tbuckley/cabot-search huggingface dataset:
Molecular predictive factors for toxicity in colorectal cancer patients
Authors: G. Tonini, B. Vincenzi, G. Perrone, A. La Cesa, C. Grilli, V. Virzì, S. Gasparro, V. Leoni, C. Rabitti, D. Santini
Journal: Journal of Clinical Oncology (2005)

3706 Background: We retrospectively evaluated the relevance of TS expression and DPD in normal colonic mucosa as predictive factors of toxicity in colorectal cancer patients receiving adjuvant 5-FU based chemotherapy. Methods: TS and DPD expression were immunohistochemically assessed on normal colonic mucosa from 64 patients with colorectal cancer Dukes’ stages B (35 patients) and C (29 patients) treated with 5-fluorouracil (5-FU) based adjuvant chemotherapy. Results: The incidence of grade 2–3 diarrhoea and stomatitis (according to WHO) was demonstrated to be significantly higher in patients with low nuclear TS expression in normal mucosa than in those with high TS expression (P<0.0001). Moreover, patients with low DPD expression in normal colonic mucosa developed more commonly grade 2–3 diarrhoea (55% vs 23%, p=0.062) and stomatitis (48% vs 23%, p=0.013). Furthermore, considering the concomitant expression of TS and DPD, we identified three groups of patients (group 1: TS + and DPD +, group 2: TS - and DPD -, group 3: only one +). The incidence of grade 2–3 diarrhoea and stomatitis were statistically significant higher in group 2 than in groups 1 and 3 (diarrhoea; 76% vs 24%, P<0.0001; stomatitis: 76% vs 24%; P<0.0001). Conclusions: Immunohistochemical TS and DPD expression in normal colonic mucosa and their combination, may represent two important predictive parameters for identifying a subset of patients with high risk of developing severe 5FU- related toxicities. No significant financial relationships to disclose.
Phase I study of ACE-041, a novel inhibitor of ALK1-mediated angiogenesis, in patients with advanced solid tumors.
Authors: J. C. Bendell, M. S. Gordon, H. Hurwitz, C. H. Condon, Y. Yang, D. Wilson, K. M. Attie, M. L. Sherman, S. Sharma
Journal: Journal of Clinical Oncology (2011)

3070 Background: Activin receptor-like kinase-1 (ALK1) is a type I receptor in the TGFß superfamily expressed on endothelial cells and required for capillary network development and vasculature maturation. ACE-041 is a soluble fusion protein consisting of the ALK1 extracellular domain linked to IgG1-Fc and is designed to bind with high affinity to BMP9 and BMP10, preventing activation of ALK1 receptors. In animal models, ACE-041 inhibited tumor angiogenesis and growth. Methods: A standard 3 + 3 dose escalation phase I study was conducted to determine the safety, tolerability, MTD, PK, PD, and antitumor activity of ACE-041 in pts with advanced solid tumors. An expansion cohort was to be treated at MTD or intermediate dose level. Results: 37 pts were enrolled in 8 cohorts: 25 in dose escalation (0.1-4.8 mg/kg SC q3wk), 12 in dose expansion (0.8-1.6 mg/kg). Median age: 65 yr (34-84), 20M/17F, ECOG: 0 (43%)/1 (57%). Most common tumor types: colorectal (19%), NSCLC (16%), sarcoma (14%). Median # prior Rx: 3 (0-11). Most common drug-related AE’s: fatigue (41%), peripheral edema (35%), anemia (30%), nausea (30%), headache (22%), dyspnea (22%), anorexia (19%), pyrexia (14%), vomiting (11%). Most common grade 3 AEs (>1 pt): anemia (3 pts), CHF (2 pts). Possibly/probably related SAEs: fluid overload (2 pts), CHF (1 pt), LV dysfunction (1 pt), fatigue (1). Edema and fluid overload were dose-dependent and responded to diuretic therapy. Due to DLT of fluid overload seen at higher dose levels, dose expansion was performed at intermediate doses. Mean Tmax was 4-7 days, t½ 13-19 days. Cmax was dose-proportional from 0.8 to 4.8 mg/kg. One pt with SCCHN had a partial response (30 wk). Six heavily pretreated pts (NSCLC [3 pts], small bowel, carcinoid, rectal) had stable disease on ACE-041 (15-30 wk). Ten pts exhibited a ≥20% decrease in 18-FDG-PET SUV. Conclusions: ACE-041 is a novel angiogenesis inhibitor that targets the ALK1 receptor pathway. Results to date suggest that ACE-041 administered SC q3wk was generally well-tolerated and demonstrated antitumor activity in patients with advanced cancer refractory to other therapies. Further studies in patients with solid tumors are planned.
Circulating endothelial progenitor cells as biomarker for anti-angiogenic therapy with sunitinib and docetaxel in prostate cancer patients.
Authors: V. Wacheck, P. Horak, T. Füreder, S. Strommer, A. Jäger-Lansky, P. Mancuso, M. Krainer
Journal: Journal of Clinical Oncology (2010)

