and clinical significance of RacGAP1 as a potential biomarker for identifying patients with lymph node metastasis and poor prognosis in CRC.
Demographic, medical, and behavioral factors associated with colorectal cancer screening and diagnostic colonoscopy in Israel.
Authors: Gofine Miriam , Paltiel Ora , Manor Orly , Cohen Arnon , Elran Einat , Valinsky Liora , Matz Eran , Jaffe Dena Hirschfield
Published: February 2017

557

Background: Colorectal cancer (CRC) is the third leading cause of cancer death worldwide and second leading cause of cancer death in Israel. Israel's universal health care system funds CRC screening (CRCS) (fecal occult blood testing or colonoscopy) for all adults aged 50-74. CRCS adherence is influenced by numerous factors including patient characteristics. In addition to screening asymptomatic individuals, those with anemia may have undiagnosed CRC and require aggressive case finding. This study’s goals were: 1) To compare the socio-demographic, health status, and health behavior characteristics of the eligible Israeli population who underwent any versus no CRCS (2009-2012); 2) To examine the relationship between anemia severity and CRCS likelihood; 3) To determine whether anemia status predicts time-to-CRCS. Methods: National retrospective cohort study of Israeli adults aged 51-71 on 1.1.2009 using electronic medical records from all 4 Israeli HMOs (n=1,009,898) over a 4-year period. Results: Differences in CRCS adherence were observed by patient characteristics. For example, ever-smokers comprised 17.9% of the screened population and 24.9% of the non-screened population (p<0.001). Increasing anemia severity was positively associated with any CRCS performance, especially colonoscopy. For example, severely anemic individuals (hemoglobin <10 g/dL for men, <8 g/dL for women) were significantly more likely to receive colonoscopy than those who were not anemic (OR = 3.23; 95% CI, 2.58-4.27). Anemia somewhat expedites CRCS. For example, 8.9% of those with anemia and 7.6% of those without anemia performed any CRCS within 30 days of hemoglobin level recording (p<0.001). Conclusions: Full CRCS adherence is not yet optimized in Israel. Particular attention directed at those at-risk for CRCS non-adherence may decrease CRC mortality. Although lower hemoglobin somewhat expedites colonoscopy performance, few individuals with anemia actually undergo colonoscopy. Further analysis accounting for confounding and effect modification is crucial for a more complete understanding of these relationships.
Metachronous cancer after endoscopic submucosal dissection of gastric neoplasia.
Authors: PARK Jae Myung , Yoon Seung Bae , Song Kyo Young , Lim Chun-Hyun , Cho Yu Kyung , Kim Sang Woo , Choi Myung-Gyu
Published: February 2017

559

Background: Metachronous recurrence after endoscopic resection (ER) of gastric cancer is known to be high. However, recurrence rate of metachrous lesions after ER of gastric adenoma has not been studied well. The aim of the study was to compare the metachronous recurrence between gastric carcinoma and adenoma patients. Methods: Four hundred eight carcinoma and 539 adenoma patients were enrolled in this study, and median follow-up period was 27 months (IQR: 16-45 months). Clinicopathological characteristics were assessed. At the follow-up endoscopy, the whole gastric mucosa was examined thoroughly to detect any gastric neoplasia. All suspicious lesions were evaluated histologically on endoscopic biopsies. Surveillance endoscopic schedule was as follows: every 3–6 months within 1 year, then once every year. Results: Forty three metachronous recurrence was diagnosed in in carcinoma patients and 45 in adenoma patients. There was no significant difference in the incidence of recurrent metachronous neoplasm between carcinoma and adenoma patients (p=0.728, log-rank test). After excluding metachronous adenoma, cancer recurrence was not different either between two groups (p=0.943). After adjusting for age, sex, multiplicity, and Helicobacter pylori status, the risk of the metachronous development of gastric cancer in adenoma patients was similar with that in carcinoma patients (HR, 0.96; 95% CI, 0.63-1.45). Conclusions: Metachronous gastric cancer after ER of gastric adenoma was as high as that of gastric carcinoma. Similar endoscopic surveillance program should be applied for both gastric carcinoma and adenoma patients after ER.
Single-center early experience of optical coherence tomography (OCT) for evaluation of high-grade dysplasia or early cancer in Barrett's esophagus.
Authors: Pai Sachin Gopalkrishn , Fuloria Jyotsna , Joshi Virendra
Published: February 2017

