tbuckley/cabot-search huggingface dataset:
A Phase 2 biomarker-enriched study of evofosfamide (TH-302) in patients with advanced melanoma.
Authors: Elaine McWhirter, Omid Hamid, Bartosz Chmielowski, Richard D. Carvajal, David A. Jaffray, Brandon Driscoll, Tina Shek, Ivan Yeung, Harald Keller, Trevor D. McKee, Tillman E. Pearce, Stew Kroll, Anthony M. Joshua
Journal: Journal of Clinical Oncology (2015)

TPS9089 Background: In melanoma, tumor hypoxia is associated with invasion, angiogenesis, and metastasis formation, as well as treatment resistance such as immune evasion. Evofosfamide (EVO, TH-302) is a hypoxia-activated prodrug designed to release the bis-alkylating DNA crosslinker bromo-isophosphoramide mustard (Br-IPM) when reduced in severe hypoxia. In the Phase 1 study (NCT00495144) of EVO monotherapy, 7 of 36 (19%) patients with advanced melanoma had partial responses and 12 of 36 (33%) stable disease. Dose limiting adverse events included skin and mucosal toxicities. A Phase 2 biomarker-enriched trial was initiated to further evaluate the efficacy of EVO in melanoma, and identify hypoxia and other biomarkers predictive of response. Methods: This Phase 2 trial is a single-arm, multi-center, study investigating the efficacy and safety of EVO monotherapy (NCT01864538). The primary endpoint is 3-mo PFS. The study incorporates a Simon two-stage design (alpha = 0.15; beta = 0.15) based on 3-mo PFS with level of disinterest of 20% and level of interest of 35%. Secondary endpoints include response rate, overall survival, pharmacokinetics, safety, and evaluation of imaging, serum, and tissue biomarkers that may be associated with tumor response and predict for efficacy and safety of EVO. EVO (480 mg/m2) is given by IV infusion over 30 - 60 minutes on Days 1, 8 and 15 of a 28-day cycle. Hypoxia PET imaging using [18F]HX4 or [18F]FAZA, in vivo hypoxia detection using pimonidazole, hypoxia biomarkers such as CA-IX, HIF1-alpha, OPN, and VEGF; DNA damage markers such as gamma-H2AX, as well as tumor immune monitoring are included. Up to 40 patients will be enrolled with histologically confirmed recurrent or metastatic melanoma, measureable disease by RECIST 1.1, and ECOG 0-1. There are no limits on the number of prior targeted therapies or immunotherapies; however, patients may not have received more than one prior chemotherapy. Patients with brain metastases are eligible, if treated and stable for 2 months. Eligible patients must also have adequate tumor tissue available for pre-therapy and post-therapy biopsies. The first patient was treated in August 2013; recruitment is ongoing. Clinical trial information: NCT01864538.
The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue
Authors: Matthew D Lynes, Luiz O Leiria, Morten Lundh, Alexander Bartelt, Farnaz Shamsi, Tian Lian Huang, Hirokazu Takahashi, Michael F Hirshman, Christian Schlein, Alexandra Lee, Lisa A Baer, Francis J May, Fei Gao, Niven R Narain, Emily Y Chen, Michael A Kiebish, Aaron M Cypess, Matthias Blüher, Laurie J Goodyear, Gökhan S Hotamisligil, Kristin I Stanford, Yu-Hua Tseng
Journal: Nature Medicine (2017)
Single center analysis of immunotherapy in mCRC patients.
Authors: Reinhard Ruckser, Selma Hoenigschnabl, Elvira Kitzweger, Georg Tatzreiter, Peter Kier, Karlheinz Habertheuer, Peter Zelenka, Veronika Buxhofer-Ausch, Angelika Reiner-Concin, Christian Sebesta
Journal: Journal of Clinical Oncology (2012)