e15130 Background: Recent data indicate, that cytotoxic drugs given at MTD in addition to their cytotoxic effects induce mobilization of circulating endothelial progenitor cells (CEP) in drug-free breaks of each cycle. In preclinical models, mobilized CEP result in tumor vasculogenesis and progression of disease. Administration of anti-angiogenic VEGFR blockers in between cycles of chemotherapy mitigates the release of CEP in animals. In the present study we investigated the effect of docetaxel and the VEGFR blocker sunitinib on CEP and clinical response in prostate cancer patients. Methods: Castration resistant prostate cancer patients were enrolled in a randomized, controlled Phase II clinical trial to receive either sunitinib 37.5mg/d day2-15 for 4 cycles in combination with docetaxel 75mg/m2 q21d x 4 or docetaxel alone. Peripheral blood cells were analyzed for CEP every cycle. The primary objective of this trial was to compare CEP pharmacodynamics between both treatment arms. The secondary objectives were to assess the safety and tolerability, ORR and length of treatment holidays. Results: To date, 12 pts have been analyzed. We observed a significant transient increase in CEP peaking at 7-14 days following treatment with docetaxel. In contrast, in patients receiving docetaxel (d1) in combination sunitinib (d2-15) the number of CEP was clearly reduced relative to pts treated with docetaxel alone beginning from the second cycle. We did not observe any effect on CEP release by standard of care pre-treatment with dexamethason. With respect to the secondary objectives, the combination of sunitinib and docetaxel was in general well tolerated. Two patients in the combination arm were excluded from study due to cardiac toxicity. Conclusions: Based on our data set, the VEGFR inhibitor sunitinib mitigates CEP spikes induced by the standard of care therapy with docetaxel in patients with castration resistant prostate cancer. Given the biological relevance of CEP suppression for angiogenesis in vivo, measurement of CEP might provide a novel biomarker for VEGF(R) targeting compounds in “proof of concept” and dose finding studies warranting further translational studies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis Pfizer, sanofi-aventis
<i>Helicobacter pylori</i> infection and the risk of colorectal cancer: A meta-analysis of epidemiologic evidence.
Authors: Basile M. Njei, Ivo C. Ditah, Juliet Appiah, Raxitkumar Jinjuvadia, John W. Birk
Journal: Journal of Clinical Oncology (2012)

408 Background: The association between Helicobacter pylori infection (HPI) and gastric cancer is well known, but it is unclear whether HPI is also a risk factor for colorectal cancer. Several epidemiological studies on the latter association have yielded conflicting results. The aim of this study is to summarize available evidence on the association between HPI and CRC, evaluating its magnitude and direction in a meta-analysis. Methods: Two reviewers independently conducted a systemic search on Medline, OvidSP and PubMed databases from January 1980 to July 2011 for studies on the association between HPI and CRC. The reference lists of eligible studies were next reviewed for additional studies on the subject. Firstly, a combined analysis including all studies was done. Next, subgroup analysis by study design and country of study (USA Vs Europe Vs Asia) were also performed. All analyses were done using the random effects model. Publication bias was assessed using the Begg’s and Egger’s tests and visual inspection of funnel plot. All analyses were performed using STATA 11. Results: Sixteen studies (14 retrospective and 2 prospective) including 12,892 participants were included in the analysis. Overall, HP was associated with a 49% significantly higher risk of CRC (OR 1.49, 95% CI: 1.22-1.82; P &lt; 0.001). By study design, the association persisted only among the retrospective studies with a pooled OR of 1.43 (95% CI: 1.31-1.56, P = 0.004). The subgroup analysis by study region showed significant associations in Europe (OR 1.35, 95% CI 1.09-1.66) and Asia (RR 1.43, 95% CI 1.29-1.58). Though there was a 17% higher risk noted among studies done in the USA, this was not statistically significant. There was no evidence of publication bias in all the analyses. Conclusions: Current evidence on the association between H. pylori infection and CRC remains inconclusive. The absence of any association among the prospective studies (with less risk of bias) suggests that the association seen among the retrospective studies could be due to residual confounding. Better quality data is required before a conclusive statement on the association between HPI and CRC can be made.
Soluble IL6R Expressed by Myeloid Cells Reduces Tumor-Specific Th1 Differentiation and Drives Tumor Progression
Authors: Hirotake Tsukamoto, Koji Fujieda, Masatoshi Hirayama, Tokunori Ikeda, Akira Yuno, Keiko Matsumura, Daiki Fukuma, Kimi Araki, Hiroshi Mizuta, Hideki Nakayama, Satoru Senju, Yasuharu Nishimura
Journal: Cancer Research (2017)

