tbuckley/cabot-search huggingface dataset:
An integrated analysis of three distinct IBC/non-IBC affymetrix gene expression data sets to study the transcriptional heterogeneity both between IBC and non-IBC and within IBC.
Authors: S. J. Van Laere, N. T. Ueno, P. Finetti, P. B. Vermeulen, A. Lucci, D. Birnbaum, F. Robertson, T. Iwamoto, P. A. van Dam, W. A. Woodward, P. Viens, L. Y. Dirix, J. M. Reuben, F. Bertucci
Journal: Journal of Clinical Oncology (2011)

10571 Background: Studies have applied expression profiling to inflammatory breast cancer (IBC). Most of these studies were underpowered, mainly because IBC sample sizes were small. Here, we present an integrated analysis of 3 distinct gene expression data sets of IBC and nIBC samples – thus with enhanced power - to further uncover the molecular biology of IBC. Methods: 3 Affymetrix expression data sets of 137 IBC and 252 nIBC samples were integrated, normalized, summarized and quality-controlled. Samples were classified according to the molecular subtypes. IBC-specific heterogeneity was investigated using clustering, coupled with silhouette analysis. Supervised analyses were performed in non-stage-, stage-, and molecular subtype-matched approaches. IBC-specific activated pathways, miRNA-families, and transcription factors were identified with a target gene analysis approach. Results: 4 Robust IBC sample clusters were identified, associated with the molecular subtypes, predominated by the combined Basal-like, ErbB2+, and Luminal B subtypes (~70% vs. ~40% in non-IBC; P<0.0001). When comparing IBC to nIBC, stage-matched and non-stage-matched differences were identified (global test, P<0.0001). When comparing IBC with nIBC samples within each of the molecular subtypes, differences persisted only within the luminal A and normal-like subtypes (global test, P<0.0001 and P=0.046, resp.). Target gene analysis identified two molecular pathways (TGFb and INFa), 16 transcription factors (e.g. NKX2.2, FOXM1), and 10 miRNA families that were differentially activated in IBC and nIBC (FDR<0.01) but not between the 4 IBC sample clusters. Conclusions: We show that IBC is indeed transcriptionally heterogeneous and that differences between IBC and nIBC are predominated by the differences in the distribution of the molecular subtypes. Taking this into account, we were able to more accurately spot IBC-specific changes in pathway, miRNA, and transcription factor activation.
An analysis of sodium <sup>18</sup>f-fluoride PET/CT and prostate specific antigen (PSA) changes in men with metastatic castration resistant prostate cancer (mCRPC).
Authors: Julius Strauss, Mark Ahlman, Fatima Karzai, Christopher Ryan Heery, Lisa M Cordes, Sheri McMahon, Anna Couvillon, Myrna Rauckhorst, Chrisa Thomas, Marc Robert Theoret, Jennifer L. Marte, Corina Millo, Maria Liza Lindenberg, Ismail B. Turkbey, Peter L. Choyke, William Douglas Figg, Jeffrey Schlom, William L. Dahut, James L. Gulley, Ravi Amrit Madan
Journal: Journal of Clinical Oncology (2016)