56

Background: Barrett’s esophagus is a well-known risk factor for esophageal cancer. Surveillance esophagogastroduodenoscopy (EGD) and procedures like endoscopic mucosal resection (EMR) and radio frequency ablation (RFA) are adopted to mitigate risk of evolution to high grade dysplasia and cancer. Newer imaging modalities are expected to improve diagnostic accuracy and guide management. Here we describe our early experience with optical coherence tomography (OCT) which is an near infra-red light imaging technique for diagnosing high grade dysplasia and early stage cancer in patients with Barrett’s esophagus. Methods: Patients who underwent EGD and diagnosed with Barrett’s esophagus and endoscopic features worrisome for high grade dysplasia or early cancer were selected for the procedure. Patients underwent OCT for further characterizations of these lesions. Clinical and endoscopic findings, imaging studies and OCT findings were recorded and analyzed. Results: 5 patients were studied in this early series and details are tabulated below. (OCT images will accompany final presentation.) Conclusions: Early detection of high grade lesions and early cancer with image directed therapy in Barrett’s esophagus may positively impact survival. Our early experience suggests OCT is helpful in detecting cryptic dysplastic changes, especially in the aftermath of previous ablation and can guide additional endoscopic treatment. Further studies are necessary to determine efficacy of such an approach. [Table: see text]
Proteomic signatures of colorectal cancer to identify distinct and reproducible subgroups independent of oncogenic mutations.
Authors: Lee Michael Sangmin , Clarke Callisia , Jiang Zhi-Qin , Manyam Ganiraju C. , Tian Feng , Lu Yiling , Morris Jeffrey , Broom Bradley McIntosh , Menter David , Vilar Sanchez Eduardo , Shureiqi Imad , Raghav Kanwal Pratap Singh , Eng Cathy , Chang George J. , Simon Iris , Bernards Rene , Mills Gordon B. , Overman Michael J. , Maru Dipen M. , Kopetz Scott
Published: February 2017

580

Background: While colorectal cancer (CRC) has classically been categorized on the basis of oncogenic mutations such as KRAS and BRAF, proteomic analyses directly elucidate the functional state of the cancer cell’s protein signaling, as recently described in a pan-cancer cohort and with mass-spectroscopy in a small CRC cohort. We performed an antibody-based proteomic analysis (reverse-phase protein array; RPPA) of a large cohort at MD Anderson (MDACC) and The Cancer Genome Atlas (TCGA) to determine patterns of protein expression in CRC. Methods: 725 archived CRC tumor samples (263 MDACC discovery set, and 462 TCGA validation set) underwent protein extraction and RPPA at MDACC to determine levels of 127 proteins. With unsupervised hierarchical clustering, samples dichotomized with distinct patterns of protein expression. The proteins with highest discriminatory utility were identified by LIMMA in the discovery set and confirmed in the validation set. Clinical variables and DNA sequencing results were available for correlation. Results: Among the top 30 discriminant proteins for the dichotomized groups in each dataset, 18 were common to both and tended to correlate with each other. One group was notable for high EMT (high fibronectin and collagen VI, low E-cadherin), while the other group was notable for high Akt/TSC/MTOR (high AKT, MTOR, Tuberin), and high RTK pathway components (high BRAF, HER2, HER3). This latter group also was notable for elevated beta-catenin and low CHK1, implicating differential activation of Wnt and cell cycle pathways, and intriguingly had elevated phospho-AMPK and phospho-NFkB. In the MDACC cohort, this latter group was more likely to have mucinous histology (p=0.009 by Fisher’s exact test) and lack lymphovascular invasion (p=0.026). When both TCGA and MDACC cohorts were examined, there was no significant difference in microsatellite instability, PIK3CA, KRAS, or BRAF mutations between the two proteomic groups. Conclusions: CRCs appear to be classifiable into distinct subsets by proteomic features. These findings reflect distinct differences in cellular signaling that are independent of common oncogenic driver mutations.
Prognostic effect of a single nucleotide polymorphism (SNP) in MIR608 in patients with high-risk locally advanced rectal cancer (LARC): Results of the EXPERT-C trial.
Authors: Sclafani Francesco , Chau Ian , Cunningham David , Lampis Andrea , Hahne Jens , Braconi Chiara , Peckitt Clare , Gonzalez David , Hullki Wilson Sanna , Capdevila Jaume , Glimelius Bengt , Cervantes Andres , Begum Ruwaida , Brown Gina , Tait Diana M. , Wotherspoon Andrew , Eltahir Zakaria , Yusuf-Adam Sandra , Oates Jacqueline Rose , Valeri Nicola
Published: February 2017

