tbuckley/cabot-search huggingface dataset:
Differential gene expression analysis and correlation with outcome in HER2-positive metastatic breast cancer treated with HER2-targeted therapy.
Authors: S. S. Badve, L. Li, M. A. Thorat, R. C. Gagnon, C. E. Ellis, J. O'Shaughnessy, K. L. Blackwell, J. Baselga, G. W. Sledge
Journal: Journal of Clinical Oncology (2010)

1036 Background: Improvement in progression-free (PFS: HR: 0.73; p=0.008) and overall survival (OS: HR: 0.74; p=0.026) was demonstrated with the combination of lapatinib (L) plus trastuzumab (T) in comparison with L alone in a randomized, phase III study of 296 women (198 per arm) with HER2-positive metastatic breast cancer (MBC) that progressed on a median of 3 prior T-based therapies. Gene expression analysis was conducted on tumor tissue from this study to identify genes correlating with efficacy outcome parameters. Methods: Tumor tissue from primary breast tumor or metastatic sites was obtained in the form of formalin-fixed, paraffin-embedded (FFPE) material. Manual microdissection was performed on 10μ m sections to isolate tumor tissue. RNA was extracted using the High Pure RNA Paraffin kit (Roche). Using 200ng of total RNA, cDNA-mediated annealing, selection, and ligation (DASL) assay (Illumina Corp) was performed to determine the expression of 502 cancer associated genes. PFS and OS were analyzed using proportional hazards regression models that included covariates found to significantly impact PFS and OS. Results: Of the 156 patients with adequate tumor tissue remaining, 133 had material suitable for DASL profiling and were representative of the entire study population (68 received L; 65 received L+T). When treatment arms were combined, higher expression of genes mapping to extracellular matrix and adhesion pathways associated with worse PFS whereas higher expression of HER2 correlated with improved PFS. Genes that mapped to pathways involved in cell cycle regulation and cytoskeletal remodeling were among the genes that associated with OS. Differential expression of HER2 was not associated with OS (p=0.16). Additional analyses will be reported. Conclusions: The determination of HER2 status, which subsequently directs treatment with HER2-targeted agents, may be feasible using RNA based assays. Gene expression analysis may be a valid approach in identifying transcriptional features that correlate with improved outcome following treatment with anti-cancer therapy thus individualizing treatment for patients with breast cancer. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline, Roche GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline
Phase II study of erlotinib + onartuzumab as first-line treatment for patients with MET-positive and EGFR-mutant NSCLC
Authors: Hiroshi Sakai, Kazuma Kishi, Takashi Seto, Toshiyuki Kozuki, Makoto Nishio, Fumio Imamura, Hiroshi Nokihara, Miyako Satouchi, Takashi Tahata, Kazuhiko Nakagawa
Journal: Annals of Oncology (2015)
Who detects melanoma? Impact of detection patterns on characteristics and prognosis of patients with melanoma
Authors: José Antonio Avilés-Izquierdo, Irene Molina-López, Enrique Rodríguez-Lomba, Ivan Marquez-Rodas, Ricardo Suarez-Fernandez, Pablo Lazaro-Ochaita
Journal: Journal of the American Academy of Dermatology (2016)
Association of disease progression on ibrutinib therapy with the acquisition of resistance mutations: A single-center experience of 267 patients.
Authors: Jennifer Ann Woyach, Amy S. Ruppert, Gerard Lozanski, Arletta Lozanski, Nyla A. Heerema, Weiqiang Zhao, Lynne Abruzzo, Amber Gordon, Jeffrey Alan Jones, Joseph M. Flynn, Samantha Mary Jaglowski, Leslie A. Andritsos, Farrukh Awan, Kristie A. Blum, Michael R. Grever, Amy J. Johnson, John C. Byrd, Kami J. Maddocks
Journal: Journal of Clinical Oncology (2014)

