tbuckley/cabot-search huggingface dataset:
Rising and Falling Trends in the Use of Chemotherapy and Targeted Therapy Near the End of Life in Older Patients With Cancer
Authors: Penny Fang, Reshma Jagsi, Weiguo He, Xiudong Lei, Eric G. Campbell, Sharon H. Giordano, Grace L. Smith
Journal: Journal of Clinical Oncology (2019)

End-of-life (EOL) chemotherapy has been described as the most widespread, wasteful, and unnecessary practice in oncology, with benchmarking aimed to reduce physician use of chemotherapy within 14 days of EOL. We evaluated the recent transformation of EOL chemotherapy and targeted therapy practices nationally.In patients older than 65 years of age who died as a result of breast (n = 19,887), lung (n = 79,613), colorectal (n = 29,844), or prostate (n = 17,910) cancer between 2007 and 2013, we evaluated the guideline-benchmarked measure of chemotherapy use within 14 days of EOL in SEER-Medicare. Comparison outcomes were nonbenchmarked measures of chemotherapy and targeted therapy across time points within 6 months of EOL. Cochran-Armitage test was used to evaluate temporal trends. Multilevel logistic models and intraclass correlation coefficient was used to evaluate variation in EOL chemotherapy use at the physician level.From 2007 to 2013, chemotherapy within 14 days of EOL declined from 6.7% to 4.9% of patients (Ptrend < .001; ∆ = -1.8%). Similar declines occurred for chemotherapy within 1 month (Ptrend < .001; ∆ = -1.8%) and 2 months (Ptrend < .001; ∆ = -1.3%) of EOL. In contrast, chemotherapy within 4 to 6 months of EOL rose (Ptrend ≤ .04; ∆ = 0.7% to 1.7%), and 43.0% of all patients received chemotherapy within 6 months of EOL. Frequency of targeted therapy use across all time points within 6 months of EOL was stable to marginally rising from 2007 to 2013 (Ptrend = .09 to .82; ∆ = -0.2% to 1.8%); overall, 1.2% received targeted therapy within 14 days and 3.6% within 1 month of EOL. By 2013, 13.2% of patients received any targeted therapy within 6 months of EOL. In a multilevel model, 5.19% (intraclass correlation coefficient) of variation in 14-day EOL chemotherapy was attributed to the physician level.With national benchmarking, chemotherapy within 14 days of EOL successfully declined to less than 5%, with comprehensive benchmark uptake by physicians. Results may inform current strategies to help to achieve high-value EOL oncology practice.
Discussion on several problems between tumor-associated venous thrombosis and driving genes status.
Authors: Xue Zhang, Da Jiang, Haiying Yang, Jing Zuo, Hui Jin, Fang Huang
Journal: Journal of Clinical Oncology (2019)

e13022 Background: The study aimed to explore clinical correlation between venous thrombosis and driving genes status in cancer patients (pts). Methods: The clinical data of cancer pts from 2014 to 2018 in our hospital were collected to calculate the overall thrombosis rate, driving gene mutation rate, and thrombosis rate in pts with mutated driving genes. Pts were divided into mutation group and non-mutation group based on the driving gene mutation status. Khorana model was used to divide each group into three subgroups and the thrombosis rate of each subgroup was calculated. The diagnostic value of the Khorana model was calculated in the whole patient set and each group. The correlation between driving gene mutation status and thrombus status was also analyzed. Results: A total of 2049 pts were enrolled, with 4.44% overall thrombosis rate and 72.13% driving gene mutation rate. The thrombosis rates in pts with EGFR, c-Met, ALK, HER-2, KRAS or ROS1 mutations were, in turn, 5.34%, 4.33%, 3.92%, 3.73%, 3.45% and 2.74%, however, there was no statistical difference in thrombosis rates between pts with or without the above gene mutations (EGFR, p = 0.90; c-Met, p = 0.23; ALK, p = 0.85; HER-2, p = 0.28; KRAS, p = 1.00; ROS1, p = 0.58). In the correlation analysis between the driving gene status and the thrombus status, the Spearman correlation coefficient was -0.024, and no statistically significant difference was observed (p = 0.69). Based on the Khorana model, the thrombosis rates of the low-, intermediate- and high-risk subgroups in the mutation group and non- mutation group were 0% vs 0%, 10.23 vs 8.33%, and 6.67% vs 12.50% respectively, which didn’t show statistically significant differences (low- risk, p = 1.00; intermediate-risk, p = 0.85; high-risk, p = 0.59). For the whole patient set, mutation group and non-mutation group, the Khorana model predicted venous thrombosis with the sensitivities of 13.33%, 10.00% and 20.00%, as well as the specificities of 92.02%, 92.55% and 90.67%; and the area under the ROC curve were 0.706 (p = 0.007), 0.719 (p = 0.02) and 0.681 (p = 0.18), respectively. Conclusions: The Khorana model has a moderate diagnostic value, and there is no correlation between the driving gene status of cancer pts and venous thrombosis.
