bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3160: Stromal markers of activated tumor associated fibroblasts predict poor survival and are associated with necrosis in non-small cell lung cancer
Authors: Alcaraz Jordi , Carrasco Josep-Lluís , Millares Laura , Benchea Iuliana-Cristiana , Fernández Francisco-Javier , Martínez Anabel , Pajares María José , Cos Julio Sánchez de , Rami-Porta Ramon , Seijo Luis , Ramírez Josep , Reguart Noemí , Barreiro Esther , Monsó Eduard
Published: August 2019

Tumor associated fibroblasts (TAFs) are essential contributors of the progression of non-small cell lung cancer (NSCLC). Most lung TAFs exhibit an activated phenotype characterized by the expression of α-SMA and fibrillar collagens. However, the prognostic value of these activation markers in NSCLC remains unclear. To address this question we conducted a retrospective multicentric study of the prognostic value of the standard markers of activated fibroblasts. For this purpose, we conducted a quantitative image analysis of α-SMA immunostaining and picrosirius red staining of fibrillar collagens imaged by bright-field and polarized microscopy, respectively, using tissue microarrays with samples from 220 surgical patients, which elicited a percentage of positive staining area for each marker and patient. Kaplan-Meier curves showed that all TAF activation markers were significantly associated with poor survival, and their prognostic value was independent of TNM staging as revealed by multivariate analysis, which elicited an adjusted increased risk of death after 3 years of 129% and 94% for fibrillar collagens imaged with bright-field (p = 0.004) and polarized light (p = 0.003), respectively, and of 89% for α-SMA (p = 0.009). We also found a significant association between all TAF activation markers and tumor necrosis, which is often indicative of hypoxia, supporting a pathologic link between tumor desmoplasia and necrosis/hypoxia. Our findings identify patients with large histologic coverage of fibrillar collagens and α-SMA+ TAFs to be at higher risk of recurrence and death, supporting that they could be considered for adjuvant therapy. Moreover it supports that antifibrotic drugs aiming to target tumor fibrosis may be an effective therapeutic approach to improve survival in NSCLC.

Citation Format: Jordi Alcaraz, Josep-Lluís Carrasco, Laura Millares, Iuliana-Cristiana Benchea, Francisco-Javier Fernández, Anabel Martínez, María José Pajares, Julio Sánchez de Cos, Ramon Rami-Porta, Luis Seijo, Josep Ramírez, Noemí Reguart, Esther Barreiro, Eduard Monsó. Stromal markers of activated tumor associated fibroblasts predict poor survival and are associated with necrosis in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3160.
Abstract 3170: BRAF expression is associated with poor survival in colorectal cancers independent of BRAF (V600E) mutation
Authors: Yang Mingli , Schell Michael J. , Yeatman Timothy J.
Published: August 2019

The RAS pathway is known to be commonly activated and a key determinant of colorectal cancer (CRC) biology, with mutational activation of RAS/RAF genes observed in ~50% of CRC patients. The relationship between gene mutation and expression is, however, poorly understood. We analyzed how the expression of RAS/RAF genes vs. their respective mutations impacted outcomes. The relationship to other rarely mutated RAS/RAF genes (HRAS, ARAF, RAF1 (i.e. c-RAF)) was also examined in these tumors. While KRAS expression was positively associated with KRAS mutations (r=0.26, p<0.0001), BRAF expression was, unexpectedly, negativelycorrelated with BRAF (V600E) mutation (r= -0.18, p=0.0001). Thus, a substantial number of patients express relatively high levels of BRAF absent of BRAF mutations. Additional analysis indicates that lower BRAF expression was significantly correlated with MSI or the CMS1 subtype that is strongly associated with BRAF (V600E). Intriguingly, despite negative association with mutant BRAF (V600E) that is well-established to be associated with poor prognosis, higher BRAF expression was also associated with poor overall survival, as indicated by Kaplan-Meier survival analysis of BRAF expression by quartiles in either 458 CRCs (Logrank test for trend p=0.0262) in 406 WT BRAF CRCs (p=0.0102). Note that the expression of all other five RAS/RAF genes (HRAS, KRAS, NRAS, ARAF and RAF1) was not associated with survival. Further analysis with the gene expression signatures measuring RAS pathway activation reveals that unlike BRAF (V600E) (or KRAS mutations or KRASexpression), BRAF expression appeared to be negatively correlated with RAS pathway activation signature scores. Taken together, these data suggest that higher BRAF expression in CRC patients may activate an “alternative” pathway to the canonical pathway directed by mutant BRAF (V600E) as yet another means to deliver tumor progression.

Citation Format: Mingli Yang, Michael J. Schell, Timothy J. Yeatman. BRAF expression is associated with poor survival in colorectal cancers independent of BRAF (V600E) mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3170.
Abstract 3174: A novel prognostic model for tongue squamous cell carcinoma based on the characteristics of tumor and its microenvironment: iBD score
Authors: Liu Xiqiang
Published: August 2019

Aims: Tumor budding and invasive depth can predict survival of patients with tongue squamous cell carcinoma (TSCC), while the prognostic value of tumor microenvironment (TME) remains unknown. Here, both characteristics of tumor and its microenvironment were examined and a novel prognostic model has been proposed.

