tbuckley/cabot-search huggingface dataset:
Change in 21-gene recurrence score (RS) (Oncotype DX) after exposure to neoadjuvant endocrine therapy.
Authors: Talal Hilal, Lanyu Mi, Karen S. Anderson, Barbara A. Pockaj, Richard J. Gray, Leslie E Dixon, Erika D. Martinez, Charanjit Singh, Donald W. Northfelt
Journal: Journal of Clinical Oncology (2018)

e12650 Background: 21-gene recurrence score (RS) assay (Oncotype DX) is routinely used to determine potential effectiveness of adjuvant chemotherapy following surgical resection of localized ER-expressing breast cancer. Neoadjuvant endocrine therapy (NET) is increasingly being utilized in clinical practice as part of the management of this disease. However, little is known about the effect of NET on gene expression as evaluated by the RS assay. Methods: We identified consecutive patients treated with NET from January 2010 to December 2017 using an IRB-approved database. Both the core biopsy (pre-NET exposure) and surgical specimen (post-NET exposure) were tested using the 21-gene expression assay. Baseline patient characteristics, tumor stage, grade, and receptor status were extracted. Differences in overall RS (plus ER, PR and HER2 scores) were calculated using paired T-test. Results: We identified 33 patients. Median age was 56 (30-79) and 55% were postmenopausal. Pre-NET T stage was T1c 6 (18%), T2 25 (76%), and T3/T4 2(6%). Histologic subtype was ductal 25 (76%), lobular 4 (12%), and mixed 4 (12%). Grade included 1 in 7 (21%), grade 2 in 20 (60%), and grade 3 in 6 (18%). Type of NET used was tamoxifen 1 (3%), aromatase inhibitor and GnRH agonist 9 (27%), AI alone in 16 (48%), and AI plus CDK 4/6 inhibitor 7 (21%). Median exposure to NET was 133 days (24-557). Post-NET T stage was T1c 14 (42%), T2 14 (42%), and T3/T4 5 (15%). Mean overall RS changed by +4.1 points (95% CI (+1.06,+7.06), p = .01), ER score by -0.5 points (95% CI (-0.93,-0.06), p = .026), and PR score by -1.3 points (95% CI (-2.02,-0.63), p = .0005). When separating overall RS to low risk ( < 18), intermediate risk (18-31), and high-risk ( > 31), 14/18 low-risk scores were classified as intermediate risk after exposure to NET, and 2/11 intermediate risk scores were classified as high-risk after exposure to NET. Conclusions: In the overall population, exposure to NET downgraded ER and PR scores thereby raising overall RS, but the rise in RS did not consistently lead to a change in risk category in intermediate and high-risk patients. Pre-NET RS Post-NET RS Low Intermediate High Total Low 4 14 0 18 Intermediate 3 6 2 11 High 0 2 2 4 Total 7 22 4 33
A prospective, multi-center study to evaluate the performance and clinical utility of a 15-gene expression profile for uveal melanoma.