IL6 produced by tumor cells promotes their survival, conferring a poor prognosis in patients with cancer. IL6 also contributes to immunosuppression of CD4+ T cell-mediated antitumor effects. In this study, we focused on the impact of IL6 trans-signaling mediated by soluble IL6 receptors (sIL6R) expressed in tumor-bearing hosts. Higher levels of sIL6R circulating in blood were observed in tumor-bearing mice, whereas the systemic increase of sIL6R was not prominent in tumor-bearing mice with myeloid cell-specific conditional deletion of IL6R even when tumor cells produced sIL6R. Abundant sIL6R was released by CD11b+ cells from tumor-bearing mice but not tumor-free mice. Notably, IL6-mediated defects in Th1 differentiation, T-cell helper activity for tumor-specific CD8+ T cells, and downstream antitumor effects were rescued by myeloid-specific deletion of sIL6R. Expression of the T-cell transcription factor c-Maf was upregulated in CD4+ T cells primed in tumor-bearing mice in an IL6-dependent manner. Investigations with c-Maf loss-of-function T cells revealed that c-Maf activity was responsible for IL6/sIL6R-induced Th1 suppression and defective T-cell-mediated antitumor responses. In patients with cancer, myeloid cell-derived sIL6R was also possibly associated with Th1 suppression and c-Maf expression. Our results argued that increased expression of sIL6R from myeloid cells and subsequent c-Maf induction were adverse events for counteracting tumor-specific Th1 generation. Overall, this work provides a mechanistic rationale for sIL6R targeting to improve the efficacy of T-cell-mediated cancer immunotherapy. Cancer Res; 77(9); 2279-91. ©2017 AACR.
Identification and validation of oncologic disease drug targets by in vivo functional genomic analysis
Authors: B. Zambrowicz, F. G. Kern, N. Zhang, P. M. Brown, A. Sands
Journal: Journal of Clinical Oncology (2005)

9562 The sequencing of the human genome has provided an unprecedented opportunity to identify novel drug targets that can enable the discovery of new therapeutics. It is critical to identify the key genetic targets that, when modulated, can produce therapeutic effects. This is particularly true of cancer in which the relationships between gene target, disease, and therapy have been explored perhaps more than any other disease. Gene knockout (KO) mice can be used to identify novel drug targets for cancer through in-depth phenotypic analysis designed to detect new mechanisms regulating cell cycle, apoptosis, DNA repair, and tissue development. By inactivation of specific genes, KO mice may be used to genetically model the actions of perfectly selective and potent chemical or biological antagonists. Careful analysis of the phenotypes of KO mice can allow one to make predictions with regard to mechanism of action and potential on-target side effects of future drugs without having to first develop a candidate therapeutic agent with which to validate the target. The power of this approach has been demonstrated by studies examining the targets of the best-selling drugs and current pharmaceutical pipelines. These analyses revealed that the therapeutic effect of established drugs show a strong correlation with the KO mouse phenotype of the corresponding target. We have implemented this target validation approach by developing systems and infrastructure to generate and comprehensively phenotype mutant mice at a rate of more than fifteen targets per week. The battery of tests encompassed by our analysis has been specifically selected to reveal those genes that encode key control points in mammalian physiology and behavior. Tests to detect potential oncology targets include: fibroblast proliferation assay, radiation sensitivity, gene expression profiling, developmental defects in the mammary gland and other tissues, angiogenesis, and embryonic lethality. For targets found to be of interest, additional assays are performed to more thoroughly examine gene function. Data will be presented illustrating the process from knockout through an oncologic phenotypic analysis as part of an integrated cancer drug discovery program. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lexicon Genetics Lexicon Genetics
Outcomes of chemoradiotherapy with a high irradiation dose using a 3D radiation treatment planning system for esophageal cancer.
Authors: Y. Murakami, Y. Nagata, I. Nishibuchi, T. Kimura, M. Kenjo, Y. Kaneyasu
Journal: Journal of Clinical Oncology (2011)