Gemcitabine and cisplatin (GP) induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) versus CCRT alone in locoregionally advanced nasopharyngeal carcinoma (NPC): A phase 3, multicenter, randomized controlled trial.
Authors: Jun Ma, Yuan Zhang, Ying Sun, Fangyun Xie, Weihan Hu, Guoqing Hu, Ning Zhang, Kun-Yu Yang, Xiaodong Zhu, Feng Jin, Zhi-Bin Cheng, Mei Shi, Fei Han, Ye Tian, Yan Sun, Hao-Yuan Mo, Jin-Gao Li
Journal: Journal of Clinical Oncology (2019)

6003 Background: GP regimen has been established as the standard first-line treatment option for patients with recurrent/metastatic NPC. However, its efficacy in locoregionally advanced disease remains unclear. Methods: Patients with previously untreated, non-metastatic stage III-IVB (except T3-4N0M0, AJCC 7 th ) NPC, aged 18–64 years without severe comorbidities were eligible. They were randomly assigned (1:1) to receive GP IC (gemcitabine 1 g/m 2 on days 1 &amp; 8, cisplatin 80 mg/m 2 on day 1, q3w for 3 cycles) plus CCRT (cisplatin 100 mg/m 2 , q3w for 3 cycles, concurrently with intensity-modulated radiotherapy) or CCRT alone. The primary endpoint was failure-free survival (FFS). The calculated sample size was 238 per group, with an 80% power (two-sided α 0.05) to detect a treatment failure hazard ratio (HR) of 0.52. Results: From Dec 2013 to Sep 2016, 480 patients from 12 centers were randomly assigned to IC+CCRT (n = 242) or CCRT alone (n = 238) group. Baseline characteristics were well balanced. After a median follow-up of 39 months, 3-year FFS was 85.8% in the IC+CCRT group and 77.2% in the CCRT alone group (intention-to-treat population; HR 0.53, 95% confidence interval 0.34–0.81; P = 0.003). In GP+CCRT group, 239 patients started GP IC and 231 (96.7%) completed all three cycles. The most common ≥grade 3 adverse events (AE) in IC+CCRT and CCRT group were mucositis (28.9% vs. 32.1%), neutropenia (28.0% vs. 10.5%) and leukopenia (26.4% vs. 20.3%). Conclusions: Adding GP IC to CCRT significantly improved FFS in locoregionally advanced NPC and is well tolerated with favorable toxicity profile. Clinical trial information: NCT01872962. [Table: see text]
Impact of pretreatment serum creatinine on outcomes in pancreatic adenocarcinoma.
