tbuckley/cabot-search huggingface dataset:
FDA review, CMS coverage, and NIH information for next generation sequencing.
Authors: Katherine B. Szarama, Brandi L. Kattman, Eunice Lee
Journal: Journal of Clinical Oncology (2018)

e18798 Background: On November 30, 2017, the Food and Drug Administration (FDA) approved the first breakthrough designated, NGS-based in vitro diagnostic, and the Centers for Medicare & Medicaid Services (CMS) in Parallel Review proposed to cover diagnostic laboratory tests using NGS when specific criteria are met, such as test registration in the National Institutes of Health (NIH) Genetic Testing Registry (GTR). A final decision is expected by February 28, 2018. Methods: FDA and CMS established Parallel Review to provide a mechanism for simultaneous review to help decrease time between FDA approval and CMS national coverage determination (NCD). Premarket approval (PMA) is the FDA process of scientific-regulatory review to evaluate safety and effectiveness of Class III medical devices. An approved PMA application is, in effect, a license granting applicant permission to market a particular medical device. Medicare coverage is limited to items and services reasonable and necessary for the diagnosis or treatment of illness or injury. NCDs are decisions CMS makes regarding whether to cover a particular service nationally through an evidence-based process recognizing patient health outcomes. GTR provides a centralized database of genetic tests to access comprehensive information. Results: Multiplexed NGS assays assess many biomarkers associated with a range of clinical evidence constantly changing as new science emerges. This range includes mutations that may be informational—supported by analytical validity with clinical or mechanistic rationale—and peaks with companion diagnostic (CDx) claims prescriptive for a specific therapeutic product—supported by analytical validity and clinical study establishing either a link to patient outcomes or clinical concordance to a previously approved CDx. CMS considers such claims to prepare a NCD. Published practice guidelines gathered by NIH GTR enables a comparison view for users and complements material gathered by a laboratory. Conclusions: This collaboration between three federal agencies will support innovative test developers seeking FDA approval or clearance, providers choosing to furnish laboratory tests, and patients who may benefit from access to precision diagnostics.
Clinical features and long-term sequelae among children with neuroblastoma and opsoclonus-myoclonus syndrome at diagnosis: Experience of the Instituto Nacional de Pediatria, Mexico City, Mexico.
Authors: Araceli Castellanos-Toledo, Claudia Selene Portillo-Zavala, Rocio Cardenas-Cardos, Jose de Jesus Figueroa Carbajal
Journal: Journal of Clinical Oncology (2018)

e22509 Background: Opsoclonus-myoclonus syndrome (OMS) occurs in 2-4% of newly diagnosed neuroblastoma (NB) patients and it is a paraneoplastic syndrome of immune cross-react between neural cells and the tumor, so that most children with this syndrome often have tumors with favorable biological features and better clinical outcomes, but also, most of them develop chronic neurological conditions associated with significant long-term neurological morbidity due to substantial consequences on the neurological development, including cognitive and motor deficits, language disorders, and behavioral abnormalities. Methods: Clinical and retrospective study of NB children with OMS at diagnosis. Results: Between January/1990-December/2012 six (3 girls and 3 boys) of 48 NB patients had OMS. Median age at diagnosis was 23.1 months (11-47 months). Median time of symptoms onset was 4.3 months (1-8 months). Primary tumor locations were adrenal gland (5 patients) and mediastinum (1 patient). Five of six patients were positive metaiodobenzylguanidine. Four patients were low-risk (INSS-1 and INSS-2 stages), 1 intermediate-risk (INSS-3 stage), and 1 high-risk (INSS-3 stage). Five patients were undergone a primary surgical resection at diagnosis (4 complete resections and one partial resection). Most patients had favorable biological features. All patients were treated for their NB according to international criteria. There were not relapses or progression of the disease. OMS was treated with gammaglobulin, prednisone and methotrexate, with an average duration of 33 months (19-48 months depending upon the clinical response). At 10-year long-term follow-up significant cognitive and motor sequelae were observed in all patients, mainly disabling ataxia, delayed language development, dysarthria and delay in learning. Conclusions: Most of these children are cured for having tumors with favorable biological features and it is essential that throughout their treatments and follow-up they also have a multidisciplinary approach focused on very early and effective motor and cognitive rehabilitation.
Correlates of work status during adjuvant chemo- or radiation therapy for breast cancer.
Authors: Victoria Susana Blinder, Carolyn E Eberle, Sujata Patil, Kevin C. Oeffinger, Cathy Bradley, Francesca Gany
Journal: Journal of Clinical Oncology (2016)