Methods: A total of 246 patients with TSCC were included. Using H&E stained sections, pathological parameters of tumor and the TME were assessed. Inflammatory response (i), tumor budding (B), and invasive depth (D) were combined as iBD score. The association between these variables and the patient survival was determined.

Results: Both tumor budding and inflammatory status were independent variables for predicting overall survival (OS) and disease-free survival (DFS) of TSCC patients. Invasive depth was correlated with differentiation, T classification, lymph node metastasis, clinical stage, and recurrence (P< 0.05). The novel iBD model was strongly correlated with T classification, lymph node metastasis, clinical stage, and recurrence, and showed clear distinction of score 0, 1 and 2. High iBD score had a strong association with reduced OS and DFS (P< 0.01).

Conclusions: iBD scoring model is strongly associated with lymph node metastasis and recurrence in TSCC and could be a promising survival predictor for TSCC patients.

Note: This abstract was not presented at the meeting.

Citation Format: Xiqiang Liu. A novel prognostic model for tongue squamous cell carcinoma based on the characteristics of tumor and its microenvironment: iBD score [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3174.
Abstract 3264: A novel TLR8 agonist induces immune responses and tumor regression
Authors: Wang Yuxun , Yang Heping , Li Huanping , Zhao Shuda , Zhang Yin , Huang Renjie , Wu Jinmiao , Zeng Yikun , Zhang Panpan , Zhang Xingzhong , Wang Longsheng , Fu Guangliang , Wu Zhiheng , Zhu Panhu , Xu Hui , Gao Yaqiao , Wang Pei , Gao Daxin
Published: August 2019

Toll like receptors (TLRs) have been a recent focus of drug discovery for cancer immunotherapy. TLRs play a crucial role in bridging innate and adaptive immunity. TLR8 is distinguished from other TLRs by its functions in reversing regulatory T (Treg) cell and myeloid derived suppressor cell (MDSC)’s immune suppression effects. Treg and MDSCs induce an immunosuppressive microenvironment that is a major cause of failed tumor immunotherapy. Therefore, activation of TLR8 can exert potent immune-mediated anticancer activity. We discovered a novel TLR8 selective agonist DN052 and demonstrated that DN052 clearly differentiated from motolimod, the only TLR8 agonist drug candidate in clinical development. DN052 was more potent than motolimod and exhibited better PK profiles and more strongly induced immune responses in the in vivo monkey and ex vivo human PBMC studies. However, it has been challenging to characterize TLR8 agonists in vivo partially due to the phylogenetic specificity of TLR8 and its diminished activity in rodents. We developed two new in vivo approaches using mouse syngeneic and mouse xenograft tumor models. Our in vivo studies showed that DN052 strongly suppressed tumor growth in a dose-dependent manner as a single agent and combination with the chemotherapeutic agent or PD-1 monoclonal antibody further enhanced the efficacy of the single agents in several tumor models. Remarkably, DN052 caused complete tumor regression as a single agent or in combination in some of the immune-competent tumor-bearing mice. GLP toxicity studies in rats and monkeys showed that DN052 had favorable safety profiles. Taken together, DN052 is a novel Best-in-Class TLR8 selective agonist for immunotherapy as a single agent or in combination with other immuno-oncology agents or chemotherapeutics for broad cancer indications. DN052 warrants further clinical development.

Citation Format: Yuxun Wang, Heping Yang, Huanping Li, Shuda Zhao, Yin Zhang, Renjie Huang, Jinmiao Wu, Yikun Zeng, Panpan Zhang, Xingzhong Zhang, Longsheng Wang, Guangliang Fu, Zhiheng Wu, Panhu Zhu, Hui Xu, Yaqiao Gao, Pei Wang, Daxin Gao. A novel TLR8 agonist induces immune responses and tumor regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3264.
Abstract 327: The impact of PIK3CA/PTEN/AKT1 genes in advanced NSCLC patients with acquired EGFR-TKI resistance and clinical response to EGFR-TKI plus everolimus combination therapy
Authors: Fang Wenfeng , Huang Yihua , Gan Jiadi , Yang Yunpeng , Wu Yifen , Huang Jingbin , Xu Zhiyong , Wang Wenjing , Zhang Li
Published: August 2019

Background EGFR-TKIs have shown remarkable effect in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. Nevertheless, several mechanisms including activation of PI3K/AKT/mTOR pathway have been proved to generate acquired assistance to EGFR-TKIs. In this study, we investigated the genomic characteristics of PI3K pathway in NSCLC patients with acquired resistance to EGFR-TKIs and whether both targeting EGFR and mTOR could reverse resistance.

Methods A total of 605 NSCLC cases who received prior TKI treatment were reviewed, in which 328 patients harboring EGFR-mutants were confirmed to have progressed on one or more TKI and finally enrolled. FFPE tumor or blood samples were collected at the onset of TKI resistance for NGS based panel assay (PIK3CA/PTEN/AKT1 genes and NSCLC driver genes are included). Six patients with co-mutations in EGFR and PI3K pathway who had been heavily treated and progressed on EGFR-TKI received EGFR-TKI plus mTOR inhibitor everolimus combination therapy.

