tbuckley/cabot-search huggingface dataset:
Epithelial-mesenchymal transition and metastatic bladder cancer profile under vinflunine treatment.
Authors: Angelica Figueroa, Vanessa Abella, Guadalupe Aparicio, Mar Haz-Conde, Javier Gayo, Luis M. Antón Aparicio
Journal: Journal of Clinical Oncology (2013)

e22021 Background: Given the role of vinflunine (VFL) in the microtubule dynamics and the link between microtubules and cell adhesions through cadherins, we have investigated the possible influence of VFL on adherens junctions through its interaction with microtubules. We have studied the implication of VFL on the reversion of epithelial-mesenchymal transition (EMT) in bladder transitional cell carcinoma and explored a possible novel molecular mechanism. Methods: Four human bladder transitional carcinoma cell lines were used to carry out the following experimental procedure: Cytotoxicity assay by using MTT assay, qRTPCR to analyze mRNA markers of the EMT, Western blotting using specific antibodies for EMT markers, and immunofluorescence images, analyzed by epifluorescence microscopy. Results: Cell growth reduction was detected in human bladder carcinoma cells under VFL treatment compared to control. VFL induces mesenchymal to epithelial phenotype and modulates the EMT markers: E-cadherin and Cytokeratin-19 were enhanced under treatment, while significantly reduction of mRNA mesenchymal markers expression (Vimentin, N-cadherin) and EMT-transcriptional factors (Snail and Zeb1) was detected. Strong reduction of Hakai protein was seen under VFL treatment. Hakai was discovered as an E3 ubiquitin-ligase that mediates the posttranslational downregulation of E-cadherin. Epifluorescence images showed that VFL treatment promotes E-cadherin localization specifically at cell-cell contact; while, Hakai expression decreases its expression in the nuclei and cytoplasm. Conclusions: These results suggest that VFL up-regulates E-cadherin contributing to mesenchymal to epithelial transition, and that Hakai modulation might be the molecular mechanism by which the increasing E-cadherin at cell-cell contacts in bladder carcinoma cell lines is detected. Given the relevant in vitro role of VFL on E-cadherin expression and on the reversion of EMT process, we hypothesized that VFL could exert a clinical benefit in delaying the metastasis in urothelial tumors.
Molecular profiling of 6,892 colorectal cancer patients to identify potential treatment options.
Authors: Wafik S. El-Deiry, Joanne Xiu, Bora Lim, Angelique Scicchitano, Eileen Feeley, Harold A. Harvey, Nelson S. Yee
Journal: Journal of Clinical Oncology (2014)

3637 Background: Colorectal cancer (CRC) especially with KRAS/BRAF mutation (MT) is aggressive and has limited treatment options when metastatic. We used a multiplatform molecular profiling (MP) approach to identify potential treatments not typically considered for CRC in order to improve the management of this disease. Methods: We evaluated6,892 CRCs referred to Caris Life Sciences by MP including sequencing (Sanger/NGS), protein expression (IHC) and gene amplification (CISH/FISH). Results: CRC metastases (mets) to liver, brain, ovary or lung (n=1507) showed expression of actionable markers including high TOPO1 (52%), low RRM1 (57%), TS (71%) and MGMT (39%), suggesting benefit from irinotecan, gemcitabine, 5FU/capecitabine and temozolomide. Brain mets had higher TOP2A (100% vs. 81%), while ovarian mets had lower TUBB3 (16% vs. 43%) than the other mets (p<0.05). Brain and lung mets had higher KRAS mutations (65% and 59%) than other mets (47%, p=0.07, <0.01), suggesting poor response to EGFR inhibitors (EGFRi). Additional analysis at other metastatic sites will be presented. BRAF-mutated CRC (n=455) showed coincident high IHC of RRM1 (56%), TS (53%) and low PDGFR (22%) compared with wild type, suggesting decreased response to gemcitabine, 5FU/capecitabine, or antiangiogenics. Mutation in other genes (APC, PTEN, HNF1A, ABL1, and RB1) may also suggest targeted therapies for these patients. KRAS-mutated CRC had higher cMET (47% vs. 36%) and lower MGMT (56% vs. 63%), suggesting cMETi and temozolomide. KRAS-mutated CRC also had high TUBB3 (42% vs. 33%) and low HER2 by IHC (0.5%) and FISH (3%), indicating less benefit from taxanes or HER2i (p <0.05). MP of CRC of ascending, descending colon or rectum showed KRAS mutations in 43%, 23%, 43%; PIK3CA in 29%, 25%, and 10% or BRAF in 27%, 18% and 3.3%, respectively. Conclusions: MP of 6,892 CRCs identified significant differences among tumors with BRAF/KRAS-MT and metastases, prompting unexpected treatment options. Agents uncommonly used in CRC metastases such as temozolomide are suggested, and etoposide or taxanes are suggested for brain or ovarian mets, respectively. Targeted therapies could be considered for KRAS or BRAF mutated tumors based on actionable targets revealed by MP.