581

Background: An association between rs4919510, a SNP of mir-608, and prognosis of patients with colorectal cancer has been reported. However, no studies have analysed the role of this SNP in LARC. We conducted a pharmacogenomic analysis of rs4919510 in EXPERT-C, a randomised phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab in high-risk LARC. Methods: SNP analysis was performed on DNA extracted from tumour tissue. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms. Results: A total of 155/164 (94.5%) patients had tumours assessable for rs4919510 genotyping. 95 (61.3%) were homozygous for CC, 55 (35.5%) heterozygous (CG) and 5 (3.2%) homozygous for GG with no deviation from the Hardy-Weinberg equilibrium (p=0.379). Genotypes were evenly distributed in the two treatment groups and no association with baseline clinico-pathological characteristics or tumour molecular status (including RAS) was observed. Complete response did not differ according to the tumour genotype in the entire population (14.7% for CC, 13.3% for CG/GG) and was not influenced by treatment (12.0% for CC and 14.3% for CG/GG in CAPOX, 17.8% for CC and 12.5% for CG/GG in CAPOX-C) (all p values>0.05). Median follow-up was 64.9 months. In the CAPOX arm the 5-yr PFS and OS rates were 54.6% and 60.7% for CC and 82.0% and 82.1% for CG/GG, respectively (HR PFS 0.13, 95% CI: 0.12-0.83, p=0.02, HR OS 0.38, 95% CI: 0.14-1.01, p=0.05). In the CAPOX-C arm the same survival figures were 73.2% and 82.2% for CC and 64.6% and 73.1% for CG/GG (HR PFS 1.38, 95% CI: 0.61-3.13, p=0.44, HR OS 1.34, 95% CI: 0.52-3.48, p=0.55). An interaction was found between study treatment and rs4919510 genotype for both PFS (p=0.02) and OS (p=0.07). Conclusions: This is the first study investigating rs4919510 in LARC. We found that the CC genotype was associated with worse prognosis compared to the CG/GG genotype in patients treated with chemotherapy alone but not in those treated with cetuximab. The addition of cetuximab to chemotherapy may mitigate the unfavourable prognostic associated with the CC genotype.
Phase II study of temozolomide (TMZ) in metastatic colorectal cancer (mCRC) patients molecularly selected by MGMT promoter hypermethylation.
Authors: Amatu Alessio , Bencardino Katia , Barault Ludovic , Cassingena Andrea , Bonazzina Erica , Ghezzi Silvia , Moutinho Catia , Tosi Federica , Ricotta Riccardo , Magni Elena , Gatto Rosalinda , Marrapese Giovanna , Esteller Manel , Bardelli Alberto , Di Nicolantonio Federica , Sartore-Bianchi Andrea , Siena Salvatore
Published: February 2017

583

Background: O(6)-methylguanine-DNA-methyltransferase (MGMT) is a DNA repair protein. About 40% of mCRC display MGMT deficiency due to promoter hypermethylation, leading to susceptibility to treatment with cytotoxic alkylating agents. We previously reported that objective clinical response to dacarbazine is confined to tumors harboring MGMT promoter hypermethylation (Amatu et al. Clin Cancer Res 2013). Based on these findings, we conducted a phase II study with TMZ in MGMT-deficient mCRCs after failure of standard therapies (EudraCT 2012-003338-17). Methods: We screened mCRC patients for MGMT promoter hypermethylation on archival FFPE specimens by methylation-specific PCR (MSP). All eligible patients underwent tumor biopsy prior to start of treatment. Patients received TMZ 200 mg/m2 po qd days 1-5 q28 until progression or intolerable toxicity. We used a Fleming single-stage design to determine whether PFS rate at 12 week would be ≥35% (H0≤15%, type I error=0.059 (1-sided) and power=0.849). Secondary endpoints included response rate (RR), disease control rate (DCR), overall survival (OS), and association of clinical outcomes with quantitative MGMT evaluation in serum and fresh tissue. Results: 150 patients were screened: 54 (36%) presented MGMT promoter hypermethylation and 29 were eligible and enrolled from December 2012 to May 2014 (M 69%, median age 60y [38-77], mean number of previous treatment lines 5.6). A median of 2 cycles of TMZ were administered (range 1-5). Primary endpoint was not achieved, since PFS rate at 12 weeks was 10.3% (90% CI: 2.9-24.6). DCR was 48.3% (90% CI: 32.0-64.8), median OS 6.2 months (95% CI: 3.7-7.6), and median PFS 2.6 months (95% CI: 1.4-2.7). G3/4 toxicities occurring in ≥10% of patients included: thrombocytopenia (10.3/13.8%), neutropenia (0/10.3%) and increased bilirubin (11.1/0%). Exploratory MGMT quantitative analysis is in progress. Conclusions: In mCRC patients treated with TMZ, selection according to MGMT promoter hypermethylation by MSP did not provide meaningful PFS rate at 12 weeks. Biomarkers analyses on serum and fresh tumor biopsy are ongoing to identify the subgroup of mCRCs benefiting from treatment. Clinical trial information: 2012-003338-17.
The impact of oxaliplatin on the gonads: From bench to bedside.
Authors: Ben-Aharon Irit , Levi Mattan , Brenner Baruch , Purim Ofer , Amit Limor , Stemmer Salomon M. , Shalgi Ruth
Published: February 2017