Authors: Taha Alrifai, Faisal Ali, Zimu Gong, Phyo Thazin Myint, Karan Nijhawan, Bibek Singh Pannu, Salman Syed, Kelley Elizabeth Kozma
Journal: Journal of Clinical Oncology (2019)

e15749 Background: Pancreatic Adenocarcinoma (PA) is an aggressive malignancy with an estimated 5-year survival of 8.5%. PA was responsible for 7.3% of all cancer deaths in 2018 in the US. We aimed to evaluate the impact of pretreatment serum creatinine (SCr) level on Overall Survival (OS) in patients with PA. Methods: A retrospective review of electronic health records of patients with PA seen at our institution between 01/2014 and 01/2018 was done. We collected patients’ SCr at the time of diagnosis, and excluded patients with a glomerular filtration rate (GFR) below 60 mL/min per 1.73 m2 or SCr &gt; 1.3 mg/dL. Patients were dichotomized around a SCr of 0.5 mg/dL. Kaplan-Meier survival estimate was performed to evaluate statistical significance. Results: A total of 83 patients, including 37 females and 46 males, with a median age at diagnosis of 67 years, were included. SCr of &lt; 0.5 mg/dL was associated with a lower median OS as compared to a SCr of ≥0.5 mg/dL, (253 days versus 364 days; P = 0.035). There were more female patients in the low SCr group (71% vs 39%, P = 0.027). Patients with SCr of &lt; 0.5 mg/dL had a lower mean BMI compared to patients with a SCr of ≥0.5 mg/dL, however this was not statistically significant (BMI = 22.45 versus 25.72; P = 0.49). Conclusions: Low SCr is predictive of a lower median OS in patients with PA. SCr has been suggested as a surrogate marker for muscle mass, which is closely associated with the degree of cancer cachexia. Our finding emphasizes the need for future larger studies to evaluate the utility of SCr as a prognostic indicator, as well as a cost-effective surrogate for measuring cancer cachexia. [Table: see text]
Comparison of mortality and second primary oropharyngeal malignancies by human papilloma virus (HPV) status in patients (pts) with oropharyngeal squamous cell carcinoma (OPSCC) using an updated Surveillance, Epidemiology, and End Results (SEER) database.
Authors: Ryan Holstead, Rehana Rasul, Anne Golden, Nagashree Seetharamu
Journal: Journal of Clinical Oncology (2019)

e17518 Background: Prognosis and patterns of failure differ between HPV positive (pos) and HPV negative (neg) OPSCC. HPV neg have an increased risk of developing head, neck, and lung SPM due to field cancerization. Second primary OPSCC in HPV pos pts may be due to persistent risk for HPV-mediated carcinogenesis and compromised immune status. The rate and location of SPM in HPV pos pts is not as well described and HPV-specific surveillance guidelines are yet to be determined. Methods: Retrospective cohort study from a custom SEER database of OPSCC diagnosed from 2013-2015 was conducted. Differences in overall survival (OS) and SPM were compared by HPV status using Gray’s test. Cox proportional hazard models were performed, adjusting for age, race, sex, year of diagnosis, tumor grade, stage, and first treatment. Results: 12,895 pts were identified, with a mean age of 61.8 (SD = 9.97) years, mostly male (83.2%), and white (87.3%), with 45.0% HPV pos, 15.3% HPV neg, and 39.7% HPV unknown (unk). Proportion of HPV pos pts increased from 2013-2015 (40.7%-49.2%). HPV pos pts tended to have higher stage and grade of tumor. Most patients were treated with chemotherapy and radiation. Median duration of follow up was 13 (5-22) months. HPV pos had significantly lower unadjusted 2-year mortality compared to neg or unk (13.7% vs. 38.9% vs. 32.8%, p &lt; 0.001). Median OS for HPV pos, HPV neg and HPV unk was 29 months (m), 25.6 m, and 24.45 m respectivey (p &lt; 0.0001). From the multivariable Cox regression, HPV neg pts had 2.25 times the risk (95% CI: 1.99-2.54) of death compared to HPV pos pts. Incidence of OP SPM was similar (0.008-0.011%) in all three HPV cohorts (aHR = 0.87, 95% CI: 0.49-1.54). Conclusions: Our study strongly supports the prognostic value of HPV status. Incidence of OP SPM is similar in HPV pos and neg OPSCC suggesting that similar surveillance strategies should be employed for all OPSCC pts. Limitations of the study include lack of data on smoking and alcohol use, high rate of HPV unk pts, and SEER-imposed restriction to SPM occurring only in the OP region.
