tbuckley/cabot-search huggingface dataset:
Clinical algorithm to predict who may benefit from CDK4/6 inhibitors in patients (p) with estrogen receptor positive and HER-2 negative (ER+/Her2-) metastatic breast cancer (MBC).
Authors: Eudald Felip-Falgàs, Iris Teruel, Juan José García Mosquera, Carlos Erasun, Vanesa Quiroga Garcia, Laura Angelats, Sofia España, Marc Cucurull, Beatriz Cirauqui, Mireia Margeli Vila
Journal: Journal of Clinical Oncology (2018)

e13060 Background: Sequential endocrine therapy is the usual practice strategy for p with ER+/Her2- MBC. Last years, cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors may change the gold standard of treatment in first line. The increase of cost to treat all the p with CDK4/6 inhibitors could be an important effort for public institutions. Furthermore, any clinical trial has showed evidence of overall survival (OS) benefit in front of endocrine therapy. We hypothesize which p may have good response to the sequential endocrine therapy. Methods: We perform a retrospective analysis of 179 p with ER+/HER2- MBC visited in medical oncology service in our centre (ICO-Badalona) from 2004 to 2014, treated with hormonal therapy. Males were excluded. We categorized different group p, such as age at diagnosis (per decades), metastatic side affected at metastatic diagnosis (3 groups: only bone, bone plus other and visceral) and time to relieve (4 groups: de novo, less than 2 years with hormonal adjuvant treatment, from 2 years to 6 years, and more than 6 years after radical treatment). Results: Describing all p, median age at MBC diagnosis was 56 y, and OS was 44,4 m (IQ 95%: 36,5-52,3). Most of the p (68,8%) received more than 2 lines of treatment. Analysing all p characteristics and different groups of patients, we found two main influence landscapes in OS: First of all, organ involvement; where visceral disease at metastatic situation had worst prognosis (median OS: 36,5 m) and inversely, but also significative, those with only bone involvement has better prognosis (median OS 101,5 m); second, those p with a late recurrence after a radical treatment has a better prognosis (median OS: 103,5). Conclusions: A clinical algorithm could help to choose which p may benefit from endocrine sequence therapy. Those p with bone only and those p with late recurrence without visceral affection could benefit from an endocrine therapy alone because of the better prognosis that presented, awaiting survival results of CDK 4/6 inhibitors. CDK4/6 inhibitors could be indicated in first line in the rest of p and added in second line in this subset of good prognostic patients.
P01.052 Updated results of the INTELLANCE 2/EORTC trial 1410 randomized phase II study on Depatux -M alone, Depatux-M in combination with temozolomide (TMZ) and either TMZ or lomustine (LOM) in recurrent EGFR amplified glioblastoma (NCT02343406)
Authors: M van den Bent, P French, M Eoli, J Sepulvado, A Walenkamp, M Weller, J Looman, P Ansell, T Gorlia, V Golfinopoulos
Journal: Neuro-Oncology (2018)

Depatux-M is a n antibody-drug-conjugate consisting of an antibody (ABT-806) specific to the activated conformation of epidermal growth factor receptor (EGFR) bound to the toxin monomethylauristatin-F. In the primary analysis on EORTC 1410 we reported a trend (p = 0.06) towards improved overall survival (OS) in patients with EGFR-amplified recurrent glioblastoma treated with Depatux-M in combination with TMZ. We now present updated results. Eligible were patients with centrally confirmed EGFR-amplified glioblastoma at 1st recurrence after TMZ chemo-irradiation, occurring ≥3 months after radiotherapy. Patients were randomized to either a) Depatux-M 1.0 mg/kg every 2 weeks intravenously, or b) the same treatment combined with TMZ 150–200 mg/m2 day 1–5 every 4 weeks, or c) either LOM or TMZ (TMZ/LOM) depending on the time of relapse. Primary endpoint was OS. Pharmacokinetic (PK) sampling was done on day (d) 1 before and after dosing, d 4–7, d 1 course 2 before and after dosing, d 5–7 course 2, d 1 course 3, and then every 2 cycles. All available PK samples were used to calculate the Depatux-M average concentration during course 1 (CavgC1). The level of EGFR amplification was determined using both qPCR, next generation sequencing and FISH. In February 2018, an updated OS comparison with longer follow-up (median: 21 mo) performed after 220 observed deaths of Depatux-M in combination with TMZ versus TMZ/LOM using log-rank test and cox models stratified by stratification factors at randomization showed a HR of 0.68 (95%CI [0.48, 0.95]; p = 0.024) and 1-year OS rates of 40% versus 28%. In multivariate analysis including performance status, MGMT, surgery for recurrence, time from last TMZ to relapse and lesion diameter, CavgC1 was a significant predictor for OS (HR 0.96, 95% CI [0.93, 0.98], p = 0.0013). In Depatux-M treated patients, EGFR status (high vs low level amplification) did not correlate with OS. At the meeting further follow-up data will be presented obtained at database cleaning done > 24 months after the end of accrual allowing definitive analysis. This updated OS analysis confirmed the OS improvement in EGFR-amplified recurrent glioblastoma after treatment with of Depatux-M in combination with TMZ. In Depatux-M treated patients, higher drug levels during course 1 were associated with improved OS but high levels of EGFR amplification at first diagnosis were not.
