tbuckley/cabot-search huggingface dataset:
Serum protein predictors of long term survival from combined ipilimumab and nivolumab therapy in metastatic melanoma patients.
Authors: Krisztian Homicsko, Michel A Cuendet, Olivier Michielin
Journal: Journal of Clinical Oncology (2018)

e21513 Background: Combined ipilimumab (IPI) and nivolumab (NIVO) is the most advanced immune therapy for metastatic melanoma patients. However, high response rates can be achieved at the price of important immune-related toxicity. Hence, patient selection is paramount. To date, no biomarker can predict the benefit or lack of it, from IPI/NIVO. Hypothesis A pretreatment serum protein marker signature could predict the long-term benefit from combined ipilimumab and nivolumab therapy. Methods: We performed a retrospective analysis of 440 proteins in the serum of 89 patients. All patients were treatment naive with advanced metastatic melanoma, treated with ipilimumab and nivolumab in the BMS Checkmate 069 study (NCT01927419). The median follow-up of patients was long, at 36 months, providing a rational basis to identify factors of long-term progression-free and overall survival. Serum proteins were analyzed using a Raybiotechnology protein array. Results: We built decision tree classifiers that maximize the difference between Kaplan-Meier survival curves, using the exponential scaling method. The output classes of the trees were subsequently grouped into two categories to predict benefit vs. no benefit. We deliberately limited the complexity of the predictors to the minimum, to avoid overfitting and to create robust predictors. We could define a three-protein signature that can discriminate benefit. At 36 months, 90% of the biomarker-positive population did not progress, whereas only 25% of biomarker-negative population was without progression (p < 0.0001). Using the leave-one-out validation, we found that the rate of false positives is remarkably low (8% for PFS and 14% for OS). The same predictors are non-discriminate in the IPI monotherapy arm of the same study. We also compared protein biomarker data to clinicopathological parameters, notably to the neutrophil/lymphocyte ratio (NLR) and LDH levels and our protein signature outperformed these markers. Conclusions: It is possible to develop a simple, three protein classifier from serum to predict long term benefit from IPI/NIVO therapy. More samples will be required to validate these findings.
Abstract 17184: Achievement Of LDL-cholesterol Reduction Targets is Associated With Reduced Cardiovascular Disease Risk Among Patients With Familial Hypercholesterolemia in a Large Electronic Medical Record Database
Authors: Sarah S Cohen, Edmond K Kabagambe, Jana Shirey-Rice, Jill Hardin, Keri Monda, Jon P Fryzek, Sergio Fazio, Joshua C Denny, Wei-Qi Wei, Loren Lipworth
Journal: Circulation (2015)

Introduction: Heterozygous familial hypercholesterolemia (FH) is common but under-recognized, with an estimated prevalence of 1:200-1:500 and an associated high risk of premature cardiovascular disease (CVD). Little is known regarding the association between change in low-density lipoprotein cholesterol (LDL-C) and long-term CVD risk in FH patients. We hypothesized that FH patients who achieved LDL-C &lt; 100 mg/dL or reduction ≥50% post-statin initiation would have reduced risk of non-fatal myocardial infarction (MI) or revascularization. Methods: Using Dutch Lipid Network criteria components, 174 “probable” and 125 “definite” FH patients with LDL-C measurements available before and after statin initiation were identified in the Vanderbilt de-identified electronic medical records (EMR) Synthetic Derivative database, 1996-2014. First non-fatal MI or revascularization was identified via validated EMR algorithm with positive predictive value=92%. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained from Cox regression models in relation to LDL-C levels (≥ vs. &lt;50% reduction or &lt; vs. &gt;100 mg/dL post-statin), adjusted for age, race, sex, blood pressure, smoking, and body mass index. Results: Mean (+/- SD) LDL-C levels prior to initiation of statin therapy were 207 (+/- 31) for probable and 304 (+/- 124) mg/dL for definite FH patients. Similar proportions of patients attained ≥50% reduction in LDL-C after statin initiation in both groups (24.1% and 26.4%), while 22.4% achieved LDL-C &lt; 100 mg/dL in the probable group compared to only 4.8% in the definite group. Over median follow-up of 5.4 years, 34 probable and 19 definite FH patients experienced non-fatal MI or revascularization. The HR (95% CI) among those with post-statin LDL-C &lt; 100 vs &gt;100 mg/dL was 0.59 (0.23-1.52) overall, with no evidence of effect modification by probable/definite FH status (likelihood ratio test (LRT) p-value=0.58). A similar pattern was observed for LDL-C change ≥50% vs &lt;50% (HR (95% CI) 0.58 (0.24-1.38), LRT p-value=0.44). Conclusions: In this small sample of FH patients, lowering LDL-C to &lt;100 mg/dL suggests a reduction in CVD risk, but few attained this LDL-C target. These results warrant further research in larger populations of this understudied condition.
Predicting treatment outcome of rectal cancer patients underwent neoadjuvant chemoradiotherapy by ctDNA: The potential use of ctDNA monitoring as organ-sparing approach.
Authors: Lifeng Yang, Yaqi Wang, Lijun Shen, Juefeng Wan, Weijuan Deng, Ji Zhu, Zhen Zhang
Journal: Journal of Clinical Oncology (2018)