e14087 Background: Immunotherapy in real-life, unselected patients with metastatic colorectal cancer (mCRC) was analyzed retrospectively at a single center in Austria. Methods: We have treated 137 mCRC patients with at least one antibody containing therapy since 2004 at our center based at data available at that time and patient eligibility. Results: Most mCRC patients were between 55 and 75 years old. The KRAS mutation testing performed routinely from 2008 onwards shows a distribution of 55 % wildtype (wt) and 45% mutant (mut) KRAS. Median overall survival (OS) was 24 months (n=82) with a trend towards greater benefit for KRAS wt patients compared to KRAS mut (26.8 vs. 20.9 months, respectively). Most patients received between 3 and 5 treatment lines. 40% of patients were treated with 5 therapies and 8% reached treatment line 8. The median OS correlated with the number of therapy lines. Chemotherapy alone regimens are decreasing constantly due to the establishment of biomarker analysis based treatment decisions and the increase in available antibodies for immunotherapy in mCRC. Based on direct positive experience with various antibodies, we were successfully treating patients repeatedly with the same antibodies in non-consecutive treatment lines. 75.7% of all patients treated with Cetuximab received the antibody only once during 3.8 therapy lines. 13% of patients who obtained the agent in two lines received on average 5.7 treatment lines resulting in improved OS. This was even more prominent in 8.5% patients receiving Cetuximab in 3 lines with a trend towards further OS benefit. These data describe that multiple applications of the same antibody is not only feasible but also very effective. Conclusions: By taping the full potential of treatment options, optimizing their usage and expanding the number of treatment lines we could achieve a median OS in real-life patients similar to that previously described in large phase III studies. Our analysis describes the following key factors for reproducing clinical benefits reported in large trials: biomarker assessment, early and if possible multiple applications of available therapeutic antibodies, treatment until progression and use of supportive therapy to alleviate possible toxicities.
Genotypes of human glioma xenografts compared with glioma stem cell-derived tumors.
Authors: Selby Chen, Timothy Peterson, S. Keith Anderson, Jeanette Eckel-Passow, Paul A. Decker, Jann Nagina Sarkaria, Ian F Parney
Journal: Journal of Clinical Oncology (2013)

2072 Background: Human glioma stem cells and xenograft lines are common translational models in neuro-oncology but it has not been established if they are genetically and phenotypically comparable. This study aimed to determine if human glioma xenografts and stem cell-derived tumors had similar genotypes. Methods: Matched glioma stem cell cultures and subcutaneous xenograft lines were generated from four human glioblastoma specimens (BT114, BT116, BT120, BT132). Comparison was made between subcutaneous stem cell-derived tumors (flank) and xenografts established in nude mice. Copy number variation (CNV) and gene expression microarray studies were performed. Results: Various differences in copy number and gene expression were seen. Observed CNVs included regions within EGFR, myc, and p16 (INK). For example, EGFR copy number was two fold higher in xenografts vs. stem cell-derived tumor in one line (BT114). This difference was corroborated by western blot. Other differences included a heat shock protein homolog (DNAJA4), tetraspanin 13, and a p53 family target gene (ISG20L1). Two lines (BT114, BT116) had a greater than two fold increase in DNAJA4 expression in xenografts vs. stem cell-derived tumors (p = 0.04, 0.01). Two cell lines (BT116, BT120) had a two to eight fold increase in tetraspanin 13 expression in xenografts (p = 0.02, 0.05). However, neither copy number nor gene expression variations were consistent across all cell lines. Conclusions: Xenografts and glioma stem cell-derived tumors established from the same patient specimens have distinct genotypes. Further work is needed to establish if these differences are random or represent characteristic changes selected by different in vitro or in vivo pressures. However, these variations raise questions regarding which model is ideal for studying glioma biology, and which ones best replicate glioma characteristics in human patients.
Lack of patient-clinician concordance (LOC) across disease and treatment status in cancer.
Authors: Kavita Dayal Chandwani, Fengmin Zhao, Gary R. Morrow, Teresa De Shields, Lori M. Minasian, Judith Manola, Michael Fisch
Journal: Journal of Clinical Oncology (2013)