TCT-831 Differences in Short-Term Outcomes and Cost between Alcohol Septal Ablation and Septal Myectomy for Hypertrophic Cardiomyopathy in the United States
Authors: Srikanth Yandrapalli, Prakash Harikrishnan, Gabriela Andries, Wilbert Aronow, Srihari Naidu, Julio Panza
Journal: Journal of the American College of Cardiology (2018)
Glucocorticoid receptor expression and survival in ovarian cancer.
Authors: Jennifer Taylor Veneris, Kathleen M. Darcy, Paulette Mhawech-Fauceglia, Suzanne D. Conzen, Gini F. Fleming
Journal: Journal of Clinical Oncology (2016)

5545 Background: Despite debulking surgery and platinum-based treatment, most ovarian cancers recur and develop chemotherapy resistance. In cell lines and xenografts, glucocorticoid receptor (GR) regulation of anti-apoptotic gene expression is associated with decreased chemotherapy response. GR modulators are therefore entering clinical trials in combination with chemotherapy in ovarian and other solid tumors. The current study investigates the association of GR expression and survival in ovarian cancer. Methods: GR expression was evaluated in tissue microarrays of specimens from 471 ovarian cancer patients. Samples were classified as GR-negative if no tumor cell staining was detected and as GR positive if any intensity was detected in > 1% of tumor cells. Association with clinical characteristics was assessed by Chi-square analysis and Spearman correlation. Progression-free (PFS) and overall survival (OS) were estimated using Kaplan-Meier method and compared by Cox regression. Results: GR was expressed in 69.2% of cases and significantly associated with histologic subtype (p < 0.001, endometrioid lowest, carcinosarcoma highest). GR expression correlated with grade (p = 0.02) and FIGO stage (p = 0.02) in the 424 patients for whom histologic classification was available. An additional 47 patients received neoadjuvant chemotherapy prior to sample collection at interval debulking. Patients receiving neoadjuvant chemotherapy were 11.45 times more likely to have GR-positive tumors than those receiving debulking surgery upfront (OR = 11.45, 95% CI 2.7-47.8, p < 0.001). Median PFS was significantly decreased in patients whose tumors were GR-positive (22.4 months) compared to those with GR-negative tumors (40.9 months, HR = 1.503 with 95% CI 1.169- 1.931). OS was not statistically different. In subgroup analysis, GR expression did not correlate with PFS or OS within high grade serous tumors. Conclusions: GR is frequently expressed in ovarian cancers, and associated with advanced stage, high grade, and poor PFS. Together, these data suggest that GR expression may be a marker of aggressive tumor biology and lend support to modulating GR-activity to improve chemotherapy response. This hypothesis is currently being tested in clinical trials.
A phase I clinical trial of AZD1775 in combination with neoadjuvant weekly cisplatin and docetaxel in borderline resectable head and neck squamous cell carcinoma (HNSCC).
