tbuckley/cabot-search huggingface dataset:
Down-regulation of KRAS-interacting miRNA-143 to predict prognosis and response to EGFR-targeted agents in colorectal cancer.
Authors: Florian Eisner, Michael Stotz, Hellmut Samonigg, Sigurd Lax, Gerald Hoefler, Martin Pichler
Journal: Journal of Clinical Oncology (2012)

e14066 Background: MicroRNA-143 is frequently down-regulated in colorectal cancer (CRC) and influence CRC cell proliferation, apoptosis and sensitivity to 5-fluorouracil. mRNA encoded by the KRAS oncogene has been identified as a target of microRNA-143. However, the prognostic significance of microRNA-143 expression and the ability to predict the patient response to EGFR-targeted agents have not been explored yet. Methods: In this study, we analyzed 77 CRC harboring wild-type KRAS and obtaining treatment with the EGFR-targeting monoclonal antibodies cetuximab or panitumumab. MicroRNA-143 expression was measured by RT-PCR in both CRC and corresponding non-neoplastic colon tissue and the expression levels were correlated with clinico-pathological characteristics. Cancer-specific survival was calculated by uni- and multivariate analyses. The progression-free survival and objective response rates on EGFR-targeted therapy were also evaluated. Results: Down-regulation of microRNA-143 was observed in 47/77 (61%) CRC. Multivariate Cox regression analysis identified low levels of microRNA-143 expression as an independent prognostic factor with respect to cancer-specific survival (HR=1.92, CI=1.1-3.4, p=0.024). A significant difference was observed with respect to progression-free survival on EGFR-targeted therapy (p=0.031, log-rank test), but there were no significant differences with regard to the objective response rate. Conclusions: Our data suggest that microRNA-143 expression levels serve as independent prognostic biomarker for KRAS wild-type CRC patients but not as predictor for EGFR-targeted therapy. In addition, we consider microRNA-143 as a potential drug target for future therapy of CRC.
A phase I study of MEDI6383, an OX40 agonist, in adult patients with select advanced solid tumors.
Authors: Todd Michael Bauer, Young Kwang Chae, Sandip Patel, Sandra P. D'Angelo, George R. Blumenschein, Jonathan Norton, Carol Pound, Mark C. Lanasa, Brendan D. Curti
Journal: Journal of Clinical Oncology (2015)

TPS3093 Background: Enhancing T-cell function in cancer patients (pts) through T-cell co-stimulatory pathways such as OX40 has the potential to overcome cancer-induced immune suppression. MEDI6469, a human OX40 agonist murine antibody, administered for a single cycle in a phase I clinical study showed both an acceptable toxicity profile and regression of ≥ 1 metastatic lesion in 12 of 30 treated pts(Curti B, et al. Cancer Res 2013;73:7189–98). Humanized OX40 agonists are expected to have reduced immunogenicity relative to murine antibody, which may allow for repeat-dose administration, potentially enhancing biologic and antitumor activity. MEDI6383 is a human OX40 ligand fusion protein that in preclinical models initiates an intracellular signaling cascade to enhance T-cell survival, proliferation of T cells and macrophage lineage cells, and cytokine production. Methods: This is a phase I, multicenter, open-label study of MEDI6383 (NCT02221960) in adult pts with select recurrent or metastatic solid tumors. In the dose-escalation phase, sequential cohorts of pts will receive 1 of up to 6 dose levels (3+3 design) of MEDI6383 IV every 2 weeks for up to 48 weeks or until progressive disease (PD). In the dose-expansion phase, tumor-type specific cohorts will be treated at the MEDI6383 dose level and treatment schedule determined during dose escalation for up to 48 weeks or until PD. Pts who achieve a response and then have PD in follow-up may have 1 round of MEDI6383 retreatment. All pts will be followed for survival through end of study. The primary endpoint is safety and determination of the maximum tolerated dose; secondary endpoints are antitumor activity (objective response and disease control by immune-related RECIST, duration of response, progression-free survival, overall survival), pharmacokinetics, immunogenicity, and pharmacodynamics. Enrollment of up to 122 pts (42 pts, dose escalation; 80 pts, dose expansion) is ongoing. Clinical trial information: NCT02221960.