e20520 Background: The number and severity of cancer patients’ concerns is associated with their distress. Discrepancies between patient (pt) and clinician reporting of cancer pts’ symptoms and concerns have been reported during treatment. However, information on LOC across the disease and treatment status is lacking. This study explored LOC between pts and clinicians about pts’ bother related to disease and treatment status in those who needed assistance with questionnaires (NA) or self-administered (SA). Methods: Cancer pts and their clinicians in the Symptom Outcomes and Practice Patterns study rated pts’ bother (scale:0=Not at all, 4=Extremely) due to difficulties related to cancer, its treatment, side effects (SE), and comorbidity (COMORB), recoded to LOC ( 0=no difference between pts and clinicians, 1=any difference). Comparison of LOC proportions was conducted based on the disease status (4 groups: no evidence of disease [NED], local/regional [LR], metastases [mets], and mets+ LR) and current treatment (yes/no) using Chi square test. Results: The majority of pts (N=3013) were Caucasian (86%) females (70%) and had ECOG PS= 0 (87%). Mean age was 61.2 years (SD=12.4). 86.7% did not need help with the questionnaires/SA. Eight subgroups defined by disease status and current treatment showed statistically significant differences in LOC proportions re: bother due to treatment, SE, and COMORB in both the SA (range: 52.8%-86.7%, 41.6%-80.0%, 52.3%-81.3%, respectively, p&lt;.001) and NA groups (range: 40.7%-82.4%, 29.6%-70.6%, 48.1%-72.8%, respectively, p&lt;.05). Differences in the proportions of pts with LOC re: bother due to cancer were statistically significant for SA group only (range: 55.6%-81.3%, p=.01). In both SA and NA groups, pts with mets or mets+ LR had higher proportion of LOC re: bother due to treatment, SE, and COMORB than pts with NED or LR (p&lt;.05). Conclusions: This study provides evidence of LOC in patient-clinician reporting of cancer pts’ bother re: disease and treatment status. Greater proportion of pts with advanced disease showed LOC. Further study of LOC in reporting bother related to various aspects of cancer experience is needed to confirm these results and to understand how they relate to outcomes of care. Clinical trial information: NCT00303914.
Treatment sequencing and outcomes in synchronous metastatic rectal cancer.
Authors: Madeleine Cornelia Strach, Margaret Lee, Anna Lomax, Michael Ng, Mario Guerrieri, Thiru Prasanna, Hui-li Wong, Belinda Lee, Joseph James McKendrick, Lionel Lim, Suzanne Kosmider, Jeanne Tie, Desmond Yip, Louise M. Nott, Julie Johns, Michael Harold, Peter Gibbs, Rachel Wong
Journal: Journal of Clinical Oncology (2017)

750 Background: Optimal sequencing of therapies in synchronous metastatic rectal cancer (SMRC) remains unknown. Aim: To compare sequencing of treatment modality and outcomes in SMRC. Methods: Retrospective audit of patients with SMRC registered on the multi-centre Treatment of Recurrent and Advanced Colorectal Cancer database between 1/1/2009 and 30/6/2015. Patients were grouped according to initial treatment mode: chemotherapy (C), chemoradiation (CRT), surgery (S) and best supportive care (BSC). Results: 247 patients were identified: median age was 62yrs, ECOG 0-1 87%, male 64%, 1-2 metastatic sites 86% (liver 56%) and treatment intent was curative in 14%. Median follow-up was 19m. Primary tumour resection occurred in 95 patients (38%). Compared to no resection, these patients had improved median OS (41 vs 16 months; p &lt; 0.0001) and PFS (15 vs 10 months; p &lt; 0.0001). There was no difference in outcome with varying treatment combinations and sequences of S with CRT/C (p &gt; 0.05). For unresected patients, the most common initial treatment was C (30%). Any active treatment was associated with better OS compared to BSC (6.4m): C (16.1m, p &lt; 0.0001), CRT (20.6m, p = 0.001) and C&amp;CRT (21.8m, p &lt; 0.0001). Most active treatments were associated with better PFS compared to BSC (6.4m): C (10.8m, p = 0.015) and C&amp;CRT (10.6m, p = 0.012). There was no significant PFS difference comparing BSC to CRT (p = 0.25). There were no OS nor PFS differences between: comparisons of C, CRT and C&amp;CRT (p &gt; 0.05). Initial treatment strategies were compared for 129 patients receiving multimodal therapy, where 22 (17%) had initial treatment with C (60% subsequent resection) compared to 85 (66%) commencing with CRT (70% subsequent resection). Commencing with CRT was associated with a longer OS compared to C (31 vs 21 months; p = 0.014). Conclusions: For patients undergoing primary tumour resection, no difference in outcomes were demonstrated with the addition of C and/or CRT. For unresected patients, there was a survival benefit associated with active therapy, with no significant difference between C, CRT or C&amp;CRT. This supports the current practice of using these modalities at clinicians’ discretion. Review of patient factors potentially influencing treatment choice is ongoing.
Novel murine anti-HER2 monoclonal antibodies to induce apoptosis and regulate miR-21 in breast cancer cell.
Authors: Alice Y. Kim, Cindy Zer, John C. Williams, Michael F. Press, Jinha Mark Park
Journal: Journal of Clinical Oncology (2013)