Results In a total of 328 patients, 294 (89.6%) of the patients were adenocarcinomas, 4(12.2%) were small cell lung cancer, while the rest were squamous carcinoma or NSCLC not otherwise specified (30, 9.2%). Forty nine (14.9%) patients with TKI resistant have genomic alterations in PI3K pathway. PIK3CA, PTEN and AKT1variations were detected in 31(9.5%), 18(5.5%) and 3(0.9%) of patients respectively. Three patients had both PIK3CA and PTEN mutations and one patient had co-mutation of PIK3CA/PTEN/AKT1. PIK3CA hotspot mutations of E545, H1047 and E542 accounted for 60.5% of PIK3CA mutations. Six patients were treated with everolimus (5mg) plus EGFR-TKI (2 patients with gefitinib, 250mg; 1 patient with afatinib, 30mg; 3 patients with osimertinib 80mg, daily) combination therapy. One (1/6, 16.7%) patient achieved partial response and the rest (5/6, 83.3%) achieved stable disease. The most common adverse events were dental ulcer (6/6), rash (2/6), pruritis (1/6) and diarrhea (1/6). One patient withdrew combination treatment due to grade 3 dental ulcer.

Conclusions Our study revealed that PI3K pathway was activated in approximately 15% of EGFR-TKI resistant patients. Combination therapy of EGFR-TKIs and everolimus revealed limited antitumor activity in EGFR-TKI resistant NSCLC patients with dysregulation of PI3K pathway.

Citation Format: Wenfeng Fang, Yihua Huang, Jiadi Gan, Yunpeng Yang, Yifen Wu, Jingbin Huang, Zhiyong Xu, Wenjing Wang, Li Zhang. The impact of PIK3CA/PTEN/AKT1 genes in advanced NSCLC patients with acquired EGFR-TKI resistance and clinical response to EGFR-TKI plus everolimus combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 327.
Abstract 3274: LTX-401 as a novel antitumor and immunotherapeutic agent in an experimental liver cancer model
Authors: Mauseth Brynjar , Camilio Ketil , Shi Ji-Hua , Rekdal Øystein , Sveinbjørnsson Baldur , Line Pål-Dag
Published: August 2019

Liver cancer is estimated to be the third most common cause of cancer-related mortality worldwide in both sexes. Hepatocellular carcinoma (HCC) is the most prevalent type of primary liver cancer in which potential curative surgical options are limited and overall survival poor. Hence, there is an unmet need for new and improved therapies. LTX-401 is a novel oncolytic compound with potent antitumor properties. Owing to its amphiphatic nature, LTX-401 may affect the integrity of cancer cell membranes and induce rapid cell death. Transmission electron microscopy indeed revealed a necrotic cell death phenotype accompanied by massive vacuolization of the cytoplasm and dilated mitochondria. Additionally, LTX-401 induces features of immunogenic cell death (ICD) as seen by the extracellular release of ATP and HMGB1, as well as the mitochondrial DAMP cytochrome C. The antitumor effects of LTX-401 has been explored in an experimental model of hepatocellular carcinoma (JM1 model) using immunocompetent rats. When injected into subcutaneously established lesions, the majority of animals went into remission followed by systemic protective immune responses. Additionally, LTX-401 could affect the growth of distal tumor deposits simulating metastases, hence indicating immune-mediated abscopal responses. Intratumoral treatment of orthotopic liver tumors resulted in cure of approximately half of the animals treated, which later displayed protection against subcutaneous tumor (re)challenge. Splenocytes harvested from immunized animals produced significantly larger amounts of IFN-y when stimulated with tumor cells ex vivo, indicating the presence of tumor-specific (memory) T cells. Histological examinations revealed that LTX-401 caused massive hemorrhagic tumor necrosis, both in subcutaneous and intrahepatic compartments, followed by increased infiltration of T cells. Taken together these results indicate that oncolytic compounds generate an immunogenic tumor environment and may be therapeutically exploited as a novel antitumor and immunotherapeutic approach in HCC.

Citation Format: Brynjar Mauseth, Ketil Camilio, Ji-Hua Shi, Øystein Rekdal, Baldur Sveinbjørnsson, Pål-Dag Line. LTX-401 as a novel antitumor and immunotherapeutic agent in an experimental liver cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3274.
Abstract 3279: All-trans-retinoic acid (ATRA) markedly augments anti-tumor immunity
Authors: Huang Lu , Chen Zibo , Williams Leila , Chen Yulong , Wang Yunfei , Kawakami Masanori , Roszik Jason , Hwu Patrick , Dmitrovsky Ethan , Peng Weiyi , Liu Xi
Published: August 2019