584

Background: Recent studies have indicated a significant increase of young colorectal cancer patients, who may then face unique survivorship issues as fertility concerns. The impact of oxaliplatin on gonadal function remains unclear. We prospectively evaluated oxaliplatin-induced gonadotoxicity in a cohort of young patients. In a preclinical setting, the impact of oxaliplatin on the gonads was prospectively studied in mice. Methods: Newly diagnosed female (< 43 years) and male (<45 years) patients who were candidates for oxaliplatin-based protocol were enrolled into the study. Hormonal profile (including AMH and menstrual pattern) was measured in female patients and in male patients at baseline and within 6 months post-treatment. In the pre-clinical setting, pubertal mice (female and male cohorts) were injected with oxaliplatin or saline (control) and sacrificed at various time-points (1 week, 1 or 3 months) post-treatment. Ovarian reserve was estimated by serial serum AMH. Testicular function was evaluated by serial serum inhibin and sperm count. Gonads had been retrieved at each time point for immunohistochemical study of apoptosis (TUNEL, Ki67) and repair (PCNA), ovarian reserve (AMH) and testicular reserve (DAZL). Results: Eighteen patients (10 women; 8 men) were enrolled. Median age for women was 34y (range 27-43) and for men 39y (33-44). AMH decreased in all women post-treatment, but was measurable in 8/10 patients (p<0.05). FSH was elevated yet in the premenopausal range in these patients. Three patients remain menstruating during treatment. Additional five patients resumed menstruation within 6 months post-treatment. In female mice oxaliplatin induced moderate apoptosis at 1-month post treatment with a recovery of the histology compared with control mice at later time points. Inhibin was slightly decreased in men post-treatment. In male mice oxaliplatin exerted moderate apoptosis and transient decrease in spermatocyte staining in histological sections and a non-significant decrease in sperm count. Conclusions: Our results in both the clinical and pre-clinical settings indicate that oxaliplatin exerts moderate transient gonadal toxicity. Future prospective large-scale studies are warranted in order to affirm these outcomes.
HER-2 as a potential target for rectal cancer treatment: Positivity rate in patients of the CAO/ARO/AIO-94 and -04 trial.
Authors: Conradi Lena-Christin , Storch Marcus , Nagelmeier Iris , Styczen Hanna , Wolff Hendrik A. , Gaedcke Jochen , Sprenger Thilo , Homayounfar Kia , Ghadimi Michael , Rüschoff Josef , Beissbarth Tim , Rödel Claus , Liersch Torsten
Published: February 2017