3081 Background: MicroRNAs play critical roles in biological and pathological processes. Of these, miR-21 is frequently observed to be overexpressed in various cancers. However, treatment of breast cancer cells with trastuzumab enhances the level of miR-21 by a relative fold of 2.26 (Ichikawa, PLos ONE, 2012, p.5). In this study, we demonstrate that two murine anti-HER2 mAbs, 10H8 and 8H11, while inhibiting cell proliferation and inducing apoptosis, do not perturb the level of miR-21 in the same way as trastuzumab. To understand the differential effects of trastuzmab and the two mAbs, epitope mapping studies were also conducted. Methods: SKBR3 cells were used to confirm HER2 binding and determine the antibodies’ impact on proliferation, apoptosis, and miRNA expression. Cell proliferation upon a 3-day antibody treatment (10 to 15 μg/ml) was measured using MTS and Crystal Violet Assays. Apoptotic cells were identified using Annexin V-FITC flow cytometry. To determine their epitope mapping, cells were grown on coverslips overnight, fixed, blocked, and incubated in AF488-mAb or AF555-mAb, and images were captured with IX81. QRT-PCR was used to measure the relative levels of miR-21, using miR-16 as the endogenous control Results: Cell proliferation assays showed that the treatment of 10H8 resulted in a better growth inhibition in SKBr3 cells than that of trastuzumab (ex: 80.2% vs 84%, respectively). Combining 10H8 and 8H11 produced less viable cells and more early- and post-apoptotic cells than those treated with trastuzumab alone. In addition, whereas trastuzumab increased the relative quantity of the known oncogene, both 10H8 and 8H11 maintained a steady level of miR-21 (0.99 and 1.2, respectively). Conclusions: Initial results indicate that 10H8 and 8H11 inhibit cell proliferation and induce apoptosis in HER2-overexpressing cells. However, unlike trastuzumab, 10H8 and 8H11 do not involve miR-21 up-regulation. Moreover, the three mAbs do not have overlapping epitopes on HER2. Further investigations of the antibodies’ impact on intracellular signaling pathways and the structural determination of the HER2 binding sites would provide further understanding of the therapeutic potentials of these two mAbs.
ABT-888 (veliparib) in combination with carboplatin in patients with stage IV BRCA-associated breast cancer. A California Cancer Consortium Trial.
Authors: George Somlo, Joseph A. Sparano, Tessa Cigler, Gini F. Fleming, Thehang H. Luu, Arti Hurria, Joanne E. Mortimer, Paul Henry Frankel, Helen K. Chew, Rita Nanda, Cynthia X. Ma, Alice P. Chen, Agustin Garcia, Linda T. Vahdat, David R. Gandara, Jeffrey N. Weitzel
Journal: Journal of Clinical Oncology (2012)

1010 Background: Platinum and PARP inhibitors have both shown activity in BRCA-associated breast cancer (BC) patients (pts). We have conducted a phase I trial of carboplatin (Carb) and velapirib [V], a PARP inhibitor, to define dose limiting toxicities [(DLT) during cycle (C) 1] and the maximum tolerated dose (MTD). Methods: BRCA 1 or 2 carriers with stage IV BC were eligible. Carb starting at an AUC of 6 was given IV every 21 days (length of planned C) and V was administered orally, BID at dose levels (L) L1 through L5 (highest L planned). Results: 22 pts (21 eligible/evaluable, 20 with measurable BC) carrying BRCA1 (10) or BRCA2 (11), or both (1) mutations were accrued. Median age: 45 years, (32-65); 68% of BCs were ER+, and 10% were HER2+. In the table below are the schema, incidence of DLTs, and # of Cs on study. Toxicities: At L1, grade ¾ DLTs with C 1 were seen in 2/6 evaluable pts (1 pt w/grade 3 hyponatremia, pleural effusion, and dehydration, and 1pt w/grade 4 thrombocytopenia [PLT]), leading to deescalation of carb (AUC 5) for pts treated at Ls 2-5. At L2, 1 of 6 pts had grade 4 PLT. There were no DLTs at Ls 3 and L4. L5 is currently being expanded to 6 pts (3 currently enrolled, 1 pt with grade 4 granulocytopenia (Gr) and grade PLT reached DLT). Non-DLT dose delays mostly due ≥ grade 2 Gr or PLT were needed at 60%, 53%, 53%, and 43% of Cs in pts treated on Ls 1-4. Response: In 12 eligible pts treated at Ls 1 and 2, 2 complete and 6 partial responders (67%) and a clinical benefit (CB) of 75% were seen. All pts at Ls 3-5 are still being treated, and in pts treated at Ls 3 and 4, 2 unconfirmed PRs, and 4 cases of stable disease were seen, with L5 too early to assess. Conclusions: The combination of Carb at an AUC of 5 and daily V at doses 150 to 200 mg BID is feasible and the MTD is being defined. In preliminary analysis, response and CB rates are better than expected with the individual agents alone, providing justification to proceed with a planned phase II randomized single agent versus combination trial. [Table: see text]
Detection of circulating tumor cells and its correlation with clinical outcome in non-small cell lung cancer.
Authors: Milena Tariki, Juliana Valim Romero, Emne Ali Abdallah, Luciana Menezes Mendonca Ocea, Natalia Breve Mingues, Jose Luiz Gasparini Junior, Vanessa Alves Silva, Marcello Ferretti Fanelli, Aldo A. Dettino, Augusto Akikubo Rodrigues Pereira, Ludmilla T. D. Chinen
Journal: Journal of Clinical Oncology (2014)

