tbuckley/cabot-search huggingface dataset:
Mutation analysis in metastatic colorectal cancers (mCRC) subjected to gene panel testing for <i>BRAF</i> and <i>KRAS</i> genes in clinical practice.
Authors: Jeremy Clifton Jones, Frank A. Sinicrope, Nathan R. Foster, Benjamin Kipp, Jesse S Voss
Journal: Journal of Clinical Oncology (2016)

e15049 Background: While RAS and BRAF mutations predict resistance to anti-EGFR therapy, the mechanisms of secondary or acquired resistance to these drugs in patients (pts) with wild-type (wt) RAS/RAF tumors are poorly understood, as are molecular alterations that confer resistance to BRAF inhibitors in BRAFMut CRCs. We compared non-RAS/RAF mutational frequencies among pts with RASmut, BRAFMut and wt RAS/BRAFtumors in an effort to identify potential drivers of resistance to targeted therapies. Methods: We identified 270 pts from a database which included all pts with mCRC who had targeted next-generation sequencing of clinical tumor specimens between 2013-2015 at Mayo Clinic. The 3 groups (RASmut, BRAFMut and wt RAS/BRAF) were compared for mutation frequencies in 46 additional cancer-related genes. Results: Among all pts with mCRC, mutations were most common in the APC, KRAS and TP53 genes which accounted for 18.8%, 20.3% and 28.0% of all mutations, respectively. There were significant differences in the frequencies of commonly mutated genes of known function within the 3 groups. Compared to wt RAS/BRAF, BRAFMut tumors had significantly fewer APC (p = 0.0194) and TP53 (p = 0.0061) mutations, yet significantly more AKT (p = 0.0048) and MET (p = 0.0235) mutations. RASmuttumors had significantly more APC (p = 0.0008) and PIK3CA (p = 0.0064) mutations and fewer TP53mutations (p = 0.0004) compared with wt RAS/BRAF. Conclusions: We found significant heterogeneity in the mutational spectrum within mCRC according to whether they harbor RAS or BRAFV600E mutations. Tumors with BRAFV600E were enriched in AKT and MET mutations that have been implicated in resistance to BRAF-inhibition in mCRC. RASmuttumors had highest rates of APC mutations indicating dependence the Wnt signaling pathway in these tumors. These data identify important pathogenic mutations that likely play a role in pathogenesis and are potentially actionable in patients with mCRCs.
Association between ERCC1 polymorphisms and nephrotoxicity in non-small cell lung cancer patients undergoing platinum-based chemotherapy.
Authors: Corine de Jong, Vera Henriëtte Deneer, Johannes Kelder, Cornelis Bernardus Hunting, Gerarda Herder
Journal: Journal of Clinical Oncology (2018)

e21177 Background: Platinum-based chemotherapy still remains the most frequently applied first-line treatment for (non)small cell lung cancer ((N)SCLC) not driven by an epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) rearrangement. Genetic polymorphisms can be considered as predictive tools for the pretreatment evaluation of the efficacy and toxicity of platinum-based chemotherapies. Earlier, single nucleotide polymorphisms (SNPs) in the excision repair cross complementation group 1 (ERCC1) protein have been suggested as potential biomarkers for toxicity. To replicate these findings, we investigated three SNPs (rs11615, rs3212986, rs321948) for association with nephrotoxicity of platinum-based chemotherapy in (N)SCLC patients. Methods: In this prospective observational study, (N)SCLC patients undergoing platinum-based (cisplatin, carboplatin) chemotherapy were recruited from two large teaching hospitals in the Netherlands (St Antonius Hospital Nieuwegein, Meander Medical Center Amersfoort). We selected three SNPs in the ERCC1 gene that might be associated with platinum-induced nephrotoxicity. Each SNP was tested for association with nephrotoxicity (grade 1-4, according to Common Toxicity Criteria (CTC) Version 4.03, and the relative change in the estimated glomerular filtration rate (eGFR)) using logistic regression and Kruskal-Wallis analyses. Results: We included 126 patients for toxicity analyses. In total, 28 patients (22.2%) developed nephrotoxicity, of which 25 patients (89.3%) grade 1, 1 patient (3.6%) grade 2 and two patients (7.1%) grade 3 toxicity. The platinum type was associated with increased risk of platinum-induced nephrotoxicity (cisplatin, crude OR 2.83, 95% CI: 1.19-7.17). The risk for nephrotoxicity was not increased in the presence of specific alleles of the ERCC1 gene. Conclusions: The results of the present study suggest no association between three SNPs in the ERCC1 gene and the development of nephrotoxicity. Since we could not replicate the previous observed association, these results warrant further validation in a larger cohort. Clinical trial information: NTR5836.
The PRONTO amyloidosis study: A randomized, double-blind, placebo-controlled, global, phase 2b study of NEOD001 in previously treated subjects with light chain amyloidosis and persistent cardiac dysfunction.
Authors: Giampaolo Merlini, Michaela Liedtke, Heather Jolie Landau, Raymond L. Comenzo, Vaishali Sanchorawala, Brendan M. Weiss, Jeffrey A. Zonder, Stefan Schönland, Spencer D. Guthrie, Jackie Walling, Gene G. Kinney, Martin Koller, Morie A. Gertz
Journal: Journal of Clinical Oncology (2016)

