tbuckley/cabot-search huggingface dataset:
The natural history of HER2-overexpressing (HER2+) metastatic breast cancer (MBC) treated with trastuzumab (T): Practical points to consider in developing treatment strategies.
Authors: Serena Di Cosimo, Danila Serpico, Anna Tessari, Luca Porcu, Leonardo Molino, Valter Torri, Filippo G. De Braud
Journal: Journal of Clinical Oncology (2014)

e11565 Background: Trastuzumab has dramatically improved the prognosis of patients with HER2+ BC. This study reports the practice patterns across different treatment lines and the major clinical outcome of MBC patients receiving T. Methods: We analyzed an institutional database containing the treatment history patients who received at least one trastuzumab-based regimen for HER2+ MBC. Time to progression (TTP) was evaluated for each line of therapy; a Cox regression model with treatment line as continuous predictor was evaluated, and a linear and a quadratic term were introduced in the model. Results: A total of 112 patients were analyzed. Median patient age was 50 (range 26 – 74) years, 16% were metastatic at debut, 71% presented with hormone receptor positive disease, 58% had soft tissue metastases (met), 49.5% visceral met, 42% bone met and 4.5% brain met. The median number of lines of treatment was 6 (range 1-17). A combination of chemo- and/or targeted-therapy was the most frequently used regimen across all lines of therapy (514 out of 664 lines, 77.4%). Remarkable, 21 out of 46 lines (45.7%) used T or lapatinib at the 10th line and beyond. The use of hormonotherapy increased as the line of therapy (OR=1.10, CI= 1.04-1.17, p=0.001) and was of choice in 20 out of 46 lines (43.5%) at the 10th line and beyond. With a median follow up of 4.2 yrs, a total of 524 TTP events among 610 (85.9%) lines were collected. Of note, the median TTP tended to decrease over treatment lines until reaching a plateau at the line number 9 (95%CI: 6-20; HRlinear term: 1.289, 95%CI: 1.173-1.416; HRquadratic term: 0.986; 95%CI: 0.978-0.993). Conclusions: These data suggest that most patients with HER2+ MBC benefit from late lines of therapy. It is in the author opinion that clinical research should focus not only in ameliorating the clinical outcome of recently diagnosed but also pretreated MBC patients.
Maintenance interleukin-2 (IL-2) and sargramostim (GM-CSF) following high-dose IL-2 (HD IL-2) therapy for metastatic melanoma.
Authors: Melinda Bernabe Chu, Mark Fesler, Eric Armbrecht, Scott Fosko, Eddy C. Hsueh, John M. Richart
Journal: Journal of Clinical Oncology (2013)

e20049 Background: At our institution, patients with metastatic melanoma who achieve partial response (PR) to HD IL-2 therapy undergo monthly maintenance treatment with IL-2 and GM-CSF with the thought that the continuous stimulation of the immune system may improve response. Our aim was to describe our experience with maintenance treatment following HD IL-2 therapy. Methods: A retrospective chart review was performed on patients with metastatic melanoma seen at Saint Louis University from January 1999-June 2011 who were partial responders to HD IL-2 therapy (720,000 IU/kg per dose intravenously; 14 doses, 2 cycles per course, maximum 2 courses) that received maintenance IL-2 therapy (continuous 42 hour infusion of three consecutive doses of 18,000,000 IU/m 2 over 6, 12 hours, then 24 hours) and GM-CSF (daily subcutaneous injection of 125 mcg/m 2 for 3 days) every 4 weeks for 13 cycles or until disease progression. Duration of response for this cohort was compared to established data for partial responders using the Mann-Whitney test. Results: Five patients were included in the analysis. Median duration of response was 9 months (3.9-53.4 months). Median overall survival was 20.6 months (15-53.4+ months). One patient who initially showed PR to HD IL-2 therapy converted to complete response during maintenance IL-2 and has the longest duration of response in the study dataset. Duration of response for the maintenance group (9 months) was longer than a benchmark of 5.9 months as reported in the literature and package insert for partial responders to HD IL-2 without maintenance therapy, p = 0.068. Conclusions: Subjects who received maintenance IL-2 and GM-CSF therapy had a longer duration of response compared to previous reports, which trended toward statistical significance in this small sample. Maintenance IL-2 and GM-CSF after HD IL-2 therapy may help to prolong partial response, possibly lead to conversion to complete response and is worthy of additional study.
Screening for aggressive prostate cancer: A single-center experience using the 4Kscore and multiparametric MRI for the detection of Gleason 7 or higher prostate cancer.
Authors: Vivek Venkatramani, Bruno Nahar, Tulay Koru-Sengul, Nachiketh Soodana-Prakash, Mark L. Gonzalgo, Chad Ritch, Dipen Parekh, Sanoj Punnen
Journal: Journal of Clinical Oncology (2017)