3608 Background: Neoadjuvant chemoradiotherapy (nCRT) is widely accepted for the treatment of locally advanced rectal cancer (LARC). Watch & wait (W&W) strategy can improve life quality, but needs strict patient selection. We investigated the ability of circulating tumor DNA (ctDNA) to predict treatment outcome and improve risk stratification. Methods: Between 2015 and 2016, we enrolled LARC (T3/T4 and/or N+) patients planned for nCRT. Plasma samples were collected pretreatment, in the middle of nCRT, post-nCRT, before surgery and one week after surgery. Somatic mutations in individual patient were identified via massively parallel sequencing of 455 genes. Responders (ypTRG 0–1) or non-responders (ypTRG 2–3) were recorded. Chi-square test was used to compared ctDNA levels to clinical, radiological and pathological response. Results: We analysed 440 serial plasma samples from 88 patients. Ten cases were pathological complete response (pCR). CtDNA was detectable in 65.9% (58/88), 14.7% (13/88) and 3.4% (3/88) of pretreatment, post-nCRT and post-surgery samples, with most frequent mutations as TP53, APC, KRAS. The rates of responders and non-responders are 24.1% (14/58) and 75.9% (44/58), but no difference was found in baseline ctDNA. 65.5% (38/58) of the patients’ ctDNA level decreased sharply to zero before the end of nCRT, which was consistent to their radiological and pathological changes. CtDNA was detectable in 60% (6/10) pCR cases, most of their ctDNA vanishing at the middle of nCRT. 29.3% (17/58) of the patients’ ctDNA status changed in irregular patterns. However, 5.2% (3/58) of the patients’ ctDNA status goes up during nCRT, all of the three developed metastatic disease during the follow up period. Increased level of ctDNA post-nCRT indicated high rates of disease progression, which was not appropriate for W&W strategy. Conclusions: The baseline ctDNA were not helpful in distinguishing responders from non-responders. Post-nCRT analysis stratifies patients with LARC into subsets at high or low risk of progression. CtDNA analysis could potentially be used to guide patient selection for W&W strategy or adjuvant chemotherapy.
Abstract 19844: Stromal Interaction Molecule 1 is Essential for the Maintenance of Cardiac Metabolism
Authors: Helen E Collins, Betty M Pat, Silvio H Litovsky, Martin E Young, John C Chatham
Journal: Circulation (2015)