Birth and maternal characteristics, and childhood cancer in the United States: An ecological study.
Authors: Guilherme Abreu Pereira, Carlos Rodriguez-Galindo, A. Lindsay Frazier, Paolo Boffetta, Karina Braga Ribeiro
Journal: Journal of Clinical Oncology (2013)

10061 Background: Childhood cancer is rare, yet it represents a major cause of mortality in this age group. Its etiology is largely unknown. The aim of this study was to identify associations between pre- and perinatal characteristics and cancer development in children below age 5. Methods: We developed an ecological study correlating birth information and childhood cancer incidence in 0-4 year old at the State level. The following variables were analyzed: birth weight (BW), preterm birth, maternal age, plurality, maternal smoking, chronic hypertension (CH), diabetes mellitus (DM), pregnancy associated hypertension (PH) and eclampsia. Birth characteristics were obtained from Centers for Disease Control and Prevention (CDC) database (1995-2009), and childhood cancer incidence data from the National Program of Cancer Registries (NPCR) and the Surveillance, Epidemiology and End Results (SEER) program (1999-2009). Spearman correlation coefficients were calculated with SAS 9.2 (Cary, NC). Bonferroni correction was applied for multiple comparisons, ie, only results with p£0.01 were considered significant. Results: Acute lymphoid leukemia (ALL) (r=0.47, p &lt;0.001), astrocytoma (AST) (r=0.59, p &lt;0.001), neuroblastoma (NB) (r=0.48, p &lt;0.001) and rhabdomyosarcoma (RMS) (r=0.51, p=0.003) were positively correlated with high BW (&gt;4000g). ALL (r=0.46, p &lt;0.001) was also positively correlated with advanced maternal age (40+ years). Moreover, a positive correlation was found between plurality and NB (r=0.50, p &lt;0.001). Regarding maternal conditions, the following positive correlations were identified: DM with AST (r=0.40, p=0.009), NB (r=0.38, p=0.01) and WT (r=0.38, p=0.01). Conclusions: Well established correlations were replicated and new associations were suggested (e.g., AST and DM). In spite of the limitation of an ecological approach, this study provided new hypotheses to be explored in further analytical studies based on individual data.
A randomized phase 2 trial of MM-121, a fully human monoclonal antibody targeting ErbB3, in combination with erlotinib in EGFR wild-type NSCLC patients.