84 Background: While non-invasive biomarkers and multi-parametric MRI (mpMRI) are routinely used for prostate cancer detection, few studies have assessed their performance together. We evaluated the performance of mpMRI and the 4Kscore for the detection of significant prostate cancer. Methods: We identified a consecutive series of men who underwent an mpMRI and 4Kscore for evaluation of prostate cancer at the University of Miami. We selected those who underwent a biopsy of the prostate. The primary outcome was the presence of Gleason 7 or higher cancer on biopsy. The 4Kscore was modeled as a continuous variable, but also categorized into low ( &lt; 7.5%), intermediate (7.5-20%), and high ( &gt; 20) risk scores. The mpMRI was categorized as being either negative or positive for a suspicion of cancer. We used logistic regression and Decision Curve Analysis to report the discrimination and clinical utility of using mpMRI and the 4Kscore for prostate cancer detection. Finally, we modeled the probability of harboring a Gleason 7 or higher prostate cancer based on various categories of the 4Kscore and mpMRI. Results: Among 235 men who underwent a 4Kscore and mpMRI, only 112 (52%) were referred for a biopsy, allowing a significant proportion of men to avoid a biopsy. Among those who had a biopsy, the AUC for using the 4Kscore and mpMRI together [0.81(0.72-0.90)] was superior to using the 4Kscore [0.71(0.61-0.81);p = 0.004] and mpMRI [0.74(0.65-0.83);p = 0.02] alone. Similarly, decision curve analysis revealed the highest net benefit for using both tests together, compared to either test alone. Finally, we found that having a positive mpMRI was a predictor of aggressive cancer in the higher two 4Kscores, but not in the lowest category, suggesting that men with a low 4Kscore may not benefit from getting an mpMRI, most likely due to the low likelihood of cancer and having a positive mpMRI. Conclusions: The 4Kscore and mpMRI provides independent, but complementary, information to enhance the prediction of aggressive prostate cancer. Prospective trials are required to confirm these findings.
MAGIC trial gene expression profiling study.
Authors: Elizabeth Catherine Smyth, Iain BeeHuat Tan, David Cunningham, Andrew Wotherspoon, Suling Joyce Lin, Alicia Frances Clare Okines, Ruth E. Langley, Matthew Nankivell, Sally P. Stenning, Patrick Tan
Journal: Journal of Clinical Oncology (2013)

4020 Background: The MRC MAGIC trial established perioperative epirubicin, cisplatin and 5FU (ECF) chemotherapy as a standard of care for patients (pts) with operable oesophagogastric (OG) cancer (Cunningham NEJM 2006). We performed transcriptomic profiling of archival MAGIC tissue to evaluate an existing intrinsic gastric cancer (GC) gene signature, to describe expression patterns of biologically informative genes and to identify prognostic or predictive markers. Methods: RNA was extracted from formalin fixed paraffin embedded (FFPE) resections and analysed with the NanoString nCounter system. Our panel comprised 151 genes including intrinsic GC (G-INT and G-DIFF) signature genes (Tan Gastroenterology 2011), and genes amplified/deleted in GC including the therapeutic targets FGFR2, EGFR, ERBB2 and c-MET (Deng Gut 2012). Data was preprocessed using nsolver analysis software with 2-step normalisation and log2 transformed. G-INT and G-DIFF subtype classification used the nearest template prediction algorithm; these were then correlated with pt characteristics and survival. The overexpression threshold was defined as deviation above the normal quantile-quantile plot. Results: Sufficient RNA for analysis was available for 209 resected pts. A pilot study (n=23) confirmed RNA quality and correlation between NanoString and Affymetrix results. RNA was more often available for pts with GC (p&lt;0.001) and pts in the surgery alone arm (p=0.049). 70% of pts were classified into G-INT or G-DIFF intrinsic signature subtype (false discovery rate (FDR) &lt;0.05); 61 (30%) were ambiguous. Predominantly mutually exclusive overexpression of receptor tyrosine kinase (RTK) targets EGFR, ERBB2, FGFR, and c-MET was seen in 5%, 12%, 9% and 6% of pts respectively. Conclusions: Although bias may exist in tissue availability for chemosensitive pts, transcriptomic profiling of archival FFPE from this mature phase 3 study provides powerful insight into the molecular heterogeneity of OG cancer. 70% of evaluable MAGIC pts were classified unambiguously into intrinsic GC subtypes. Mutually exclusive overexpression of targetable RTKs supports a personalized approach in OG cancer evaluating targeted drugs in relevant biological subgroups. Survival analyses are ongoing.
Hydrogel Based Biosensors for In Vitro Diagnostics of Biochemicals, Proteins, and Genes
Authors: Il Young Jung, Ji Su Kim, Bo Ram Choi, Kyuri Lee, Hyukjin Lee
Journal: Advanced Healthcare Materials (2017)

