tbuckley/cabot-search huggingface dataset:
Genetically Predicted Levels of DNA Methylation Biomarkers and Breast Cancer Risk: Data From 228 951 Women of European Descent
Authors: Yaohua Yang, Lang Wu, Xiao-Ou Shu, Qiuyin Cai, Xiang Shu, Bingshan Li, Xingyi Guo, Fei Ye, Kyriaki Michailidou, Manjeet K Bolla, Qin Wang, Joe Dennis, Irene L Andrulis, Hermann Brenner, Georgia Chenevix-Trench, Daniele Campa, Jose E Castelao, Manuela Gago-Dominguez, Thilo Dörk, Antoinette Hollestelle, Artitaya Lophatananon, Kenneth Muir, Susan L Neuhausen, Håkan Olsson, Dale P Sandler, Jacques Simard, Peter Kraft, Paul D P Pharoah, Douglas F Easton, Wei Zheng, Jirong Long
Journal: JNCI Journal of the National Cancer Institute (2019)

Abstract Background DNA methylation plays a critical role in breast cancer development. Previous studies have identified DNA methylation marks in white blood cells as promising biomarkers for breast cancer. However, these studies were limited by low statistical power and potential biases. Using a new methodology, we investigated DNA methylation marks for their associations with breast cancer risk. Methods Statistical models were built to predict levels of DNA methylation marks using genetic data and DNA methylation data from HumanMethylation450 BeadChip from the Framingham Heart Study (n = 1595). The prediction models were validated using data from the Women’s Health Initiative (n = 883). We applied these models to genomewide association study (GWAS) data of 122 977 breast cancer patients and 105 974 controls to evaluate if the genetically predicted DNA methylation levels at CpG sites (CpGs) are associated with breast cancer risk. All statistical tests were two-sided. Results Of the 62 938 CpG sites CpGs investigated, statistically significant associations with breast cancer risk were observed for 450 CpGs at a Bonferroni-corrected threshold of P less than 7.94 × 10–7, including 45 CpGs residing in 18 genomic regions, that have not previously been associated with breast cancer risk. Of the remaining 405 CpGs located within 500 kilobase flaking regions of 70 GWAS-identified breast cancer risk variants, the associations for 11 CpGs were independent of GWAS-identified variants. Integrative analyses of genetic, DNA methylation, and gene expression data found that 38 CpGs may affect breast cancer risk through regulating expression of 21 genes. Conclusion Our new methodology can identify novel DNA methylation biomarkers for breast cancer risk and can be applied to other diseases.
Survival and clinical outcomes of ovarian cancer patients enrolled in phase I clinical trials.
Authors: Bradley Corr, Marisa Moroney, Jeanelle Sheeder, Brandon Sawyer, S. Gail Eckhardt, Kian Behbakht, Jennifer Robinson Diamond
Journal: Journal of Clinical Oncology (2019)

5559 Background: Ovarian cancer patients who enroll in Phase I clinical trials are typically platinum resistant, heavily pretreated patients with a poor prognosis. Historically, clinical benefit of Phase I trials in this patient population has been uncertain. We assessed prognostic factors and survival in women with recurrent, previously treated ovarian cancer who enrolled in Phase I clinical trials. Methods: We performed a retrospective analysis of all ovarian cancer patients who were treated on Phase I clinical trials from 2008 through 2018 at the University of Colorado Cancer Center. Patient characteristics, treatment-related toxicities and survival data were assessed. Descriptive statistics and Cox proportional hazards models were utilized to identify risk factors associated with survival time. Results: A total of 132 individual patients were treated on Phase I clinical trials. Patients had a median age of 59 years (range 33-88) with a median of 5.5 (range 1-13) previous chemotherapy lines. 53/132 (40%) of patients were treated on multiple Phase I trials with a median of 1 (range 0-5) prior Phase 1 clinical trial enrollments. All patients had an ECOG performance status of 0 or 1. Overall response rate (defined as complete or partial response) was 9% and disease control rate (defined as complete or partial response or stable disease as best response) was 33%. Median overall survival (OS) was 11.5 months (95% CI: 9.3-13.7). Two patients died on trial due to progression of disease while no patients died due to treatment-related toxicity. In multivariate analysis, independent risk factors predicting shorter survival were elevated CA-125 (HR 2.8; 95% CI: 1.6-5.2) and albumin &lt; 3.5 g/dL (HR 2.5; 95% CI: 1.65-3.79). BMI &gt; 25 predicted longer survival (HR 0.65; 95% CI: 0.44-0.96). Conclusions: Phase I clinical trials for heavily pretreated ovarian cancer patients are safe by a standard of no patients experiencing toxicity-related deaths in our study. They are clinically efficacious with patients experiencing OS of 11.5 months, which is comparable to existing approved therapies. Elevated CA-125 and low albumin levels predict shorter survival, while BMI &gt; 25 predicts longer survival. Phase I clinical trial options should be considered for all heavily pretreated ovarian cancer patients if available to them.
A multicenter, phase II study of soluble LAG-3 (Eftilagimod alpha) in combination with pembrolizumab (TACTI-002) in patients with advanced non-small cell lung cancer (NSCLC) or head and neck squamous cell carcinoma (HNSCC).
Authors: Julio Antonio Peguero, Pawan Bajaj, Enric Carcereny, Timothy Dudley Clay, Bernard Doger, Enriqueta Felip, Matthew Krebs, Martin Forster, Santiago Ponce Aix, Patricia Roxburgh, Frederic Triebel
Journal: Journal of Clinical Oncology (2019)

