tbuckley/cabot-search huggingface dataset:
Safety and pharmacokinetics (PK) of AMG 706 in combination with gemcitabine for the treatment of patients (pts) with solid tumors
Authors: T. J. Price, L. Lipton, J. Williams, J. McGreivy, S. McCoy, Y. Sun, B. Aguero-O’Neill, M. A. Rosenthal
Journal: Journal of Clinical Oncology (2007)

14005 Background: AMG 706 is an oral, investigational multikinase inhibitor (MKI) with antiangiogenic and direct antitumor activity achieved by selectively targeting VEGF, PDGF and Kit receptors. Methods: This is a fully enrolled, phase 1b, open-label, dose- finding study. The objectives are to determine the maximum tolerated dose and to assess safety and PK of AMG 706 in pts with solid tumors receiving AMG 706 plus gemcitabine. Pts =18 years with ECOG 0–2 and no prior treatment with bevacizumab or VEGFr MKIs were assigned to cohorts receiving escalating doses of AMG 706 (50mg QD, 125mg QD or 75mg BID continuously from day 2 of cycle 1) plus gemcitabine (1000mg/m 2 weekly for 7/8 wks, then 3/4 wks per cycle) for up to 11 cycles. Assessments include dose-limiting toxicities (DLT) (weeks 1–4) and tumor response (every 3 months). Results: 26 pts were enrolled and received at least 1 dose of AMG 706 (50mg QD n=11; 125mg QD n=6; 75mg BID n=9). All but 2 pts have completed the study. Median (range) age was 57 (25–77) yrs. 65% of pts received prior chemotherapy; 4 pts received prior gemcitabine (50mg QD n=2; 125mg QD n=1; 75mg BID n=1). There were 2 DLTs: grade 4 neutropenia (125mg QD), grade 3 deep vein thrombosis (75mg BID). Treatment-related adverse events (AE) occurring in = 10% of pts are shown in the table . The mean AMG 706 PK profiles were not markedly different when AMG 706 was dosed on the same day or 24 hours after gemcitabine administration. Objective tumor responses per RECIST for 26 evaluable pts were: 2 unconfirmed PR (50mg QD n=1; 125mg QD n=1), 7 SD (50mg QD n=3; 125mg QD n=1; 75mg BID n=3), 11 PD (50mg QD n=7; 125mg QD n=3; 75mg BID n=1), and 6 not available (125mg QD n=1; 75mg BID n=5). Conclusions: These preliminary data suggest that, in pts with solid tumors, AMG 706 combined with gemcitabine had an expected AE profile at the target once-daily dose of 125mg QD, with little effect on AMG 706 PK. The data provide a foundation for conducting further trials, potentially including biliary tumors. Final data will be presented. [Table: see text] No significant financial relationships to disclose.
A randomized phase II trial comparing docetaxel plus cyclophosphamide with epirubicin plus cyclophosphamide followed by docetaxel as neoadjuvant chemotherapy for hormone receptor-negative breast cancer: Kanagawa Breast Oncology Croup (KBOG) 1101 study.
Authors: Takashi Ishikawa, Daisuke Shimizu, Mikiko Tanabe, Mari S.Oba, Takeshi Sasaki, Satoshi Morita, Kumiko Kida, Shuichi Nawata, Masatoshi Mogaki, Takako Doi, Koichiro Tsugawa, Haruki Ogata, Yoshimasa Kosaka, Norihiko Sengoku, Yasuhiro Suzuki, Akihiko Suto, Takashi Chishima, Yasushi Ichikawa, Itaru Endo, Yutaka Tokuda
Journal: Journal of Clinical Oncology (2013)