6556 Background: Low-income breast cancer patients who take time off during adjuvant therapy are at increased risk of long-term job loss. The reasons why some women do not work during treatment are undefined. Methods: Pre-diagnosis employed women aged 18-65 who were undergoing chemo or radiation therapy for stage I-III breast cancer were recruited to a prospective, longitudinal study of post-treatment employment outcomes. Participants completed a baseline survey during the period of active treatment; all variables were self-reported. The primary outcome was working during treatment, defined as working full or part-time. All other answers (e.g. sick leave) were coded as “not working.” Univariate and multivariate logistic regression models of work status on covariates were fit to the data. Results: Of 265 participants, 138 (52%) worked during treatment. In the multivariate analysis, significant positive correlates (p < 0.05) of working during treatment were (OR, 95% CI): salaried employment (2.67, 1.31-5.44), perceived employer accommodation (2.61, 1.32-5.15), household income (2.47, 1.18-5.46), education (2.41, 1.02-5.69), and self-confidence asking an employer for accommodation (2.09, 1.06-4.13). Significant inverse correlates were job tasks involving stooping/kneeling (0.45, 0.24-0.86) or analyzing data (0.33, 0.14-0.82). Variables included in the final model but not significantly correlated with the outcome were age, race/ethnicity, English proficiency, availability of sick leave, and resilience. Conclusions: Our analysis identifies a group of women at increased risk of not working during treatment, which can to lead to long-term job loss. Potentially modifiable variables associated with not working include employer accommodation, self-confidence asking an employer for accommodation, and specific job tasks. Interventions should be developed to increase patients’ ability to obtain accommodations and thereby optimize their ability to work during treatment.
Identifying targetable genetic alterations in advanced gastric cancer through broad, hybrid capture-based next generation sequencing.
Authors: Dong Liu, Helei Hou, Chuantao Zhang, Na Zhou, Congmin Liu, Yurong Niu, Tianjun Li, Jinping Zhang, Zhuokun Li, Xiaonan Yang, Yonghui Xie, Xiaochun Zhang
Journal: Journal of Clinical Oncology (2016)

e15512 Background: The high gastric cancer mortality rate is largely due to the lack of effective medical treatment. The development of next generation sequencing (NGS) technology provides a high-throughput and systematic method to identify the genetic alterations in the cancer genome. In this study, we used a broad, hybrid capture-based NGS to discover targetable genetic alterations from advanced gastric cancer (AGC) tissue so that approved molecular target drugs or available agents on clinical trials could be selected. Methods: 31 AGC patients were enrolled and cancer tissue samples were collected after informed consent provided by all patients. 7708 exons of 508 tumor related genes and 78 introns of 19 frequently rearranged genes were assessed for base substitutions, indels, copy number alterations, and gene fusions. The average median sequencing depth was 470×. Results: Somatic mutations were detected in 100% of patients. 9.7% (3/31) could select NCCN guideline approved targeted drugs according to the identified actionable genetic alterations (HER2 gene amplification/ mutation). Remarkably, other targetable genetic alterations were detected in 13 of 31 (41.9%) AGC patients, which applied to mTOR inhibitors, PARP inhibitors, FGFR inhibitors, etc. Conclusions: 51.6% (16/31) of AGC patients harbored at least one actionable genetic alteration identified by NGS testing. NGS based targetable alterations detection might help identify available targeted drugs to personalize target therapy for AGC patients. Targeted genetic alterations identified by NGS in AGC. Targeted genetic alterations No. Rates Therapeutic implications HER2 (mut/CNV) 3 9.7% Trastuzumab ATM (mut) 2 6.5% PARP inhibitors FGFR2 (CNV) 2 6.5% FGFR inhibitors KRAS (mut) 2 6.5% Selumetinib TP53 (mut) 2 6.5% APR-246 MK-1775 CCNE1 (CNV) 1 3.2% CDK4/6 inhibitors EGFR (mut) 1 3.2% TKI inhibitors EGFR (CNV) 1 3.2% anti-EGFR therapy ERBB3 (mut) 1 3.2% Sapitinib FBXW7 (mut) 1 3.2% mTOR inhibitors MET (CNV) 1 3.2% Crizotinib MLH1 (mut) 1 3.2% Pembrolizumab NF1 (mut) 1 3.2% mTOR inhibitors PIK3CA (mut) 1 3.2% mTOR inhibitors PTEN (mut) 1 3.2% mTOR inhibitors RB1 (mut) 1 3.2% CDK4/6 inhibitors
Effect of age, gender, and performance status (PS) on the duration results of adjuvant chemotherapy for stage III colon cancer: The IDEA collaboration.
Authors: Anthony Frank Shields, Fang-Shu Ou, James Paul, Alberto F. Sobrero, Takayuki Yoshino, Julien Taieb, Ioannis Souglakos, Qian Shi, Rachel Kerr, Roberto Labianca, Takeharu Yamanaka, Dewi Vernerey, Ioannis Boukovinas, Takeshi Kato, Valter Torri, Stylianos Kakolyris, Thierry Andre, Axel Grothey, Jeffrey A. Meyerhardt, Timothy Iveson
Journal: Journal of Clinical Oncology (2018)