Authors: Eduardo Mendez, Cristina P. Rodriguez, Michael Kao, Richard A. Harbison, Renato G. Martins, Neal D. Futran, Rafael Santana-Davila, Laura Quan Man Chow
Journal: Journal of Clinical Oncology (2017)

6034 Background: The WEE1 tyrosine kinase regulates G2/M transition and maintains genomic stability. In TP53-deficient tumors (via mutation or HPV inactivation), inhibiting WEE1 with AZD1775 can lead to unrestrained mitosis and cell death. We conducted a Phase I clinical trial of AZD1775 in combination with chemotherapy to define the toxicity profile, establish the maximal tolerated dose (MTD) and assess preliminary efficacy in borderline resectable HNSCC. Methods: Stage III/IVB HNSCC deemed borderline resectable by a multidisciplinary team were enrolled in a phase 1, 3 + 3 design to evaluate escalating doses of AZD1775 starting at 125 mg PO BID x 2.5 days alone as lead-in and in combination with cisplatin (25mg/m2) and docetaxel (35 mg/m2) for three additional weeks. Tumors were sequenced with UWOncoPlex (262 cancer genes); HPV status assessed via p16 IHC; toxicities graded with CTCAE v. 4.04; responses measured via RECIST 1.1 and through pathologic assessment when available. Trial is open but primary endpoints were met. Results: Eleven patients were screened; 10 enrolled and were evaluable for toxicities. The most common Grade ≥ 2 toxicities were diarrhea (4), fatigue (4), neutropenia (3) and nausea (3). The drug-limiting toxicity was Grade 3 diarrhea (2). The MTD was established at 150mg PO BID x 2.5 days, alone and in combination with neoadjuvant cisplatin and docetaxel. Two patients were HPV+/TP53wt, 1 was HPV+/ TP53 mut; 6 were TP53mut/HPV-; 1 was TP53 wt/HPV-. Seven out 10 patients had a response. Two patients dropped out after the first week with AZD1775, one due to an allergic reaction to docetaxel and another due to non-compliance. Eight completed neoadjuvant therapy and 7 of those converted to surgery: 2 had pathologic CRs (both HPV+/TP53wt); 4 had PR (all TP53 mutants); 1 (TP53wt/HPV-) had a PR by RECIST, but SD by pathology and 1 had PD. Conclusions: AZD1775 is safe and tolerable in combination with neoadjuvant cisplatin and docetaxel. Results show this combination to have promising anti-tumor efficacy in borderline resectable HNSCC with TP53 deficiency, and merits further investigation with the established MTD as the recommended Phase II dose. Clinical trial information: NCT02508246.
Primary pulmonary sarcomas (PSRC): A comprehensive genomic profiling (CGP) study.
Authors: Sophie Beaucaire-Danel, Nicolas Girard, Julia Andrea Elvin, James Suh, Jo-Anne Vergilio, Shakti H. Ramkissoon, Eric Allan Severson, Sugganth Daniel, Jonathan Keith Killian, Siraj Mahamed Ali, Alexa Betzig Schrock, Jon Chung, Robert John Corona, Vincent A. Miller, Laurie M. Gay, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2018)

11553 Background: In an exploratory study to find biomarkers for both targeted and immunotherapy treatments, we performed CGP on a series of PSRC to search for novel therapy options for patients with clinically advanced disease. Methods: Hybrid capture-based CGP was performed on 21 cases of PSRC, with 17 PSRC also undergoing RNA sequencing to enable expanded gene fusion detection. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined by principal components analysis of optimal homopolymer loci. Results: There were 10 sarcoma NOS, 5 pulmonary artery intimal sarcomas, 4 pleomorphic/MFH sarcomas, 1 primary inflammatory myofibroblastic tumor (IMT) and 1 primary solitary fibrous tumor (SFT) cases. There was 1 stage I, 1 stage II, 9 stage III and 10 Stage IV tumors. The patients had a median age of 58 years (range 33 to 81 years). There were 7 female and 14 male patients. The mean number of genomic alterations (GA) per sarcoma was 5.8. Notable alterations not considered presently actionable included TP53 (47%), CDKN2A (36%), CDKN2B (25%) and RB1 (13%). Clinically relevant GA (CRGA) affected PDGFRA, RICTOR, CDK4 and KIT, all at 11%. When considering additional CRGA in EGFR, TSC2, ALK and BRAF (each at 5%), a total of 10 (48%) PSRC featured ≥1 CRGA. The case with an ALK fusion represents an IMT initially localized to the lung and diagnosed as a primary lesion. The mean TMB in the PSRC was 8.3 mutations per Mb with 14% having TMB of > 10 mut/Mb and 10% having TMB > 20 mut/Mb. MSI status was available for 9 (43%) of the PSRC cases, and the remainder were all microsatellite stable. Assessment of therapeutic intervention and responses to targeted and immunotherapies is ongoing. Conclusions: PSRC is characterized by a relative high frequency of GA, including driver mutations or fusions in tyrosine kinases and cell cycle regulatory genes. In addition, this study identified a significant proportion of PSRC that feature an intermediate or high TMB, indicating the potential for use of immunotherapies for these patients. Further study of CGP to assist in management of patients suffering from this rare form of pulmonary malignancy appears warranted.