1047 Background: Taxane-based regimens have been widely used to treat breast cancer. Accordingly, it has become important to identify subgroups in which anthracyclines are indispensable. Thus, we initiated a randomized phase II neoadjuvant chemotherapy (NAC) study to compare taxane with and without anthracycline in hormone-negative subtypes. Methods: Eligibility criteria were hormone-negative, an age younger than 80 years and ECOG PS0-1. According to HER2 status, patients were randomly assigned to TC (75/600 mg/m 2 ) q3wks ×6 or FEC (500/100/500 mg/m 2 ) q3wks ×3 followed by D (100 mg/m 2 ) q3wks ×3. The primary endpoint was the rate of pathological complete response (pCR; Grade 3 and Quasi-pCR; Grade 3+2b). Secondary endpoints were safety, breast-conserving surgery ratio, disease-free survival, overall survival, and predictive factors (HER2, Ki-67, P-53, CK5/6, EGFR, and TOP2A by IHC and TOP2A by FISH) for each regimen. Results: 97 out of 103 patients were successfully analyzed (47 for TC6 and 50 for FEC-D). Severe adverse events (Grade ≥2) were frequently observed in FEC-D-treated patients with statistical significance (poor appetite, nausea/vomiting: p&lt;0.001; febrile neutropenia: p=0.016). The pCR rate tended to be higher in FEC-D-treated patients compared with that of TC6-treated patients (pCR: 36.0 vs. 25.5%, n.s.; Quasi-pCR: 46.0 vs. 40.4%, n.s.). There was no significant difference of pCR rates in the HER2 and triple negative (TN) subtypes between each regimen. Among predictors, only positive markers CK5/6 and EGFR predicted the superiority of the FEC-D treatment (p=0.05). Conclusions: TC6 was safe and relatively active even in HER2 subtype patients. Therefore, the concurrent use of trastuzumab with TC could be a reasonable option for NAC in HER2 subtype patients. However, anthracyclines are required to treat basal-type TN cancer. Clinical trial information: UMIN000002215.
Trump’s order on climate policy threatens public health, say US doctors
Authors: Michael McCarthy
Journal: BMJ (2017)

The American College of Physicians and American Public Health Association have denounced President Donald Trump’s executive order to roll back environmental policies put in place by Barack Obama, calling the new president’s action a threat to public health.

Trump’s order, issued on 28 March, revokes half a dozen presidential orders and memoranda signed by Obama to tackle climate change.1 The order calls for the US Environmental Protection Agency to review Obama’s “Clean Power Plan,” which sought to reduce greenhouse gas emissions from US coal burning power plants and was a key element of his …
Clinical significance of p53 protein, beta-catenin, and HER2 in patients with Epstein-Barr virus-associated gastric cancer.
Authors: Dong Won Baek, In Hee Lee, Soo Jung Lee, Byung Woog Kang, Yee Soo Chae, Jong Gwang Kim
Journal: Journal of Clinical Oncology (2017)

22 Background: Epstein-Barr virus (EBV) infection can cause cancer tumorigenesis and malignant transformation of host cells through the activation of oncogenic pathways. Therefore, we assessed the expression of p53 protein, beta-catenin, and HER2 and their prognostic implication in patients with EBV-associated gastric cancer (EBVaGC). Methods: After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, 117 patients were identified as EBV-positive using EBV-encoded RNA in-situ hybridization. The results of immunohistochemistry were interpreted as follows: strong p53 nuclear expression in at least 50% of tumor nuclei was interpreted as a positive result; strong positive cytoplasmic-nuclear expression patterns for β-catenin ( ≥ 10%) were considered altered expression; moderate or strong complete or basolateral membrane staining in 10% of tumor cells for HER2 was reported as a positive results. Results: The median age of the patients was 62 years (32-80) and 93 (79.5%) were male. The pathologic stages were as follows : stage I (n = 74), stage II (n = 25), and stage III (n = 18). Among the 117 patients, immunohistochemical staining for p53 was performed in 105 patients and 25 patients (23.8%) were positive. Beta-catenin was positive in 10 patients (17.5%) and HER2 was positive in 8 patients (6.8%), respectively. The positive expression of p53 was significantly associated with a high T stage (p = 0.006). Conversely, more patients without lymph node metastasis were p53 positive (p = 0.013). In the univariate analysis, the patients with p53 positive tumors showed a significantly improved disease-free survival (DFS) compared to the patient with negative tumors (p = 0.022), although the p53 status was marginally associated with overall survival (OS)(p = 0.080). However, p53 expression showed no prognostic significance on DFS in the multivariate analysis. Meanwhile, beta-catenin and HER2 was not found to be associated with DFS and OS in the survival analysis. Conclusions: The current study found a significant correlation between p53 expression and tumor progression in patients with EBVaGC.
Randomized multicenter, phase II study of CO-101 versus gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and a prospective evaluation of the of the association between tumor hENT1 expression and clinical outcome with gemcitabine treatment.
Authors: Elizabeth Poplin, Harpreet Wasan, Lindsey Rolfe, Mitch Raponi, Tone Ikdahl, Ihor Bondarenko, Irina Davidenko, Volodymyr Bondar, August Garin, Stefan Hubert Boeck, Volker Heinemann, Claudio Bassi, T. R. Jeffry Evans, Cynthia Voong, Paramjit Kaur, Jeffrey D. Isaacson, Andrew R. Allen
Journal: Journal of Clinical Oncology (2013)