Authors: Kristen Meldi, Robert W. Cook, Tony Tsai, Yevgeniy Shildkrot, Brooke Middlebrook, Derek Maetzold, Clare Johnson, Kristen M. Oelschlager, Thomas Aaberg
Journal: Journal of Clinical Oncology (2016)

9575 Background: Most uveal melanoma (UM) patients do not present with metastatic disease at diagnosis, yet 50% will develop metastases following primary tumor control. A validated 15-gene expression profile test enables risk-appropriate clinical management by using primary tumor tissue to predict metastatic risk, classifying patients as low risk Class 1A, intermediate risk Class 1B, or high risk Class 2. Methods: We performed an unplanned analysis of 70 patients in the prospective CLinical Application of DEcisionDx-UM Gene Expression Assay Results (CLEAR) registry (NCT02376920) because primary endpoints replicated in several prospective studies were met and accrual is terminating at the 4 participating centers. CLEAR aims at tracking clinical management and 5-year metastatic outcomes of Class 1 and 2 patients without evidence of distant metastasis at the time of primary tumor treatment. Surveillance modes and frequencies were independently determined by participating physicians as they deemed appropriate for Class 1 and 2 patients. Analysis cut-points paralleled a prior retrospective, multi-center decision impact study. Results: 37 (53%) patients had Class 1 results and 33 (47%) were Class 2. Overall, 12 Class 2 patients and 2 Class 1 patients had developed metastases (p = 0.002) with a median follow-up of 28.5 months (range, 2.6-94.0). At 3 years, metastasis-free survival rates were 100% for Class 1 and 62% for Class 2 (p = 0.002). All Class 2 patients and only 5/37 (14%) Class 1 patients were managed with high intensity surveillance (imaging and liver function tests every 3-6 months). This reflects a significant difference in management of Class 1 and Class 2 patients (p = 5.2x10-15). Only 4 Class 1 patients (11%) compared to 11 (33%) Class 2 patients were referred to medical oncology for surveillance and/or clinical trial enrollment (p = 0.04). Conclusions: Results support the prognostic accuracy of the 15-gene expression test for metastatic risk in UM patients. DecisionDx-UM risk classification impacts clinical decision-making as demonstrated by differences in frequency of imaging and bloodwork based on metastatic risk (higher intensity in Class 2 patients).
Exploiting machine learning in local treatment strategies in cancer patients with bone metastases.
Authors: Wang Zhiyu, Yang Mengdi, Sun Jin, Yao Guangyu, Zhou Yiyi, Hui Zhao
Journal: Journal of Clinical Oncology (2018)

e18505 Background: With the rising life expectancy in cancer patients with bone metastases (BM), the need for local treatment (LT) is expanding. But indications for LT are still controversial. Machine learning (ML) could learn from the observed data to create reasonable generalizations. The purpose of this article was to evaluate the use of ML model in LT strategies of cancer patients with BM. Methods: In clinical practice, the interdisciplinary team formulated made LT decision,including open surgery or percutaneous osteoplasty (POP) . Logistic regression, decision tree (DT) and support vector machine models which structured and published at 2014, were also used to calculate LT probability. Pre- and post-treatment Visual analog scale (VAS) and EORTC QLQ-BM22 were analyzed. Kaplan-Meier analysis was used to calculate survival. Results: Between Jan 2014 and Sep 2016, 384 patients were eligible for this prospective study, and 92 patients underwent LT (29 patients surgery, 63 patients POP). Among 3 models, DT model was the best compared with interdisciplinary team decision with sensitivity 82.6%, specificity 86.9% and accuracy 85.9%. VAS and pain characteristics of QLQ-BM22 dropped significantly at 1 and 3 months after LT, while functional interference and psychosocial aspects of QLQ-BM22 increased significantly at 3 months (p< 0.05). VAS, pain characteristics of 76 patients with right prediction in DT model (4.0±1.4, 29.4±17.9 respectively) was significantly lower than 16 patients with wrong prediction (4.9±1.6, 35.3±21.5) from 1 month after LT (p< 0.05), while functional interference in patients with right prediction (67.3±19.6) was significantly higher than patients with wrong prediction (61.7±21.1) at 3 months (p< 0.05). The median overall survival time (OS) in 92 patients after LT was 11.0±0.5 months. The OS in patients with right prediction (11.1±0.6 months) was longer than patients with wrong prediction (10.1±0.9 months), but without significant difference (p> 0.05). Conclusions: Appropriate LT provided significant pain relief and improvement of quality of life. ML model is an effective tool for help physicians to identify patients with BM who may be a candidate for LT, or would get more benefit from LT.
Expression of some molecular and biological markers in tissue of squamous cell carcinoma of the vulva.