Hydrogel‐based biosensors have drawn considerable attention due to their various advantages over conventional detection systems. Recent studies have shown that hydrogel biosensors can be excellent alternative systems to detect a wide range of biomolecules, including small biochemicals, pathogenic proteins, and disease specific genes. Due to the excellent physical properties of hydrogels such as the high water content and stimuli‐responsive behavior of cross‐linked network structures, this system can offer substantial improvement for the design of novel detection systems for various diagnostic applications. The other main advantage of hydrogels is the role of biomimetic three‐dimensional (3D) matrix immobilizing enzymes and aptamers within the detection systems, which enhances their stability. This provides ideal reaction conditions for enzymes and aptamers to interact with substrates within the aqueous environment of the hydrogel. In this review, we have highlighted various novel detection approaches utilizing the outstanding properties of the hydrogel. This review summarizes the recent progress of hydrogel‐based biosensors and discusses their future perspectives and clinical limitations to overcome.
Clinical and biologic relevance of interferon (IFN) regulated proteins in esophageal squamous cell carcinoma
Authors: D. P. Guimaraes, I. M. Oliveira, G. R. Paiva, D. M. Souza, C. B. Marques, D. B. Olmedo, C. E. Pinto, P. Hainaut, I. Small, C. G. Ferreira
Journal: Journal of Clinical Oncology (2006)

20077 Background: The prognosis for SCCE is poor, with less than 10 percent of patients surviving beyond five years. The ability to identify specific markers associated with biological behavior may provide information about the likelihood of both localized and locally advanced disease. The Interferon regulatory factor 1 (IRF-1) act as a tumor suppressor protein by affecting cell cycle progression and/or apoptosis. The Guanylate binding protein-2 (GBP-2) is an interferon regulated protein whose induction requires the IRF-1 activation. Methods: We analyzed the IRF-1 and GBP-2 expression by IHC in 42 patients (pts) with surgically ressected SCCE. A detailed pathologic examination was conducted by selecting single histologic section, which contained a clear transition zone from normal epithelium to invasive cancer. Staining was semiquantitatively scored by two observers based on both intensity and percentage of stained cells. Clinical data information was obtained from medical records. Results: The median age was 58 (39–75); Male/female 61.9/38.1%; Of 39 pts, 53,8% had localized disease (I/IIA) and 46,2% had locally advanced disease (IIB/III). Nineteen pts received standardized radiochemotherapy before surgery. The IRF-1 and GBP-2 were expressed in 100% and 75% of tumors, respectively. Normal epithelium was stained for both IRF-1 and GBP-2 with distinct expression patterns. There was a significant correlation between scores for GBP-2 and IRF-1 tumor staining (p = 0.23). Interestingly, the score for GBP-2 tumor staining was inversely correlated to clinical stage (p = 0.001), tumor invasion of the esophageal wall (T) (p = 0.26), involvement of lymph nodes (N) (p = 0.035) and tumor extension (p = 0.007). There was no correlation between the score of IRF-1 staining and the clinical-morphological parameters. Conclusions: We reported for the first time the expression of GBP-2 protein in esophageal cancer. Our results suggest that GBP-2 expression is related to less aggressive behavior of SCCE. Further studies are required to clarify biological GBP-2 protein function, and possible prognostic implications. No significant financial relationships to disclose.
An update on rectal cancer evaluation by magnetic resonance imaging in neoadjuvant therapy decision making: Retrospective case review.
Authors: Alejandro Recio Boiles, Krisha Howell, Bobby T. Kalb, Steve Malangone, Valentine N. Nfonsam, Emad Elquza
Journal: Journal of Clinical Oncology (2017)