4007 Background: Gemcitabine requires membrane transporter proteins to cross the cell membrane. Low expression of the human equilibrative nucleoside transporter-1 (hENT1) may play a role in gemcitabine resistance in PDAC. CO-101 (also known as CP-4126), a lipid-drug conjugate of gemcitabine, was rationally designed to enter cells independently of hENT1 and to circumvent transporter-mediated resistance. We conducted a randomized, controlled trial (LEAP) in patients with mPDAC to determine whether CO-101 improved survival vs gemcitabine in patients with low hENT1 tumors. The study also prospectively tested the hypothesis that gemcitabine is more active in patients with hENT1 high than hENT1 low tumors in metastatic disease. Methods: Patients were randomized to CO-101 or gemcitabine. An immunohistochemistry test measuring tumor hENT1 expression was developed in parallel with the recruitment phase of LEAP. To dichotomize the population, a hENT1 cut-off was defined using primary PDAC tumor samples from an adjuvant trial. LEAP participants provided a metastasis sample during screening for blinded hENT1 assessment, and the cut-off was applied to these samples. The primary endpoint of the study was overall survival in the low hENT1 subgroup. Results: 367 patients were enrolled, with metastasis hENT1 status available for 358/367 (97.5%). 232/357 (65%) were hENT1 low. There was no difference in overall survival between CO-101 and gemcitabine in the hENT1 low subgroup, or overall, with hazard ratios of 0.994 [95% CI 0.746, 1.326] and 1.072 [95% CI 0.856, 1.344] respectively. Within the gemcitabine arm, there was no difference in survival between the hENT1 high and low subgroups (HR 1.147 95% CI 0.809, 1.626). The observed side effect profile was typical of gemcitabine and was similar in both treatment arms, in the hENT1 low subgroups and overall. Conclusions: CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1 expression. Metastasis hENT1 expression did not predict gemcitabine treatment outcome in patients with mPDAC. Clinical trial information: NCT01124786.
Phase II trial of DJ-927, an oral tubulin depolymerization inhibitor, in the treatment of metastatic colorectal cancer
Authors: M. R. Moore, C. Jones, G. Harker, F. Lee, B. Ardalan, M. W. Saif, P. Hoff, J. Coomes, C. Rollins, K. Felt
Journal: Journal of Clinical Oncology (2006)

3591 Background: DJ-927, a novel oral tubulin depolymerization inhibitor, causes apoptosis and DNA cell division arrest. It is not a substrate for the MDR and has excellent activity in preclinical colorectal cancer models. Methods: We are conducting a two-stage, multi-center, phase II trial to assess the efficacy of DJ-927 administered initially as second-line therapy following failure of irinotecan or oxaliplatin based therapy (n= 39). DJ-927 is given as a single oral dose on day 1 of a 21-day cycle at a dose range of 27 - 35 mg/m 2 . Results: Thirty-nine patients were enrolled, including 14 with prior irinotecan based therapy and 25 who had received prior oxaliplatin therapy. The median age was 56 years (range: 30–87) and the median ECOG PS at baseline was 1 (range: 0–2). A total of 155 courses (range: 1–24) have been administered with a median of 2 courses. Nine patients required dose reduction due to toxicity. Thirty-seven patients were evaluable for efficacy. There were 2 CRs and 2 PRs (10.3%) reported that were confirmed as per RECIST criteria. Fourteen patients (35.9%) had SD, including 6 patients (15.4%) with SD &gt;12 weeks. The most common Grade 3 or 4 AEs were neutropenia (48.7%), fatigue (10.3%), neuropathy (7.8%), and nausea (5.0%).Six patients experienced febrile neutropenia, all requiring hospitalization but tolerated treatment with subsequent dose reduction. There were 13 episodes (33.3%) of peripheral neuropathy reported; however, only 3 (7.8%) were grade 3 or 4. Six patients withdrew due to adverse events. Conclusions: The results of this study indicate activity of DJ-927 as second line therapy in patients with metastatic colorectal cancer. Severe toxicity was generally limited to reversible neutropenia and peripheral neuropathy. This novel oral agent is well tolerated and warrants further evaluation in combination with other active agents. [Table: see text]
Post-surgical highly sensitive C-reactive protein (hsCRP) and prognosis in early stage in breast cancer (BC).
Authors: Ariadna Tibau Martorell, Pamela Jean Goodwin, Marguerite Ennis
Journal: Journal of Clinical Oncology (2013)