All-trans-retinoic acid (ATRA) engages diverse actions on populations of immune cells. These include effects on regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), Th17 and other immune cells. Prior work found that ATRA can induce anti-tumor immunity through MDSCs and CD8+ T cells and pro-tumor immunity by increasing Treg cells. In this study, we explored how ATRA modulated anti-tumor immunity in solid tumors. To do this, syngeneic lung cancer and colon cancer models were independently developed by optimizing subcutaneous injections of ED1SQ4 lung cancer and MC38 colon cancer cells into immune-competent mice. ATRA-treatment markedly repressed both syngeneic lung cancer and colon cancer growth as compared to vehicle-treated mice. To exclude the possibility that ATRA directly suppressed growth of cancer cells, ED1SQ4 and MC38 cells were independently implanted subcutaneously into athymic mice in order to allow these lung and colon cancer xenografts to grow. Notably, ATRA-treatment did not reduce the growth of these respective xenograft tumors. Intriguingly, ATRA did not suppress in vitro proliferation of either ED1SQ4 or MC38 cells. This implicated ATRA as engaging mechanisms that affect the tumor microenvironment. To learn if the observed anti-tumorigenic activity was mediated by regulation of T cell immunity, CD4+ or CD8+ T cell populations were depleted in syngeneic mice before in vivo ATRA-treatment. CD4+ and CD8+ T cell depletion from syngeneic mice at least partially reversed the tumor suppressive activity of ATRA. Flow cytometry assays conducted on intratumoral immune cells revealed that ATRA-treatment decreased the CD8+ T to Treg cellular ratios while increasing the ratios of CD8+ T to Treg cells. Cytokine and chemokine assays were performed on these syngeneic cancers as well as on peripheral blood harvested from ATRA or vehicle-treated syngeneic mice in order to identify mediators of the observed anti-tumorigenic effects. Findings will be presented. Taken together, this study uncovered a previously unrecognized role for ATRA in augmenting immunotherapy. These preclinical immunotherapy findings can be translated into the cancer clinic.

Citation Format: Lu Huang, Zibo Chen, Leila Williams, Yulong Chen, Yunfei Wang, Masanori Kawakami, Jason Roszik, Patrick Hwu, Ethan Dmitrovsky, Weiyi Peng, Xi Liu. All-trans-retinoic acid (ATRA) markedly augments anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3279.
Abstract 3281: The association between body mass index (BMI) and risk of pancreatic cancer depends on age at BMI assessment
Authors: Jacobs Eric J. , Newton Christina C. , Patel Alpa V. , Stevens Victoria L. , Islami Farhad , Flanders W. Dana , Gapstur Susan M.
Published: August 2019

Importance: Pancreatic cancer rates in the United States have steadily increased since the early 2000’s despite declines in smoking. This increase is not easily explained by population increases in body mass index (BMI) given the relatively weak association between BMI and pancreatic cancer risk typically observed in epidemiologic studies. Most of these studies, however, assessed BMI in older adulthood, which may be less strongly associated with pancreatic cancer than BMI earlier in adult life.

Objective: To examine the association between BMI and pancreatic cancer mortality by age at BMI assessment.

Design: Prospective cohort study.

Setting: Cancer Prevention Study II (CPS-II), a nationwide study of cancer mortality enrolled in 1982 and followed through 2014.

Participants: 963,317 US adults aged 30 to 89 years at enrollment.

Exposure: BMI calculated from height and weight reported at enrollment.

Main outcomes and measures: A total of 8,354 participants died of pancreatic cancer during follow-up. Hazard ratios (HRs) for BMI were calculated using multivariable proportional hazards regression models. Population attributable fractions by birth cohort were calculated using HRs from CPS-II and BMI distributions from nationally representative National Health and Examination Surveys (NHANES).

Results: HRs declined with increasing age at BMI assessment. HRs per 5 BMI units among those aged 30-49, 50-59, 60-69, and 70-89 years at assessment were 1.25 (95% confidence interval (CI) 1.18-1.33), 1.19 (95% CI 1.14-1.23), 1.14 (95% CI 1.08-1.21) and 1.13 (95% CI 1.02-1.26), respectively (p-trend = 0.005). The prevalence of obesity in early middle age is substantially higher in more recent US birth cohorts than in earlier ones. Therefore, based on a HR of 1.25 per 5 BMI units at age 45 years, we estimate that 28% of pancreatic cancer deaths in the US among those born from 1970-74 will be attributable to BMI levels > 25 kg/m2, nearly twice the equivalent percentage in those born in the 1930s.

Conclusions and Relevance: BMI before age 50 may be more strongly associated with pancreatic cancer risk than BMI at older ages. These results underscore the importance of preventing excess weight gain before middle age for reducing rates of this highly fatal cancer.

Citation Format: Eric J. Jacobs, Christina C. Newton, Alpa V. Patel, Victoria L. Stevens, Farhad Islami, W. Dana Flanders, Susan M. Gapstur. The association between body mass index (BMI) and risk of pancreatic cancer depends on age at BMI assessment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3281.
Abstract 3283: Associations of change in BMI before surgery with disease-free and overall survival in colorectal cancer patients: Results from the ColoCare Cohort
Authors: Ose Jennifer , Gigic Biljana , Lin Tengda , Boehm Juergen , Schrotz-King Petra , Schrotz-King Petra , Hardikar Sheetal , Himbert Caroline , Schneider Martin , Ulrich Alexis , Ulrich Cornelia M.
Published: August 2019

BACKGROUND Body weight in colorectal cancer patients may change substantially before and after diagnosis and treatment. The prognostic significance of pre-surgery weight loss is still unclear. We investigated the association of pre-surgery weight loss with clinical outcomes in colorectal cancer patients.