The ER/SR Ca 2+ sensor, Stromal Interaction molecule 1 (STIM1), a key regulator of store-operated calcium entry is expressed in cardiomyocytes and has been implicated in regulating hypertrophic signaling. We have recently shown that mice with a cardiomyocyte-restricted deletion of STIM1 develop dilated cardiomyopathy. Given the importance of Ca 2+ in regulating cardiac metabolism we examined whether a lack of STIM1 alters cardiac metabolism. We found that hearts isolated from 20 week cr STIM1-KO mice exhibit significant changes in cardiac metabolism, observed by a significant reduction in both glucose oxidation (0.75 ± 0.06 v 0.46 ± 0.04 μmol/min/g dry wt, p &lt; 0.01) and net lactate release (15.38 ± 1.29 v 10.23 ± 0.87 μmol/min/g dry wt, p &lt;0.02) in an isolated perfused working heart model in comparison to control mice. These changes occurred independent of any changes in contractile function or oleate oxidation (0.22 ± 0.03 v 0.26 ± 0.02 μmol/min/g dry wt, ns ). Consistent with a reduction in glucose oxidation we also found significant increase in the expression of Pyruvate dehydrogenase kinase and a reduction in the expression of GLUT4 protein levels. Hearts from 20 week cr STIM1-KO contained an increased number of lipid droplets (3.35 ± 0.35 v 2.08 ± 0.20, no of lipid droplets per 4400x grid square, p &lt;0.002) and increased triglyceride levels (51.95 ± 5.84 v 32.55 ± 2.41 v 36.05 ± 1.73 mg/dL, p &lt; 0.05) in comparison to age-matched controls and cr STIM1-KO +/- hearts respectively. In addition to these metabolic changes there were was also significant disruption in mitochondrial morphology and structure in cr STIM1-KO; interesting these same abnormalities were also present in cr STIM1-KO +/- hearts. We found that 12 week cr STIM1-KO +/- and cr STIM1-KO hearts contained smaller mitochondria compared to controls and that cr STIM1-KO were significantly smaller than cr STIM1-KO +/- (1140.6 ± 28.3nm v 973.9 ± 15.8nm v 887.3 ± 17.1nm, p &lt; 0.01) These data demonstrate for the first time a novel yet critical role for STIM1 in regulating cardiac metabolism and in maintaining mitochondrial morphology and organization. This work was supported by NIH grant R21-HL-110366 (JCC) and an American Heart Association Greater Southeast Postdoctoral fellowship 15POST25260004 (HEC).
What role should value play in cancer care?
Authors: Risha Gidwani, Douglas W. Blayney, Manali I. Patel, Steven M Asch, P. Adam Kelly, Andrea Nevedal
Journal: Journal of Clinical Oncology (2016)

6629 Background: Value in cancer care has been garnering much attention, with different approaches proposed by the American Society of Clinical Oncology and the National Comprehensive Cancer Network regarding the use of value to inform care. Medical oncologists play a large role in purchasing cancer treatment, yet there is currently a paucity of evidence regarding U.S. oncologists’ attitudes towards the appropriate use of value in making treatment decisions. Here, we evaluate oncologists’ views towards value-based cancer treatment. Methods: A pilot study with semi-structured interviews of 31 U.S. based oncologists practicing in Academic Medical Centers, the Veterans Health Administration and the community. Physicians were asked about: their definitions of value; the role of value in making treatment decisions for patients with advanced cancer; assessing value at the individual versus population level; conversations about cost and value with patients; perceptions of employing fee-for-value reimbursement in cancer care; and the relationship between palliative chemotherapy and value. Transcribed interviews were analyzed using matrix and thematic analysis. Results: Almost all oncologists thought the costs of cancer care were too high, yet most reported not having conversations about costs with their patients. Oncologists had widely varying definitions of value as well as varying perceptions about the potential of fee-for-value reimbursement in oncology. Definitions of value ranged cost relative to health outcomes to providing care that is congruent with patient values. Many oncologists did not include cost in their definition of value. Those defining value as cost relative to health outcomes differed as to whether value should be assessed at an individual or societal level, as well as which party should be responsible for determining a value threshold. Oncologists expressed disparate opinions about the value of palliative chemotherapy for patients with metastatic disease. Conclusions: Oncologists have a wide range of opinions about value and its appropriate role in guiding treatment decisions. However, oncologists almost uniformly felt costs of cancer care were excessive. Findings should be further explored to properly inform policy and clinical guidance.
Use of cell-free circulating RNA (cfRNA) levels in plasma and expression of HER2 and PD-L1 to monitor disease status in metastatic cancer patients.
Authors: Luis E. Raez, Kathleen Danenberg, Aurelio Bartolome Castrellon, Michel Velez, Joshua L. Usher, Shahrooz Rabizadeh, Yolanda S Jaimes, Brian Hunis, Cheryl Habaue, Peter Danenberg
Journal: Journal of Clinical Oncology (2018)