Authors: Lecia V. Sequist, Ariel Lopez-Chavez, Robert Charles Doebele, Jhanelle Elaine Gray, Wael A. Harb, Manuel R. Modiano, David Michael Jackman, Maria Quintos Baggstrom, Akin Atmaca, Enriqueta Felip, Mariano Provencio, Manuel Cobo, Christopher J. Kripas, Gavin MacBeath, Akos Gabor Czibere, Byoung Chul Cho, Keunchil Park, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2014)

8051 Background: Heregulin induced activation of ErbB3 has been implicated as a mechanism of resistance to many targeted therapies such as EGFR-TKIs in preclinical models. MM-121 is a monoclonal antibody designed to interfere with this mechanism of resistance. Methods: This Phase 2 trial was a global, multi-center, open-label, parallel cohort study of MM-121 and erlotinib in 3 predefined NSCLC patient groups. Here we report final results from one of the 3 groups: EGFR WT patients. This group comprised 132 patients with WT EGFR who progressed on ≥1 platinum-based SOC therapy and were EGFR TKI-naive. Patients were randomized 2:1 to receive MM-121 20 mg/kg every other week plus daily erlotinib at 100 mg (M) or daily erlotinib alone at 150 mg (E). The primary objective was to compare the progression-free survival (PFS) between M and E. Fresh tissue biopsies were mandatory for evaluation of a pre-specified set of biomarkers mechanistically-linked to ErbB3 signaling. Results: 121 patients (85 (M), 36 (E)) were included in the safety and efficacy analyses. PFS was analyzed after 105 events (73 (M), 32 (E)). Median PFS was 8.1 weeks for arm M and 7.7 weeks for arm E with a HR of 0.898 (95%CI [0.592, 1.363]), log-rank p=0.6129. The objective response rate was 4.7% (95%CI [1.85 - 11.48]) on arm M, and 5.6% (95%CI [1.54 - 18.14]) on arm E. The median overall survival estimate was 27.3 weeks for arm M and 37.3 weeks for arm E, with a HR of 1.499 (95% CI [0.855, 2.629]). The majority of adverse events were reported as mild to moderate in severity and included the following (M vs. E): rash (74% vs. 37%), diarrhea (59% vs. 27%), dermatitis acneiform (28% vs. 11%), dry skin (54% vs. 47%), nausea (29% vs. 14%), fatigue (31% vs. 13%), stomatitis (20% vs. 5%), decreased appetite (37% vs. 16%), weight decreased (27% vs. 11%), and dyspnea (22% vs. 9%). The adverse events were overall manageable and did not impact compliance on treatment. Conclusions: Addition of (M) to (E) was not effective at prolonging PFS in this study population. Overall survival favored the control arm. The observed safety profile is consistent with the expected adverse events associated with ErbB-family inhibitors. Biomarker data will be presented. Clinical trial information: NCT00994123.
Atezolizumab (atezo) in patients with metastatic urothelial carcinoma (mUC): A 2-year clinical update from a phase Ia study.
Authors: Daniel Peter Petrylak, Thomas Powles, Joaquim Bellmunt, Fadi S. Braiteh, Yohann Loriot, Rafael Morales, Howard A. Burris, Joseph W. Kim, Beiying Ding, Dannis Chang, Marcella Fasso, Carol O'Hear, Nicholas J. Vogelzang
Journal: Journal of Clinical Oncology (2017)

290 Background: Atezo (anti–PD-L1) has demonstrated safety and efficacy in a broad range of cancers and is approved in the United States for mUC previously treated with platinum-based chemotherapy. Here we report long-term results in mUC from Phase Ia study NCT01375842 (PCD4989g). Methods: Previously treated mUC patients received atezo 15 mg/kg or 1200 mg IV q3w. Enrollment in this Phase Ia expansion cohort initially required PD-L1–selected status and later opened to patients regardless of PD-L1 expression on tumor-infiltrating immune cells. The primary endpoint was safety/tolerability. Secondary endpoints included investigator-assessed RECIST v1.1 ORR (confirmed), DOR and OS. Results: 95 patients were safety evaluable (Table). Median age was 66 years, 76% were male and 80% had primary bladder tumors. 61% had ECOG PS 1. 52% received ≥ 3 prior systemic therapies for mUC (70% platinum). Median treatment duration was 3 months (range: 0-32 months); 24% were treated for ≥ 1 year. Treatment-related AEs occurred in 66% (all Grade) and 8% (Grade 3-4) of patients. No treatment-related deaths were reported. In 94 objective response–evaluable patients (follow-up ≥ 12 weeks), the ORR was 27% (95% CI: 18, 37%), and the CR rate was 10%; the SD rate was 19%. mDOR was 22.1 months (95% CI: 12.1, NE months) in all patients; 56% of responses (7/9 CRs and 7/16 PRs) were ongoing at the December 15, 2015 data cutoff. With a 24-month median follow-up duration (range: 1+ to 32 months), the 1-year OS rate was 47% (95% CI: 36, 58%), and the 2-year rate was 29% (19, 40%); mOS is in the Table. Updated clinical data with further follow-up and analyses by PD-L1 status will be presented. Conclusions: Long-term treatment with atezo was well tolerated, without new safety signals in heavily pre-treated mUC patients. The durability of responses, including CRs, along with extended OS, confirm atezo as a new standard for previously treated mUC patients. Clinical trial information: NCT01375842. [Table: see text]
Impact of cyclophilin A on survival in gastric cancer patients who received platinum-based chemotherapy.