TPS8073 Background: In light chain (AL) amyloidosis, the accumulation of misfolded light chain (LC) protein may lead to organ failure and death. Patients are treated primarily with plasma cell–targeting agents that reduce LC production. Organ function can improve over time but is often incomplete. There is a substantial need for therapies that treat organ dysfunction. NEOD001, a monoclonal antibody that targets misfolded LC, is hypothesized to neutralize circulating soluble LC and to clear insoluble deposits from organs. In an ongoing phase 1/2 study (NCT02613182; Gertz M et al, J Clin Oncol, 2016) in 27 patients with AL amyloidosis and persistent organ dysfunction, monthly NEOD001 infusions were well tolerated and produced no infusion-related hypersensitivity reactions. In a best response analysis of subjects who fulfilled eligibility criteria at baseline, 57% met cardiac and 60% met renal response criteria. The current study (PRONTO; NCT02632786) is a randomized, double-blind, placebo-controlled, phase 2b trial of NEOD001 in patients with AL amyloidosis who responded to previous systemic therapy but have persistent cardiac dysfunction. Methods: Eligible patients (estimated enrollment, 100) with AL amyloidosis, ≥ 1 previous systemic treatment ( > 6 months earlier with partial hematologic response [HR] or better), and cardiac dysfunction (N-terminal pro-brain natriuretic peptide [NT-proBNP] 650-5000 pg/mL; clinical heart failure signs; left ventricular wall thickness > 12 mm, or cardiac biopsy–detected amyloidosis) will be randomly assigned (1:1) to receive NEOD001 (24 mg/kg q28d) or placebo and will be stratified according to NT-proBNP ( < 1800 vs ≥ 1800 pg/mL) and HR to initial plasma cell therapy (complete/very good partial vs partial response). The primary end point is cardiac best response (NT-proBNP; baseline to month 12). Key secondary end points include change in Short Form-36 Questionnaire response, 6-minute walk test distance, Neuropathy Impairment Score–Lower Limb, progression free-survival, renal best response (defined by Palladini G et al, Blood 2014), and safety. Clinical trial information: NCT02632786.
Impact of different timing of radiation therapy in patients with brain metastases from epidermal growth factor receptor-mutant non-small cell lung cancer.
Authors: Xiaozhen Ying, Shuiyun Han, Chenxue Jiang, Xiaojiang Sun, Yaping Xu, Weimin Mao
Journal: Journal of Clinical Oncology (2017)

