tbuckley/cabot-search huggingface dataset:
Disparities in the prognostic significance of proliferation amongst different molecular subtypes in node-negative breast cancer.
Authors: M. Schmidt, I. Petry, D. Boehm, A. Lebrecht, S. Gebhard, H. Koelbl, M. Gehrmann, J. G. Hengstler
Journal: Journal of Clinical Oncology (2011)

10566 Background: Proliferation has an important prognostic impact in breast cancer. We examined the importance of proliferation amongst different molecular subtypes (luminal, basal-like, erbB2-like) in 766 node-negative breast cancer patients without adjuvant systemic therapy. Methods: Microarray based gene-expression data of three independent and previously published cohorts of node-negative breast cancer patients (Mainz, Rotterdam, TRANSBIG) were analysed. After unsupervised hierarchical cluster analysis co-regulated genes related to proliferation were identified. Then a metagene as a surrogate for all genes within the proliferation cluster was calculated. The patients were assigned to different molecular subtypes according to the gene-expression of estrogen receptor (ESR1) and erbB2 (ERBB2). Metastasis-free survival (MFS) was compared with the Log-rank test as well as univariate and multivariate Cox regression which accounted for traditional prognostic factors like age, tumor size, estrogen receptor, histological grade and erbB2. Results: Patients with higher expression of the proliferation metagene showed worse MFS in the whole cohort of patients (HR 1.65, 95% CI 1.39-1.96, p<0.001). Using multivariate Cox regression, the proliferation metagene retained its independent prognostic significance (HR 1.58, 95% CI 1.16-2.27, p=0.004). Besides the proliferation metagene only tumor size (HR 1.79, 95% CI 1.18-2.72, p=0.007) showed an independent association with MFS. 521 patients (68%) belonged to the luminal subtype, 106 (14%) were erbB2-like, and 139 (18%) basal-like, respectively. Prognostic impact of IGKC was limited to the luminal subtype (HR 2.30, 95% CI 1.80-2.95, p<0.001). The proliferation metagene failed to show an association with survival both in erbB2-like (HR 0.95, 95% CI 0.50-1.78, p=0.868) as well as basal-like (HR 0.83, 95% CI 0.55-1.25, p=0.371) subtypes, respectively. Conclusions: Proliferation plays a crucial and independent role in the whole cohort of node-negative patients. However, the prognostic significance of proliferation is confined to the luminal subtype and lost in basal-like and erbB2-like breast cancer, respectively.
Randomized, double-blind, placebo-controlled phase II study of erlotinib with and without entinostat, a class 1 isoform selective histone deacetylase inhibitor (HDAC), in patients with advanced non-small cell lung cancer (NSCLC; ENCORE-401).
Authors: R. Jotte, S. E. Witta, M. A. Neubauer, A. I. Spira, K. Konduri
Journal: Journal of Clinical Oncology (2010)

LBA7532 The full, final text of this abstract will be available in Part II of the 2010 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on June 5, 2010, and as a supplement to the June 20, 2010, issue of the Journal of Clinical Oncology.
PULSE: An open-label, phase II study assessing double positivity (phospho-insulin-growth factor receptor-1 [pIGF-IR] and matrilysin [MMP7]) expression as a predictive marker of resistance in previously untreated metastatic colorectal cancer (mCRC) wild-type KRAS patients (pts) treated with panitumumab plus mFOLFOX6—A GEMCAD study.
Authors: J. Maurel, X. Garcia-Albeniz, C. Méndez Méndez, M. Martin-Richard, C. Pericay, R. Vera, J. Aparicio, M. Rubini, M. Cuatrecasas
Journal: Journal of Clinical Oncology (2011)