585

Background: Members of the EGFR family are established targets for specific therapy approaches in a variety of malignancies. Especially HER-2 has been targeted for more than a decade in breast cancer and more recently in gastric cancer and adenocarcinomas of the gastroesophageal junction. Applying the HER-2 scoring algorithm established in gastric cancer we here investigated HER-2 expression in rectal cancer using FFPE tumor samples from both large trials of the German Rectal Cancer Study Group (GRCSG)-(CAO/ARO/AIO-94 and -04). Methods: Overall, FFPE samples from 839 patients from 63 sites were available. All patients received standardized multidisciplinary treatment according to protocols of the phase-III-trials. 104 patients were treated by primary tumor resection followed by adjuvant CRT, all other patients (n=547) had preoperative CRT either with concomitant 5-FU mono therapy (n=329, 60.1%) or a combination of 5-FU and oxaliplatin (n=218, 39.9%). The HER-2-status was determined in resection specimens using immunohistochemistry scoring and S-ISH-amplification detection. Tumors with IHC 3+ or S-ISH ratios of ≥2.2 were classified HER-2-positive; these results were correlated with clinicopathological parameters (e.g., resection status, nodal-status ((y)pN)), time to recurrence (TTR) and cancer specific survival (CSS). Results: Positive HER-2-status was found in 13.8% of resected specimens. Positivity rate in primary resection specimens was 11.5% (n=12), while after preoperative CRT 13.2% (n=78 ) patients showed a HER-2 positive tumor; 13.1% (n=43) after 5-FU mono and 13.3% (n=35) after combination of 5-FU and oxaliplatin. There was no prognostic difference according to the HER-2 status regarding TTR (p=0.90) and CSS (p=0.68) overall. However in the 5-FU mono subgroup the HER-2 expression was of prognostic relevance as measured by CSS (p=0.034). Conclusions: Analysis of 839 patients from the GRCSG validated a relevant HER-2 amplification of 13.8% in samples of rectal adenocarcinoma. Besides its potential as an independent predictor of survival HER-2 may represent a promising target for innovative therapies and should be further assessed.
Clinical and molecular characterization of refractory BRAF mutant metastatic colorectal carcinoma (mCRC): Vall d’Hebron Institute of Oncology phase I program cohort.
Authors: Sanz-Garcia Enrique , Elez Elena , Argiles Guillem , Hernandez-Losa Javier , Vivancos Ana , Moreno Debora , Macarulla Teresa , Capdevila Jaume , Alsina Maria , Sauri Tamara , Hierro Cinta , Azaro Analia , Cruz Zambrano Cristina , Vilaro Marta , Jimenez Jose , Landolfi Stefania , Nuciforo Paolo , Ramon y Cajal Santiago , Rodon Jordi , Tabernero Josep
Published: February 2017

587

Background: BRAF mutation (mt) occurs in 5-8% of mCRC and its role as a negative prognostic factor is well known. The up-front detection of BRAF mt is not standardized beyond the boundaries of research. However, since novel emerging specific therapies are increasingly available in clinical trials, the prior determination of this mutation is now warranted. Methods: From 07/2010 to 01/2014, 581 patients (pts) with advanced refractory mCRCunderwent genetic tumor profiling as part of the VHIO Phase I Trial Molecular Prescreening Program. BRAF mt was determined by Sanger sequencing or multiplex PCR and mass detection (MassARRAY, Sequenom) of 268 frequent hotspots in 25 oncogenes including, KRAS, NRAS, and PIK3CA. PTEN status was also assessed by immunohistochemistry. Results: 581 samples were analyzed detecting BRAF mt in 56 (9.6%). In the BRAF mt population, median age was 61 years (45-80) and 54% had right-sided CRC. Metastatic sites were found at: liver 61%; peritoneum 52%; lung 39%. Median number of standard treatment was 4 (0-8) including cetuximab and/or panitumumab in 73%. BRAF V600E mutation was detected in 53 samples whereas V600K, D594V and D594G were seen in one sample each. PTEN was analyzed in 44.6% of samples resulting in low expression (H-score <50) in 56%. Other co-existing mutations were PIK3KCA H1047R, PIK3CA E545K, NRAS G12V, GNAS R201C and EGFR S768I. 22 pts were enrolled at least in one phase I trial with drugs targeting either BRAF alone (n=12) or combined with anti-EGFR (n=5), MEK (n=2), PI3K (n=1) inhibitors or double MEK/PI3K inhibition (n=2). Partial responses (PR) were seen in 3 pts (2 with BRAF inhibitor and EGFR inhibitor and 1 with BRAF inhibitor as a single agent). Conclusions: BRAF mt mCRC pts in our institution have a similar pattern to other series reported. Notably, PTEN low expression was present in almost half of the samples analyzed and other co-existent mutations in the ERK and PI3K pathways were detected. This observation, coupled with the clinical outcome observed with single agent BRAF inhibition in this population, suggests that these patients may derive greater benefit from dual BRAF and either EGFR, MEK or PI3K inhibition.
Ziv-aflibercept (Z) in combination with FOLFIRI for second-line treatment of patients with metastatic colorectal cancer (mCRC): Interim safety data from the global Aflibercept Safety and Quality-of-Life Program (ASQoP and AFEQT) in patients age 65 or older.
Authors: Bordonaro Roberto , Frassineti Giovanni Luca , Ciuffreda Libero , Aprile Giuseppe , Thomas Anne , Vishwanath Raghu L. , Zilocchi Chiara , Dochy Emmanuelle , Taïeb Julien , Sobrero Alberto F.
Published: February 2017