7010 Background: The Bruton’s Tyrosine Kinase (BTK) inhibitor ibrutinib (I) is very effective in chronic lymphocytic leukemia (CLL), with progression free survival of 76% at 26 months (mo) for patients (pts) with relapsed disease (Byrd J et al, NEJM 2013). We evaluated pts treated with I to explore features associated with progressive disease (PD) and subsequent outcomes. Methods: 267 pts from The Ohio State University Comprehensive Cancer Center participating in 3 previously reported Institutional Review Board approved trials of I were included; 196 pts received single agent I and 71 received I plus ofatumumab. A subset of pts with PD had Ion Torrent deep sequencing (DS) performed on peripheral blood at baseline and relapse. Results: With a median follow-up of 16 mo (<1 mo-42 mo), 201 pts remain on I, and 66 have discontinued due to PD (24), infection (22), toxicity (8), transplant (4), or other (8). PD includes Richter’s transformation (RT; n=16) or progressive CLL(n=8). RT tended to occur early, with 10 pts transforming prior to 12 mo of I. CLL progression tended to occur later, with 1 pt relapsing prior to 12 mo of I. 9 RT pts have died, with 6 deaths occurring within 1 mo without further therapy. Of pts with CLL PD, only 3 of 8 have died at day 25, 142, and 180 after going off study. 3 patients have survived >1 year after PD. 6 pts with CLL PD received further therapy <2 mo post PD, most in ≤ 2 weeks. DS on 4 pts with RT revealed 2 with mutations in BTK and 2 without mutations in BTK or PLCγ2. DS on 6 pts with CLL PD revealed BTK or PLCγ2 mutations in all. 1 pt had both BTK C481S and 3 mutations of PLCγ2, 2 had BTK C481S (1 previously reported; Chang B et al, ASCO 2013), 1 had BTK C481F, and 1 had PLCγ2 R665W (previously reported). An additional 2 pts who have relapsed outside of these studies both have BTK C481S. Conclusions: This single institution experience with I confirms it to be a well tolerated and effective therapy. Patients with PD require therapy quickly due to rapid disease progression. These DS confirm initial reports associating mutations in BTK and PLCγ2 with PD, and require further study in larger populations.
Early Diagnosis of Brain Metastases Using a Biofluids-Metabolomics Approach in Mice
Authors: James R. Larkin, Alex M. Dickens, Timothy D. W. Claridge, Claire Bristow, Kleopatra Andreou, Daniel C. Anthony, Nicola R. Sibson
Journal: Theranostics (2016)

Over 20% of cancer patients will develop brain metastases.Prognosis is currently extremely poor, largely owing to late-stage diagnosis.We hypothesized that biofluid metabolomics could detect tumours at the micrometastatic stage, prior to the current clinical gold-standard of blood-brain barrier breakdown.Metastatic mammary carcinoma cells (4T1-GFP) were injected into BALB/c mice via intracerebral, intracardiac or intravenous routes to induce differing cerebral and systemic tumour burdens.B16F10 melanoma and MDA231BR-GFP human breast carcinoma cells were used for additional modelling.Urine metabolite composition was analysed by 1 H NMR spectroscopy.Statistical pattern recognition and modelling was applied to identify differences or commonalities indicative of brain metastasis burden.Significant metabolic profile separations were found between control cohorts and animals with tumour burdens at all time-points for the intracerebral 4T1-GFP time-course.Models became stronger, with higher sensitivity and specificity, as the time-course progressed indicating a more severe tumour burden.Sensitivity and specificity for predicting a blinded testing set were 0.89 and 0.82, respectively, at day 5, both rising to 1.00 at day 35.Significant separations were also found between control and all 4T1-GFP injected mice irrespective of route.Likewise, significant separations were observed in B16F10 and MDA231BR-GFP cell line models.Metabolites underpinning each separation were identified.These findings demonstrate that brain metastases can be diagnosed in an animal model based on urinary metabolomics from micrometastatic stages.Furthermore, it is possible to separate differing systemic and CNS tumour burdens, suggesting a metabolite fingerprint specific to brain metastasis.This method has strong potential for clinical translation.
WASP, Tregs, and food allergies — rare disease provides insight into a common problem
Authors: Yun Liang, Johann E. Gudjonsson
Journal: Journal of Clinical Investigation (2016)