3599 Background: The IDEA collaboration pooled data from nearly13,000 patients (pts), comparing 3 vs. 6 months (m) of adjuvant fluoropyrimidine plus oxaliplatin to test noninferiority for disease-free survival (DFS) in stage III colon cancer. We reported that duration of adjuvant therapy (Rx) should be individualized with consideration of recurrence risk, regimen, and toxicity. Here we consider the influence of age, gender, and PS. Methods: Using stratified Cox proportional hazard models we stratified the IDEA cohort by age (≤ 70 or > 70), gender, and PS (0 v 1/2), testing for interactions with subgroups and duration of Rx. Results: Overall, DFS results comparing 3 vs 6m of Rx did not significantly differ across age, gender or PS subgroups. However, significant (sig) interactions were detected within subgroups (Table). For pts ≤ 70 who received CAPOX, 3m Rx is as good as 6m (HR 0.9). 6m of Rx is required for pts ≤70 (HR 1.16) with FOLFOX and may be best for pts > 70 on either regimen (p = .068, 3 way interactions). It was found that gender influenced the impact of risk group on the duration comparison (p = .078, 3 way interaction); 3m Rx was as good as 6m for male low-risk pts (HR 0.94) but 6m is required for high risk male (HR 1.18). For females, risk group did not alter the relative merits of 3 v 6m of Rx. PS did not influence the impact of regimen/risk group on the duration comparison. Conclusions: Overall age, gender, or PS didn't modify the comparison of 3 v 6m Rx. The biologic and clinical rationales for the differences observed within certain subgroups need to be explored before they are used to make treatment choices. Clinical trial information: NCT01150045. Events/Total HR(3 v 6m) 95% CI Pi 2-way Age < = 70 FOLFOX 1439/5845 1.16 1.05-1.29 < 0.01 CAPOX 917/3759 0.9 0.79-1.03 Age > 70 FOLFOX 505/1813 1.12 0.94-1.33 0.7 CAPOX 380/1290 1.19 0.97- 1.46 Male T1-3N1 789/4220 0.94 0.82-1.08 0.01 T4 or N2 1126/2964 1.18 1.05-1.33 Female T1-3N1 523/3247 1.09 0.91-1.29 0.7 T4 or N2 809/2290 1.04 0.9 -1.20
Abstract A089: Challenging the free hormone hypothesis for vitamin D in the prostate has implications for the prostate cancer disparity in African American men
Authors: Zachary Richards, Larisa Nonn
Journal: Cancer Research (2018)