Authors: Chi Hoon Maeng, Sun Kyung Baek, Ji-Youn Sung, Si-Young Kim
Journal: Journal of Clinical Oncology (2017)

73 Background: Cyclophilin A (CypA), which is a protein that mediates protein folding and trafficking, has known to be associated with cancer progression and drug resistance such as cisplatin. However, the actual effect in cancer patients has not been elucidated. Methods: We collected clinical data from the cohort of 289 gastric cancer patients. Subjects were selected as following criteria: 1) adjuvant or first-line palliative chemotherapy containing platinum, 2) available FFPE tissue for immunohistochemical stain for CypA. We divided the population into two groups; Group A was patients who received adjuvant chemotherapy and Group P was those of palliative chemotherapy-treated group. The score of CypA immunohistochemistry was calculated depending on the intensity of stain and the percentage of stained cells. We performed survival analysis based on CypA expression. Results: 1) Group A (N = 147) Patients with lower expression of CypA ( &lt; vs. ≥ median IHC score) showed significantly worse progression-free survival (PFS, 2.4 years vs NR, p = 0.043), and overall survival (OS, 3.4 months vs. NR, p = 0.002). In subgroup analysis, level of CypA expression discriminated PFS significantly in patients with age less than 65, poorly differentiated histology, signet ring cell type, and OS for those with use of oxaliplatin, age less than 65, stage III, poorly differentiated histology, diffuse type of Lauren classification, and signet ring cell type favoring higher expression of CypA. 2) Group P (N = 142) There was no relationship between expression level of CypA and PFS/OS in patients with palliative settings. However, in patients who were treated with oxaliplatin-containing chemotherapy, lower expression of CypA showed worse OS (8.3 vs 11.1 months, p = 0.003) Conclusions: Lower level of CypA expression was associated with worse PFS and OS in patients with adjuvant setting, especially in case of advanced stage, and high grade histology. Although CypA did not have significant effect on survivals in palliative chemotherapy-received patients, those who received oxaliplatin showed worse OS with lower CypA.
Neo-escape: Neoadjuvant extended sequential chemotherapy with adjuvant postoperative treatment for epithelial nonmucinous advanced inoperable peritoneal malignancy.