Dysregulation of the type 2 immune system presents with various manifestations, including allergic inflammation, and has emerged as an alarming public health issue. The pathological mechanisms that underlie T helper type 2 cell-driven (Th2-driven) allergic diseases remain unclear. In particular, it is not completely understood how type 2 immunity is restricted in inflammatory responses. In this issue of the JCI, Lexmond et al. use Wiskott-Aldrich syndrome as a model disease and establish that the Wiskott-Aldrich gene product (WASP) serves an essential role in T regulatory cells to contain Th2 effector cell differentiation and prevent allergic sensitization to dietary antigens.
Sodium Excretion, Cardiovascular Disease, and Chronic Kidney Disease
Authors: Jaume Almirall
Journal: JAMA (2016)

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P2-037: Estrogen and progesterone receptors in women with non-small-cell lung cancer: a potential therapeutic target?
Authors: Katia Bencardino, Mariangela Manzoni, Sara Mariucci, Patrizia Morbini, Sara Delfanti, Sofia Chatzileontiadou, Bianca Rovati, Caterina Nascimbene, Ernesto Pozzi, Marco Danova
Journal: Journal of Thoracic Oncology (2007)
Chemotherapy plus cetuximab in patients with liver-limited or non-liver-limited <i>KRAS</i> wild-type colorectal metastases: A pooled analysis of the CRYSTAL and OPUS studies.
Authors: Claus-Henning Kohne, Carsten Bokemeyer, Gunnar Folprecht, Ute Sartorius, Michael Schlichting, Philippe R Rougier, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2012)

3562 Background: In the CRYSTAL and OPUS studies, adding cetuximab (cet) to first-line chemotherapy (CT) improved clinical benefit in patients (pts) with KRAS wild-type (wt) metastatic colorectal cancer. In a pooled analysis of these trials the benefit of treatment according to whether pts had liver-limited disease (LLD) or non-LLD was analyzed. Methods: Cox‘s proportional hazards model for overall survival (OS) and progression-free survival (PFS) or logistic regression model for best overall response and R0 resection were used on individual pt data, stratified by study. Likelihood ratio tests were used to explore interactions. Results: Adding cet to CT significantly improved PFS and overall response rate (ORR) in LLD pts, and OS, PFS and ORR in non-LLD pts and increased R0 resection rates (table). No treatment-by-study interactions were found. Treatment effects did not vary significantly by LLD status (PFS p=0.60, OS p=0.68, ORR p=0.0737, R0 resection p=0.71). However LLD vs non-LLD pts had improved outcome in each treatment arm: PFS, CT hazard ratio, HR=0.74, p=0.0910; CT + cet HR=0.66, p=0.0309; OS, CT HR=0.70, p=0.0091; CT + cet HR=0.74, p=0.0388; ORR, CT odds ratio=1.20, p=0.47, CT + cet odds ratio=2.32, p=0.0015; R0 resection, CT odds ratio=3.15, p=0.0496, CT + cet odds ratio=3.82, p=0.0018. Kaplan Meier survival plots will be shown. Conclusions: The OS benefit from adding cet to CT is more pronounced in non-LLD pts, thus strengthening the value of cet in palliative treatment.LLD status is associated with improved prognosis and may be predictive for response in pts receiving CT + cet, facilitating potentially curative resection. More pts (with R0 resection and longer follow-up) may be needed to confirm an OS benefit from CT + cet in LLD pts. [Table: see text]
Oral cinacalcet HCI (AMG 073) for the treatment of hemodialysis patients with secondary hyperparathyroidism (HPT): Results of a European/Australian-Phase 3 study
Authors: Alm de Francisco, M Suranyi, J Cunningham, P Messa, F Locatelli, Pieter Evenepoel, A Fournier, MT Gonzalez, P Urena, H Holzer, HS Brink, D Johnson, Zani, N Baker, SA Turner, T Drueke
Journal: Journal of the American Society of Nephrology (2003)
Induction of pathologic complete response by long-term neoadjuvant chemotherapy for gastric cancer: Early results of a randomized phase II study—A COMPASS trial.
Authors: Kazuaki Tanabe, Takaki Yoshikawa, Akira Tsuburaya, Kazuhiro Nishikawa, Seiji Ito, Takanori Matsui, Haruhiko Cho, Yuichi Ito, Takahisa Suzuki, Satoshi Morita, Yumi Miyashita, Junichi Sakamoto
Journal: Journal of Clinical Oncology (2013)