203 Background: Recently there has been growing evidence that 18 F-Fluoride PET/CT has increased sensitivity relative to technetium-99m diphosphonate (Tc-99m MDP) bone scan for evaluating metastatic bone disease. This analysis studied changes in 18 F-Fluoride PET/CT and evaluated associations with PSA changes for mCRPC patients (pts) on enzalutamide (enz). Methods: As part of a randomized phase II study evaluating enz with or without vaccine therapy, men with mCRPC electively underwent 18 F-Fluoride PET/CT at 3 month (mos) intervals [NCT01867333]. At these points serum PSA was collected. Data was taken on max SUV and volume of presumed cancerous lesions and a variable, Σ SUV*Volume , was calculated which was defined as the sum of the products of SUV max and volume of cancerous lesions. Results: At the time of our analysis, 19 pts had PSA and PET/CT data for at least 2 time points within 1 year of initiating therapy. The median baseline PSA was 19.6 ng/ml (0.76-587). All pts had predominantly bone disease with 10 having small volume lymphadenopathy. Only 1/19 pts progressed by PSA Working Group criteria. An analysis found that 18/19 pts (95%) had an association between changes in PSA and Σ SUV*Volume . Of these 18 pts, 13 had a major ( &gt; 50%) and 1 had a minor ( &gt; 30%) PSA response and all 14 had an accompanying decrease in Σ SUV*Volume. For 11/14 pts with PSA responses, the change in Σ SUV*Volume paralleled the change in PSA at all time points, while for 3 pts an associated change between Σ SUV*Volume and PSA was delayed by 3 mos. 4/14 pts had short term responses lasting only 3 mos followed by PSA increases. For these 4 pts the changes in Σ SUV*Volume paralleled PSA changes, decreasing at 3 mos and increasing thereafter. Finally 4/18 patients had no PSA response to therapy. All 4 pts had increases in Σ SUV*Volume which paralleled rising PSA values. Conclusions: Preliminary data from a small cohort suggests that findings on 18 F-Fluoride PET/CT are associated with PSA changes. This represents a substantial difference from standard Tc-99m MDP and further suggests that 18 F-Fluoride PET/CT may provide a more sensitive analysis of bone disease. Additional data from this and other studies are required.
Early detection of colorectal cancer: A proteomic screening study for plasma biomarkers.
Authors: Stine Buch Thorsen, Martin Lundberg, Erika Assarsson, Nick Gee, Mick Knowles, Ib Jarle Christensen, Hans J. Nielsen, Bjorn Ekstrom, Claes Andersson, Mats Gustafsson, Nils Brünner, Jan Stenvang, Simon Fredriksson
Journal: Journal of Clinical Oncology (2012)

415 Background: Colorectal cancer (CRC) is the third most frequent cancer disease in the US. As the 5 year survival is closely associated to stage of disease at the time of diagnosis, patients with localized tumor limited to the colon or rectum have more than 90% chance of 5 year survival, while tumors spreading to regional lymph nodes or to distant organs, have a 5 year survival rate of 69% and 12%, respectively. Since late diagnosis is equal to a poor prognosis for the patients, biomarker guided early detection could make a difference for these patients. One strategy is blood based assays, where we hypothesis that a tumor and its microenvironment will lead to a deposition of specific proteins in the blood. However, due to the complexity of plasma, it is not only a biological but also a technical challenge to detect the proteins specific for CRC. Consequently, we combined the technical evaluation of multiplex proximity probing assays (PPA) with the search for relevant biomarkers for CRC. Each of the protein assays were based on thorough literature studies on the biology of CRC. Methods: Proteins were measured using multiplex PPA. Each assay was constructed from commercially available antibodies conjugated to two DNA oligonucleotides. When the antibodies from one assay bind the target protein simultaneously, it enables the DNA oligonucleotides to be either enzymatic ligated or extended to a PCR amplicon. This PCR amplicon reflects the identity of the proteins and can be quantified by real-time PCR. We evaluated the assays and searched for potential early markers using a collection of case-control plasma samples from a larger endoscopy study. In total we measure the levels of 150 different proteins in 296 human plasma samples from 74 CRC patients, 74 healthy individuals, 74 adenoma patients, and 74 patients with non-cancer diseases. Results: We have a successrate of 80%, the sensitivity is for most assays below 5 pM, and we find no cross-reactivity in chicken plasma for any of the assays. We previous reported that CEA, TIMP-1, CA242, and IL8 were upregulated in CRC plasma. These proteins were also identified in our extended study and the data will be presented. Conclusions: We find potential early markers, which we will validate in new sample material.
Health-related quality of life (HRQOL) in the Nordic randomized trial of adjuvant intermediate-dose interferon alfa-2b in high-risk melanoma.
Authors: J. Hansson, S. Aamdal, L. Bastholt, M. Hernberg, B. Nilsson, U. K. Stierner, H. von der Maase, Y. Brandberg
Journal: Journal of Clinical Oncology (2011)