TPS2667 Background: Eftilagimod alpha (efti, IMP321) is a recombinant LAG-3Ig fusion protein that binds to MHC class II and mediates antigen-presenting cell (APC) activation followed by CD8 T-cell activation. Pembrolizumab binds to the PD-1 receptor, blocking both immune-suppressing ligands, PD-L1 and PD-L2, from interacting with PD-1 to help restore effector T-cell responses. The rationale to combine efti and pembrolizumab comes from their complementary mechanisms of action. Efti activates APCs and lead to an increase in activated T cells which effect potentially reduces the number of non-responders to pembrolizumab. Combining an APC activator like efti to pembrolizumab is therefore fundamentally different from many other trials combining two checkpoint inhibitors like an anti-LAG-3 mAb with an anti-PD-1 mAb. In a previous phase I study (NCT 02676869) in metastatic melanoma the combination was found to be safe and well tolerable with encouraging signs of clinical activity. Methods: In the course of this multicenter, open label, Phase II study, patients will be recruited for each of three indications: A: 1st line, PD-X (PD-1 or PD-L1) naïve non-small cell lung cancer (NSCLC); B: 2nd line, PD-X refractory NSCLC; C: 2nd line PD-X naive head and neck squamous cell carcinoma (HNSCC). The study is designed according to Simon's optimal two-stage design, with objective response rate acc to iRECIST as primary endpoint. Secondary endpoints include progression free survival and overall survival. In case there are more responses achieved than a predefined threshold (each part counted separately) in pts recruited in the initial stage (n = 58), additional pts (51) will be recruited in stage 2. Efti will be administered for a maximum of 18 cycles (1 cycle = 3 weeks) as 30 mg subcutaneous injection every 2 weeks for the first 8 and every 3 weeks for the 10 following cycles. Pembrolizumab (200 mg intravenous infusion every 3 weeks) is administered in parallel for up to 35 cycles. Patients are followed up for progression and survival. Clinical trial information: 03625323.
Analysis of circulating tumor DNA to monitor metastatic breast cancer patients treated with first-line chemotherapy (CAMELLIA study).
Authors: Zongbi Yi, Fei Ma, Guohua Rong, Jin Li, Lianpeng Chang, Yanfang Guan, Binliang Liu, Xiuwen Guan, Lixi Li, Chunxiao Li, Jingtong Zhai, Haili Qian, Binghe Xu
Journal: Journal of Clinical Oncology (2019)