Authors: Evgeniya M. Nepomnyashchaya, Oleg Ivanovich Kit, Galina Andreevna Nerodo, Inna Arnoldovna Novikova, Victoria A. Ivanova, Vera Nikitina, Ekaterina V. Verenikina, Oksana E. Kravtsova, Natalia V. Chernikova, Elena Petrovna Ulianova, Galina I. Zakora, Elena Bondarenko, Ekaterina A. Nerodo
Journal: Journal of Clinical Oncology (2016)

e17034 Background: The purpose of the study was to assess the expression and prognostic value of molecular and biological markers that control apoptosis, angiogenesis and proliferation in tissue of squamous cell carcinoma of the vulva. Methods: Tissues of primary squamous cell carcinoma of the vulva of patients aged 27-85 years were studied. Patients were divided into two groups: with a short remission (up to 2 years, n = 19) and a longer one (over 2 years, n = 26) with maximum observation time over 10 years. Immunohistochemical study was performed on paraffin block sections. Primary mouse monoclonal antibodies ki-67, p53, CD31 and CD34 Thermo scientific were used; Reveal Biotin-Free Polyvalent DAB detection system was used for visualization. Number of vessels was determined in each area of sight using objective lens with 40x magnification and AxioVs40 v-4.8.1.0 program. For ki-67 and p53 markers, nuclear localization of staining was evaluated taking into account the number of positive tumor cells in areas with their maximal content. Results: Immunohistochemical study in comparison with clinical course of the disease revealed some characteristics. Primary tumors with a short remission showed higher ki-67 and p53 expression (85±5% and 71.4±5.1%, respectively) in comparison with the longer remission group (8.7±4.1% and 4.2±2.8%, respectively) (p˂0.05). Quantitative assessment of intratumoral microvessel density demonstrated that the average number of microvessels in the area of sight for a short remission was: CD31- 3.97±0.62 and CD34- 5.47±1.31; for a long remission: CD31- 3.36±0.39 and CD34- 3.25±0.43. The results for CD34 expression were statistically significant (p˂0.05). Conclusions: The differences revealed in expression of ki-67, p53 and CD34 in tissue of primary squamous cell carcinoma of the vulva allow prognosis of the tumor process course and recurrence development in the early and late periods.
Multi gene panel testing in unselected patients (pts) with endometrial cancer (EC).
Authors: Karen Anne Cadoo, Deborah DeLair, Diana Mandelker, Richard R. Barakat, Carol L. Brown, Dennis Chi, Ginger J. Gardner, Elizabeth Lin Jewell, Mario M. Leitao, Kara Long, Jennifer Jean Mueller, Yukio Sonoda, Oliver Zivanovic, Michael F. Berger, Liying Zhang, Mark E. Robson, Kenneth Offit, Carol Aghajanian, Nadeem Abu-Rustum, Zsofia Kinga Stadler
Journal: Journal of Clinical Oncology (2017)

e17119 Background: Inherited mutations (muts) in Lynch Syndrome genes (LS) &amp; PTEN are associated with EC. The prevalence of other cancer predisposition genes is unclear. The majority of studies have selected pts by age, family history or specific tumor features. We sought the prevalence of cancer predisposition genes in unselected pts attending for surgical consultation. Methods: 03/2016-10/2016, pts with new EC diagnosis were offered to consent to an IRB approved protocol. Tumor-normal sequencing, was performed via a custom next-generation sequencing panel (MSK-IMPACT) with return of results for 76 cancer predisposition genes. Per institutional standard, all ECs undergo reflex screening for LS with IHC for mismatch repair proteins (MMR P). Results:77 pts consented, median age 60 (27-84), median BMI 27 (16-66), 27% Ashkenazi Jewish (AJ) descent. Tumors: 56 (73%) stage 1, remainder stage 3 or 4, majority (52, 68%) endometrioid histology, of which 31 (60%) grade 1. 15 pathogenic germline variants were identified in 14 pts (18%) including 3 (4%) in LS genes (2 MSH6, 1 MLH1) with corresponding abnormal MMR P. One pt with a known BRCA1 mutation, without prior cancer, with prior risk reducing salpingo-oophorectomy had stage III grade 3 endometrioid EC at 47 yo, tumor LOH at BRCA1 was identified. Of the 4 pts with high-penetrance muts, 3 met criteria for genetic testing for the implicated gene due to personal/family cancer history, 1 pt with MSH6 mutation was identified via absent MMR P only. The remaining 11 pathogenic variants were incremental findings in moderate penetrance ( CHEK2 I157T, MRE11, ATM, APC I1307K, MUTYH) or autosomal recessive genes ( MUTYH, RECQL4, ATM). 5 pt had moderate penetrance variants in known AJ founder muts. Conclusions: In this cohort of unselected EC pts the prevalence of LS was as expected &amp; reflex IHC screening captured all pts appropriately. While all high-penetrance muts were captured by clinical criteria, the incremental identification of moderate penetrance muts in these largely early stage/ low risk EC pts may alter personal &amp; at-risk family member breast &amp; colon cancer screening recommendations. Continuing accrual will reveal the extent to which additional high penetrance genes are seen in unselected EC pts.