e22020 Background: The presence of circulating tumor cells (CTCs) is a necessary process for cancer progression. In fact, its detection has surged as a potential biomarker for clinical response in treatment of patients with non-small cell lung cancer (NSCLC). This study analyzed level of CTCs and clinical outcome, as well as expression of genes related to drug resistance. Methods: Consecutive patients of a single institution with stage I-IV NSCLC were included. Isolation, counting and characterization of CTCs were made by ISET (Isolation by Size of Epithelial Tumors; RareCell Diagnostics, Paris, France). Levels of CTCs in blood samples were analyzed before systemic treatment and every two months thereafter. Serum levels of CTCs were correlated with DFS. Expression of ERCC1 was correlated with response to cisplatin-based treatment. Results: 45 patients were included, 2.2% stage I (1 pt), 2.2% stage II (1 pt), 11.1% stage III (5 pts and 75.6% stage IV (34 pts). There were 24 men (53.3%) and 21 women (46.7%) and the median age was 65 years (34-81 years). There was no significant correlation between CTCs´ levels and clinical outcome. However, we observed a non-significant better survival at first follow-up for those found to have less than 2 CTCs/mL (mean = 12.6 months) compared to those with 2 or more CTCs/mL (mean = 5.8 months; p= 0.06). Four patients expressed ERCC1 in their CTCs and three of them showed disease progression, sugesting that this protein has potential to be used as a biomarker. Conclusions: Serum levels of 2 or more CTCs/mL could be a predictor of poor outcome in patients with NSCLC, as was seen in previous studies. The correlation between CTCs expression of ERCC1 and disease progression observed in our analysis needs to be explored in other prospective studies.
FOLFIRINOX for the treatment of pancreatic adenocarcinoma: Australian single institute experience.
Authors: Andrew Peter Dean, Arthur Mulvey, Ingrid Hayden
Journal: Journal of Clinical Oncology (2014)

e15246 Background: Combination chemotherapy with FOLFIRINOX has been shown to be effective in advanced pancreatic adenocarcinoma with impressive response rates of 32% in the initial study but with significant toxicity. Studies have therefore excluded elderly patients and those with poor performance status. We report a prospective review of all patients treated with FOLFIRINOX for pancreatic adenocarcinoma at St. John of God Hospital, Subiaco, Perth, Western Australia. Methods: All patients who received FOLFIRINOX chemotherapy at our institution from August 2011 to February 2014 were prospectively followed for dose density and response. Results: Twenty-two patients were identified (10 males and 12 females). The median age was 61 (27-84), including 7 over 70 yrs. 4 patients received FOLFIRINOX in the adjuvant setting and 18 in the palliative setting. All patients had received prior chemotherapy with gemcitabine. In total 138 cycles were administered, with a median number of 4.5 cycles (1-27) per patient. All patients received dose attenuation (16 in the first cycle). Dose density achieved was 71% oxaliplatin, 66% irinotecan, 45% 5-FU, which is consistent with that reported by Conroy and the recent Yale study (Gunturu KS 2013). The over 70-year subgroup achieved similar dose density. There was one case of febrile neutropenia, one case of Grade 3 sensory neuropathy, one case of Grade 3 hepatitis. Disease control rate was 55% (57% in the over 70 subgroup), comparing favorably to that reported by Conroy and Gunturu (32% and 47% respectively). One 84 year old patient with metastatic disease continues on therapy after 27 cycles with excellent quality of life. Conclusions: FOLFIRINOX was well tolerated as a second line therapy for advanced pancreatic adenocarcinoma. Prior studies have excluded elderly patients because of fears of toxicity, however our results demonstrate similar levels of dose density and response rates in over 70’s as younger patients. FOLFIRINOX can be safely administered to elderly patients with appropriate precautions and sensible dose escalation.