e14568 Background: Our precious study indicated that the dynamic changes in circulating tumor DNA (ctDNA) could reflect changes in tumor burden. We conduct this study to validate the role of ctDNA as a therapeutic response biomarker in a larger cohort prospective phase III randomized multicenter study. Methods: In this study, we collected 292 serial ctDNA samples from 125 metastatic breast cancer patients treated with first line chemotherapy. Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA. Results: 81.4% patients had detectable ctDNA at baseline. An undetectable ctDNA at baseline was associated with a lower disease volume (p &lt; 0.05). The commonly mutated genes were PIK3CA (35.0%), TP53 (34.2%), MLL3 (9.4%) and ESR1 (9.4%). Kaplan–Meier analysis showed that TP53 gene mutations and remaining C2 (detected at base line and remaining at the second cycle of chemotherapy) were significantly associated with poor PFS. Longitudinal monitoring of 27 patients during treatment showed that the molecular tumor burden index ([mTBI] a measure of the percentage of ctDNA in samples) was positively correlated with tumor size as evaluated by computed tomography (P &lt; 0.05). The evaluations based on mTBI values were consistent with those based on CT scans in 87.5% of cases at the endpoint of clinical observation. Conclusions: ctDNA could be used to predict treatment outcomes and the mTBI is a potential method to assess therapeutic response in metastatic breast cancer. Clinical trial information: NCT01917279.
Real-time monitoring of circulating stromal cells in the blood to predict responsiveness of new-line therapies in metastatic breast cancer.
Authors: Daniel Adams, R Katherine Alpaugh, Stuart S Martin, Rena G. Lapidus, Saranya Chumsri, Cha-Mei Tang, William Williams, Markus Lacher, Massimo Cristofanilli
Journal: Journal of Clinical Oncology (2019)

e14048 Background: Cancer associated macrophage like cells (CAMLs), a circulating stromal cell subtype, has been shown as an independent prognostic indicator of survival in late stage metastatic breast cancer when cells enlarge to ≥50µm. However, no study has evaluated the clinical relationship between changes in CAML size and their ability to predict treatment response. While CAMLs are prognostic for progression, we hypothesized that monitoring changes in CAMLs after initiation of therapy may be predictive for responsiveness of new treatment regimens. Methods: A prospective 12 months blind multi-institutional pilot study was undertaken to evaluate CAMLs before, and after, induction of a new line of investigational therapy based on CT scans. Patients with progressive metastatic breast cancer (n = 29) who had failed at least 2 prior therapies were recruited. A baseline (BL) blood sample was taken prior to induction of a new therapy and a 2nd sample (T1) taken after initiation (~30 days). Blood was filtered by CellSieve filtration.The quantities and sizes of CAMLs were analyzed based on PFS hazard ratios (HRs) by censored univariate analysis. Results: CAMLs were found in 97% of BL samples and 93% of T1 samples. At first CT scan, after the assigned dose of investigational treatment, 17 of 29 patients had clinical progression with 14/17 (82%) patients having an increased CAML size and 3/17 (18%) having a decreased CAML size. The remaining 12 of 29 patients saw clinically stable, or regression, of disease with 10/12 (83%) having decreased CAML size and 2/12 (17%) having increased CAML size. Overall CAML size change after therapy induction was 83% accurate at predicting response or progression based on CT scans. Further, patients with increasing CAML size at T1 had a 4 month mPFS vs 10 month mPFS for decreasing CAMLs, with a lower 12 month PFS HR = 3.7 (95%CI = 1.5-10.1, p = 0.020). Conclusions: Our data suggests that in metastatic breast cancer, monitoring CAMLs changes over the first 30 days of treatment accurately predicts responsiveness of disease to new treatments. Further, we suggests using blood sampling may increase the clinical value of blood based diagnostics by rapidly predicting the benefit of subsequent therapies.
Neoantigen-based personalized DC vaccine for lung cancer: An update of translational study.
Authors: Zhenyu Ding, Li Yang, Heng Xu, Qing Li, Qiu Li
Journal: Journal of Clinical Oncology (2019)