Paradoxical behavior of time to RECIST progression as a metric for treatment effect.
Authors: Dean Bottino, Axel Gomez, Jackson Burton, Katherine Williams, Douglas White, Arijit Chakravarty
Journal: Journal of Clinical Oncology (2017)

e14022 Background: RECIST time to progression (RTTP) is the cornerstone of widely used surrogates for patient benefit such as RECIST progression-free survival (RPFS), which in turn is used either for accelerated regulatory approval or to study the effects of factors such as drug exposure and drug target expression levels on RPFS. While one might expect increased antitumor effect to result in longer RTTP and RPFS, we will show that this is often not the case due to a fundamental mathematical property of the RECIST definition of disease progression. Methods:We use a simple mathematical model that treats patient tumor burden dynamics as an evolutionary process consisting of a decreasing drug-sensitive subpopulation of tumor cells and an independently growing drug-resistant subpopulation. This model has successfully described tumor dynamics in NSCLC, melanoma (CPT Pharmacometrics Syst. Pharmacol. (2017) 6, 29–39), and ovarian cancer (internal data). In the presence of drug, we represent the net fitness of the sensitive cells in terms of an exponential decay or “kill” rate k &gt; 0, and the net fitness of the resistant cells as an exponential growth rate g &gt; 0, and the initial fraction of drug-resistant cells by 0 ≤ f ≤ 1. For a given virtual patient (parameter set), we simulate RTTP as the time after start of treatment at which tumor burden V(t) is 20% higher than its lowest value (per RECIST criteria). We then vary the kill rate k and check whether RTTP increases or decreases with increasing k. Results: There is a large set of parameter values for which RTTP is predicted to vary inversely with increasing kill rate k. These parameter values are attained clinically in ovarian cancer patients taking alisertib and paclitaxel (internal data). Conclusions: While RECIST progression criteria may be useful for patient care to identify when a patient is losing her response, care must be taken in interpreting RTTP as a metric of treatment effect due to the real possibility that a stronger treatment effect results in shorter RTTP. We recommend that alternative metrics for patient benefit, such as a generalization of Days Gained (Neal et al PLoS ONE 8(1)e51951), be evaluated. We will present results of these evaluations currently in progress.
Impact of anti-infectious and corticosteroids on immunotherapy: Nivolumab and pembrozilumab follow-up in a French study.