TPS164 Background: By transactivaction, p-IGF-IR can activate epidermal growth factor receptor (EGFR). Matrilysin (MMP-7), can activate IGF-IR by degrading IGFBP-3 and releasing IGF-I. Concomitant expression of MMP-7 and p-IGF-IR (using a specific monoclonal antibody (p-1316) recognizing the phosphorylated carboxy-terminal part of the IGF-IR) (DP) correlates with poor prognosis in WT KRAS pts treated with anti-EGFR antibodies plus irinotecan (Horndler et al, Cancer Biol Ther 2011). Methods: Trial Design: the primary objective of this trial is to estimate the progression free survival (PFS) by DP immunohistochemistry (IHC) expression in patients with wild-type KRAS mCRC treated with panitumumab and mFOLFOX6. Two groups are established by DP status (MMP7+/p-IGF-IR+ vs. MMP7+/p-IGF-IR-, MMP7-/p-IGF-IR+ or MMP7-/p-IGF-IR-). With a power of 80% and a bilateral alpha level of 0.05, assuming an accrual period of 12 months (m) and a follow-up period of 18 m, 40 patients are planned to be included in each group to detect a Hazard Ratio of 2. The median PFS of the DP group is expected to be 6 m and the total number of expected events is 56. Secondary objectives include disease control rate, duration of response, time to response and survival according the DP status. Treatment: Both groups will receive panitumumab 6 mg/kg and mFOLFOX6 every 2 weeks. If pts have not progressed after 6 m of treatment they will continue with panitumumab monotherapy until disease progression. Major eligibility criteria: Previously untreated wild type KRAS mCRC, ECOG PS of 0 or 1, at least 1 unidimensionally measurable lesion, and age > 18 years. Correlative studies: PTEN and p-EGFR by IHC and BRAF, PI3K, PTEN, IGFR-II, EGFR (3’) and NRAS mutations according microsatellite instability. Blood sample collection (MMP-7, IGFBP-2,3,5, IGF-I and IGF-II) basally and every 2 month until progressive disease. The study has just initiated enrollment.
A Novel Inhibitor of Homeodomain Interacting Protein Kinase 2 Mitigates Kidney Fibrosis through Inhibition of the TGF-β1/Smad3 Pathway
Authors: Ruijie Liu, Bhaskar Das, Wenzhen Xiao, Zhengzhe Li, Huilin Li, Kyung Lee, John Cijiang He
Journal: Journal of the American Society of Nephrology (2017)

Homeodomain interacting protein kinase 2 (HIPK2) is a critical regulator of multiple profibrotic pathways, including that of TGF-β1/Smad3. Genetic ablation of HIPK2 was shown previously to significantly reduce renal fibrosis in the experimental unilateral ureteral obstruction model and Tg26 mice, a model of HIV-associated nephropathy. To develop specific pharmacologic inhibitors of HIPK2 for antifibrotic therapy, we designed and synthesized small molecule inhibitor compounds on the basis of the predicted structure of HIPK2. Among these compounds, we identified one, BT173, that strongly inhibited the ability of HIPK2 to potentiate the downstream transcriptional activity of Smad3 in kidney tubular cells. Notably, binding of BT173 to HIPK2 did not inhibit HIPK2 kinase activity but rather, interfered allosterically with the ability of HIPK2 to associate with Smad3. In vitro, treatment with BT173 inhibited TGF-β1-induced Smad3 phosphorylation and Smad3 target gene expression in human renal tubular epithelial cells. In vivo, administration of BT173 decreased Smad3 phosphorylation and mitigated renal fibrosis and deposition of extracellular matrix in unilateral ureteral obstruction and Tg26 mouse models of renal fibrosis. Our data indicate that BT173 is a novel HIPK2 inhibitor that attenuates renal fibrosis through suppression of the TGF-β1/Smad3 pathway and may be developed as an antifibrotic therapy in patients with kidney disease.
A randomized, placebo-controlled phase II study of AMG 386 plus bevacizumab (Bev) and paclitaxel (P) or AMG 386 plus P as first-line therapy in patients (pts) with HER2-negative, locally recurrent or metastatic breast cancer (LR/MBC).
Authors: V. Dieras, J. Jassem, L. Y. Dirix, J. P. Guastalla, P. Bono, S. A. Hurvitz, A. Gonçalves, G. Romieu, S. A. Limentani, G. H. M. Jerusalem, K. Lakshmaiah, H. H. Roche, P. Sánchez-Rovira, T. Pienkowski, M. A. Seguí-Palmer, A. Li, Y. Sun, C. A. Pickett-Gies, H. Wildiers
Journal: Journal of Clinical Oncology (2011)