550 Background: Obesity, commonly associated with inflammation, is associated with poor prognosis in BC. Previous research suggests CRP, an obesity-associated marker of systemic inflammation, may mediate the adverse prognostic effects of obesity and be associated with fatigue. We examined the association of hsCRP with obesity-related factors, fatigue and distant disease-free and overall survival (DDFS, OS) in an early BC cohort. Methods: 501 non-diabetic women with T1-3, N0-1, M0 BC diagnosed 1989-96 provided fasting blood (mean 7.7 ± 4.3 weeks after surgery, prior to systemic therapy, stored at -80°C) which was analyzed for hsCRP (Roche Elecsys immunochemistry). 359 women also completed the EORTC QLQ-C30 (mean 8 ± 3.9 weeks post-surgery). Women were followed prospectively to 2007. Data were analyzed using Spearman's rank correlation coefficients (r) and Cox models. Results: Mean age was 50.5 ± 9.7 years; 282/159/24/36 subjects had T1/T2/T3/TX cancers; 350 were N0; 306 had ER+ and 278 PgR+ cancers (HER2 was not performed); 76/208/142 cancers were grade 1/2/3; adjuvant treatment involved radiation (369 subjects), chemotherapy (196), tamoxifen (107). Median hsCRP was 0.9 mg/L (25 th /75 th percentiles: 0.4/2.4 mg/L). hsCRP was correlated (all p &lt; 0.0001) with age (r = 0.25), Body Mass Index (BMI, r = 0.6), insulin (r = 0.44), Homeostasis Model Assessment (r = 0.45) and leptin (r = 0.54), but not with EORTC fatigue (r = 0.02), T or N stage, grade or ER/PgR status (any + vs. both -). Median follow-up was 12 years. hsCRP was not associated with DDFS or OS in univariate analyses (Q4 vs. Q1 HR 1.03, 95% CI 0.69-1.52, p = 0.9 and HR 1.27, 95% CI 0.86-1.86, p = 0.24 respectively) or multivariate analyses adjusting for age, T, N, grade, ER/PgR status, treatment (HR 1.02, 95% CI 0.66-1.59, p = 0.93 and HR 1.17, 95% CI 0.76-1.81, p = 0.48 respectively). Conclusions: hsCRP (measured post-op, prior to systemic therapy) was associated with age, BMI and obesity associated physiologic factors; it was not associated with fatigue, DDFS or OS. Funded by The Breast Cancer Research Foundation (New York), The Canadian Cancer Society Research Institute (formerly The Canadian Breast Cancer Research Initiative).
Qualitative study of social and working life aspects of patients with metastatic renal cell carcinoma (mRCC) on palliative therapy.
Authors: Sandra Meyer-Moock, Berit Eberhardt-Wetherington, Ulrike Mueller, Sarah Schmitter, Viktor Gruenwald, Christina Claussen, Thomas Kohlmann
Journal: Journal of Clinical Oncology (2014)

TPS4602 Background: The backbone of medical treatment of metastatic renal cell carcinoma (mRCC) consists of targeted agents. Inhibitors of VEGFR or mTOR with chronic exposure have led to the recent improvement in mRCC therapy. To assess health-related quality of life (HRQoL) of patients with mRCC, several generic and disease-specific instruments are available (eg. EQ-5D or the FKSI). Yet, little is known about the impact of mRCC on social and working life aspects as well as treatment-related decisions of patients on a palliative treatment. The aim of this study is to identify relevant dimensions as well as to develop and validate an instrument to close this gap. Methods: The study consists of three parts with qualitative and quantitative methods. In part I (development), we conducted 2 focus group interviews with 15 patients in patients support groups in Germany. In a pretest (part II), patients were asked to complete a draft questionnaire and to comment on it briefly during an interview. Qualitative data analysis (focus groups, field testing) consisted of content analysis methods (qualitative content analysis); software for qualitative data analysis (MAXQDA) was used. In part III (validation), the questionnaire will be validated by testing the psychometric properties in a sample of 100 patients with mRCC. Psychometric methods used will include factor analysis, assessment of distributional properties, floor and ceiling effects, percentage of missing values and subgroup analysis.
Determining whether functional subtyping with BluePrint 80-gene profile could potentially identify two distinct triple positive subtypes with and without trastuzumab/chemo-sensitivity.
Authors: Pat W. Whitworth, Peter D. Beitsch, Michael C. Rotkis, James V. Pellicane, Mary Murray, Paul Baron, Carrie L. Dul, Angela Marie Mislowsky, Charles H. Nash, Paul D. Richards, Laura A. Lee, Lisette Stork, Femke De Snoo, Sarah Untch, Mark Gittleman, Stephanie Akbari, Jennifer Beatty
Journal: Journal of Clinical Oncology (2015)