Authors: Jean-Philippe Metges, Emmanuelle Michaud, Delphine Deniel Lagadec, Fanny Marhuenda, Anicet Chaslerie, Francoise Grude
Journal: Journal of Clinical Oncology (2018)

e15157 Background: Immunotherapy is a new paradigm with EMA approval in melanoma and lung cancer. However, recent study has underlined potential drug interactions between immunotherapy and antibiotics or corticoids with decrease of overall survival. The Observatory of Drugs, Medical Devices and Therapeutic Innovations (OMEDIT) Bretagne/ Pays de la Loire (B-PL), in collaboration with the Medical Department of the French Regional Health Insurance, wanted to carry out a study about the impact of these treatments on the efficacy of immunotherapy. Methods: French Regional Health Insurance System (PL) has made an extract in its database for patients who initiated treatment with Nivolumab/Opdivo® and Pembrolizumab/Keytruda® between 02/01/2016 and 30/06/2017. Dispensing of antibiotics, corticoids and antifungals 60 days before initiation of immunotherapy and after the beginning of treatment (within 30 days after). The patient's clinical data (age, sex; diagnosis, indication, grade III/IV side-effects, response rate, survival) would be crossed with the use or not of anti-infectious drug treatment in order to define the impact of taking these drugs on the treatment of immunotherapy. Results: 798 patients were identified including 377 in 2016 and 421 in the first half of 2017: 148 with malignant melanoma and 650 with lung cancer. 763 were treated with nivolumab and 35 with pembrolizumab. Before the beginning of immunotherapy (within 60 days before initiation), 14% of these patients received an antibiotic, 17% a corticoid and 2% an antifungal. After the beginning of immunotherapy (within 30 days after), 8% received a corticoid, 6% an antibiotic and 2% an antifungal. Response to treatment, Progression Free Survival (PFS) and Overall Survival (OS) in correlation with the use or not of these drugs would be presented at the meeting. Conclusions: The good use of immunotherapy was crucial to optimize the response rate and to increase OS. Use of anti-infectious and corticosteroids was usual in routine. Antibiotics were found to be prescribed in 22% of the patients receiving immunotherapy. Results about their impact in term of response, PFS and OS would be shown at the meeting.
Abstract 16991: Predicting Mortality for Initial Survivors of Acute Respiratory Compromise Events
Authors: Ari Moskowitz, Lars W Andersen, Mathias Karlsson, Anne Grossestreuer, Maureen Chase, Michael Cocchi, Katherine Berg, Michael W Donnino
Journal: Circulation (2016)

Introduction: Acute respiratory compromise (ARC) is a common and highly morbid event in hospitalized patients. To date, however, few investigators have explored predictors of outcome in initial survivors of ARC events. Hypothesis: In this study, we aimed to leverage the Get with the Guidelines Resuscitation (GWTG-R) ARC data registry to develop a prognostic score for initial survivors of ARC events. Methods: Using the GWTG-R ARC data registry, we identified 13,193 index ARC events occurring in hospitalized patients. These events were divided into a derivation cohort (9,807 patients) and a validation cohort (3,386 patients). A score for predicting in-hospital mortality was developed using multivariable modeling with generalized estimating equations. Results: The two cohorts were well balanced in terms of baseline demographics, illness-types, pre-event conditions, event characteristics, and overall mortality rates. After model optimization, 9 variables associated with the outcome of interest were included. ...
TCT-53 Role of Single OCT Morphological Variable in the CLIMA Trial (Relationship between Coronary pLaque morphology of the left anterIor descending artery and long terM clinicAl outcome)
Authors: Enrico Romagnoli, Laura Gatto, Alessio La Manna, Francesco Burzotta, Valeria Marco, Alberto Boi, Massimo Fineschi, Franco Fabbiocchi, Nevio Taglieri, Giampaolo Niccoli, Giovanni Ruscica, Francesco Versaci, Mario Albertucci, Filippo Crea, Fernando Alfonso, Eloisa Arbustini, Francesco Prati
Journal: Journal of the American College of Cardiology (2018)
Association between health-related quality of life (HRQoL) and clinical outcomes in non-metastatic castration-resistant prostate cancer (M0 CRPC): Results from the PROSPER study.