Abstract African American (AA) men are disproportionately at risk for both prostate cancer (PCa) and vitamin D (vitD) deficiency compared to European American (EA) men. Based on the numerous chemopreventative properties of vitD and its status with PCa aggressiveness and mortality, vitD deficiency has been hypothesized as a biologic contributor to the PCa disparity in AA men. We recently reported that despite having deficient levels of vitD in the serum, AAs have higher levels of vitD in their prostate tissue compared to EAs. This suggests a mechanism of active vitD transport across the membrane and challenges the longstanding free hormone hypothesis, which asserts that the activity of a hormone is due to the bioavailable fraction and its passive diffusion across the membrane. The majority of VitD circulates bound to D binding protein (DBP) and is sequestered in the serum, rendering it unavailable for passive diffusion. A mechanism of active DBP-vitD endocytosis has been well characterized in the kidney by the extracellular receptor megalin. We hypothesized that megalin is functional in prostate epithelium and facilitates adequate prostatic vitD levels in AAs with vitD deficiency. Here, we report megalin protein expression in prostate tissue, LNCaP, and primary human prostate cells. Megalin function was further assessed in primary human-derived organoids treated with 25D in the presence or absence of DBP. Surprisingly, vitD import and metabolism occurred faster in +DBP conditions and suggests that DBP-vitD active transport is more efficient than passive diffusion of vitD alone. VDR activation was diminished in a dose-responsive manner by addition of a megalin antagonist. Additionally, megalin protein levels in PCa were significantly lower compared to benign (p&amp;lt;0.05) on a tissue microarray quantified by immunofluorescent staining. In summary, our data support a model of megalin-mediated active transport for vitD in the prostate and demonstrate ancestry-related and PCa differences in megalin regulation. These findings challenge the free hormone hypothesis and postulate that vitD deficiency is more complex than previously thought. Citation Format: Zachary Richards, Larisa Nonn. Challenging the free hormone hypothesis for vitamin D in the prostate has implications for the prostate cancer disparity in African American men [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A089.
Utilizing Federally Qualified Health Centers in Milwaukee to decrease colorectal cancer disparities.
Authors: Noelle K. LoConte, Allison Antoine, A. Michelle Corbett, David Frazer, Carrie Stehman, Sarah Kerch
Journal: Journal of Clinical Oncology (2018)

e18611 Background: In 2014, the National Colorectal Cancer Roundtable established a goal to screen 80% of adults, aged 50-75 for colorectal cancer (CRC) by 2018. In that year, 74% of Wisconsin adults, aged 50-75 were up-to-date on CRC screening compared to only 30% of Milwaukee-area federally qualified health center (FQHC) patients. Since 2015, Wisconsin’s Collaborative Approach to Increase Colorectal Cancer Screening has been funded through the CDC’s Colorectal Cancer Control Program to support FQHCs in screening underserved, average risk adults through evidence based interventions (EBIs). The project goal is to decrease disparities in CRC screening and mortality among FQHC patients who are primarily urban African American, Hispanic, and Hmong, and living in poverty. Methods: Partnerships with seven organizations were established in order to engage in this continuous quality improvement project. In-depth clinical/environmental assessments were conducted to guide EBI selection. Each FQHC selected most needed EBIs to support their existing CRC screening programs. FQHCs selected from provider assessment and feedback, provider or patient reminders, reducing structural barriers, small media, community-clinical linkages, health information technology, professional development, or patient navigation. CME/CEU sessions highlighting current information on screening options and guidelines were also offered. Results: CME/CEU session were performed at each FQHC, with 220 participants. At the end of year two, the overall weighted colorectal screening rate for all FQHC in Milwaukee improved to 46.4%, which is an increase of 13.3% over the weighted baseline rate of 33.1%. Conclusions: FQHCs are an integral partner to consider in achieving the national goal of screening (80% by 2018). By focusing on strategic EBI implementation and ongoing programmatic support, FQHCs can improve their internal processes and create or strengthen existing policies to ensure that eligible patients receive their recommendation for CRC screening and their patients have the necessary support to follow through with their cancer screening. Cancer centers are logical partners in this work to decrease the burden of colorectal cancer.
A phase 1/2 dose-escalation and expansion study of a conditionally active anti-AXL humanized monoclonal antibody (BA3011) in patients with advanced solid tumors.
Authors: Jordi Rodon Ahnert, Matthew H. Taylor, Eileen Mary O'Reilly, Jingsong Zhang, Robert Charles Doebele, Yong Ben, Leslie L. Sharp, William J. Boyle, Cathy Chang, Gerhard Frey, Wei Chen, Michael Melnick, Jay M. Short, Howard A. Burris
Journal: Journal of Clinical Oncology (2018)