544 Background: AMG 386 is an investigational peptide-Fc fusion protein that inhibits angiogenesis by neutralizing the interaction between the Tie2 receptor and angiopoietin-1 and -2. We assessed the efficacy and safety of AMG 386 plus P with or without Bev in previously untreated HER2-negative LR/MBC. Methods: Pts received P 90 mg/m2 IV QW 3 wk on/1 wk off and were randomized 1:1:1:1 to also receive blinded Bev 10 mg/kg IV Q2W plus AMG 386 10 mg/kg IV QW (Arm A) or 3 mg/kg IV QW (Arm B), or placebo IV QW (Arm C); or open-label AMG 386 10 mg/kg IV QW (Arm D). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) per RECIST, adverse events (AEs), safety and pharmacokinetics. Results: 228 pts were randomized (Arms A/B/C/D, n=56/57/58/57). Median PFS was 11.3, 9.2, 12.2 and 10.0 mo for Arms A/B/C/D. The hazard ratios (HR) (80% CI) for Arms A, B, or D vs C were 0.98 (0.72–1.34; P=.95), 1.12 (0.82–1.52; P=.64) and 1.28 (0.93–1.76; P=.31), respectively. Median AMG 386 Cmax and Cmin at steady state following coadministration with P plus Bev were dose-proportional; Bev Cmax and Cmin at steady state were generally similar between the placebo and AMG 386 groups. Preliminary analyses showed that median PFS was 12.8 and 7.4 mo in pts from Arm D with AMG 386 high and low exposure (AUCss ≥ 8.4 vs < 8.4 mg·h/mL), respectively (HR High:Low=0.67, P=.27). Historical data for median PFS with P monotherapy is 5.9 mo and 11.8 mo for P plus Bev (Miller et al, N Engl J Med 2007;357:2666). Most frequent grade ≥3 AEs included neutropenia (Arm A/B/C/D, 18/19/28/18%), hypertension (18/23/19/4%) and peripheral neuropathy (20/7/10/11%). The incidence of any grade peripheral edema in Arm A/B/C/D was 36/46/19/55%. Conclusions: Although the study was designed as an estimation study, there was no apparent prolongation of PFS with the addition of AMG 386 to P and Bev at the doses tested. Toxicity was consistent with prior experience with individual treatments. The data support additional studies in LR/MBC of P plus AMG 386 at doses >10 mg/kg based on the exposure-response analysis.
Understanding oral chemotherapy use at the end of life: Analysis of a Massachusetts claims database.
Authors: Jessica A. Zerillo, Sherri Oliver Stuver, Belen Fraile, Anton Dodek, Joseph O. Jacobson
Journal: Journal of Clinical Oncology (2014)

8 Background: Receipt of chemotherapy in the last 14 days of life is a measure of potential overuse of care. But the appropriateness of oral chemotherapy specifically is not yet described, and there are little available data on utilization of oral chemotherapy at the end of life. Methods: We analyzed results from 200 patients of Dana-Farber Cancer Institute, covered by the Blue Cross/Blue Shield of Massachusetts (BCBSMA) pharmacy benefit, and who died in 2012. We collected data on chemotherapy use in the last 6 months of life. We analyzed oral chemotherapy use in the categories of any oral prescription and timing of first oral prescription. We compared results to intravenous (IV) and any other administration route. Results: Most of our target population had gastrointestinal, thoracic, or breast malignancies. In the last 6 months of life, 75% received some form of chemotherapy, including 23.5% who were prescribed an oral agent. 11 patients were prescribed oral chemotherapy in the last 30 days of life. For 45% (n=5) this was the first oral prescription. In the last 14 days of life, only 5.5% of patients received any chemotherapy, including one patient prescribed an oral agent. Conclusions: The collection of oral chemotherapy utilization data through insurance claims was feasible. Use of any chemotherapy, including oral, sharply declined during the last 30 and 14 days of life, consistent with a shift to palliative end-of-life management. This analysis highlights the need for a more comprehensive understanding of oral chemotherapy use at the end of life. Furthermore, with the growing use of oral chemotherapy, the development of measures to define quality of end-of-life care with these agents is warranted. [Table: see text]
The effect of cisplatin dose administered during concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.
Authors: H. H. F. Loong, B. Ma, F. Mo, S. F. Leung, E. P. Hui, M. K. Kam, S. L. Chan, A. T. C. Chan
Journal: Journal of Clinical Oncology (2011)