89 Background: The standard irradiation dose of chemoradiotherapy (CRT) for esophageal cancer is 50.4 Gy, however, the trials in which this standard dose was originated were based on 2D radiation treatment planning. In this study we assessed the survival and toxicities of CRT with a dose of 60-66 Gy using a 3D radiation treatment planning system (3DRTPS) for esophageal cancer. Methods: One hundred and two eligible patients with esophageal cancer treated by definitive CRT between 2000 and 2006 were assessed. Median age was 67 years old. There were stage I in 22 patients, stage II-III (without T4) in 27 and T4/M1Lymph legions in 53. There were 100 patients with squamous cell carcinoma histology and 2 with small cell carcinoma. Main tumor sites were cervical/upper/middle/lower thoracic in 15/19/43/25 patients. Treatment planning of irradiation was performed using a CT based 3DRTPS. Total irradiation dose of our protocol was 60-66 Gy. Accomplishment rate of planned irradiation was 93%. All patients received chemotherapy concurrently with radiotherapy. Fluorouracil based chemotherapy was performed in 96 patients (94%). Results: The data was updated in August 2010. The median follow-up was 67 months. Cause-specific survival rates at 5 years for stage I, II-III (without T4) and T4/M1lymph were 100%, 49% and 17%, respectively and overall survival rates were 66%, 35% and 13%, respectively. Complete response (CR) rates were 100%, 79% and 35%, respectively and failure rates of CR cases were 5%, 43% and 42%, respectively. Late adverse effects (≥ grade 3) were observed in 11 patients (10%); pneumonitis in 4 (4%), pleural effusion in 4 (4%) and pericardial effusion in 5 (5%). Treatment related deaths were observed in 2 cases (pneumonitis developed during treatment in 1 and debility due to treatment in 1). Conclusions: Toxicities of CRT with a high irradiation dose using 3DRTPS for esophageal cancer were acceptable and survival was promising. Dose intensification study of 50.4 Gy versus ≥ 60 Gy in CRT using a 3D-conformal radiation therapy technique for esophageal cancer should be considered. No significant financial relationships to disclose.
Referral of early onset renal cell carcinoma for clinical cancer genetic assessment.
Authors: Lynda Corrigan, Trudi McDevitt, Andrew J. Green, David Barton, David J. Gallagher
Journal: Journal of Clinical Oncology (2016)

613 Background: Approximately 1-8% of renal cell carcinomas (RCCs) are associated with inherited predisposition. No consensus referral guideline exists for genetic assessment for RCC. Early age of onset, the presence of a family history and type II papillary RCC should trigger clinical genetics referral. We investigated the pattern of cancer genetics referral for early-onset RCC in Ireland. Methods: The number of patients with RCC diagnosed under the age of 50 between 2005 and 2013, was obtained from the National Cancer Registry of Ireland. RCC was defined by the WHO/IARC Classification. The number of patients referred for genetic work-up with RCC &lt; 50 years of age was ascertained from The National Centre for Medical Genetics. Individuals unaffected by RCC but with a family history of RCC were excluded. The database was searched using the following search terms: Von Hippel-Lindau (VHL), Birt-Hogg-Dube (BHD) and RCC; and the clinical reason for referral recorded. Results: 580 patients were diagnosed with RCC below the age of 50. 71 percent were between 40 and 49 years of age (n=410). 52 patients were referred to The National Centre for Medical Genetics. Indications for referral are listed in Table 1. 7 patients were referred for a diagnosis of RCC &lt; 50 years of age. The average age of these patients was 37.8 years. Three of the referrals were for early age of onset of RCC; two referrals were made for early age of onset with a family history of RCC; and two with early onset RCC and bilateral RCCs. This represents a referral rate of approximately 0.01% for early onset RCC in Ireland. Conclusions: Most early onset RCC is not referred for clinical cancer genetics assessment. The heritability of RCC is incompletely understood. Improved referral patterns, increased clinical genetics assessment and a better understanding of the genetic aetiology of RCC may have preventive and therapeutic implications for this disease. [Table: see text]
Phase II randomized, double-blind, placebo-controlled study of tivantinib in men with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Paul Monk, Glenn Liu, Walter Michael Stadler, Susan Michelle Geyer, Jennifer L. Sexton, John Joseph Wright, Miguel Angel Villalona-Calero, James Lloyd Wade, Russell Zelig Szmulewitz, Shilpa Gupta, Amir Mortazavi, Robert Dreicer, Roberto Pili, Matthew M. Cooney, Nancy Ann Dawson, Saby George, Jorge A. Garcia
Journal: Journal of Clinical Oncology (2015)