Authors: Gerhardt Attard, Fred Saad, Bertrand F. TOMBAL, Maha Hussain, Cora N. Sternberg, De Phung, Shevani Naidoo, Katharina Modelska, Arlene Reisman, Cristina Ivanescu, David F. Penson
Journal: Journal of Clinical Oncology (2018)

5043 Background: We used the PROSPER trial (NCT02003924) to assess (a) the relationship between time to HRQoL deterioration and prostate-specific antigen (PSA) response and (b) the association between HRQoL and metastasis-free survival (MFS). Methods: In PROSPER, 1401 men with M0 CRPC at high risk of metastasis were randomized 2:1 to enzalutamide (ENZA) or placebo. HRQoL was assessed with the Functional Assessment of Cancer Therapy–Prostate (FACT-P) at baseline (BL) and every 16 weeks during treatment. Association between time to first HRQoL clinically meaningful deterioration and PSA response (defined as a ≥50% decline from BL) was explored with stratified Cox regression analyses, and between longitudinal HRQoL changes and MFS with joint models including HRQoL as longitudinal covariate, after adjusting for treatment and relevant clinical/demographic variables. Results: Overall, 723 of 1401 (52%) patients were confirmed PSA responders, significantly less likely to deteriorate on all FACT-P scores than non-responders (hazard ratio [HR] 0.56–0.82), except on physical well-being (PWB) [HR 0.90; p = 0.244]. When treatment is included in the model, stronger effects were observed, explained by 98% of PSA responders receiving ENZA. Most FACT-P scores were prognostic for MFS (7 of 10 scores). Every 10-point increase in FACT-P total score (i.e. improvement) was associated with a 6% decreased risk of metastasis (HR [95% confidence interval] 0.94 [0.88, 1.00]). Every 3-point increase in PWB, emotional well-being, or prostate cancer subscale was associated with a 14% (0.86 [0.81, 0.92]), 12% (0.88 [0.78, 0.99]), and 9% (0.91 [0.86, 0.96]) decreased risk of metastasis, respectively. Conclusions: The research indicates a ≥50% reduction in PSA from BL would result in reduced risk of HRQoL deterioration, also showing a relationship between changes from BL in HRQoL and metastases. Thus, patient-reported outcomes are not only useful in describing patient experience in clinical trials, but may complement traditional clinical practice methods to monitor disease progression. Clinical trial information: NCT02003924.
Hedgehog pathway influence in the immune escape of tumor cells through PDL-1 modulation
Authors: F. Napolitano, C. Di Mauro, A. Pesapane, R. Rosa, V. D'Amato, A. Santaniello, A. Servetto, L. Formisano, R. Marciano, R. Bianco
Journal: Annals of Oncology (2018)

Background: In recent years, immunotherapy has shown remarkable success in the treatment of several cancers. Masking PDL-1 on cancer cellular surface or PD1 on T-cells may increase the lymphocyte activity against the tumor. Intracellular regulation of PDL-1 may thus be a promising therapeutic strategy. However, the mechanism regulating PDL-1 expression remains unclear. Moreover, there are evidences supporting the idea that deregulation of Hedgehog (Hh) signalling has a role in immunity and inflammation. Therefore, we investigated whether activation of the Hh signalling contributes to regulate PDL-1 or PD1 expression and whether its pharmacological modulation affects the anti-tumor function of activated lymphocytes. Methods: We used a panel of human pancreatic and breast cancer cell lines, with different ER, PR and HER2 expression patterns. The effects induced by Hh inhibition, through the Smo-inhibitor NVP-LDE225, on signal transduction in cancer cells were investigated. We also tested how the overexpression of GLI1, tGLI1 and GLI3, main transcription factors in the Hh pathway, could affect the expression of PDL1. Results: Hh inhibition reduced the expression of PDL1 in all analysed cell lines. This effect is counteracted by upregulation of PDL-1, when GLI1 and, even more, tGLI1 are overexpressed. NVP-LDE225 treatment modulates the production of several secreted factors, such as secreted IL6-receptor which acts as an anti-inflammatory molecule. Conclusions: Our results suggest that Hh pathway has a specific role in cancer immune evasion trough PDL-1 modulation. The inhibition of the Hh pathway could represent an interesting therapeutic approach in combination with anti-PD1 drugs. Legal entity responsible for the study: Prof. Roberto Bianco. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.