Capivasertib (AZD5363) plus fulvestrant versus placebo plus fulvestrant after relapse or progression on an aromatase inhibitor in metastatic ER-positive breast cancer (FAKTION): A randomized, double-blind, placebo-controlled, phase II trial.
Authors: Robert Hugh Jones, Margherita Carucci, Angela Claire Casbard, Rachel Butler, Fouad Alchami, Catherine Jane Bale, Pavel Bezecny, Johnathan Joffe, Sarah Moon, Chris Twelves, Ramachandran Venkitaraman, Simon Waters, Sacha Jon Howell
Journal: Journal of Clinical Oncology (2019)

1005 Background: The PI3K/AKT signalling pathway is frequently activated in patients (pts) with estrogen receptor (ER) positive breast cancer (ER+BC) and has been implicated in endocrine therapy resistance. Capivasertib (AZD5363) is a highly-selective, oral, small molecule AKT inhibitor. The FAKTION trial investigated the addition of capivasertib to fulvestrant for postmenopausal women with ER+ and HER2 negative BC after relapse or disease progression on an aromatase inhibitor (AI). Methods: FAKTION is an investigator-led, double-blind, placebo-controlled, randomised phase II trial. Patients were recruited from 21 UK sites and randomly assigned (1:1) to fulvestrant 500mg (day 1 and 15 of cycle 1 and day 1 only of subsequent 28 day cycles) with either capivasertib 400mg bd or placebo (4 days on/3 days off starting C1D15) until disease progression, unacceptable toxicity or withdrawal of consent. Allocation was balanced by minimisation according to PIK3CA mutation and PTEN expression status, measurable/non-measurable disease, and primary/secondary endocrine resistance. The primary endpoint was progression-free survival (PFS). The trial had 90% power to detect a hazard ratio of 0.65 at the one-sided 20% significance level. Secondary endpoints included overall survival (OS), objective response and clinical benefit rates, safety and the effect of PI3K/Akt pathway activation on PFS. Results: Between Mar 2015 and Mar 2018, 140 pts were randomised to fulvestrant + capivasertib (n = 69) or fulvestrant + placebo (n = 71). In the Intention-to-treat analysis, after 112 events, median PFS was 10.3 months (m) for capivasertib compared to 4.8m for placebo (Hazard Ratio (HR) 0.57; 95% CI: 0.39 to 0.84; one-sided p = 0.0017; two-sided 0.0035). Fifty-two deaths were reported. Median OS was 26.0m for capivasertib compared to 20.0m for placebo, with a survival difference starting to emerge after 12m (HR = 0.59; 95% CI: 0.34 to 1.05; two-sided p = 0.071). Toxicity data and subgroup analyses including relative capivasertib benefit by PI3K/Akt pathway alteration will be presented at the conference. Conclusions: The trial met its primary endpoint. Addition of capivasertib to fulvestrant for patients with endocrine resistant advanced breast cancer resulted in significantly longer PFS and an improvement in OS. The FAKTION results warrant further investigation of capivasertib for the treatment of ER positive breast cancer. Clinical trial information: NCT01992952.