e15013 Background: Analysis ofcell-free circulating tumor RNA (cfRNA) extracted from plasma of cancer patients (pts) provides a means of measuring dynamic changes in gene expression as well as levels of cfRNA, allowing us the evaluation of disease status and prediction of outcomes to anti-tumoral therapy. Methods: Blood was drawn from pts under various treatments (tx) every 6-8 weeks, at the same time that CT scans were done. CfRNA was extracted from the resulting plasma and reverse transcribed with random hexamers to cDNA. Levels of cfRNA were quantitated by RT-qPCR and correlated with pt response (CR/PR/SD/PD), as determined by CT scans. Results: 96 pts (48 breast, 30 lung and 18 colon cancer) were enrolled in a 2-year study. Breast: 34 pts completed the first two cycles of tx. Of these, 8/11 pts with PD showed increasing (INC) levels of cfRNA, 16/17 pts with SD showed either no change (NC) or a decrease (DEC) in levels of cfRNA, and 4/6 pts with PR had DEC cfRNA (82% concordance between cfRNA and pt response). Of pts with PR, 3 were treated with HER2 inhibitors and in 2 of these pts, HER2 cfRNA expression levels disappeared. Lung: 23 pts completed the first two cycles of tx. Of these, 6/8 pts with PD showed INC levels of cfRNA, 8/12 pts with SD showed either NC or DEC cfRNA, and 3/3 pts with PR had DEC cfRNA, corresponding to 74% concordance between cfRNA and pt response. Among 7 pts treated with immunotherapy, 3/3 pts with PD showed INC PD-L1 expression (PDL-1), 3/3 pts with SD had NC in PD-L1, and 1 pt with PR showed DEC PD-L1, corresponding to 100% correlation between PD-L1 and response. Colon: 11/18 pts completed the first 2 cycles. Of these, 2/3 pts with PD showed INC cfRNA, and 3/4 pts with SD showed DEC cfRNA, as did 4/4 pts with PR (82% concordance between cfRNA and response). Conclusions: A significant concordance was observed between clinical response and changes in cfRNA levels in breast, lung and colon cancer pts (82%, 74% and 82%). Levels of PD-L1 correlated with response in 7/7 lung pts, and HER2 expression correlated with response in 2/3 breast pts. We conclude that cfRNA levels can indicate tx response, and PD-L1 and HER2 could be used to monitor response to immunotherapy and HER2 inhibitors.
P04.43 Pre-diagnostic plasma metabolites linked to future brain tumor development
Authors: B Björkblom, P Jonsson, F Späth, B Melin, H Antti
Journal: Neuro-Oncology (2018)

The Northern Sweden Health and Disease Study is a unique population-based biobank linked to the clinical data registries. The samples originate from over 133 000 individuals living in the northern part of Sweden, and primarily collected during health checkups from the age of 40 years. Our project aims to investigate alterations in metabolite signatures in blood plasma of healthy blood donors that later in life developed a tumor. Brain tumors, especially glioblastoma is associated with poor prognosis. To explore early events of metabolic reprograming linked to future diagnosis, we investigated alterations in metabolite concentrations in plasma collected several years before diagnosis with matched healthy controls. In total 392 analytical samples (256 repeated timepoint and 136 single timepoint, case-control samples) were analyzed using GC-TOFMS. Constrained randomization of run order was utilized to maximize information output and minimize the false discovery rate. By use of reference databases, we could with high confidence quantify and identify 150 plasma metabolites. We detected metabolites with significant alterations in concertation between pre-clinical glioma cases and healthy controls by the effect projection approach based on orthogonal partial least squares (OPLS-EP). For the repeated blood samples, we designed and applied a novel multivariate strategy for high resolution biomarker pattern discovery. We utilize the fact that we have available samples from two repeated time points prior to diagnosis for each future glioma case and their matched controls to construct a small design of experiment (DoE) of four samples for each match pair. The data for each individual DoE was evaluated by OPLS-EP to determine the effect of each individual metabolite in relation to control-case, time and their interaction. Finally, latent significance calculations by means of OPLS were used to extract and evaluate the correct latent biomarker and highlight true significance of individual metabolites. Our study presents an approach to minimize confounding effects due to systematic noise from sampling, the analytical method, as well as take into account personalized metabolic levels over time, enabling biomarker detection within a smaller sample group. We will present and discuss the latest results and biomarkers from this exploratory metabolomics study at the meeting.
Age as a predictive and prognostic factor for targeted therapy treatment in metastatic chemorefractory colorectal cancer (CRC): An analysis of NCIC CTG CO.17 and CO.20.
Authors: Connor Wells, Lillian L. Siu, Jeremy David Shapiro, Dongsheng Tu, Derek J. Jonker, Christos Stelios Karapetis, John Simes, Geoffrey Liu, Timothy Jay Price, Niall C. Tebbutt, Christopher J. O'Callaghan
Journal: Journal of Clinical Oncology (2017)