Comparison of recurrent and nonrecurrent ovarian and uterine cancer patients undergoing adjuvant folate receptor vaccine therapy.
Authors: Erika J Schneble, Kevin Byrd, Timothy J. Vreeland, John S. Berry, Alfred F Trappey, Guy T. Clifton, Sathibalan Ponniah, Elizabeth Ann Mittendorf, William McGuire, Thomas P Conrads, Kathleen M. Darcy, G. Larry Maxwell, Chad Hamilton, J C Elkas, George Earl Peoples
Journal: Journal of Clinical Oncology (2014)

5559 Background: Folate Receptor Alpha (FRa) (aka Folate Binding protein (FBP)) is an immunogenic protein that is over-expressed in breast, lung, endometrial (EC) and ovarian cancers (OC). In fact, FRa expression in malignant cells is 20-fold higher compared to normal cells. We are conducting a phase 1 clinical trial with E39, an HLA-A2 restricted, FRa peptide + GM-CSF vaccine, administered in the adjuvant setting to prevent recurrences in high-risk EC and OC patients (pts) rendered clinically disease-free after standard-of-care therapy. In this analysis, we compare in vivo immunologic responses (IR) and disease features between vaccinated recurrent (vR) and vaccinated non-recurrent (vNR) pts. Methods: HLA-A2+ pts enrolled into the vaccine group received 6 monthly intradermal inoculations of E39+250 mcg GM-CSF during the primary vaccine series (PVS). In vivo IR was assessed by both local reaction (LR) after each inoculation (R1-R5) and delayed hypersensitivity (DTH) reaction measured pre-vaccination (DTH1) and post-PVS (DTH2). The LR index is calculated by dividing LR at each time point by the corresponding LR at R0. Results: Overall, 30 pts have been enrolled. Of 14 control pts, 7 (50%) have recurred. Of 16 vaccinated pts, 4 (25%) have recurred after completing the PVS and 2 (12.5%) recurred prior to completing the PVS. One vaccinated pt withdrew due to an intercurrent illness leaving 6 vR and 9 vNR pts for analysis. vR were younger than vNR (60.4 v 65.6, p=0.14) although no significant differences in age, grade, stage, or nodal status existed between groups (all p>0.05). LR index was lower in vR pts at every time point (R1: 1.5 v 3.4, R2: 2.0 v 4.8, R3: 1.9 v 5.5, R4: 1.8 v 4.1, R5: 2.1 v 4.7). vR also displayed lower DTH1 (9.7mm±3.5 v 12.6mm±2.6, p=0.5) and DTH2 (14.4mm±11.4 v 7.4mm±4.8, p=0.78). Conclusions: Comparison between vR and vNR pts demonstrates recurrences are likely related to trends in both disease features (age but not stage) as well as diminished response to the vaccine as seen by LR and DTH. As decreased vaccine response may be related to more aggressive disease, the most viable way to address this is to vaccinate less advanced disease. Clinical trial information: NCT01580696.
A phase II, randomized, double blind comparison of calcium aluminosilicate clay (CASAD) versus placebo (dibasic calcium carbonate) for the prevention of diarrhea in patients (pts) with metastatic colorectal cancer (mCRC) treated with irinotecan (I).