5532 Background: Concurrent chemoradiotherapy (Chemo-RT) is superior to RT alone in the treatment of locoregionally advanced nasopharyngeal carcinoma (NPC). There is no published data on minimum dose of cisplatin required to achieve such a survival benefit. This study aims to evaluate the prognostic significance of the total dose of cisplatin administered during chemoradiotherapy in locoregionally advanced NPC patients. Methods: A single-centre retrospective analysis on patients with AJCC Stage II to IVB NPC who were treated with Chemo-RT at the Prince of Wales Hospital between May 1994 and August 2006. Median follow-up = 56.5 months. All patients received intravenous cisplatin at 40mg/m2/ week during a 6-7 week course of RT. Multivariate analysis was performed with covariates including overall stage, TNM stage, age and sex. A planned subgroup analysis based on overall, T and N-stages was performed. Results: 241 patients were included in this analysis (Stages II = 33, III = 109, IV = 99). Median number of cycles of cisplatin = 5. At median follow-up, 38.6% (n=93) patients experienced disease relapse (47 local recurrences and 65 distant recurrences). No significant association between cycles of cisplatin and survival endpoints were found in the overall population. However, in the subgroup of stage II and III NPC patients (n=142), multivariate analysis showed that patients who received > 5 cycles of concurrent cisplatin chemotherapy (i.e > 200mg/m2) had significantly improved OS than those who received ≤ 5 cycles (HR 0.46; 95% CI (0.24 – 0.89); p=0.02). Conclusions: Total dose of cisplatin received during chemo-RT has prognostic significance in patients with Stage II and III NPC. Patients who received > 5 cycles of weekly cisplatin during RT had significantly improved OS and also a trend towards longer time to distant recurrence. Multivariate analyses in stage II and III subgroup Chi square HR for death 95% CI P value OS ≤ 5 vs. > 5 cycles cisplatin 5.33 0.44 0.23–0.85 0.02* Progression-free survival ≤ 5 vs. > 5 cycles 2.33 0.63 0.35–1.14 0.13 Time to Local Recurrence ≤ 5 vs. > 5 cycles 0.38 0.76 0.32–1.81 0.54 Time to distant recurrence ≤ 5 vs. > 5 cycles 2.74 0.55 0.28–1.11 0.098
High DNA polymerase η gene expression is associated with shorter survival in advanced non-small cell lung cancer treated with platinum based chemotherapy
Authors: S. Novello, P. Ceppi, M. Papotti, A. Cambieri, V. Monica, M. Giaj Levra, M. Longo, E. Cappelletto, B. Crida, G. V. Scagliotti
Journal: Journal of Clinical Oncology (2008)

14611 Background: Nucleotide excision repair (NER) is known as the main process responsible for resistance to cisplatin and more recently the impact of translesion DNA synthesis system in conferring tolerance of cancerous cells to cisplatin was reported. DNA Polymerase η (Pol η, POLH) is part of the translesion synthesis mechanism and can overcome DNA damages caused by cisplatin conferring in vitro resistance (Albertella et al. Cancer Res. 2005; Alt et al. Science. 2007). Aim of the present study was to test whether the expression of tumor mRNA in the patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based therapy is associated with prognostic information. Methods: Pol η mRNA expression was quantified by Real-Time PCR in formalin-fixed paraffin- embedded, microdissected biopsies of 46 consecutive patients with NSCLC (median age 64 years; male=78%; never smokers=19%; PS 0=70%; stage IV=63%; squamous/non-squamous/NSCLC-NOS=17%/69%/14%) treated with platinum (cisplatin 20%/carboplatin 80%)-based doublets and enrolled in clinical trials. Assessment of gene expression levels was performed using 2-ΔΔCt method with ß-actin as a reference gene and total RNA as calibrator. Pol η transcript levels and clinical-pathological variables were correlated with outcome using univariate and multivariate survival analysis. Results: Overall median survival (MS) and time to progression (TTP) were 8.5 and 7 months, respectively. Using the median value as a cut-off, a significant shorter MS (5.9 vs 11.6, p=0.01) was observed in patients with higher Pol η expression. Moreover, Cox multivariate analysis of survival adjusting for major clinical-pathological parameters, indicated Pol η expression (HR=2.60; p=0.005), female gender (HR=0.31; p=0.008) and response to therapy (HR=0.65; p=0.04), as independent prognostic factors for survival. Conclusions: The negative prognostic role of Pol η mRNA expression in NSCLC patients receiving platinum- based chemotherapy suggests that alternative DNA repair mechanisms, other than NER, could justify cisplatin resistance and indicate Pol η as a potential prognostic factor worth of further investigation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology, Eli Lilly, Janssen Cilag, Millennium, sanofi-aventis
Observational transversal study to relate functional status and age with the doublet or triplet chemotherapy based on capecitabine in advanced gastric cancer patients.
Authors: B. Martinez Amores, M. Alsina, E. Jiménez, M. Jorge, J. Martin Valades, P. López, E. Falcó, C. Hinojo, C. Llorca, C. Molins
Journal: Journal of Clinical Oncology (2011)