3555 Background: There is minimal data on the efficacy and improvement of quality of life (QoL) of these targeted therapies, like cetuximab, in elderly CRC patients (≥70yo). We analyzed outcomes from two randomized phase III clinical trials from the Canadian Clinical Trials Group, CO.17 and CO.20. Methods: CO.17 and CO.20 were retrospectively analyzed. CO.17 compared cetuximab (CETUX) with best supportive care (BSC), CO.20 compared CETUX + brivanib (BRIV) with CETUX + placebo. Key eligibility criteria were similar between each trial. Patients were dichotomized by age (≥70yo/ &lt; 70yo) for comparisons. Outcomes included overall survival (OS), progression free survival (PFS), adverse events (AEs), and QoL deterioration. In CO.17, only patients with wild type K-RAS were included in analysis. Multivariate analysis with Cox regression controlled for additional variables. Results: 980 patients were included in this analysis. 257 (26.2%) were ≥70yo at the time of enrollment. In CO.17, OS and PFS were similar between young and elderly patients treated with CETUX (OS 9.7m vs 8.0m, p = 0.45; HR 0.73 95%CI 0.39-1.37). Compared to the BSC arm, elderly patients treated with CETUX had a non-significant increase in OS (8.0m vs 5.1m, p = 0.11). In patients treated with CETUX, grade 3/4 AEs were similar between age groups, however elderly patients had a faster deterioration in global QoL than younger patients (3.6m vs 5.7m p = 0.046). In CO.20, younger patients had longer OS than elderly (9.2m vs 7.6m, p = 0.02; HR 0.81 95% 0.68-0.97, p = 0.02). AEs in the BRIV+CETUX arm were higher in the elderly than young (88% vs 77%, p = 0.03). Both young and elderly treated with BRIV+CETUX had more rapid decreases in global QoL than the CETUX arm. Conclusions: Age was neither prognostic nor predictive of response to targeted therapy in the single agent CO.17 trial. In CO.20, age conferred a worse prognosis. Elderly patients who are eligible for clinical trials may garner similar survival benefits as younger patients with single agent therapy, but may not derive the same improvement in QoL.
Efficacy of oral vinorelbine in advanced/progressive desmoid tumours: An updated retrospective study in 50 patients.
Authors: Olivier Mir, Chahinez Rahal, Françoise Rimareix, Julien Adam, Philippe Terrier, Julien Domont, Sarah Dumont, Arslane Skander Rahal, Andrea Cavalcanti, Isabelle Sourrouille, Nicolas Leymarie, Charles Court, Gilles Missenard, Leila Haddag-Miliani, Charles Honoré, Axel Le Cesne
Journal: Journal of Clinical Oncology (2016)

11050 Background: Desmoid tumors (DT) are locally aggressive neoplasms, with a need for effective systemic treatment in locally advanced or progressive disease, in order to avoid the short- and long-term burden of local treatments (radiotherapy or surgery). Methods: Retrospective, electronic records review of adult patients (pts) with recurrent/progressive DT treated with weekly oral vinorelbine (90 mg once weekly) in Gustave Roussy Cancer Campus. Results: With a median follow-up of 38 months, 50 pts were eligible for this analysis [26% males, 10% with familial adenomatous polyposis, median age 35 (range: 18-61), 20% with deep (intra-abdominal or pelvic) DT]. Overall, 88% of pts had documented progressive disease according to RECIST v1.1 before treatment initiation. Vinorelbine was given alone in 50% of pts, or concomitantly with previously initiated hormonal therapy (tamoxifen + LHRH agonist) in 50% of pts. Median tumor size was 11cm (3.7-29cm). Pts were pre-treated by surgery (36%), hormonal therapy (52%), imatinib (14%), radiotherapy (10%), or vinblastine-methotrexate (6%). Median duration of treatment was 10.8 months (range: 2.0-26.2). Toxicity profile was excellent, without any grade 3-4 toxicity. Symptomatic relief at 3 months was seen in 80% of patients. Best response (RECIST v1.1) was: 32% PR, 58% SD, 10% PD. Progression-free rates at 3, 6 and 12 months were: 98%, 92% and 88%, respectively. No baseline parameter significantly influenced treatment efficacy. After subsequent progression, rechallenge of oral vinorelbine was needed in 6 pts (12%), resulting in 2 PR and 4 SD. Conclusions: Oral vinorelbine is a highly effective, affordable and well tolerated regimen in pts with advanced/ progressive DT. A prospective evaluation of its effectiveness in this setting is warranted.