8547 Background: A total of 855 patients with histologically verified resected cutaneous melanoma in AJCC stage IIb (T4 N0 M0) or stage III (Tx N1-3 M0) were randomized to: Arm A: Observation only (n=284), to Arm B: One year treatment - Induction: IFN-α2b, 10 MU (flat dose), SC, 5 days/w, 4 weeks, Maintenance: IFN-α2b, 10 MU (flat dose), SC, 3 days/w for 12 months (n=285), or to Arm C: Two years treatment - Induction: Same as arm B Maintenance: IFN- α2b, 10 MU (flat dose), SC, 3 days/w for 24 months (n=286). Adjuvant intermediate-dose IFN-a2b was delivered with moderate and expected toxicities in both 1- and 2 year treatment arms. No significant effect of adjuvant IFN treatment on overall survival was observed (J Hansson et al. Lancet Oncol, 12: 144-152, 2011). Aim: To compare HRQOL between the three randomization arms during two years from inclusion in the study. Methods: HRQOL was assessed by the EORTC-QLQ C30 questionnaire before randomization, and at 3, 6, 9, 12, 16, 20 and 24 months after inclusion. Questionnaire completion rate was high at all points of assessment (>80%). Results: Overall, Arm A improved or remained at the same level as at inclusion, while functioning and quality of life decreased and symptoms increased during treatment in Arms B and C. Arm B improved, reaching levels comparable to Arm A, between months’ 12 and 16 assessments when IFN alfa-2b treatment was stopped. In the longitudinal analyses, statistical significant interactions between randomization arm and time were found for all the HRQOL scales, indicating that treatment effect differed over time (p<0.001). Conclusions: The results of this study revealed significant effects of IFN alfa-2b treatment on HRQOL. The impact on HRQOL is important to consider as part of the decision process on whether or not to use adjuvant Interferon.
A randomized, double-blind, placebo-controlled phase III study of ramucirumab versus placebo as second-line treatment in patients with hepatocellular carcinoma and elevated baseline alpha-fetoprotein following first-line sorafenib (REACH-2).
Authors: Andrew X. Zhu, Peter R. Galle, Masatoshi Kudo, Richard S. Finn, Ling Yang, Paolo Abada, Shao-Chun Chang, Josep M. Llovet
Journal: Journal of Clinical Oncology (2016)

TPS478 Background: Ramucirumab (Ram) is a human IgG1 monoclonal antibody that inhibits ligand activation of the vascular endothelial growth factor receptor 2 (VEGFR2). The Phase 3 REACH study assessed Ram in the treatment of patients with advanced hepatocellular carcinoma (HCC) after prior sorafenib. Ram was well tolerated. A significant improvement in overall survival (OS) in the overall population (N = 565) was not demonstrated (Hazard Ratio [HR] = 0.866; p = 0.1391). However, a meaningful improvement in OS was observed in the pre-specified subgroup of patients with baseline alpha-fetoprotein (AFP) ≥ 400 ng/mL (N = 250)(HR = 0.674; p = 0.0059) and warrants confirmation. Methods: REACH-2 is a randomized, double-blind, placebo-controlled phase III study of Ram and best supportive care (BSC) versus placebo and BSC in patients with HCC and elevated baseline AFP following prior therapy with sorafenib. Eligible patients will be randomized 2:1 to receive Ram (8mg/kg, IV) or placebo on Day 1 of each 14-day cycle until disease progression or other discontinuation criteria. Eligible patients must have a diagnosis of HCC (tissue or tumor with classical imaging characteristics); prior sorafenib; Child-Pugh score &lt; 7; Barcelona Clinic Liver Cancer Stage C or Stage B disease not amenable/refractory to locoregional therapy; AFP ≥ 400 ng/mL; ECOG performance status &lt; 2. Patients with history of encephalopathy, ongoing clinically meaningful ascites, liver transplant, or hepatic locoregional therapy after sorafenib are not eligible. The primary objective is to assess the OS for patients treated with Ram versus placebo, and assumes an OS HR of 0.7 (85% power; 2 sided type I error 0.05). Target enrollment is 399 patients with the primary analysis at 318 events (20% censoring). Secondary objectives include progression free survival, objective response rate, safety, and patient focused outcomes. Additional objectives include assessment of biomarkers relevant to angiogenesis and HCC. Clinical trial information: NCT02435433.
Gemcitabine (G) and nab-paclitaxel (nab-P) in patients with refractory advanced pancreatic cancer (PC).
Authors: Vinicius Ernani, Ikechukwu Immanuel Akunyili, Peter Joel Hosein, Jessica Macintyre, Caio Max S. Rocha Lima
Journal: Journal of Clinical Oncology (2012)