m<b>6</b>A Regulates Neurogenesis and Neuronal Development by Modulating Histone Methyltransferase Ezh2
Authors: Junchen Chen, Yi-Chang Zhang, Chunmin Huang, Hui Shen, Baofa Sun, Xuejun Cheng, Yu-Jie Zhang, Yun-Gui Yang, Qiang Shu, Ying Yang, Xuekun Li
Journal: Genomics Proteomics & Bioinformatics (2019)

N6-methyladenosine (m6A), catalyzed by the methyltransferase complex consisting of Mettl3 and Mettl14, is the most abundant RNA modification in mRNAs and participates in diverse biological processes. However, the roles and precise mechanisms of m6A modification in regulating neuronal development and adult neurogenesis remain unclear. Here, we examined the function of Mettl3, the key component of the complex, in neuronal development and adult neurogenesis of mice. We found that the depletion of Mettl3 significantly reduced m6A levels in adult neural stem cells (aNSCs) and inhibited the proliferation of aNSCs. Mettl3 depletion not only inhibited neuronal development and skewed the differentiation of aNSCs more toward glial lineage, but also affected the morphological maturation of newborn neurons in the adult brain. m6A immunoprecipitation combined with deep sequencing (MeRIP-seq) revealed that m6A was predominantly enriched in transcripts related to neurogenesis and neuronal development. Mechanistically, m6A was present on the transcripts of histone methyltransferase Ezh2, and its reduction upon Mettl3 knockdown decreased both Ezh2 protein expression and consequent H3K27me3 levels. The defects of neurogenesis and neuronal development induced by Mettl3 depletion could be rescued by Ezh2 overexpression. Collectively, our results uncover a crosstalk between RNA and histone modifications and indicate that Mettl3-mediated m6A modification plays an important role in regulating neurogenesis and neuronal development through modulating Ezh2.
Desire to address costs at time of treatment decisions among patients with metastatic breast cancer.
Authors: Yvonne Y. Lei, Katharine M. Quain, Don S. Dizon, Rachel Jimenez, Jennifer Adrienne Shin, Karen Sepucha, Giselle Katiria Perez, Jeffrey M. Peppercorn
Journal: Journal of Clinical Oncology (2019)

6640 Background: Costs of cancer care may impact access to therapy, adherence, and distress among patients. However, the degree to which patients with metastatic breast cancer (MBC) wish to discuss financial issues when making treatment decisions is unknown. Methods: In a single arm feasibility trial, 40 women with newly diagnosed or progressive MBC completed a 1-page survey regarding goals and priorities for discussion with the oncology team. The survey included 17 potential priorities for discussion in the domains: treatment options, symptom management, emotional concerns, planning for the future, and lifestyle. We evaluated participants’ interest in prioritizing discussion of financial issues and sociodemographic and clinical correlates of this preference. We examined the relationship between desire to discuss financial issues and both distress on the Distress Thermometer (DT) and satisfaction with cancer care using Fisher’s exact test. Results: Among 40 participants, 11 (28%) reported interest in discussing financial issues when making treatment decisions, 29 (72%) were not interested. Average age was 57 (range 31-73), and the majority were white (85%) and college graduates (66%). Only 18% of white patients were interested in addressing cost, while 83% of non-white patients were interested (p &lt; 0.01). Those with a college education were less likely to prioritize financial discussion compared to no college (16% vs. 47%, p = 0.04). Patients interested in discussing cost were more likely to have a household income &lt; $50,000 (50% vs. 22% &gt; $50,000, n.s.) and to have Medicaid (50% vs. 25% other insurance, n.s.). Additionally, patients with higher levels of distress (35% vs. 21% DT &lt; 4, n.s.) and those on novel targeted or biologic therapy (42% vs. 21% other therapy, n.s.) were more likely to prioritize discussion of costs. Desire to discuss cost was not related to satisfaction with care. Conclusions: A substantial minority of patients with MBC, particularly those from less advantaged backgrounds, wish to discuss financial issues at time of treatment decisions. Financial toxicity research should recognize that not all patients desire this discussion and evaluate methods to screen for financial concerns and barriers to care.
A large multicenter, randomized, double-blind, crossover study in healthy volunteers, comparing pharmacokinetics and pharmacodynamics of Sandoz proposed biosimilar pegfilgrastim with European and United States reference pegfilgrastim.