METHODS We used prospectively collected data from n=148 newly diagnosed colorectal cancer patients (stage I-IV) from the ColoCare Cohort. Data on body mass index (BMI; (kg)/ m2) 1 year before surgery and at the time of surgery were collected. We calculated BMI differences between these time points. We applied Cox proportional hazard models to investigate associations of BMI change (continuous), biological sex (male, female) and tumor stage (I, II, III, IV) and neoadjuvant chemo- and/or radiotherapy (no/yes).

RESULTS After 24 months of follow-up n=22 patients were deceased and n=19 patients had a recurrence. Pre-surgery change in BMI was associated with poorer overall and disease-free survival: for every loss in one unit in BMI patients had a 47% increase in risk of overall death: Hazard Ratio (HR): 1.47; 95% confidence interval (CI) (1.21-1.76), p=0.0001 and a 44% increase in risk for either death or recurrence: HR: 1.44; 95% CI (1.19-1.73), p=0.0002.

CONCLUSIONS Pre-surgery weight change is, independently of tumor stage, age, biological sex and neoadjuvant therapy, associated with long-term clinical outcomes in colorectal cancer survivors.

Citation Format: Jennifer Ose, Biljana Gigic, Tengda Lin, Juergen Boehm, Petra Schrotz-King, Petra Schrotz-King, Sheetal Hardikar, Caroline Himbert, Martin Schneider, Alexis Ulrich, Cornelia M. Ulrich. Associations of change in BMI before surgery with disease-free and overall survival in colorectal cancer patients: Results from the ColoCare Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3283.
Abstract 3295: GPRASP1:A novel potential biomarker for neuroendocrine carcinoma
Authors: Xiong Minggang , Wang Fuhao , Zhau Haiyen E. , Huang Xin , Chung Leland , Zhang Jian , Lu Yi
Published: August 2019

Neuroendocrine differentiation has been observed to correlate with the progression and prognosis of prostate cancer (PCa), gastric cancer and pancreatic cancer, but the mechanisms remain unclear. GPRASP-1, a G protein coupled receptor-associated sorting protein 1, is known as a significant modulator of lysosomal sorting, and functional down-regulation of G- protein coupled receptors by interacting with Beclin2. The GPRASP-1 was originally considered as a serum tumor biomarker for breast cancer and later it was confirmed as a ubiquitous tumor marker among lung, liver and brain cancers. Based on its function as a tumor biomarker, we conducted serum ELISA analysis of GPRASP-1, and correlated results with RNAseq and gene copy numbers among a large cohort of PCa patients. We found overexpression and gene amplification of GPRASP-1 in 24 of 77 patients (31%) with neuroendocrine PCa (NEPCa). The patients with elevated serum GPRASP-1 level had a higher risk of metastasis to liver, lung and lymph nodes. Furthermore, immunohistochemical analysis for GPRASP-1 showed a strong staining of the pathological section from pancreatic neuroendocrine carcinoma patients and their liver metastases. Knocking down of the GPRASP-1 in a NEPCa PC3 cell line showed dramatic downregulation of TACR family, Tachykinin Receptor, which is known to be involved in the neuroinflammation and neurotransmitter transport and cancer proliferation. Our results offer a novel link among GPRASP-1, neuroendocrine differentiation and castration resistance in human PCa. We proposed serum GPRASP-1 can serve as a novel biomarker differentiating cancers with and without neuroendocrine differentiation. (Supported by NSFC projects 81773146; Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, 2017B030301018); JCYJ20170412152943794, JCYJ20170412154619484, JCYJ20170307105128101, JCYJ2017030711041760)

Note: This abstract was not presented at the meeting.

Citation Format: Minggang Xiong, Fuhao Wang, Haiyen E. Zhau, Xin Huang, Leland Chung, Jian Zhang, Yi Lu. GPRASP1:A novel potential biomarker for neuroendocrine carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3295.
Abstract 3297: Prediagnostic circulating concentrations of vitamin D binding protein and survival among colorectal cancer patients
Authors: Yuan Chen , Song Mingyang , Wolpin Brian M. , Meyerhardt Jeffrey A. , Ogino Shuji , Hollis Bruce W. , Chan Andrew T. , Fuchs Charles S. , Wu Kana , Wang Molin , Smith-Warner Stephanie A. , Giovannucci Edward L. , Ng Kimmie
Published: August 2019

Higher total 25-hydroxyvitamin D [25(OH)D] levels are associated with an improvement in survival among colorectal cancer (CRC) patients, but the relationships between plasma vitamin D binding protein (VDBP), bioavailable or free 25(OH)D, and CRC survival remain unknown. In two prospective cohort studies, the Health Professionals Follow-Up Study and the Nurses’ Health Study, we examined the association between prediagnostic plasma levels of VDBP, bioavailable 25(OH)D, and free 25(OH)D and survival among 604 participants diagnosed with CRC between 1991 and 2011. Plasma 25(OH)D and VDBP were directly measured, while bioavailable and free 25(OH)D were calculated using a validated formula based on total 25(OH)D, VDBP, and albumin levels. Cox proportional hazards models were used to estimate hazard ratios (HRs) for overall and CRC-specific mortality, adjusted for other prognostic markers and potential confounders. During the follow-up, there were 279 deaths, 177 of which were due to CRC (63%). Higher VDBP levels were associated with a significant improvement in overall and CRC-specific survival (Ptrend=0.005 and 0.02, respectively). Compared to patients in the lowest quartile, those in the highest quartile of VDBP had a multivariable-adjusted HR of 0.61 (95% confidence interval [CI], 0.42-0.89) for overall mortality and 0.56 (95% CI, 0.35-0.92) for CRC-specific mortality. The results remained similar after further adjustment for total 25(OH)D levels. In contrast, no association with overall or CRC-specific mortality was observed for bioavailable or free 25(OH)D levels. In conclusion, higher prediagnostic plasma VDBP levels were associated with improved survival among CRC patients. The clinical utility of VDBP as a prognostic marker warrants further exploration, as well as research into underlying mechanisms of action.