373 Background: There is no standard chemotherapy regimen for PC patients who have progressed on G and fluoropyrimidine-based therapy. Single agent nab-P had limited activity on a second-line phase II trial in PC. Synergistic preclinical studies with G and taxanes have been reported. Nab-P targets stromal cells and leads to improved delivery of chemotherapy to PC cells. The combination of G + nab-P might be an effective approach in pretreated PC. Methods: A retrospective analysis of advanced refractory PC patients treated from Sep 2010 to Aug 2011 with the combination of G + nab-P was performed at the Sylvester Comprehensive Cancer Center. Patients received G 1000mg/m 2 and nab-P 100mg/m 2 on D1, 8 and 15 of a 28 day cycle. Treatment response was assessed by review of imaging studies using the RECIST criteria, CA19-9 response and symptomatic improvement. The progression-free survival (PFS) and overall survival (OS) were calculated from time of commencement of G + nab-P until documented progression or death respectively. Results: 10 patients were treated with G + nab-P; 60%, 30% and 10% of patients had received 3, 2 and 1 prior chemotherapy regimen. 90% and 80% received prior G or fluoropyrimidine-based regimen respectively. Therapy was discontinued in one patient following only one dose of G + nab-P (Cycle 1, day 1) due to grade 2 thrombocytopenia. The remaining 9 patients received a median of 4 cycles. Two (22.2%) patients had confirmed PR, 3(33.3%) patients had confirmed stable disease while 4 (44.4%) patients progressed on therapy. The median PFS was 13.7 weeks. The median PFS was 20 weeks in patients with PR or SD and 9.9 weeks in patients with PD. Recurrent malignant ascitis resolved in a patient with peritoneal carcinomatosis. Treatment was well tolerated; grade 3-4 hematologic toxicity included anemia, thrombocytopenia and neutropenia in 2, 1 and 2 patients respectively. 70% of patients required G-CSF support. Non hematologic Grade 3-4 toxicities included fatigue, peripheral neuropathy; nausea and vomiting in 3, 2 and 1 patient respectively. Conclusions: G + nab-P resulted in clinical benefit in half of this group of advanced PC patients who had previously progressed on G and fluoropyrimidine-based regimens.
HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.
Authors: Francesco Sclafani, Amitesh Chandra Roy, Ian Chau, Andrew Wotherspoon, Clare Peckitt, Alice Dewdney, Jacqueline Rose Oates, David Cunningham
Journal: Journal of Clinical Oncology (2013)

e14616 Background: HER-2 is a well established therapeutic target in breast and gastric cancer. The role of HER-2 in rectal cancer is unclear, as conflicting data on prevalence of HER-2 expression have been reported. Preclinical data indicate a potential role of HER-2 in mediating resistance of rectal cancer to chemoradiotherapy and cetuximab. This analysis evaluates the prevalence of HER-2 and its impact on the outcome of high risk rectal cancer patients treated with neoadjuvant CAPOX and CRT ± cetuximab in EXPERT-C. Methods: Eligible patients with available tumour tissue for HER-2 analysis were included. HER-2 expression was determined by immunohistochemistry (IHC) in biopsy and/or surgical specimens (score 0 to 3+). Tumours with equivocal IHC result (2+) were tested for HER-2 amplification by B-DISH. Tumours with IHC 3+ or B-DISH ratio ≥2.0 were classified as HER-2 positive. The impact of HER-2 on primary (CR) and secondary endpoints (RR, PFS, OS) of the study was analyzed. Results: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3/104 (2.9%) and 3/114 (2.6%) were HER-2 positive, respectively. In 77 patients with paired specimens, concordance for HER-2 status was found in 74 (96%). Overall 141 patients were assessable for HER-2; 6/141 (4.3%) had a HER-2 positive tumour in at least 1 specimen. The median follow-up was 58.7 months. HER-2 expression or amplification was not associated with a difference in outcome for any of the study endpoints, including in the subset of 90 KRAS/BRAF wild type patients treated ± cetuximab. In an exploratory analysis, 44 IHC 0/1+ random specimens were tested by B-DISH and HER-2 amplification was found in 3/38 (7.9%, insufficient material in 6 cases). Conclusions: Based on the low prevalence of expression (according to the classical criteria for defining HER-2 positivity) as recorded in EXPERT-C, HER-2 does not appear to represent a useful therapeutic target for high risk rectal cancer. We did not confirm the role of HER-2 as prognostic factor or potential predictive biomarker for cetuximab-based treatment.
Randomized phase II trial of first-line gefitinib, gemcitabine or docetaxel in performance status (PS) 2 or 3 non-small-cell lung cancer (NSCLC) patients (IFCT-0301)
Authors: J. Morere, V. Westeel, F. Morin, V. Gounant, B. Lebeau, F. Vaylet, F. Barlesi, T. Urban, J. M. Brechot, D. Morot- Sibilot
Journal: Journal of Clinical Oncology (2008)