762 Background: During the last decade, MRI used for staging of rectal cancer has been reported to up or down stage rectal cancer by 20%. Poor staging affects guided pre-operative decision-making. Adequate staging would enable to stratify treatment, avoiding unnecessary surgical morbidity and allowing aggressive interventions according to patient risk. After novel techniques and image acquisition for MRI became available at our Cancer Center, we aimed to analyze perfusion pattern and qualitative T2 signal before and after chemoradiationtherapy (CRT) tumor response to the gold standard pathological stage. Methods: Data was retrospectively reviewed from our institution cancer registry. Patients were selected with a diagnosis of rectal cancer by biopsy, between 2011-2015. Inclusion criteria were to have documented radiological AJCC 7 th edition &lt; IV, accessible diffusion weighted MRI for apparent diffusion coefficient analyzes, completed CRT and pathology report. Results: A total of 57 patients were diagnosed with rectal cancer during this time period, of which 20 fulfilled inclusion criteria; median 61 years old, 80% males, stage IIA (6) IIIB (10) and IIIC (4), LAR 60% and APR 40%. After CRT, 90% of patients (N18) were downstaged (and 2 upstaged) on pathological review. 10 patients had a repeat pre-operative MRI. Post-treatment MRI re-stage correlated with surgical pathological stage in all 10 patients (Table). 4 patients received unnecessary APR and 2 may had benefit from further CRT or total pelvic exanteration. Conclusions: In retrospective, tumor response evaluation post CRT with high-resolution MRI correlated with pathological stage. Our analysis pointed 20% patients may avoid a morbid surgery while 10% would have required more aggressive therapy. Future clinical decisions will be complemented by repeat MRI analysis aiding surgical and clinical decision-making. [Table: see text]
Prospective study of early detection of malignancies in individuals at risk for developing pancreatic cancer.
Authors: Courtney Edwards Snyder, Susan Haag, Domenica Adams, Breann Paskett, Jade Hess, Erkut Hasan Borazanci
Journal: Journal of Clinical Oncology (2017)

TPS500 Background: It is estimated that by 2030 pancreatic cancer will be the second leading cause of cancer deaths in the US. Currently, only 9% of newly diagnosed pancreatic cancer is localized and 5-year survival is 7%. Due to most pancreatic cancers (PC) presenting at a later stage with poor overall survival, early detection methods must be implemented to improve treatment outcomes. Yet, effective early screening guidelines do not exist for pancreatic cancer. Our Early Detection Program (EDP) provides personalized early detection including risk assessment, screening, and genetic testing. We aim to evaluate risk assessment criteria, establish a database to delineate a pattern of characteristics, and utilize a biospecimen repository and molecular based technologies to map novel biomarkers for early detection. Methods: The EDP screens those with a family history or germline mutation consistent with potential increased risk for developing PC. Patients are eligible based on risk assessment and stratified into 3 groups based on the CAPS Consortium criteria (average, moderate, and high risk). Screenings may include genetic testing for germline mutations, blood testing including Hemoglobin A1C (HgBA1C), complete blood count (CBC), complete metabolic profile (CMP), cancer antigen 19-9 (CA 19-9), vitamin D 25-OH, lipid panel, and thyroid stimulating hormone (TSH). Serum and urine collection will be offered for banking for future studies. Patients have yearly screenings including thorough history and physical exam and cases are discussed at a multi-disciplinary pancreatic tumor board. If indicated, patients undergo MRI/MRCP abdomen, GI consult and EUS. Study participants also complete a cancer anxiety index. The EDP is still recruiting patients. Next-generation sequencing and molecular based technologies are being explored for mapping novel biomarkers for early detection. The Institute is expanding to include those at risk for breast and ovarian cancer. We are evaluating risk assessment criteria and are developing a valid and reliable EDP index (EDP-I) anxiety instrument.
Gene expression changes during acquired resistance to tamoxifen; a preclinical model of post-menopausal breast cancer
Authors: N. Macpherson, S. Moore, A. Brodie, T. Olivotto, A. Thiantanawat, B. Long, D. Jelovac, C. Nelson
Journal: Journal of Clinical Oncology (2004)

