In this issue, Smyth and colleagues investigate the natural history of
-mutant metastatic breast cancer using the AACR Project GENIE, a novel research platform comprised of real-world, clinicogenomic ...data. A rare subset of tumors,
-mutant breast cancers demonstrated similar clinical and demographic characteristics and overall survival as
-wild-type tumors, but a longer duration of therapy on mTOR inhibitors.
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Abstract
Context
BRAFV600E mutant thyroid cancers are often refractory to radioiodine (RAI).
Objectives
To investigate the utility and molecular underpinnings of enhancing lesional iodide uptake with ...the BRAF inhibitor vemurafenib in patients with RAI-refractory (RAIR).
Design
This was a pilot trial that enrolled from June 2014 to January 2016.
Setting
Academic cancer center.
Patients
Patients with RAIR, BRAF mutant thyroid cancer.
Intervention
Patients underwent thyrotropin-stimulated iodine-124 (124I) positron emission tomography scans before and after ~4 weeks of vemurafenib. Those with increased RAI concentration exceeding a predefined lesional dosimetry threshold (124I responders) were treated with iodine-131 (131I). Response was evaluated with imaging and serum thyroglobulin. Three patients underwent research biopsies to evaluate the impact of vemurafenib on mitogen-activated protein kinase (MAPK) signaling and thyroid differentiation.
Main Outcome Measure
The proportion of patients in whom vemurafenib increased RAI incorporation to warrant 131I.
Results
Twelve BRAF mutant patients were enrolled; 10 were evaluable. Four patients were 124I responders on vemurafenib and treated with 131I, resulting in tumor regressions at 6 months. Analysis of research tumor biopsies demonstrated that vemurafenib inhibition of the MAPK pathway was associated with increased thyroid gene expression and RAI uptake. The mean pretreatment serum thyroglobulin value was higher among 124I responders than among nonresponders (30.6 vs 1.0 ng/mL; P = 0.0048).
Conclusions
Vemurafenib restores RAI uptake and efficacy in a subset of BRAF mutant RAIR patients, probably by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Higher baseline thyroglobulin values among responders suggest that tumor differentiation status may be a predictor of vemurafenib benefit.
The BRAF inhibitor vemurafenib increased radioiodine uptake in a subset of patients with BRAF mutant, radioiodine-refractory thyroid cancer.
There were no significant differences in the effect size for increased APC with CADe based on physician baseline ADR and YOE. In procedures with adequate bowel preparation and withdrawal times of ≥8 ...minutes, CADe increased APC suggesting that existing guidelines for high quality colonoscopy must be maintained with the use of CADe. Adenoma Prevalence Measured by Adenomas Per Colonoscopy (APC) According to Colonoscopy Procedure Factors and Endoscopist Factors Between Subgroups of Different Study Arms n (%) or Mean (Standard Deviation) APC (Control Group) Mean APC (SKOUT Group) Mean Difference (SKOUT-Control) (95% CI) Difference (SKOUT-Control) (95% CI) Colonoscopy procedure factors Site of procedure Academic endoscopy centers 656 (46.1%) 0.688 0.866 0.178 (-0.019, 0.377) 0.62 Community endoscopy centers 767 (53.9%) 0.942 1.200 0.258 (0.016, 0.500) Procedure time of day Before 12 pm 1018 (72.1%) 0.855 1.070 0.215 (0.016, 0.416) 0.87 12 pm or later 394 (27.9%) 0.771 1.016 0.244 (-0.007, 0.499) Total Withdrawal Time, n (%) < 8 min 267 (19.0%) 0.362 0.336 -0.026 (-0.194, 0.134) 0.25 ≥ 8 min 1135 (81.0%) 0.976 1.189 0.213 (0.030, 0.388) Bowel preparation, n (%) Inadequate or Poor 20 (1.72%) 0.923 0.571 -0.352 (-1.235, 0.525) 0.65 Fair or Good 632 (54.3%) 0.939 1.241 0.302 (0.016, 0.586) Excellent 512 (44.0%) 0.738 0.977 0.238 (0.018, 0.455) Endoscopist factors Baseline adenoma detection for endoscopists (based on control), n (%) < 45% 876 (61.6%) 0.719 1.016 0.297 (0.112, 0.484) 0.23 ≥45% 546 (38.4%) 0.996 1.095 0.098 (-0.172, 0.355) Endoscopists’ years of experience, n (%) 1-10 years 204 (14.3%) 0.718 0.683 -0.035 (-0.367, 0.316) 0.27 11-20 years 536 (37.7%) 0.955 1.196 0.241 (-0.034, 0.510) > 20 years 683 (48.0%) 0.756 1.035 0.279 (0.077, 0.484) Author Notes *Presenter
With real world application of CADe, our data on potential differences by sex and age can help to create risk-adapted screening strategies and inform benchmarks for colonoscopy quality metrics.Table ...1. Adenoma Prevalence Measured by Adenomas Per Colonoscopy (APC) According to Age and Sex Between Subgroups of Different Study Arms Control group CADe group mean (SD) Difference (Treatment-Control) (95% CI) P-value of difference RR (Treatment vs. Control) (95% CI) P-value of relative risk APC Age < 65 years 0.724 0.883 0.159 (-0.010, 0.321) 0.029 1.22 (1.06, 1.41) 0.006 ≥ 65 years 1.055 1.367 0.312 (0.006, 0.663) 0.032 1.30 (1.10, 1.53) 0.002 Sex Male 1.022 1.308 0.286 (0.034, 0.534) 0.009 1.28 (1.12, 1.46) < 0.001 Female 0.615 0.758 0.143 (-0.043, 0.331) 0.064 1.23 (1.03, 1.48) 0.026 ADR Age < 65 years 0.396 0.450 0.054 (-0.007, 0.117) 0.054 1.14 (0.94, 1.38) 0.20 ≥ 65 years 0.523 0.532 0.009 (-0.083, 0.104) 0.42 1.02 (0.79, 1.31) 0.89 Sex Male 0.478 0.547 0.069 (-0.004, 0.139) 0.069 1.14 (0.94, 1.40) 0.19 Female 0.388 0.400 0.012 (-0.060, 0.085) 0.39 1.03 (0.81, 1.31) 0.81 APPC Age < 65 years 1.830 1.962 0.132 (-0.152, 0.434) 0.18 1.07 (0.93, 1.24) 0.34 ≥ 65 years 2.018 2.568 0.551 (0.053, 1.022) 0.009 1.27 (1.08, 1.51) 0.005 Sex Male 2.136 2.389 0.253 (-0.090, 0.611) 0.082 1.12 (0.98, 1.28) 0.10 Female 1.583 1.894 0.311 (-0.008, 0.651) 0.032 1.20 (1.00, 1.44) 0.06 Abbreviations: CADe, computer-aided detection; CI, confidence interval; RR, relative risk; SD, standard deviation.