59 Background: The available evidence suggests that selection of treatment for advanced gastric cancer (AGC) correlates with age and ECOG PS. This study was conducted to analyze whether previously mentioned variables are relevant for the choice of doublet or triplet regimens with capecitabine and determining prognosis. Methods: Multicenter, cross-sectional, observational study in patients with AGC who received at least 2-cycles of capecitabine-based doublet or triplet chemotherapy, with or without measurable disease. The age, as a continuous and categorical (&gt; 64 vs ≤ 64) variable, and ECOG PS were analyzed by logistic regression. Results: A total of 175 patients were evaluated. Median age 65.5 (56-72) years, male: 68% ECOG 0/1/2: 32.7%/55.6%/11.1%. 33% underwent doublet and 67% triplet chemotherapy. Tumour histology: signet-ring cell carcinoma (29%), papillary (13%), mucinous (12%) and tubular (3.5%). Most common sites of metastases: lymph nodes (48%), peritoneum (41%), liver (38%) and lung (12%). Multivariante analysis demonstrated that age ≤ 64 (OR 2.326; p = 0.016) and ECOG 0 (vs 2) (OR 3.937; p = 0.016) were risk factors for the choice of triplet chemotherapy, and failed to show an association between ECOG 1 and regimen. While in patients underwent triplet regimen 51% were aged ≤ 64 and 49% &gt; 64, in those treated with doublet these rates were 32% and 68% respectively; (p = 0.016, Chi-square test). A statistical difference was found for ECOG 0/1/2/4 and regimen chosen. Concretely, among patients who received triplet regimen, 15% had ECOG 2 and 85% ECOG 0 while in case of doublet regimen these rates changed to 43 and 57%; (p = 0.01, Fisher's exact test). Main grade 1/2 capecitabine-related toxicities: diarrhea (10%), mucositis (7%), hand-foot syndrome (5%) and emesis (4%). Most frequent grade 3 were diarrhea in 5% and emesis, asthenia and febrile neutropenia in 2%. No toxicity grade 4 occurred. Conclusions: Age ≤ 64 years and ECOG 0 are risk factors of choice of capecitabine-based triplet chemotherapy in AGC. These results support previous reports showing that age and ECOG PS are associated with treatment choices for AGC. No significant financial relationships to disclose.
A phase I dose-finding study of sorafenib (S) in combination with gemcitabine (G) and radiotherapy (RT) in patients (pts) with unresectable pancreatic carcinoma (UPC): A GEMCAD study.
Authors: J. Aparicio, C. Garcia-Mora, M. Martin-Richard, L. Petriz, J. Feliu, E. Sanchez-Santos, J. R. Ayuso, C. Conill, J. Maurel
Journal: Journal of Clinical Oncology (2011)

e14525 Background: Sorafenib, an inhibitor of B-raf, VEGFR2, and PDGFR-beta, has activity against pancreatic cancer in pre-clinical models. Due to the radio-sensitization activity of S and G we designed a phase I multi-center trial to evaluate the safety and efficacy of this combination with concomitant RT. Methods: Pts with biopsy-proven UPC, based on spiral CT vascular invasion, were treated with G 300 mg/m2 iv weekly (QW) x 5 weeks concurrently with RT (45 Gy) in 25 fractions and S in a dose escalated in a ''3+3'' design from 200mg QD, 400 mg QD and 400 mg BID. Radiation portals included the primary tumor alone, without inclusion of regional lymph nodes. Pts with planning target volume (PTV) over 500 cc were excluded. Pts not progressing during chemo-RT were allowed to receive S till progression. Results: 12 pts were enrolled. Three pts received 200mg QD, six pts 400mg QD and three pts 400mg BID. The median age was 59 years (range 39-69), 5 male, ECOG PS 0/1 (1/11). No DLTs occurred. The most common grade 2 toxicities were fatigue (4), neutropenia (3), nausea (5), and transaminitis (4). Treatment was discontinued in one patient because reversible posterior leukoencephalopathy. No other pts required admission due to therapy. There were no toxic deaths. PTV ranged between 105-500cc. All pts were evaluable for response with 2 objective partial responses and 7 SD. Median progression free-survival and overall survival were 4.4 (95% CI 3.4-5.4) and 10 months (95% CI 5.7-14.3), respectively. Conclusions: The addition of S to G-RT without prophylactic nodal irradiation, demonstrated a safe toxicity profile and modest activity in UPC.
Targeting Bcl-2 Family Proteins in Adult T-Cell Leukemia/Lymphoma: In Vitro and In Vivo Effects of a Novel Bcl-2 Family Inhibitor ABT-737.
Authors: Kenji Ishitsuka, Chie Ishikawa, Fusanori Yotsumoto, Hiroo Katsuya, Naoko Kunami, Shigeki Sawada, Hiroe Tanji, Morishige Takeshita, Shingo Miyamoto, Naoki Mori, Kazuo Tamura
Journal: Blood (2009)