e20674 Background: DC vaccine is a promising strategy for cancer therapy. We conducts a personalized, neoantigen-loaded DC therapy trial in advanced NSCLC (NCT02956551 &amp; ChiCTR-ONC-16009100). Here we provide the updated data. Methods: Advanced lung cancer patients in their later lines of therapy were enrolled. Whole exon dequencing was performed from freshly obtained tumor tissues as well as the peripheral blood, while RNA-seq was performed in tumor-derived RNA. Somatic mutations were submitted ot systematical progream of neoantigen predication, considring personalized MHC affinity, gene expression, tumor herogeneity, and etc. 10-15 peptides with the highest score were synthesized and pulsed in PBMC-dericed DC, which was introduced to patients. All cells were prepared in a GMP workshop. The primary endpoint was safety and toleratility. Results: Totally 11 patients were enrolled up to now. Most (n = 5) were adenocarcinoma, and the rest were squamous cancer (n = 4) and NET (n = 2). They were heavily treated (lines of previous therapy: 2-5, median 2). 1 patient failed in re-biopsy, 1 lacked candidate neoantigen, and another died rapdily during the preparation of DC vaccine. 8 patient finally received vaccination (n = 6, male; n = 2, female). The number of neoantigens identified from each patient vairied greatly (35-441, median n = 68). Totally 37 times of vaccination was performed (5-17, median 5). The cell infusion was safe and highly tolerable and no significant side effects were observed, even for those with poor performance. The treatment achieved SD in 7 patients, and only 1 with PD. The median PFS was 5.7m (range: 3.8-10.0m). 5 patients are now maintained on therapy. Conclusions: The neoantigen based personalized DC vaccine is highly tolerable without obvious side effects. The vaccination strategy shows promise in efficacy. Clinical trial information: NCT02956551.
Health-related quality of life (HRQoL) evaluation in the REGOMA trial: A randomized, phase II clinical trial analyzing regorafenib activity in relapsed glioblastoma patients.
Authors: Giuseppe Lombardi, Paola Del Bianco, Alba Ariela Brandes, Marica Eoli, Roberta Ruda, Toni Ibrahim, Ivan Lolli, Andrea Pace, Bruno Daniele, Francesco Pasqualetti, Simona Rizzato, Eleonora Bergo, Mario Caccese, Giovanna Magni, Riccardo Soffietti, Gian Luca De Salvo, Vittorina Zagonel
Journal: Journal of Clinical Oncology (2019)

2045 Background: REGOMA trial showed that regorafenib (REG) significantly improved OS and PFS in relapsed glioblastoma (GBM) patients (pts) with respect to lomustine (LOM). REG showed a different toxicity profile compared to LOM. Here, we report final results of the HRQoL assessment, a secondary end point. Methods: HRQoL was measured using the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and brain module (QLQ-BN20) administered before any MRI assessments, every 8 weeks (+/- 2 weeks) until disease progression. To evaluate treatment impact on HRQoL, questionnaires at progression were excluded. Mixed-effect linear models were fitted for each of the HRQOL domain to examine the change over progression-free time within and between arms. The models included the time of questionnaire assessment, the treatment group and their interaction, as fixed effects, and a compound symmetry covariance structure for the random effects. Differences of at least 10 points were classified as a clinically meaningful change. To correct for multiple comparisons and to avoid type I error, the level of significance was set at P = 0.01 (2-sided). Results: Of 119 randomized pts, 117 participated in the HRQoL evaluation, and 114 had a baseline assessment (n = 56 REG; n = 58 LOM). No statistically significant differences were observed in any generic or cancer specific domain during treatment in the REG and LOM arms, or between the two arms, except for the appetite loss scale which was significantly worse in PTS treated with REG (Global mean 14.7 (SD = 28.6) vs 7.6 (SD = 16.0); p = 0.0081). The proportion of pts with a clinically meaningful worsening for appetite loss was not statistically different between the two arms (9 out of 24 and 0 out of 13 in the REG and LOM arm, respectively; p = 0.0146). Conclusions: In the REGOMA trial, HRQoL did not change during REG treatment. Pts treated with REG and LOM reported no significant difference in HRQoL. Clinical trial information: NCT02926222. [Table: see text]
Comprehensive analysis of lymphocyte loss kinetics in patients treated with focal fractionated radiation therapy.
Authors: Anirudh Yalamanchali, Jian-Yue Jin, Hong Zhang, Stuart A. Grossman, Robert F Hobbs, Susannah G. Ellsworth
Journal: Journal of Clinical Oncology (2019)