BACKGROUND:Overuse, the provision of health services for which harms outweigh the benefits, results in suboptimal patient care and may contribute to the rising costs of cancer care. We performed a ...systematic review of the evidence on overuse in oncology.
METHODS:We searched Medline, EMBASE, the Cochrane Library, Web of Science, SCOPUS databases, and 2 grey literature sources, for articles published between December 1, 2011 and March 10, 2017. We included publications from December 2011 to evaluate the literature since the inception of the ABIM Foundation’s Choosing Wisely initiative in 2012. We included original research articles quantifying overuse of any medical service in patients with a cancer diagnosis when utilizing an acceptable standard to define care appropriateness, excluding studies of cancer screening. One of 4 investigator reviewed titles and abstracts and 2 of 4 reviewed each full-text article and extracted data. Methodology used PRISMA guidelines.
RESULTS:We identified 59 articles measuring overuse of 154 services related to imaging, procedures, and therapeutics in cancer management. The majority of studies addressed adult or geriatric patients (98%) and focused on US populations (76%); the most studied services were diagnostic imaging in low-risk prostate and breast cancer. Few studies evaluated active cancer therapeutics or interventions aimed at reducing overuse. Rates of overuse varied widely among services and among studies of the same service.
CONCLUSIONS:Despite recent attention to overuse in cancer, evidence identifying areas of overuse remains limited. Broader investigation, including assessment of active cancer treatment, is critical for identifying improvement targets to optimize value in cancer care.
Activation of the PI3K/mTOR signaling pathway is common in head and neck squamous cell carcinoma (HNSCC). BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with ...cetuximab, a Food and Drug Administration-approved radiosensitizing agent in the treatment of HNSCC. The agent independently has been shown to enhance radiosensitivity. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC.
This is a single-institution, phase 1 study. Patients with American Joint Committee on Cancer seventh edition stage III to IVB HNSCC received standard cetuximab (400 mg/m
intravenous loading dose) before intensity modulated radiation therapy (IMRT) followed by 250 mg/m
weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels: (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose-escalation design.
Eleven patients were evaluable. Dose level 2 was the maximum tolerated dose for BYL719. Two patients on dose level 3 had dose-limiting toxicities of oral mucositis that required a dose reduction of BYL719. One patient on dose level 2 had a dose-limiting toxicity of nausea that led to withdrawal of on-study treatment. Related grade 3 or higher adverse events consisted of decreased lymphocyte count, oral mucositis, dysphagia, hyperglycemia, maculopapular rash, and palmar-plantar erythrodysesthesia syndrome. All 11 patients had a complete response on posttreatment imaging, and 10 remain disease free. Of the 8 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intratreatment magnetic resonance imaging scans.
The recommended phase 2 dose of BYL719 is 250 mg/d in combination with cetuximab and IMRT in patients with locally advanced HNSCC. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab and IMRT in the treatment of locally advanced HNSCC is warranted.
Eighteen percent of incident malignancies in the United States are a second (or subsequent) cancer. Second primary neoplasms (SPNs), particularly solid tumors, are a major cause of mortality and ...serious morbidity among cancer survivors successfully cured of their first cancer. Multiple etiologies may lead to a cancer survivor subsequently being diagnosed with an SPN, including radiotherapy for the first cancer, unhealthy lifestyle behaviors, genetic factors, aging, or an interaction between any of these factors. In this article, we discuss these factors and synthesize this information for use in clinical practice, including preventive strategies and screening recommendations for SPNs.
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