TPS12126 Background: The AXL receptor tyrosine kinase is often highly expressed in certain cancers. AXL appears to sustain resistance to anticancer therapies including chemotherapy, targeted therapy and immune checkpoint inhibitors (1, 2). BA3011 is an anti-AXL humanized monoclonal antibody conjugated to monomethyl auristatin E using a cleavable linker (CAB-AXL-ADC) and specifically binds to AXL under conditions found within the tumor microenvironment. The pharmacokinetic (PK) and toxicity profile of BA3011 has been established in cynomolgus monkeys; anti-tumor activity has been shown in non-small-cell lung cancer (NSCLC), pancreatic, castration-resistant prostate cancer (CRPC) and other tumor models. Methods: A multi-center, open-label, Phase 1/2 study will evaluate the safety, tolerability, PK, immunogenicity, and antitumor activity of BA3011 in patients with advanced solid tumors. The study consists of a dose-escalation phase (Phase 1) and a dose-expansion phase (Phase 2). The primary objective of Phase 1 is to define the safety profile (including dose-limiting toxicity [DLT]), maximum tolerated dose, and recommended Phase 2 dose (RP2D). BA3011 will be administered every 3 weeks (q3w) via intravenous infusion, with a starting dose of 0.3 mg/kg, escalating to 2.4 mg/kg using a modified Fibonacci method, until DLT occurs. In Phase 2, patients will receive the RP2D. Treatment will continue q3w until disease progression or unacceptable toxicity; safety and efficacy will be evaluated in specific tumor types (NSCLC, CRPC, and pancreatic ductal adenocarcinoma). Approximately 120 patients will be enrolled (11-30 in Phase 1 and approximately 90 in Phase 2). Patients must have histologically or cytologically confirmed locally advanced, unresectable or metastatic solid tumors and have failed available standard-of-care therapy and for whom no curative therapy is available. Follow-up information will be collected approximately every 3 months after the last dose until disease progression for patients with stable disease or better at the end of treatment. Clinical trial information: NCT 03425279.
Sarcoma tumor size (T) staging: Are radiology or pathology measurements more appropriate?
Authors: Angela Pang, Mariana Carbini, Elizabeth Demicco, Robert G. Maki
Journal: Journal of Clinical Oncology (2017)

e22522 Background: In the AJCC version 7 TNMG staging of soft tissue sarcomas (STS), the longest dimension (1D) of the primary tumor at pathology analysis is the gold standard for tumor size (T) staging. However, measurements may differ between scans and actual tissue measurement, due to tissue elasticity, deformation, and/or formalin fixation. Thus, tumor size may change compared to preoperative imaging. Should STS T stage be defined by imaging or by direct tumor measurement? We examined the variability of the measurements between radiology and pathology data, examining 1D, cross sectional area (2D), and tumor volume (3D) to assign a T stage. Methods: We reviewed all patients (pts) with extremity STS who had surgery at Mt Sinai Hospital New York (2010-2015). MRI or CT and resected gross tumor measurements were available for 79 pts. After eliminating 10 samples with grossly irregular shapes and 11 samples with incomplete data, 58 tumors had complete 3D measurements. We calculated Pearson correlation coefficients for paired variables (radiology vs pathology size in 1D, 2D and 3D). Results: Imaging measures correlated well with direct tumor measurements. Pearson correlation coefficients for 1D, 2D and 3D measurements were 0.93, 0.72 and 0.78, respectively (all p &lt; 0.01). The SEM (radiology/pathology size) = 0.13, i.e. 13% for 1D measurements. Thus, T stage could be incorrectly assigned in up to 13% of samples near 5 cm in size; this proportion decreases the further the tumor is from the 5 cm cutoff. Conclusions: As shown previously in the rationale for RECIST, 1D measures provide the smallest variance between radiology and pathology. The situation is made more complex in AJCC version 8, with four T categories. It remains unclear how to stage the 10-15% of primary STS with irregular shapes. These data support the use of nomograms for risk assessment rather than using bins created by the AJCC tumor staging system. 3D tumor volumes, if used at all, may play a greater role when assessing therapy responses or contending with tumors of irregular shape, rather than for routine STS staging.