146 Background: Tivantinib is a putative non-ATP competitive inhibitor of c-MET receptor tyrosine kinase that has additional cytotoxic mechanisms including tubulin inhibition. Prostate cancer demonstrates higher c-MET expression as the disease progresses to more advanced stages and to castration resistance. Methods: 80 patients (pts) with asymptomatic or minimally symptomatic mCRPC were assigned (2:1) to either tivantinib 360 mg PO BID or placebo (P). The primary endpoint was progression free survival. PCWG2 guidelines were utilized for determining eligibility and progression. Results: Of the 80 pts enrolled, 78 (52 tivantinib, 26 P) received treatment and were evaluated. Median age was 67 yrs (range: 43 to 85). Baseline characteristics were balanced between arms for ECOG PS, Gleason score, PSA, LDH, hemoglobin, Alk Phos, prior treatment, bone and organ involvement. More African Americans and those with lymph node involvement were randomly assigned to placebo. Median follow up is 8.2 months (range: 1.4 to 27.6). To date 59 patients have progressed. Patients treated with tivantinib had significantly better PFS vs. those treated with placebo (medians: 5.6 mo vs 3.8 mo, respectively; HR = 0.53, 95% CI: 0.32 to 0.89; p=0.015). Toxicity was mild overall. Grade 3 febrile neutropenia was seen in 1 patient on tivantinib while grade 3 and 4 neutropenia were recorded in 1 patient each on tivantinib and placebo. Grade 3 sinus bradycardia was recorded in two men on the tivantinib arm. 8 deaths (3 P and 5 tivantinib) have been recorded and were all considered unrelated to therapy. Conclusions: Tivantinib significantly improved PFS in men with asymptomatic or minimally symptomatic mCRPC. Given the favorable toxicity profile and evidence of anti-tumor activity, investigation of tivantinib with other agents may be a rational strategy. Clinical trial information: NCT01519414.
Predictive value of sphingosine kinase-1 expression in neoadjuvant treatment of breast cancer.
Authors: E. Ruckhäberle, T. Karn, C. Denkert, S. Loibl, B. Ataseven, T. Reimer, L. C. Hanker, N. Sänger, U. Holtrich, M. Kaufmann, S. Darb-Esfahani, V. Nekljudova, G. Von Minckwitz
Journal: Journal of Clinical Oncology (2011)

615 Background: Sphingolipids play important roles in apoptosis, senescence, cell proliferation and angiogenesis. Spingosine kinase 1 (SphK1) expression was shown to have prognostic impact in primary breast cancer. However, the predictive value of SpHK1 in neoadjuvant treatment of breast cancer is currently unknown. Methods: A total of 112 breast cancer specimen from a prospective neoadjuvant chemotherapy trial (GeparDuo, 4x AC-Doc vs. 4x ADoc) were studied. Using tissue microarrays of pre-treatment core cut biopsies we determined the expression of SphK1 by immunohistochemistry. The upper quartile of the cohort according an immune reactive score of Sphk1 was used as cutoff for high expression. Fisher's Exact Test was used for cross tabulation. The predictive value of SphK1 expression for a pathological complete response (pCR) was analyzed using logistic regression. Impact of SphK1 on survival was analyzed by the Kaplan Meier method using follow up data from the clinical trial. Results: We observed a larger number of samples with high SphK1 expression among ER negative cancers (36.8% vs. 20.5% among ER positive cancers; p=0.073). Eighteen of the 112 patients demonstrated a pathological complete response. Hormone receptor status (p<0.001), age under 40 years (P=0.030), and tumor grade (P=0.049) were significant factors for a pCR. A trend for an increased pCR rate was observed in tumors with high SphK1 expression, especially in the luminal A subtype (27.3 vs. 5.6%; p=0.076). When analyzing the follow up information of the patients no significant difference in survival was detected between patients with high or low SphK1 expression. Conclusions: Our preliminary results suggest that SphK1 could be a predictive factor for higher pCR rates in neoadjuvant treatment of breast cancer and warrants further investigation.