71 Background: Prognosis for stage III gastric cancer was not satisfactory even by D2 gastrectomy followed by S-1 adjuvant chemotherapy. Neoadjuvant chemotherapy will be another promising approach to improve the survival as demonstrated in some European trials, however, optimal duration and regimen have not been clarified yet. Methods: This trial compared efficacy of neoadjuvant chemotherapy using two and four courses of SC regimen; S-1 (80 mg/m2 for 21 days with 1 week rest) / cisplatin (60 mg/m2 at day 8), or PC regimen; paclitaxel / cisplatin (80 mg/m2 and 30 mg/m2, respectively at days 1, 8, and 15 with 1 week rest), by a two by two factorial design for stage II schirrhous / junctional tumors, stage III, or resectable stage IV. The primary endpoint was 3-year OS. Key secondary endpoints included pathological / clinical response, R0 resection, and adverse events. Sample size was set at 60 to 80 to achieve 10% improvement of 3-year OS by four courses or by PC with approximately 80% probability of the correct selection. Results: Between Oct 2009 and July 2011, 83 patients were assigned to arm A (2 courses of SC, n=21), arm B (4 courses of SC, n=20), arm C (2 courses of PC, n=21), and arm D (4 courses of PC, n=21). Clinical response (arm A/B/C/D) was 29%/40%/33%/24%. R0 resection (arm A/B/C/D) was 76%/75%/57%/76%. Pathological response (arm A/B/C/D), defined as tumor regression more than two third in the primary tumor, was 43%/40%/29%/38%. Pathological complete response (arm A/B/C/D) was 0%/10%/0%/10%. Major grade 3/4 toxicities (arm A/B/C/D) were anemia (14%/15%/0%/28.6%), neutropenia (10%/15%/14%/33%), nausea (0%/10%/5%/5%), and appetite loss (5%/10%/0%/5%). No surgical mortality was observed. Grade 3 morbidity classified by Clavien-Dindo was leakage in 5% (arm A), pancreatic fistula in 5% (arm C), and postoperative hemorrhage in 5% (arm B). Conclusions: This randomized phase II study suggested that pathological complete response could be induced by long-term neoadjuvant chemotherapy without increase of toxicities regardless of SC or PC regimen. Clinical trial information: UMIN000002595.
Genomic Amplification of <i>CD274</i> (PD-L1) in Small-Cell Lung Cancer
Authors: Julie George, Motonobu Saito, Koji Tsuta, Reika Iwakawa, Kouya Shiraishi, Andreas H. Scheel, Shinsuke Uchida, Shun-ichi Watanabe, Ryo Nishikawa, Masayuki Noguchi, Martin Peifer, Se Jin Jang, Iver Petersen, Reinhard Büttner, Curtis C. Harris, Jun Yokota, Roman K. Thomas, Takashi Kohno
Journal: Clinical Cancer Research (2016)

Purpose: Programmed death ligand-1 (PD-L1), encoded by the CD274 gene, is a target for immune checkpoint blockade; however, little is known about genomic CD274 alterations. A subset of small-cell lung cancer (SCLC) exhibits increased copy number of chromosome 9p24, on which CD274 resides; however, most SCLCs show low expression of PD-L1. We therefore examined whether CD274 is a target of recurrent genomic alterations.Experimental Design: We examined somatic copy number alterations in two patient cohorts by quantitative real-time PCR in 72 human SCLC cases (cohort 1) and SNP array analysis in 138 human SCLC cases (cohort 2). Whole-genome sequencing revealed the detailed genomic structure underlying focal amplification. PD-L1 expression in amplified cases from cohorts 1 and 2 was further examined by transcriptome sequencing and immunohistochemical (IHC) staining.Results: By examining somatic copy number alterations in two cohorts of primary human SCLC specimens, we observed 9p24 copy number gains (where CD274 resides) and focal, high-level amplification of CD274 We found evidence for genomic targeting of CD274, suggesting selection during oncogenic transformation. CD274 amplification was caused by genomic rearrangements not affecting the open reading frame, thus leading to massively increased CD274 transcripts and high level expression of PD-L1.Conclusions: A subset (4/210, 1.9%) of human SCLC patient cases exhibits massive expression of PD-L1 caused by focal amplification of CD274 Such tumors may be particularly susceptible to immune checkpoint blockade. Clin Cancer Res; 23(5); 1220-6. ©2016 AACR.
Breast cancer testing strategies and the utilization of targeted therapies: Data from the real world
Authors: J. Haas, K. A. Phillips, M. J. Hassett, S. Liang, C. Keohane, J. Armstrong, M. Toscano
Journal: Journal of Clinical Oncology (2009)