Citation Format: Chen Yuan, Mingyang Song, Brian M. Wolpin, Jeffrey A. Meyerhardt, Shuji Ogino, Bruce W. Hollis, Andrew T. Chan, Charles S. Fuchs, Kana Wu, Molin Wang, Stephanie A. Smith-Warner, Edward L. Giovannucci, Kimmie Ng. Prediagnostic circulating concentrations of vitamin D binding protein and survival among colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3297.
Abstract 3309: Healthcare resource utilization in follicular lymphoma patients treated with maintenance rituximab in the Veterans Health Administration
Authors: Halwani Ahmad S. , Li Catherine , Rasmussen Kelli M. , Patil Vikas , Yong Christina , Burningham Zachary , Sauer Brian C.
Published: August 2019

OBJECTIVES: Examine healthcare resource utilization (HCRU) in follicular lymphoma (FL) patients treated with or without maintenance rituximab (MR).

METHODS: FL patients treated in the Veterans Health Administration (VHA) between 2006-2014 were identified by linking information from the VA Cancer Registry System (VACRS) and the Corporate Data Warehouse. HCRU was defined as the total number of outpatient visits (OPV), inpatient visits (IPV), and the number of emergency department visits (EDV) during follow-up time, which was approximately four years. To avoid immortal time bias, a prescription time distribution matching method was performed, followed by an inverse probability weighted regression analysis to account for variation in the follow-up period. The observational period was partitioned into four-yearly intervals. The observed HCRU value was weighted by the inverse of the probability of not being censored by the end of the yearly interval. A generalized linear model with Poisson distribution and log link was performed for each of the four intervals while adjusting for the covariates. Using a 95% bootstrap confidence interval, the change of HCRU was summed across the four-yearly intervals to obtain the cumulative change of HCRU between FL patients who received MR or did not receive MR.

RESULTS: From 2006-2014, 2,290 FL patients were diagnosed at VHA. After excluding patients with a prior cancer, documented grade 3b or stage I disease, 905 MR-eligible patients remained, of which 319 (35%) received MR and 586 (65%) did not receive MR. When compared with non-MR patients, MR patients were slightly more likely to have a mean increase in OPV (0.69%; CI: 0.44%-0.94%) and a mean decrease in IPV (14.83%; CI: 16.09%-13.58%). There was no significant change in the number of EDV between the MR treated and non-MR treated patients.

CONCLUSIONS: This nationwide real-world study suggests that on average FL patients treated with MR have fewer IPV and more OPV than non-MR patients.

Note: This abstract was not presented at the meeting.

Citation Format: Ahmad S. Halwani, Catherine Li, Kelli M. Rasmussen, Vikas Patil, Christina Yong, Zachary Burningham, Brian C. Sauer. Healthcare resource utilization in follicular lymphoma patients treated with maintenance rituximab in the Veterans Health Administration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3309.
Abstract 3336: Changes in prescriptions for breast cancer medications after Medicaid expansion
Authors: Maclean Johanna Catherine , Halpern Michael T. , Hill Steven C. , Pesko Michael F.
Published: August 2019

Introduction: As of summer 2018, 34 states have expanded Medicaid eligibility under the Affordable Care Act. While the Medicaid expansions decreased rates of being uninsured among women with breast cancer and increased early breast cancer detection, it is unknown whether expansions increased receipt of medications used to prevent and treat breast cancer. This study examines differences over time in receipt of two types of breast cancer hormonal therapies (tamoxifen and aromatase inhibitors) and associated payments for these medications in states that did vs. did not expand Medicaid during the period 2011-2017.

Methods: The study’s data source is the Medicaid State Drug Utilization Database (SDUD). This data set, compiled by the Centers for Medicaid and Medicare (CMS), is administrative data submitted by state Medicaid programs. The data comprise outpatient prescription medications that are covered under the Medicaid Drug Rebate Program for which Medicaid serves as a third-party payer; this includes aggregate numbers of prescriptions and associated payments for individuals enrolled in both fee for service and managed care Medicaid programs. Both branded and generic prescriptions for three aromatase inhibitors (anastrozole, exemestane, and letrozole) were included in the study’s analyses. Analyses used differences-in-differences and event study models (controlling for state characteristics) to compare changes in Medicaid expansion states to changes in non-expansion states before vs. after expansion.

Results: Initial regression analyses indicate that prescriptions for all hormonal therapy medications increased by 27% (p<0.05) and prescriptions for aromatase inhibitors (branded and generics combined) increased by 29% (p<0.05) in expansion states relative to non-expansion states. Prescriptions for tamoxifen and for generic aromatase inhibitors only also increased significantly. Post-expansion, both total payments and Medicaid payments for all hormonal therapies increased by 13% (p<0.01) in expansion states relative to non-expansion states. The similar increases for total and Medicaid payments suggest that state Medicaid programs, not patients, financed the increased hormonal therapy prescription payments.