596 Background: Classification by molecular subtype can aid in the selection of therapy for patients with breast cancer. However at present, the methodology for molecular subtyping is not standardized. The aim of the prospective NBRST study is to compare chemosensitivity as defined by pathological Complete Response (pCR) using the 80-gene BluePrint (BP) functional subtype profile vs. conventional IHC/FISH subtyping. Methods: The study includes women aged 18–90 with histologically proven breast cancer, written informed consent, no excision biopsy or axillary dissection, and no prior therapy for breast cancer. Neo-adjuvant Chemotherapy (NCT) was at the discretion of the physician adhering to NCCN approved or other peer-reviewed regimens. BP in combination with MammaPrint classifies patients into 4 molecular subgroups: Luminal A, Luminal B, HER2 and Basal. Results: 721 patients had definitive surgery. 58/335 (17%) IHC/FISH HR+/HER2- patients were re-classified by BP as Basal (57) or HER2 (1). 92/222 (41%) IHC/FISH HER2+ patients were re-classified as BP Luminal (67) or BP Basal (25). 7/164 (4%) IHC/FISH triple negative (TN) patients were re-classified as BP Luminal (5) or BP HER2 (2). NCT pCR rates were 3% in Luminal A and 9% in Luminal B patients versus 10% pCR in IHC/FISH luminal patients. The NCT pCR rate was 54% in BP HER2 patients. This is significantly superior (p = 0.02) to the pCR rate in IHC/FISH HER2+ patients (40%). BP Basal and IHC/FISH TN had a pCR rate of 35%. Functional BP subtyping divided the 137 IHC/FISH triple positive patients into two major subgroups: BP Luminal (n = 66, pCR = 11%) and BP HER2 (n = 60, pCR = 45%).11 patients were re-classified as BP Basal with pCR = 45%. Conclusions: Molecular subtyping using BP leads to a reclassification of 23% of tumors. The re-classification is most prominent in classically assessed triple positive patients where 48% of patients are re-assigned to the less responsive BP Luminal-type group vs. 44% of patients assigned to the responsive BP HER2-type group. These findings confirm the more accurate identification of molecular subgroups for treatment decision by BluePrint functional subtype classifier. Clinical trial information: NCT01479101.
Exercise physiology in cancer care.
Authors: Sarah Sangermano, Terrence Pugh, Susan I Yaguda
Journal: Journal of Clinical Oncology (2017)

135 Background: Cancer survivors can benefit from exercise at many points in the cancer care continuum. The Exercise Physiology Internship was developed by the University of North Carolina at Charlotte and Levine Cancer Institute (LCI) to address the exercise needs of patients with cancer. Although the interns had a background in physical fitness, they required training regarding the medical complexity of this population and how this affects their ability to exercise. To bridge this gap, LCI approached Carolinas Rehabilitation to assist in providing safe and effective exercises to cancer survivors. Methods: The intern program was modified to include cancer rehabilitation. Education was performed by the rehabilitation team, with emphasis on treatment-related side effects, contraindications for exercise, cancer-related fatigue, and safety considerations. Interns assisted therapists with impairment based rehabilitation to learn how physical fitness integrates with rehabilitation. Prior to 1:1 intern consults, the therapist and intern reviewed the most recent oncology notes, and the intern consulted the therapist regarding safety considerations or exercise modifications. The intern also worked with a clinical nurse specialist at LCI who provided information regarding disease processes, treatment side effects and potential residual implications of treatment and disease. Results: Following modification of the program, interns reported feeling more prepared and confident when providing 1:1 consults to survivors. Referrals from providers within LCI grew, with 5 consults in Spring 2016, 13 consults in Summer 2016, and at least 19 consults to be completed this semester. Interns also became more integrated into the cancer center, providing consults during infusion and in physician clinics. Conclusions: Exercise physiology interns are an asset to the cancer survivorship and rehabilitation teams. By collaborating with the rehabilitation team, interns can provide safe and effective exercise prescriptions to cancer survivors. Interns can also provide rehabilitation referrals for patients who require impairment-based therapy. With continued program development, opportunities for intervention may present throughout the continuum of care.