Authors: Bryan K. Kee, Rebecca Slack, Todd S. Crocenzi, Lucas Wong, Benjamin Esparaz, Michael J. Overman, Katrina Y. Glover, Jeffrey Morris, Michael Fisch
Journal: Journal of Clinical Oncology (2013)

3600 Background: CASAD is a naturally occurring calcium montmorrilonite clay that serves as a cation exchange absorbent. One of the active metabolites of Irinotecan is SN-38, which is adsorbed by CASAD in vitro. The study hypothesis was that oral CASAD would reduce the rate of grade 3/4 diarrhea in mCRC patients treated with irinotecan. Methods: The study is a multicenter, prospective, randomized, double blinded placebo-controlled phase II trial. One hundred patients receiving I-based chemotherapy were randomized equally between CASAD (1000 mg po 4x daily) and placebo in order to have 75% power to detect a difference in the proportions of patients with grade 3/4 diarrhea within 6 weeks at a 1-sided 5% significance level. We also compared symptom burden using the MDASI questionnaire summed over the 13 symptom items for weeks 0, 3, 5, and 6. Results: Between 5/2009 and 5/2012, 100 patients were randomized in a 1:1 ratio between study arms. Median age 57 yrs, 54% male, 74% Non-Hispanic White, 93% performance status 0 or 1. Serious diarrhea was less frequent than expected based upon prior studies with Irinotecan. In evaluable patients, no significant difference in the rate of G3/4 diarrhea was seen (the primary endpoint): CASAD arm: 7/43 pts (16%), Placebo arm: 3/32 pts (9%), p=0.70. The rate of any diarrhea among all pts was also similar: CASAD arm 64% vs. Placebo arm 70%. The rate of study dropout was 14% in CASAD and 38% for placebo (p=0.01; 2-sided). No differences were found in symptom burden or individual symptom items or serious adverse events. Conclusions: Compared with placebo, CASAD use was safe but ineffective in preventing diarrhea in mCRC patients treated with irinotecan-containing chemotherapy regimens. There were no favorable or unfavorable signals in terms of the patient experience related to symptoms, but there were significantly more dropouts in the placebo arm. Future CASAD trials are focused on active treatment of diarrhea. Clinical trial information: NCT00748215.
The use of five-alpha reductase inhibitors and their association with reclassification and pathologic outcomes in the Canary Prostate Active Surveillance Study (PASS).
Authors: James T Kearns, Anna V Faino, Lisa F Newcomb, James D. Brooks, Peter Carroll, Atreya Dash, William J Ellis, Michael Fabrizio, Martin Gleave, Todd Matthew Morgan, Peter S Nelson, Ian Murchie Thompson, Andrew Wagner, Yingye Zheng, Daniel W. Lin
Journal: Journal of Clinical Oncology (2017)

22 Background: The outcomes of patients who enroll in active surveillance (AS) programs for prostate cancer (PCa) while currently taking five-alpha reductase inhibitors (5-ARIs) have not been well defined. Previous studies suggest that the initiation of 5-ARIs after enrolling in AS decreases the rate of reclassification and/or treatment for PCa, but there is still an FDA black box warning about the risk of grade risk prostate cancer while on 5-ARI. The objective of this study was to evaluate the safety of remaining on a 5-ARI after initiating AS for PCa. Methods: All men were enrolled in PASS. Inclusion criteria were current or never 5-ARI user, Gleason 3+3 or 3+4 PCa at diagnosis, ≤ 34% core ratio at diagnosis and ≥ 1 surveillance biopsy. Reclassification was defined as an increase in Gleason score and/or ratio of biopsy cores positive for cancer to ≥ 34%. Results: 1045 men were included in this study, 938 who had never used a 5-ARI and 107 5-ARI users. 5-ARI users had larger prostate volume (51 cc vs 40 cc, p &lt; 0.01), a higher rate of BPH (77% vs 29%, p &lt; 0.01) and older age (65 vs 62 years, p &lt; 0.01). All other clinical parameters, including serum PSA, were statistically similar. Kaplan Meier analysis of any reclassification is shown in the figure. There was no significant difference in any reclassification (p = 0.12). The use of 5-ARI at diagnosis was significantly protective for reclassification in a proportional hazards model (HR 0.68, p = 0.03); this difference was not significant after accounting for serum PSA, BMI, prostate size and positive cores ratio at diagnosis (HR 0.78, p = 0.18). There was no significant effect on adjusted analysis when evaluating for disease upgrading. 171 patients underwent radical prostatectomy (RP), 158 never 5-ARI users and 13 5-ARI users. There were no statistically significant differences when evaluating for Gleason grade or adverse pathology. 5-ARI users had a longer median time to RP (3.6 vs 2.1 years, p = 0.045). Conclusions: There is no association between 5-ARI use at diagnosis and reclassification on AS for men in the Canary PASS cohort. 5-ARI users have a longer median time to RP and do not have more severe PCa at RP.
Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma
Authors: Aditi Qamra, Manjie Xing, Nisha Padmanabhan, Jeffrey Jun Ting Kwok, Shenli Zhang, Chang Xu, Yan Shan Leong, Ai Ping Lee Lim, Qianqao Tang, Wen Fong Ooi, Joyce Suling Lin, Tannistha Nandi, Xiaosai Yao, Xuewen Ong, Minghui Lee, Su Ting Tay, Angie Tan Lay Keng, Erna Gondo Santoso, Cedric Chuan Young Ng, Alvin Ng, Apinya Jusakul, Duane Smoot, Hassan Ashktorab, Sun Young Rha, Khay Guan Yeoh, Wei Peng Yong, Pierce K.H. Chow, Weng Hoong Chan, Hock Soo Ong, Khee Chee Soo, Kyoung-Mee Kim, Wai Keong Wong, Steven G. Rozen, Bin Tean Teh, Dennis Kappei, Jeeyun Lee, John Connolly, Patrick Tan
Journal: Cancer Discovery (2017)

Abstract Promoter elements play important roles in isoform and cell type–specific expression. We surveyed the epigenomic promoter landscape of gastric adenocarcinoma, analyzing 110 chromatin profiles (H3K4me3, H3K4me1, H3K27ac) of primary gastric cancers, gastric cancer lines, and nonmalignant gastric tissues. We identified nearly 2,000 promoter alterations (somatic promoters), many deregulated in various epithelial malignancies and mapping frequently to alternative promoters within the same gene, generating potential pro-oncogenic isoforms (RASA3). Somatic promoter–associated N-terminal peptides displaying relative depletion in tumors exhibited high-affinity MHC binding predictions and elicited potent T-cell responses in vitro, suggesting a mechanism for reducing tumor antigenicity. In multiple patient cohorts, gastric cancers with high somatic promoter usage also displayed reduced T-cell cytolytic marker expression. Somatic promoters are enriched in PRC2 occupancy, display sensitivity to EZH2 therapeutic inhibition, and are associated with novel cancer-associated transcripts. By generating tumor-specific isoforms and decreasing tumor antigenicity, epigenomic promoter alterations may thus drive intrinsic tumorigenesis and also allow nascent cancers to evade host immunity. Significance: We apply epigenomic profiling to demarcate the promoter landscape of gastric cancer. Many tumor-specific promoters activate different promoters in the same gene, some generating pro-oncogenic isoforms. Tumor-specific promoters also reduce tumor antigenicity by causing relative depletion of immunogenic peptides, contributing to cancer immunoediting and allowing tumors to evade host immune attack. Cancer Discov; 7(6); 630–51. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 539
Impact of gender on efficacy and acute toxicity in standard risk localized (SR) Ewing sarcomas (ES) in the Euro-Ewing99-R1 trial.