Conclusions: Our findings indicate that states that expanded Medicaid with the ACA experienced increased prescriptions for breast cancer hormonal therapies relative to states that did not expand Medicaid; this effect of Medicaid expansion increased over time. The increased prescriptions were financed by Medicaid, not by patients.

Citation Format: Johanna Catherine Maclean, Michael T. Halpern, Steven C. Hill, Michael F. Pesko. Changes in prescriptions for breast cancer medications after Medicaid expansion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3336.
Abstract 3340: Lung cancer stigma: A ten year look at public attitudes about lung cancer
Authors: Rigney Maureen , Rapsomaniki Eleni , King Jennifer C.
Published: August 2019

Background: Lung cancer is the leading cause of cancer death in the United States in both men and women (ACS Facts and Figures, 2018). The presence of lung cancer stigma is well documented (Chapple et al, 2004; Chambers et al, 2012; Marlow et al, 2015) and has been shown to impact the care and treatment of lung cancer survivors (Tod et al. 2008; Carter-Harris et al 2014). In 2008, a large survey of over 1000 members of the general population revealed that most participants felt lung cancer was principally caused by external factors, that it was preventable, and that lung cancer patients were at least partly to blame for their illness (Weiss et al. 2014; 2017). We replicated the survey to understand whether perceptions have changed over the last decade.

Methods: 1001 members of the general public were surveyed with the identical survey instrument from 2008 survey along with three additional questions at the end. The survey was carried out by phone and online between June 6 and July 26, 2018. Statistical analysis was performed comparing 2008 and 2018 datasets using paired t-tests if normally distributed or Mann-Whitney U tests for continuous data and Chi-squared or Fisher’s exact test for categorical data.

Results: General awareness about lung cancer has significantly improved over the last decade with 94% of the public reporting familiarity with lung cancer (p<.001). Sixty five percent of respondents reported increased visibility of lung cancer in the media. Despite the increased visibility of the disease, stigma remains a critical problem. There were no statistically significant changes in the proportion that felt that patients are at least partly to blame for their illness (56% in 2018). Sixty-eight percent of respondents felt that patients experience the same or more stigma than 10 years ago. In addition, despite the increased awareness there was no increase in the proportion of people who donate or volunteer time to lung cancer organizations and no increase in those selecting lung cancer as the type of cancer they believe should receive more research support.

Conclusions: After a decade of research progress in lung cancer, these data show that lung cancer awareness has been considerably elevated. Unfortunately, they also indicate that the stigma surrounding the disease remains pervasive. This work underscores the need to address stigma with proactive multilevel approaches (Hamann, 2018).

Citation Format: Maureen Rigney, Eleni Rapsomaniki, Jennifer C. King. Lung cancer stigma: A ten year look at public attitudes about lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3340.
Abstract 3341: Rural and urban disparities in colonoscopy use persisted despite cost-sharing reduction among Medicare beneficiaries
Authors: Lee Min Jee , Jenkins Wiley , Boakye Eric Adjei , Ganai Sabha
Published: August 2019

Background: Due to passage of the Patient Protection and Affordable Care Act (ACA), Medicare began waiving Part B deductibles and eliminating coinsurance for all colonoscopies in 2011. As rural populations have significantly lower income than urban, there is hope the cost reduction would decrease rural screening disparities. We thus examined rural-urban colonoscopy use pre-/post-ACA implementation.

Methods: We used Behavioral Risk Factor Surveillance System data (2008-2016) to examine colonoscopy utilization for two years pre-ACA (2008 and 2010) and three years post-ACA (2012, 2014, and 2016) with stratification by rural/urban residence. Multivariate logistic regression was used to examine the differences in screening likelihood across rural and urban groups, while controlling for other factors such as age, sex, marital status, race/ethnicity, household income, educational attainment, gastroenterologist availability, exercise, smoking, and years.

Results: Of the 302,941 eligible Medicare beneficiaries, 203,426 (67.2%) received a colonoscopy. Colonoscopy receipt increased from 62.8% pre-ACA to 70.2% post-ACA years (p<.001). Across rural-urban areas, we found a significant increase in the receipt of colonoscopy from pre- to post-ACA (p<.001). The receipt of colonoscopy was higher among urban residents (69.2%) compared to rural residents (63.5%, p<.001). After adjusting for covariates, urban residents were more likely to receive colonoscopy both pre-ACA (OR=1.11, 95% CI: 1.06-1.15) and post-ACA (OR=1.11, 95% CI: 1.06-1.16).

Conclusions: Despite cost-sharing reduction of Medicare coverage for colonoscopy, rural and urban differences in colonoscopy use persisted over time among Medicare beneficiaries. Although the receipt of colonoscopy increased over time, the gap between rural and urban populations has remained.