Authors: Gordon P. Otto, Roumen Nakov, Steven Schussler, Stefanie Schier-Mumzhiu, Celine Schelcher, Sven D. Koch, Andrej Skerjanec, Jessie Wang, Andriy Krendyukov, Anne Bellon
Journal: Journal of Clinical Oncology (2019)

e23118 Background: Similarity of the pharmacokinetic (PK)/pharmacodynamic (PD) profiles of Sandoz proposed biosimilar pegfilgrastim and EU-reference biologic was confirmed in a pivotal Phase I study. In order to confirm PK/PD similarity to the US reference biologic, and to bridge between the two references, a 3-way study was conducted. Methods: A randomized, double-blind, single-dose, 3-treatment, 6-sequence crossover Phase I study was performed in healthy volunteers (HVs) to demonstrate similarity in PK, PD, safety and immunogenicity between Sandoz proposed biosimilar, US reference, and EU reference pegfilgrastim administered subcutaneously (6 mg/0.6 mL) in each treatment period. The primary objective was to demonstrate PK (AUC 0-inf , AUC 0-last , C max ) and PD similarity (ANC AUEC 0-last , ANC E max ). The study was powered (90%) to achieve confidence intervals (CIs) within biosimilarity margins 0.8─1.25 in pairwise comparisons. Secondary objectives were additional PK/PD parameters, safety and immunogenicity. Results: The study included 577 male and female HVs. PK and PD similarity were demonstrated between Sandoz proposed biosimilar and US reference (Table), as well as EU reference and between both reference biologics since the 90% CIs of the geometric mean ratios were contained within the pre-defined margins of 0.80‒1.25. Safety, immunogenicity and secondary PK/PD parameters were also similar across treatment groups. Conclusions: This large randomized, double-blind, single-dose, 3-treatment, 6-sequence crossover study demonstrated PK and PD similarity between Sandoz proposed biosimilar, US reference and EU reference pegfilgrastim with similar safety, local tolerability and immunogenicity. Clinical trial information: 2016-003549-27. [Table: see text]
Brigatinib in pretreated patients with ALK-positive advanced NSCLC.
Authors: Renaud Descourt, Maurice Perol, Gaelle Rousseau-Bussac, David Planchard, Bertrand Mennecier, Marie Wislez, Alexis B. Cortot, Florian Guisier, Radj Gervais, Loick Galland, Roland Schott, Eric Dansin, Jennifer ARRONDEAU, Jean-Bernard Auliac, Christos Chouaid
Journal: Journal of Clinical Oncology (2019)

9045 Background: Brigatinib is a next-generation ALK inhibitor initially developed in pre-treated ALK+ NSCLC. Data on the efficacy of brigatinib in real world remain rare. Methods: This retrospective multicentric study analyzed ALK-+ advanced NSCLC patients pretreated with at least two tyrosine-kinase inhibitors, including crizotinib, and enrolled in the brigatinib French early access program. The primary endpoint was investigator-assessed progression-free survival (PFS). Results: 104 patients were included (mean age, 56.6 years; never smokers, 61.5%; adenocarcinoma, 98.1%). Patients had received a median of 3 previous treatment lines, including at least 2 ALK inhibitors, mainly crizotinib then ceritinib in 93% patients. At brigatinib initiation, 59.1% had performance status 0-1, 51.9% had ≥ 3 metastatic sites, 74.5% had central nervous system metastases (CNS) and 8.8% had carcinomatous meningitis. Median duration of brigatinib treatment was 6.7 (0.06–20.7) months. Median PFS was 6.6 (95% CI, 4.8–9.9) months for the entire population. In the 91 evaluable patients, disease control rate was 78.2% (stable, 28.2%; partial response, 45.7%; complete response, 4.3%). From brigatinib start, median overall survival was 17.2 (95% CI:11.0–not reached) months. Among the 68 patients with progressive disease after brigatinib, CNS was involved in 29.4% of cases. Ten (9.6%) patients had treatment discontinuation due to intolerance or patient request. Median OS from the diagnostic of NSCLC was 75,3 (95% CI, 38,2-174,6) months. Conclusions: This study confirms the efficacy of brigatinib in a cohort of patients heavily pretreated for ALK-+advanced NSCLC. These real-world results are consistent with clinical data reported in clinical trials.