Authors: Christopher John Poole, Andrea Marshall, Helen B Higgins, Julie Fletcher, Sarah Jane Williams, Nangi Lo, Indrajit Nalinika Fernando, Richard Osborne, S. Michael Crawford, Saeed Rafii, Sandeep Gill, Janet A Dunn
Journal: Journal of Clinical Oncology (2012)

5046 Background: Neo-Escape was designed to exploit fully the modest non-cross resistance of carboplatin (CBDCA) and paclitaxel (ptx) in an extended sequential regimen, with dose-dense ptx, and address feasibility of combining gemcitabine (gem) with either CBDCA or ptx. Methods: A randomised phase II trial in patients (pts) with untreated (FIGO stage 3C/4) inoperable ovarian, fallopian, or primary peritoneal carcinoma to assess feasibility of two regimens of sequential neoadjuvant-then-adjuvant chemotherapy (CT); (a) CBDCA AUC 2.5 and gem 1000mg/m 2 repeated days 1 and 8 q 3 wks x 6 cycles, then ptx 175mg/m 2 q 2 wks x 6 cycles (CG-P) or (b) CBDCA AUC 6 q 3 wks x 6 cycles, then ptx 175mg/m 2 and gem 2000mg/m 2 q 2 wks x 6 cycles (C-PG). All pts were considered for delayed 1 o debulking surgery after neoadjuvant CT. The 1 o feasibility outcome was % pts completing 12 cycles of CT. Using Fleming’s single stage procedure 44 patients on each arm were needed to test null hypothesis of feasibility ≤60% with 5% 1-sided significance level and 90% power. 2 o outcomes included safety, PFS and ORR. Pts were stratified by serum albumin, stage and tumor differentiation. Results: 75 pts were recruited Sept 2007 - May 2011 (28 CG-P; 47 C-PG), median age 62 yr (range 21-75). Recruitment to CG-P closed early due to futility. 52% had albumin &gt;35g/L, 68% FIGO stage 3C and 80% poorly differentiated tumors. 64% on CG-P and 55% on C-PG had debulking surgery as planned and a further 4% on CG-P and 13% on C-GP after completion of all CT. For CG-P 35% achieved 0cm, 35% &lt;1cm and 30% ≥ 1cm residuum; for C-GP 34% 0cm, 13% &lt;1cm and 34% ≥1cm, 19% TBC. 14/28 pts on CG-P completed all 12 cycles (feasibility 50%; 95% CI 31-67%); 37/47 pts on C-PG (feasibility 79% (95% CI 64-88). Main reason for early discontinuation was toxicity on CG-P and disease progression on C-PG. Similar proportions of pts on each arm had dose reductions (68%) or delays (86% on CG-P; 89% on C-PG), mainly for toxicity. 82% of pts experienced grade 3/4 toxicity on CG-P; 72% on C-PG. Median PFS for CG-P is 14.3 mths (95% CI 11.6-15.7mths) and 13.0 mths (95% CI 11.5-15.4mths) for C-PG. Conclusions: CG-P was not feasible at these doses using pre-specified criteria, but C-PG is feasible.
Assessment of blood and tissue myeloid derived suppressor cells (MDSC), clinicopathologic factors, and treatment response in urothelial carcinoma (UC) patients (pts) undergoing surgery.
Authors: Moshe Chaim Ornstein, C. Marcela Diaz-Montero, Patricia A. Rayman, Paul Elson, Samuel Haywood, Jin Sub Kim, Paul G Pavicic, James Finke, Brian I. Rini, Andrew J. Stephenson, Marcelo Lamenza, Priscilla Dann, Nicole DiBiase Brey, Sarah Devonshire, Jennifer S Ko, Amr Farouk Fergany, Marc S. Ernstoff, Christopher J. Hoimes, Jorge A. Garcia, Petros Grivas
Journal: Journal of Clinical Oncology (2017)

362 Background: MDSC are heterogeneous immunosuppressive cells with potential predictive/prognostic role in cancer. The association between MDSC, clinicopathologic factors and pathologic response in pts with UC merits evaluation. Methods: Peripheral blood and/or tissue was collected from 120 pts. MDSC were measured in fresh unfractionated whole blood (WB), in peripheral blood mononuclear cells (PBMC) and fresh tumor tissue. MDSCs were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- ((T)otal MDSC). MDSC subsets were defined as LinloCD33+/HLADR- and (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-, CD11b+ ). MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations, clinicopathologic factors and pT0N0%. Results: Of 120 pts, 82 were non-metastatic: 58 had only blood, 23 had blood &amp; tissue, 1 had only tissue available for analysis. Of these 82 non-metastatic pts, 70 were men, median age 68; 81 pts had primary UC histology, 1 small cell cancer, 24 had mixed UC histology; 24 had prior intravesical therapy, 34 had neoadjuvant therapy (79% cisplatin-based, 21% unknown), 4 pts had post-op recurrence. At cystectomy: 15/82 pT0, 22/82 pT3/4; 37/82 CIS; 8/78 pN+. Significant associations were seen between MDSC blood levels and mixed histology, CIS, pN+, and lower pT0N0% (Table). Tumor M-MDSCs were associated with pN+ (p=0.05). There was significant correlation between tumor and WB % M-MDSC (r=0.55, p=0.007), and tumor and WB % G-MDSC (r=0.46, p=0.03). Conclusions: Blood MDSC levels correlate with several clinicopathologic factors and may predict pathological complete response (pT0N0). Assessment of association between MDSC levels, outcome and immunotherapy response is ongoing including in metastatic pts. [Table: see text]
Tivozanib in patients treatment-naive for metastatic renal cell carcinoma: A subset analysis of the phase III TIVO-1 study.
Authors: Cora N. Sternberg, Tim Eisen, Piotr Tomczak, Andrew Louis Strahs, Brooke Esteves, Anna Berkenblit, Robert John Motzer
Journal: Journal of Clinical Oncology (2013)

4513 Background: Tivozanib (T) is a potent, selective inhibitor of all three VEGF receptors with a long half-life of 4.5–5.1 days. Superior progression-free survival (PFS) and overall response rate (ORR) with T versus sorafenib (S) were demonstrated in a Phase III trial (TIVO-1) in patients (pts) with metastatic renal cell carcinoma (mRCC) (in ITT population, PFS: 11.9 vs 9.1 months HR=0.797, 95% CI 0.639–0.993; P=0.042; ORR: 33% vs 23%, P=0.014). Hypertension was more common with T, while lower rates of certain off-target AEs and fewer dose adjustments relative to S were reported (J Clin Oncol 2012;30[suppl]:Abstract 4501). Here we present efficacy and safety analyses for the pre-specified subset of pts who received no prior systemic therapy for mRCC. Methods: In the ITT population (N=517), pts were treatment-naïve or had received no more than 1 prior systemic therapy for metastatic disease; pts receiving prior VEGF- or mTOR-targeted therapy were excluded. Pts were randomized 1:1 to T 1.5 mg/d (once daily, 3 weeks on, 1 week off) or S 400 mg/d (twice daily, continuously). Of these, 181 pts (70%) in each treatment arm had not received prior systemic therapy for mRCC. Results: In pts who received no prior systemic therapy for mRCC, demographics were well balanced between the 2 arms. Median PFS was 12.7 for T vs 9.1 months for S (HR=0.756, 95% CI 0.580–0.985, P=0.037). ORR was 34% for T vs 24% for S (P=0.038). The most common adverse event (AE; All grades/Grade ≥3) for T was hypertension (T: 40%/25% vs S: 35%/18%), suggesting “on-target” biological activity and was manageable medically, while the most common AE for S was hand-foot syndrome (T: 11%/2% vs S: 52%/16%). Other common AEs were diarrhea (T: 22%/2% vs S: 32%/7%), fatigue (T: 19%/6% vs S: 15%/3%), and weight decrease (T: 18%/1% vs S: 17%/2%). Dose reduction (T: 12% vs S: 42%) and interruption (T: 18% vs S: 35%) rates were lower in the T arm and similar to the ITT population. Conclusions: T demonstrated significant improvement in PFS and ORR compared with S in pts who had received no prior systemic therapy for metastatic RCC. T was generally well tolerated, with low rates of treatment-related reduction/interruption in this pre-specified subgroup of pts. Clinical trial information: NCT01030783.