Authors: Hendrik Van Den Berg, Michael Paulussen, Nathalie Gaspar, Ian Lewis, Uta Dirksen, Bernadette Brennan, Gwenael Le Teuff, Jeremy Whelan, Andreas Ranft, Jean Marie Michon, Ruth Lydia Ladenstein, Perrine Marec-Berard, Lars Hjort, Keith Wheatley, Ian Robert Judson, Odile Oberlin, A. W Craft, Herbert Juergens, Marie-Cécile Le Deley
Journal: Journal of Clinical Oncology (2013)

10031 Background: The randomized Euro-EWING99-R1 trial assessed noninferiority of cyclophosphamide- vs ifosfamide-based consolidation regimens (VAC vs VAI) in SR localized ES patients. Overall, efficacy of VAC was deemed acceptable compared to VAI, with hazard ratio of event HR = 1.12 [0.89 - 1.41]. Based on its gender-stratified randomization, influence of gender on efficacy and acute toxicity were additionally explored. Methods: Impact of gender on EFS, acute toxicity by course, switches between treatment arms, and cumulative dose of alkylating agents was evaluated in multivariable models, including terms to test for heterogeneity of treatment effect by gender. Analysis was performed on the intention to treat population. Results: 856 patients (509 males, 347 females) were recruited between 2000 and 2010: 425 VAI and 431 VAC. EFS did not significantly differ between genders (p=0.33), but a marginal interaction was seen between treatment and gender (p=0.083): VAC was associated with poorer EFS in males than VAI, HR(VAC/VAI) = 1.34 [0.96 - 1.86], whereas, in females, VAC was slightly better than VAI, HR = 0.83 [0.54 - 1.28]. Similarly, males had a worse EFS than females with VAC, HR(M/F) = 1.42 [0.97 – 2.08], whereas results by gender were very similar with VAI, HR = 0.91 [0.62 – 1.33]. Severe hematological toxicity was more frequent with VAC than VAI whereas tubular renal impairment was more frequent with VAI. Severe toxicity was more frequent in females than in males, whatever the toxicity type, with no significant interaction between treatment and gender effect. 30 patients switched from VAI to VAC (21 F, 9 M) mostly due to renal toxicity, and 3 from VAC to VAI (1 F, 2 M). A reduction of alkylating agent cumulative dose &gt;20% was more frequent in females (15% vs 9%, p=0.01), with no major difference between VAI and VAC (13% vs 10%, p=0.21). Conclusions: The marginal interaction between gender and type of alkylating agent on EFS has to be validated on external data. Differences of acute toxicity rate and compliance are not sufficient explanation. Effects of gender-dependant polymorphism/activity of metabolic enzymes (e.g. known for CYP2B6) of ifosfamide vs cyclophosphamide should be explored. Clinical trial information: NCT00020566.
Primary tumor resection to improve survival and local disease control in stage IV inflammatory breast cancer.
Authors: Catherine Liebig Akay, Naoto T. Ueno, Gary B. Chisholm, Gabriel N. Hortobagyi, Wendy A. Woodward, Ricardo H. Alvarez, Anthony Lucci, Isabelle Bedrosian, Henry Mark Kuerer, Kelly Hunt, Lei Huo, Gildy Babiera
Journal: Journal of Clinical Oncology (2012)

1102 Background: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer typically presenting with early metastasis. Optimal outcomes are achieved with multimodality treatment strategies in the non-metastatic setting. Data is limited, however, on the benefit of surgery in patients with metastatic IBC. We evaluated the effect of primary tumor resection on outcomes in patients with newly diagnosed stage IV IBC. Methods: We reviewed records of 172 patients with metastatic IBC treated at our institution from 1994 - 2009. All patients received systemic therapy with or without locoregional therapy (LRT). Patient demographics, receptor (ER) and HER2-neu status, grade, histology, presence of lymphovascular invasion, margin status, number of distant disease sites, pathologic response of primary tumor and clinical response to systemic therapy (CRS) at distant disease sites were recorded. Overall survival (OS), distant progression-free survival (DPFS), and chest/skin involvement at last follow-up were evaluated. Kaplan-Meier survival analyses, univariate (UV) and multivariate (MV) logistic regression models were used. Chest/skin involvement was compared between groups using Kruskal-Wallis test. Results: Seventy-nine (45%) patients underwent primary tumor resection. Average age was 51 (22-78). Median live-patient follow-up was 33 months. OS and DPFS were significantly better for patients who underwent LRT versus none (p&lt;0.0001). Factors associated significantly for improved DPFS on MV analysis were ER and HER2-neu status (HR 0.61,0.60 p=0.02,0.05 ,respectively), LRT (HR .38, p=0.002) and CRS (HR 0.62, p=0.03). ER status (HR .45, p&lt;0.001), LRT (HR .30, p&lt;0.001) and CRS (HR 0.54, p=0.02) were significant predictors for higher OS on MV analysis. At last follow up, chest/skin involvement was moderate/severe in 11% of patients in LRT group versus 35% of patients in no LRT group (p&lt;0.0001). Conclusions: This latest retrospective study demonstrates metastatic IBC patients who undergo LRT in addition to systemic therapy may have improved survival and local control outcomes. CRS may be used to guide LRT. A prospective randomized trial is needed to validate these findings.