e14191 Background: Radiation (RT)-induced lymphopenia (RIL) is associated with worse survival in patients with solid tumors as well as lower response rates to checkpoint inhibitors. This analysis aimed to model the kinetics of lymphocyte depletion during RT to assist in predicting RIL risk. Methods: This registry-based study included 419 patients who received either total body irradiation (TBI; n = 30), stereotactic body RT (SBRT; n = 73), or conventional chemoradiation (CRT; n = 316). For each patient, serial absolute lymphocyte counts (ALCs) were plotted against RT fraction number. The initial 3 weeks of treatment for conventionally irradiated patients and the entirety of treatment for SBRT and TBI patients were fit to exponential decay in the form ALC(x) = ae -bx . From those fits, percent per fraction loss in ALC (PFLAC) was calculated as PFLAC = (1 – e -b )*100, and multivariable regression was performed to find its significant predictors. Results: Curves were well fitted by exponential decay for all RT techniques (median linearized R 2 0.98, 0.93, and 0.97 for patients treated with TBI, SBRT, and CRT, respectively). In CRT patients, apparent ALC loss rate slowed after week 3, potentially due to lymphocyte repopulation or other factors. TBI and SBRT patients completed RT before the end of the exponential decay phase, and their ALC loss rates remained unchanged throughout RT. Initial PFLAC varied significantly with treatment technique. Mean PFLAC was 35.5%, 24.3%, and 10.77% for patients treated with TBI, SBRT, and CRT, respectively (p &lt; 0.001). Significant predictors of PFLAC varied by site and included field size, dose per fraction, mean spleen dose, chemotherapy backbone, and age. In pancreas cancer patients, gemcitabine was associated with a higher PFLAC (mean = 10.7) than 5-FU (mean = 8.3) after adjustment for covariates (p &lt; 0.001). Finally, total % ALC loss during RT was highly correlated with PFLAC (p &lt; 0.001). Conclusions: Lymphocyte depletion kinetics during the initial phase of fractionated RT are characterized by pure exponential decay. Initial PFLAC is strongly correlated with RT planning parameters and predicts total % ALC loss. The highest ALC loss rates were associated with RT-only regimens, implying that concurrent chemotherapy is not solely responsible for lymphopenia in patients receiving CRT. This work may also assist in selecting patients for adaptive RT approaches to mitigate RIL risk.
RAP: A phase II trial with ramucirumab, avelumab, and paclitaxel as second line treatment in gastro-esophageal adenocarcinoma of the arbeitsgemeinschaft internistische onkologie (AIO).
Authors: Anica Högner, Kirstin Breithaupt, Alexander Stein, Axel Hinke, Mario Lorenz, Salah-Eddin Al-Batran, Peter C. Thuss-Patience
Journal: Journal of Clinical Oncology (2019)

TPS4148 Background: Combination of ramucirumab and paclitaxel resembles the standard treatment option in second line therapy with improvement of response rate and overall survival (REGARD, RAINBOW). Response rates to PD-1/L1 blockade in gastro-esophageal cancer patients rank within 10–20%, whereby PD-1/L1 blockade is reported to impressively extend survival rates in responders. Trials investigating either the synergistic effect of anti-angiogenesis and anti-PD-L1 or chemotherapy combined with anti-PD-L1 are promising. Based on these data we hypothesize benefit from combining immunotherapy by checkpoint inhibition with VEGF-directed treatment and chemotherapy induced increase of immunogenicity of tumor cells. This study investigates the incorporation of PD-L1 blockade by avelumab in the second line setting by combination with the actual best second-line chemotherapy regimen in metastatic gastric cancer patients (paclitaxel+ramucirumab). Methods: The RAP trial (AIO-STO-0218, registered at ClinicalTrials.gov) is a single arm multicenter phase II trial. A total of 59 patients with metastatic or locally advanced gastric or gastro-esophageal junction adenocarcinoma, ECOG 0–1, who progressed after having received first-line therapy with platinum and fluoropyrimidine doublet with or without anthracycline, docetaxel or trastuzumab within the last six months will receive avelumab and ramucirumab on day 1, 15 and paclitaxel on day 1, 8 and 15 of a 28-day cycle until disease progression (RECIST v1.1), intolerable toxicity, withdrawal of consent or at a maximum treatment of 1 year. The primary endpoint is the overall survival rate (OSR) at 6 months. Sample size calculation is based on a Simon 2-stage design with a one-sided alpha error of 10% and a power of 80%, an expected OSR at 6 months of ≥ 65% and a 0 hypothesis ≤ 50%. Secondary endpoints include OS, OSR at 12 months, PFS, safety and tolerability, duration of response. Ethics commission approved the study protocol in January 2019. Updated patient accrual will be presented. Clinical trial information: AIO-STO-0218.
Statins for over 75s: the data don’t justify medicalising a whole population
Authors: Nick Mann
Journal: BMJ (2019)

Hawkes looks behind the megaphone headlines about giving statins to older people and gives a very different picture to patients from the crafted health paradigm. 1

Something would have to be very good to justify medicalising a whole population, but statistical validity can be achieved here only by taking a figure of 12% relative risk reduction (0.1% absolute risk reduction) from averaging data that …