3147 Background: Most metastatic breast cancers initially respond to hormonal treatment but all become resistant to these treatments over time. The genetic events that occur during acquired resistance are unknown. To examine the gene expression changes during acquired hormonal resistance, we used a model that mimics ER positive breast cancers in the post-menopausal setting with the tumors responsive to both Tamoxifen (TAM) and aromatase inhibitors. Tumors were analyzed with high density cDNA microarrays to identify genes associated with TAM resistance. Methods: Aromatase-transfected MCF-7Ca human breast cancer cells were grown as tumor xenografts in female ovariectomized athymic nude mice in which an androstenedione supplement was converted to estrogen to stimulate tumor growth. When tumor volume was approximately 300 mm3, the animals were grouped (4 groups, each with n=20) for continued supplementation with androstenedione (Δ4A) only (control), Letrozole (an aromatase inhibitor) 10 μg/day + Δ4A, TAM 100 μg/day + Δ4A, or vehicle. Tumors were then retrieved at various time points during the development of hormone resistance. Tumor RNA samples were compared to reference RNA from Stratagene and incubated with 14K microarrays (Array-Ready Oligo Set, Qiagen). Expression results were analyzed with Genespring 6.1 (Silicon Genetics). Results: We have identified 15 TAM-resistant associated genes that are over-expressed by at least 2-fold, after controlling for genes associated with house-keeping function (vehicle and short term control), proliferation (freely growing tumors without TAM), and TAM inducible genes. They include; cystatin A, TGFbeta1-induced anti-apoptotic factor, cadherin1 E-cadherin, Snf2-related CBP activator protein, and chromatin-remodelling genes. At the meeting we will also present data on the expression changes seen in the Her-regulin family, cyclin family and MAP kinase genes during acquired TAM resistance. Patient biopsies are currently being collected and analyzed to validate these observations. Conclusions: Chromatin remodeling genes are over-expressed in acquired TAM-resistance. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis
Phase III study of Palbociclib in combination with Exemestane vs. Capecitabine, in Hormonal Receptor (HR) positive/HER2 negative Metastatic Breast Cancer (MBC) patients with Resistance to non-steroidal Aromatase inhibitors (NSAI): PEARL study (GEICAM/2013-02_CECOG/BC.1.3.006)
Authors: Miguel Martin, Moshe J. Inbar, Eva Maria Carrasco, Istvan Lang, Maria Jose Escudero, Zsuzsanna Kahan, Cynthia Huang Bartlett, Begona Bermejo, Einav Gal Yam, Jose Ignacio Chacon, Zanete Zvirbule, Jose Angel Garcia Saenz, Juan de la Haba-Rodriguez, Maria Koehler, Miguel J. Gil Gil, Eva Maria Ciruelos Gil, Montserrat Munoz-Mateu, Serafin Morales Murillo, Jose Luis Alonso, Christoph Zielinski
Journal: Journal of Clinical Oncology (2015)

TPS631 Background: Endocrine therapy (ET) is the cornerstone treatment for HR–positive, HER2-negative breast cancer (BC) patients. AIs have become the treatment of choice in postmenopausal patients. The high efficacy with ET in these patients is partially undermined by the resistance developed by most of them over time. On early disease recurrence/progression to AIs, treatment options include other AI, estrogen-receptor antagonists or chemotherapy (being capecitabine one of the best options). Preclinical data suggest that ER+/HER2- BC are dependent on cyclin-dependent kinases 4/6 (CDK4/6) function; inhibition of this target may be effective in delaying/reverting endocrine resistance. Palbociclib is an oral novel CDK4/6 inhibitor that seems to be synergistic with ET in preclinical and clinical studies. Methods: Phase III, international (5 countries) study. Patients are randomized 1:1 to exemestane (25 mg daily) plus palbociclib (125 mg daily x3 weeks q4w) vs. capecitabine (1,250 mg/m2 twice daily x2 weeks ...