Survival of non-small cell lung cancer (NSCLC) patients with and without diabetes mellitus (DM): Findings from the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS).
Authors: Taher Abu Hejleh, Elizabeth A. Chrischilles, Jane F Pendergast, Aaron T Porter, Robert B Wallace
Journal: Journal of Clinical Oncology (2013)

6602 Background: DM increases all-cause mortality in the general population. It is also associated with more complications from chemotherapy, increased risk of radiation pneumonitis and worse surgical-wound healing. In this study, we explored the effect of DM on NSCLC overall survival. Methods: This study utilized the surveys and abstracted medical record resources of NSCLC patients studied by CanCORS, an inception cohort of newly diagnosed lung and colon cancer patients from the United States. Patients with NSCLC stage I-IV were included. The log-rank test was used to compare the survival curves of patients with and without DM. Cox proportional hazard models were used to adjust for other variables in the survival model. Results: Of the 2243 NSCLC patients, 359 (16%) had DM. Survival for patients diagnosed with DM was significantly worse than patients without DM [hazard ratio (HR) 1.28; 95% confidence interval (CI) 1.13-1.45]. The median overall survival for patients with and without DM was 561 and 833 days, respectively. DM was also associated with poorer survival (HR 1.20; 95% CI 1.05, 1.36) after adjusting for age, smoking status, stage, treatment (radiation, chemotherapy), brain metastasis, severity of respiratory symptoms at diagnosis, and comorbidities. While a significant interaction between stage and DM was not detectable after adjusting for the above, the estimated Kaplan-Meier plots present more prominent differences in stages I-III, with virtually overlapping plots in stage IV. Conclusions: DM was associated with worse survival in NSCLC patients. Although this finding can be utilized when counseling diabetic NSCLC patients, it is unknown if improving DM care will result in a better survival. The effect of DM on survival in the various stages of NSCLC needs further study.
Risk of Second Cancer in Hodgkin Lymphoma Survivors and Influence of Family History
Authors: Amit Sud, Hauke Thomsen, Kristina Sundquist, Richard S. Houlston, Kari Hemminki
Journal: Journal of Clinical Oncology (2017)

Purpose Although advances in Hodgkin lymphoma (HL) treatment have led to improved disease-free survival, this has been accompanied by an increased risk of second cancers. We sought to quantify the second cancer risks and to investigate the impact of family history. Patients and Methods Using the Swedish Family-Cancer Project Database, we identified 9,522 individuals with primary HL diagnosed between 1965 and 2012. We calculated standardized incidence ratios and cumulative incidence of second cancer in HL survivors and compared the standardized incidence ratios of lung, breast, colorectal, and all second cancers in HL survivors with and without a site-specific family history of cancer. Interactions between family history of cancer and HL treatment were evaluated under additive and multiplicative models. Results Overall, the risk of a second cancer in HL survivors was increased 2.39-fold (95% CI, 2.29 to 2.53). The 30-year cumulative incidence of breast cancer in women diagnosed with HL at younger than 35 years of age was 13.8%. We observed no significant difference in cancer risk over successive time periods. The risk of all second cancers was 1.3-fold higher for HL survivors with a first-degree relative with cancer ( P < .001), with 3.3-fold, 2.1-fold, and 1.8-fold differences shown for lung, colorectal, and breast cancers, respectively. Moreover, a greater than additive interaction between family history of lung cancer and HL treatment was shown ( P = .03). Conclusion HL survivorship is associated with a substantive risk of a second cancer. Notably, the risk is higher in individuals with a family history of cancer. This information should be used to inform risk-adapted therapy and to assist in screening to reduce long-term morbidity and mortality in patients with HL.