8086 Background: PS 2 or 3 patients are usually excluded from clinical trials. Optimal treatment in this setting remains a challenge. The aim of this study was to evaluate 3 monotherapy modalities. Methods: PS 2 or 3 patients with confirmed stage IIIB or IV NSCLC were enrolled into a multicenter randomized phase II trial: arm A, gefitinib (250 mg/day, every 3 weeks), arm B gemcitabine (1250 mg/m², day 1 and 8, every 3 weeks) and arm C docetaxel (75 mg/m², day 1, every 3 weeks). Treatments were maintained until progression or unacceptable toxicity. Second-line treatment consisted of: arm A, docetaxel (75 mg/m², day 1, every 3 weeks) and arm B and C, gefitinib (250 mg/day). The primary endpoint was Progression-Free Survival (PFS). Results: Between December 2004 and June 2007, 128 patients were enrolled. The characteristics of the 127 eligible patients (43 in arm A, 42 in arm B and 42 in arm C) were balanced: median age 71 years (range 30–80), male 83 %, PS=2 69%, PS=3 31%, adenocarcinoma 49%, squamous cell 28%, stage IV 82%, stage IIIB 18%, 72 % of patients had at least a 5% weight loss. The median number of cycles administered was 2 in arm A, 2 in arm B and 3 in arm C. 46 patients received a second-line treatment (12 in arm A, 13 in arm B and 21 in arm C). PR and stable disease rates were 20.9 % in arm A, 33.4% in arm B and 38.1% in arm C. Median PFS was 1.9 months in arm A, 2.1 in arm B and 2 in arm C. Median overall survival was 2.2 months in arm A, 2.4 in arm B and 3.5 in arm C. In PS 2 patients, median overall survival was 3.4 months in arm A, 3.2 in arm B and 6.6 in arm C. The number of fatal events related to treatment was: 3 in patients treated with docetaxel (febrile neutropenia) and 1 patient treated with gefitinib (bowel obstruction). Grade 4 toxicity occurred in 4% of patients in arm A, 14% in arm B and 11% in arm C. Conclusions: Docetaxel, gemcitabine or gefitinib were well tolerated and showed comparable PFS in this poor prognosis population. There was a trend in favour of first line docetaxel regarding overall survival in the entire population and in the subgroup of PS 2 patients. Survival results will be updated for the conference. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Lilly, sanofi-aventis Lilly
Peer review in radiotherapy (RT): A national quality improvement initiative.
Authors: Michael Donald Brundage, Brenda H Bass, Sophie Foxcroft, Ross Halperin, Thomas McGowan, Michael F. Milosevic, Matthew Parliament, Padraig Richard Warde
Journal: Journal of Clinical Oncology (2014)

221 Background: Peer review (PR) in Radiation Oncology has been shown to be effective in improving quality of treatment by detecting and correcting deficiencies in proposed treatment plans prior to treatment. PR is also effective in: guiding departmental treatment planning policies and processes; reducing variation in practice; providing a venue for multi-disciplinary communication, and increasing staff and trainee awareness of evolving treatment processes. The importance of PR is reflected in the inclusion of 3 PR-specific quality indicators in the Canadian Partnership for Quality Radiotherapy QA Guidelines for Radiation Oncology programs. Given this endorsement, we aim to enhance PR implementation across all Canadian cancer centres using a knowledge-translation and implementation framework. Methods: This project will facilitate increased uptake of PR in Canadian RT programs by implementing the top-down model used with success in Ontario. This model has several key components, including: a) engaging the leadership of provincial cancer agencies to promote PR at every Provincial cancer centre; b) providing modest financial support for the acquisition of the required hardware and/or staff time for coordinating PR activities; c) systematic collection of each centre’s baseline PR activities, perceived barriers and potential facilitators of PR at each centre; d) creation of a continuous quality improvement cycle by monitoring PR quality indicators over time; e) systematic knowledge and information sharing regarding effective PR processes. Results: Funding for this initiative was obtained from the Canadian Partnership against Cancer (CPAC) in April 2014. A steering committee consisting of stakeholders from across Canada has been struck and provincial launches, based on the tenets used in Ontario, have commenced in 7 of 13 provinces with others expressing interest. A national survey to obtain baseline data relating to PR activities, perceived barriers, and facilitators is underway and will be reported. Conclusions: Preliminary evidence suggests a “snowball effect” of increasing PR uptake across Canada. The implementation model could be applied in other jurisdictions interested in increasing PR in radiation oncology.