Abstract 13796: Global Longitudinal Strain (GLS) Predicts Progression to Severe Aortic Stenosis (AS) in Patients With Normal or Minimally Dysfunctional Bicuspid Aortic Valve (BAV)
Authors: Aline Iskandar, Linda Pape, Dennis Tighe, Gerard P Aurigemma
Journal: Circulation (2015)

Background: While prior research has documented the rate of progression of BAV to severe AS, myocardial function factors have received less attention. We hypothesized that reduced GLS might conceivably identify a high risk subset of BAV patients, as it has in other instances of severe valvular heart disease, such as chronic severe aortic regurgitation. Methods: We computed GLS (apical 2-, 3-, and 4-chamber views, Arena Software,TomTec) on baseline studies in two groups of pts with BAV. All had (1) EF ≥ 50%, (2) were free of wall motion abnormality and (3) were free of any significant valve dysfunction. Pts were followed for mean of 70 ± 18 months. In group 1 (STABLE) the BAV remained hemodynamically non-significant (absent or mild aortic regurgitation or stenosis) throughout follow-up and in group 2 (PROGRESS) the disease progressed from no or mild aortic disease to severe AS. Results: 21 patients were included, 11 STABLE patients and 10 PROGRESS patients. Baseline characteristics were similar for the two groups (Table 1). All patients in PROGRESS had abnormal GLS (&lt; -18%), whereas STABLE patients had GLS greater than -18%. GLS was significantly impaired in PROGRESS compared to STABLE (-15.9% vs -21.2%, p = 0.0001). Summary: 1. Baseline GLS was impaired in patients who progressed from normal or mild aortic disease to severe aortic stenosis. 2. Baseline GLS was grossly within normal limits in those in whom the bicuspid aortic valve remained normal or minimally dysfunctional. Conclusions: A normal baseline GLS appears to predict a more benign course for patients with normal or minimally dysfunctional BAV, whereas a reduced GLS might identify a group at high risk for progression. Whether reduced baseline GLS relates to abnormalities in load or contractility, or signifies a ‘myocardial factor’ which is related to the BAV syndrome all remain to be elucidated.
The prognostic significance of breast cancer stem cells in patients with metastatic breast cancer.
Authors: Kamel Farag, Sameh Sayed Ahmed Shamaa
Journal: Journal of Clinical Oncology (2018)

e12565 Background: Breast cancer ranks as the first malignancy affecting females.There is increasing evidence that this cancer is originated in and maintained by a small population of undifferentiated cells with self-renewal and proliferation capacities that called breast cancer stem cells (BCSCs). Methods: This study was conducted on 60 patients with metastatic breast cancer, presented to outpatient clinics in Oncology Center, Mansoura University from December 2010 till November 2014. All patients received treatment according to protocols and guidelines. The presence of breast cancer Stem cells was evaluated by immunohistochemistry expression of CD44 and CD24 to assess its possible prognostic and predictive values via correlation with overall survival, tumor response and different clinico-pathological features of the patients. The expression patterns were analyzed according to the clinico-pathologic prognostic parameters as well as overall survival. Results: Median age was 50 (31-70) years. Twenty six patients (43.3%) were premenopausal and 34 patients (56.7%) were postmenopausal. This study classified the breast tumor tissues into four subgroups according to CD44 and CD24 expression patterns (CD44+ CD24- group that carry stem cell property were 41.7% and the remaining three groups ( CD44- CD24-, CD44+ CD24+ , CD44- CD24+) were 58.3%. 64% of tumors with CD44+ CD24- BCSCs were IDC histology, 84% of cases belongs to this group were grade 3, 88% were stage III on presentation, 56% were luminal subtype, 68% of them developed both bone and visceral metastasis. Our study showed that presence of BCSCs (CD44+ CD24-) carry significantly shorter OS (19 vs. 44 months) compared to other three groups. Also, a multivariate analysis, showed that presence of BCSCs (CD44+ CD24-) was significant independent prognostic factor for poor overall survival. Conclusions: This study is a prospective trial testing the concept of detecting breast cancer stem cells in tumor tissue biopsies, according to CD44 & CD24 expression status. As such, it has demonstrated both the feasibility of this approach and its implication as a future prognostic marker, and has paved the way for future research in this field.