588

Background: The prespecified analysis of patients (pts) ≥65 y in the VELOUR study demonstrated a safety profile similar to that of ziv-aflibercept (Z) (known as aflibercept outside the United States) plus FOLFIRI in the overall VELOUR population. The global ASQoP/AFEQT Program comprises 2 clinical studies (ASQoP [NCT01571284]; AFEQT [NCT01670721]) designed to capture QoL and safety data from a population similar to VELOUR but treated in a real-life setting. We report safety data from the fourth interim analysis of pts ≥65 y. Methods: ASQoP/AFEQT are single-arm, open-label trials evaluating Z in metastatic colorectal cancer pts previously treated with an oxaliplatin-containing regimen. Eligible pts received Z (4 mg/kg) q2w on day 1 of each cycle followed by FOLFIRI until disease progression, unacceptable toxicity, death, or investigator/pt decision. Initial starting doses of FOLFIRI and dose modifications are at treating physician’s discretion. The % of pts ≥65 y with grade (G) 3 or 4 AEs in the combined safety population of ASQoP/AFEQT are compared with the prespecified analysis in pts ≥65 y from the Z + FOLFIRI arm of VELOUR. Results: At data cutoff, the overall safety population comprised 688 pts with ≥1 completed treatment cycle; 303 (44.1%) were ≥65 y. In the overall safety population ≥1 G3/4 AE was reported in 72.2% of pts vs. 83.5% in overall VELOUR. Most G3/4 AEs were G3. There were no reports of G4 hypertension, diarrhea, or fatigue. Median number of cycles was 6 in ASQoP/AFEQT and 9 in the Z + FOLFIRI arm of VELOUR. Table shows summary of AEs in pts ≥65 y. Conclusions: This interim analysis from ASQoP/AFEQT in pts ≥65 y has identified no new safety signals and provides additional safety data suggesting an acceptable toxicity profile in this real-life setting. Clinical trial information: NCT01571284. [Table: see text]
IL-6/STAT3 signaling impaired induction of cancer-antigen specific T cells via down-regulation of dendritic cells in tumor microenvironment.
Authors: Ohno Yosuke , Kitamura Hidemitsu , Ohtake Junya , Kaneumi Shun , Sumida Kentaro , Homma Shigenori , Kawamura Hideki , Takahashi Norihiko , Taketomi Akinobu
Published: February 2017

590

Background: Immunosuppression in tumor microenvironments is a critical issue for cancer immunotherapy. Recently, the effectiveness of immuno-check point therapy has been reported on various types of solid tumors. But, the effectiveness in colorectal cancer was poor compared to other cancers, such as melanoma and renal cell carcinoma. Correct regulation of dendritic cell (DC) function in tumors is important for inducing anti-tumor immunity. We have been demonstrated that IL-6 inhibits antigen presentation by DCs through STAT3 activation in tumor-bearing mice. In this study, we focused on the role of the IL-6/STAT3 signaling cascade in human DCs. Methods: Both IL-6 and pSTAT3 expressions in tumor sites of colorectal cancers was verified by immunohistostaining. CD11b+CD11c+DCs in cancer tissues and PBMCs were isolated by fluorescence-activated cell sorting system and investigated about the surface molecules such as HLA-DR, T cell stimulating ability, and effector gene expression levels. Moreover, we investigated influence of IL-6/STAT3 signaling in human DCs in vitro. Results: The results of IHC revealed that IL-6 was preferentially produced by cancer-associated fibroblasts and immune cells in the tissues of colorectal cancers. In addition, it was confirmed that STAT3 was activated in tumor-infiltrating immune cells. Tumor infiltrating CD11b+CD11c+ DCs highly induced IL-6 gene, down-regulated surface expression of HLA-DR, and attenuated T cell stimulating ability. In vitro experiments showed that IL-6-mediated STAT3 activation reduced surface expression of HLA-DR. COX2, cathepsin L (CTSL), and arginase activity were are involved in the IL-6-mediated down-regulation of surface expression levels of HLA-DR expression levels on DCs. Gene expressions of CTSL, ARG1 as well as IL6 in tumor infiltrating CD11b+CD11c+DCs were much higher than those of PBMCs. Conclusions: IL-6-mediated STAT3 activation inhibits functional maturation of DCs, causing suppression of anti-tumor immunity in colorectal cancer. Therefore, inhibition of the IL-6/STAT3 signaling pathway could be a promising strategy for improving immunotherapies for colorectal cancer patients.