Colonoscopy Use Before and After Implementation of The ACAPreACAPost ACARuality%OR95%CI%OR95%CIRural59.4166.61Urban64.91.111.061.1572.11.111.061.16

Citation Format: Min Jee Lee, Wiley Jenkins, Eric Adjei Boakye, Sabha Ganai. Rural and urban disparities in colonoscopy use persisted despite cost-sharing reduction among Medicare beneficiaries [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3341.
Abstract 3344: Effect of anticoagulation on the cancer stage at time of diagnosis of endometroid adenocarcinoma in a cohort of postmenopausal patients
Authors: Shukr Ghadear , Pham Tra , Buekers Thomas
Published: August 2019

Objectives: We sought to determine whether postmenopausal women on chronic anticoagulation were diagnosed with endometrial cancer at an earlier stage.

Methods: A retrospective case-control study of women at a tertiary care medical center with a diagnosis of Endometrioid Adenocarcinoma on chronic anticoagulation at time of diagnosis in comparison with patients not on anticoagulation was performed. Patients with personal history of cancer, including breast cancer, non-postmenopausal bleeding, and non-Endometrioid Adenocarcinoma histopathology were excluded. Anticoagulation was defined as use of Enoxaparin, Warfarin, Apixaban, Rivaroxaban or Clopidogrel. Indications for anticoagulation included atrial fibrillation, deep vein thrombosis/pulmonary embolism, or stroke. The primary outcome was Endometrioid Cancer stage (I, II, III/IV and X). The secondary outcomes were duration of bleeding to presentation and presentation to diagnosis. Statistical analysis was performed using Wilcoxan-Rank Sum Test and Cochran-Armitage Trend Test.

Results: 25 postmenopausal patients met the inclusion criteria for being treated in the last 10 years. 100 controls not on anticoagulation (non-AC) were identified for a 4:1 comparison to obtain a 2-sided alpha level of 0.05. Results were divided into 3 groups: 1) All patients, 2) Non-white patients, 3) White patients. Subjects were controlled for age (P<0.001) and BMI (P<0.049). The results indicated that non-AC patients were more likely to be diagnosed at Stage 1 when compared to the AC patients in all 3 categories. The trend was not statistically significant for the non-white patients (p=0.133), but was statistically significant in the overall population (p<0.001) and White patients (p<0.001). No statistical significance was detected for duration from bleeding to presentation and presentation to diagnosis between the AC and non-AC groups. However, median days from bleeding to presentation are considerably larger for the non-AC than AC (Group 1: 42 vs 14 days, Group 2: 75 vs 33 days Group 3: 30 vs 14 days, respectively).

Conclusion: Non-anticoagulated patients had an earlier cancer stage at diagnosis. Although anticoagulated patients may present earlier, they have advanced cancer stage. These findings should prompt immediate evaluation of patients on chronic anticoagulation to optimize oncologic management and prognosis.

Citation Format: Ghadear Shukr, Tra Pham, Thomas Buekers. Effect of anticoagulation on the cancer stage at time of diagnosis of endometroid adenocarcinoma in a cohort of postmenopausal patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3344.
Abstract 3353: Four vs six cycles of docetaxel and cyclophosphamide (TC) in early stage triple-negative breast cancer
Authors: Basu Aparna , Mohammed Hadi A. , Mahmood Sharmeen , Dabak Vrushali , Loutfi Randa
Published: August 2019

Background: ABC trials established the use of non-anthracycline containing regimen, docetaxel and cyclophosphamide (TC) in the adjuvant setting in early stage breast cancer. In clinical practice, TC is commonly used in Stage I Triple-Negative Breast Cancer (TNBC). However, no specific recommendations exist in literature, regarding the number of cycles that can be used. i.e. TC4 vs TC6. Our aim, was to determine if TC4 is non-inferior to TC6 when used as adjuvant therapy in early stage TNBC.

Methods: We retrospectively reviewed 77 patients who were diagnosed with early stage TNBC between 2007 to 2017, at our institution who had received either TC4 or TC6 as adjuvant therapy. The number of cycles the patients received were based on provider preference. The two groups (TC4, TC6) were compared in regard to stage of cancer at diagnosis based on AJCC 7thedition, grade of adverse events, recurrence and death from breast cancer recurrence.

Results: Out of 77 patients, based on T stage, 25 (32.5%) were T1b, 38(49.4%) were T1c, 13(16.9%) were T2 and 1(1.3%) was T3. All patients were node negative. 53(68.8%) received TC4 and 24(31.2%) received TC6. Regarding side effects, adverse of any grade were seen in 42(79.2%) patients who received TC4 and 23(95.8%) in patients who received TC6(p=0.091). Adverse events which were grade 3 or higher were seen in 7(15.9%) in TC4 group and 3(13%) in the TC6 group (p=1.000). Recurrence in the TC4 group was seen in 4 patients (7.5%) and 3(12.5%) patient in the TC6 group (p=0.259). Death due to breast cancer recurrence was seen in 1 patient (1.9%) in the TC4 group and 1(4.1%) patient in the TC6 group.

Conclusions: In this limited series, TC4 appears to be equally effective to TC6, with fewer adverse events of any grade. However, a longer follow up and a larger patient base is required to be studied for a more definitive conclusion.

Citation Format: Aparna Basu, Hadi A. Mohammed, Sharmeen Mahmood, Vrushali Dabak, Randa Loutfi. Four vs six cycles of docetaxel and cyclophosphamide (TC) in early stage triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3353.