P04.31 Defining Tumor Treating Fields (TTFields) dosimetry using Power Density Loss and related measures
Authors: N Urman, H S Hershkovich, A Naveh, S Levy, Z Bomzon
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) are alternating electric fields known to inhibit cancer cell growth. TTFields are approved for the treatment of Glioblastoma Multiforme. Historically, TTFields dose has been quantified using the magnitude of the electric field, which is indicative of the force that the field applies on charged objects. However, when considering the dose of a physical modality such as TTFields, it is important to consider the amount of energy transferred from the modality to the tissue. This is because, the extent to which the modality can alter the state of the objects on which it operates depends on the amount of energy that the modality transfers to those objects. Power loss density quantifies the energy transferred by an electric field to tissue through electric conductance. Here analyze how power density loss can be used to quantify TTFields dose, shedding new light on the mechanism of action of this anti-cancer modality. The power density loss of TTFields is defined as, L=12σE2 where, L represents power loss density, σ is the conductivity of tissue and E is the magnitude of the electric field. The unit for measuring the power loss density of TTFields is milli-Watts per cubic centimeter (mW/cm3). To examine the distribution of power loss density when delivering TTFields to the brain, we numerically simulated delivery of TTFields to realistic head models of Glioblastoma patients. We then created colormaps that visualized the field intensity distribution and the power loss density distribution within the models and qualitatively compared the two. Finally, we calculated the total power loss within the models to gain a measure of the power delivered by TTFields to the brain during treatment. The electric field intensity tends to increase in regions of low conductivity, such as white matter, and tends to be lowest in regions of high conductivity such as the ventricles and resection cavities. However, the power loss density tends to increase in regions of higher conductivity. Within the highly conductive ventricles and resection cavity, it can take on values comparable to those observed in other tissue types. The average power loss density within the gross tumor volumes of all patients was 5 mw/cm^3. The total power loss of TTFields within the simulated cases was between 20–40 Watts, which is equivalent to 412–825 Kcalories per day, on-par with the resting metabolic rate of the brain (about 20% of the body’s resting metabolic rate). This analysis shows that power loss density is a viable physical measurement to accurately quantify TTFields dose in treatment planning. The analysis also shows that the power delivered by TTFields to cells is comparable to the metabolic rate of the cells. This observation could lead to new hypotheses about the mechanism of action of TTFields.
The plasma lipidome in castration-resistant prostate cancer.
Authors: Lisa Horvath, Hui-Ming Lin, Kate Lynette Mahon, Jacquelyn Weir, Piyushkumar Mundra, Calan Spielman, Karen P. Briscoe, Howard Gurney, Girish Mallesara, Gavin M. Marx, Martin R. Stockler, Robert Parton, Andrew Hoy, Roger J. Daly, Peter Meikle
Journal: Journal of Clinical Oncology (2017)

5055 Background: Biomarker studies of metastatic castration-resistant prostate cancer (CRPC) have mainly focused on changes in the cancer, however, the host environment and its interactions with cancer is increasingly important, especially given the increasing association of PC outcomes and obesity. We sought associations between the plasma lipidome and clinical outcome in CRPC. Methods: Plasma samples were obtained from a Phase 1 discovery cohort of 96 CRPC patients before and after the first cycle of docetaxel chemotherapy. Lipidomic profiling of the plasma samples was performed by liquid chromatography and electrospray ionisation-tandem mass spectrometry. Results were subsequently assessed in a Phase 2 validation cohort of 63 CRPC patients. Results: Lipidomic profiling detected 323 lipid species in plasma samples from the Phase 1 cohort. Patients could be classified into two subgroups with significant survival differences according to their baseline lipidomic profiles (median overall survival 13.7 vs 21.7 months; HR 2.31, 95% CI 1.44-3.68, p = 0.0005). The baseline levels of 46 lipids were individually prognostic (p &lt; 0.01) and predominantly sphingolipids. A prognostic three-lipid signature was derived (ceramide (d18:1/24:1), sphingomyelin (d18:2/16:0), phosphatidylcholine (16:0/16:0)) (11.7 versus 21.7 months, p = 0.00001; HR 2.94, 95% CI 1.80-4.81, p = 0.00002). The signature was associated with shorter overall survival in the Phase 2 cohort (HR 4.78, 95% CI 2.06-11.1, p = 0.0003), and was an independent prognostic factor when modeled with clinicopathological factors and metabolic characteristics (BMI, cholesterol and triacylglycerol). The AUC of ROC analysis of 12 month survival for a clinicopathological model (AUC 0.70, 95% CI 0.54-0.87, p = 0.03) was enhanced by the addition of the 3-lipid signature (AUC 0.73, 95% CI 0.57-0.89, p = 0.01). Conclusions: Our study is the first to comprehensively profile the plasma lipidome of men with CRPC using cutting-edge lipidomic profiling technology, to identify a plasma lipid signature that can reproducibly predict outcome in CRPC and can improve on clinicopathological models. Therapeutic modulation of the levels of these lipids by targeting their metabolic pathways may improve patient outcome.