e17518 Background: HER2 testing and the use of trastuzumab is considered a prototype for the translation of a genomic therapy, yet almost nothing is known about use in practice. Uncertainties about the performance of the two types of HER2 tests, immunohistochemistry (IHC) and fluorescence-in-situ-hybridization (FISH) have led to debate about how best to identify women who are most likely to benefit from this costly treatment. Similarly, little is known about the use of gene expression profiling (GEP - e.g., OncotypeDx), which offers the possibility of better recurrence estimation to tailor the use of adjuvant chemotherapy. Methods: Cross-sectional record review of women, 36–64 years, with a new diagnosis of breast cancer in 2006–2007, identified using claims from a large, national health plan (n = 392 to date). Results: Almost all women had a HER2 test (97.7%): 56.2% had IHC alone, 17.4% had FISH alone, and 24.0% had both (2.4% had documentation of a test but not test type). Data for women with both IHC and FISH is shown below. Using the maximum of all available results, 24.9% were HER2-positive, 11.1% intermediate, and 63.9% HER2-negative. Only 55.2% of HER2-positive women received trastuzumab, compared to 16.7% of women with an intermediate score, and no HER2-negative women. The majority of women (85.7%) did not have GEP. Among women with GEP, 58.9% indicated low recurrence risk, 21.4% medium risk, and 5.4% high risk. Adjuvant chemotherapy was received by 27.3%, 91.7%, and 100% respectively (p &lt; 0.001). Conclusions: HER2 tests, primarily IHC, are widely used. There are discrepancies in classification of HER2 status based on IHC vs. FISH. We did not find evidence of overuse of trastuzumab by women who were HER2-negative. Further work should clarify whether the lack of trastuzumab for HER2-positive women is clinically appropriate. We found modest adoption of GEP, and GEP score was associated with the use of adjuvant chemotherapy. [Table: see text] No significant financial relationships to disclose.
Clinical outcome of resection of liver metastasis in patients with ovarian cancer
Authors: U. P. Neumann, C. Fotopoulou, P. Neuhaus, J. Sehouli
Journal: Journal of Clinical Oncology (2009)

e16545 Background: Hepatic resection has become the standard treatment for resectable colorectal liver metastases. However, in patients with ovarian cancer resectable liver metastases are rare and the issue is discussed controversially due to the lack of relevant published data. The aim of this retrospective study was to evaluate the efficacy of hepatic resections in patients with ovarian cancer. Methods: Between 1991 and 2006 a total of 73 women with liver metastases underwent surgery for ovarian cancer. The median age of the patients was 59 years. 18 patients had primary and 55 suffered from recurrent disease. The median follow-up was 7 months (1–145 months). In 40 patients a liver resection was performed. In the remaining 33 patients the disease was unresectable. Additional procedures were: hysterectomy 15.1%, bilateral salpingo-oophorectomy 24.7%, omentectomy 32.9%, colon resection 50.7%, small bowel resection 32.9%, gastric resection 5.5%, and pancreatic resection 9.6%. Results: Residual tumor after surgery was by far the strongest predictor for outcome. Median survival in patients with no residual tumor was 65 months, &lt; 0.5 cm 29 months, 1cm 6 months. This data clearly show that macroscopically complete surgical cytoreductive therapy improves long-term survival in patients with ovarian cancer and liver metastases. Conclusions: We still need to identify factors associated to complete debulking to minimize the number of ineffective operations. Therefore, liver resection should be always discussed if complete resection is achievable and should be part of the multimodal strategy in advanced ovarian cancer. No significant financial relationships to disclose.
P3-142: Epidermal growth factor receptor (EGFR) and KRAS mutations in non-small cell lung cancer (nsclc) patients treated with gefit-inib
Authors: Hee-Jung Sohn, Sang-We Kim, Jene Choi, Se Jin Jang, Dae Ho Lee, Cheolwon Suh, Jung-Shin Lee
Journal: Journal of Thoracic Oncology (2007)