e20667 Background: To perform a retrospective analysis of patients with brain metastases (BM) from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) to evaluate the preferred treatment timing of EGFR-tyrosine kinase inhibitors (TKIs) in this population. Methods: Of 94 initial or recurrent patients diagnosed BM from EGFR-mutant NSCLC between Jan 1, 2012, and Jun 31, 2016, 30 received upfront brain RT followed by EGFR-TKI, 39 EGFR-TKI combined with concurrent brain RT, and 25 upfront EGFR-TKI then brain RT. Disease-specific-graded prognostic assessment was similar among all 3 groups. The primary endpoint was overall survival (OS), and the second endpoint was intracranial progression-free survival. Results: Although the median OS was not significantly different among the upfront RT, concurrent treatment, and upfront EGFR-TKI groups (29.0 vs 24.0 vs 17.0 months; P = 0.186), however, it was longer in the upfront RT group compared with the upfront EGFR-TKI group (P = 0.035). On subgroup analysis, the exon 19 deletions patients had longer OS than the exon 21 mutations patients in upfront EGFR-TKI group (23.0 vs 15.0 months; P = 0.048), but the upfront RT (34.0 vs 23.0 months; P = 0.186) and the concurrent treatment groups (24.0 vs 13.0 months; P = 0.827) did not. According to multivariate COX analysis, KPS (≥ 70) and intracranial metastasis alone was associated with a longer OS. The median intracranial progression-free survival was significantly improved in patients receiving upfront RT compared with those receiving concurrent treatment or upfront EGFR-TKI (not reached vs 40.0 vs 9.0 months; P = 0.003). Conclusions: The present study suggests that the use of upfront brain radiotherapy, and the deferral of EGFR-TKI may result in superior OS in patients with brain metastases from EGFR-mutant NSCLC. Also, upfront brain radiotherapy management could significantly reduce the risk of intracranial progression. A prospective, multi-institutional, randomized trial of upfront EGFR-TKI then RT versus upfront RT followed by EGFR-TKI is urgently needed, especially based on different subgroup population.
Low income subsidy status outweighs insurance cost-sharing in predicting adherence to tyrosine kinase inhibitors among Medicare Part D beneficiaries with chronic myeloid leukemia.
Authors: Chan Shen, Bo Zhao, Shouhao Zhou, Lei Liu, Ya-Chen T. Shih
Journal: Journal of Clinical Oncology (2016)

6531 Background: Tyrosine kinase inhibitors (TKIs) have transformed chronic myeloid leukemia (CML) from a deadly cancer to chronic disease. While these drugs dramatically improve survival, non-adherence could lead to suboptimal care. Previous research has found lower adherence among privately insured patients with high cost sharing. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) registry data linked with Medicare Part D data, 2007-2012, to construct our study cohort of CML patients who were new TKI users with continuous Medicare Part D insurance coverage from 6 months before starting TKI therapy to 6 months after. We measured non-adherence using a binary variable indicating whether the number of days of TKIs supply covered less than 80% of the 180 day period after therapy initiation. We used chi-square test to examine the group difference in non-adherence by patient and plan characteristics. We used logistic regression to examine the relationship between treatment non-adherence and out-of-pocket (OOP) costs per 30-day supply of TKIs and patient characteristics for a subset of patients who did not receive any subsidies. Results: Overall 244 (29%) of the 836 CML patients were non-adherent to TKI therapy during the study period. The rate of non-adherence among heavily subsidized patients was significantly higher compared with patients without subsidies (36% vs. 27%) even though OOP costs per 30-day supply were low (below the median of the whole cohort) for the heavily subsidized. Among those without subsidies, the multivariable logistic regression showed that patients whose OOP payments per 30-day supply were at the top quartile were five times (95% CI: 3.12~8.00) more likely to be non-adherent than others. Conclusions: This population-based study found a strong association between OOP costs and non-adherence among CML patients enrolled in Medicare Part D without subsidy. The higher rate of non-adherence among heavily subsidized patients, despite their substantially lower OOP costs, suggests the need for future research to explore factors other than coverage barriers in this vulnerable population.
DNA cytometric parameters as prognostic factors of chemoimmunotherapy for ovarian cancer.
Authors: Galina Andreevna Nerodo, Oleg Ivanovich Kit, Inna Arnoldovna Novikova, Anna Ardzha, Ekaterina V. Verenikina, Vera P. Nikitina, Oksana E. Kravtsova, Elena Bondarenko, Stanislav Stanislavovich Mezentsev
Journal: Journal of Clinical Oncology (2017)

e17041 Background: The aim of the study was to analyze chemoimmunotherapy influence on DNA cytometric parameters in patients with ovarian cancer. Methods: The study included stage IIIC-IV ovarian cancer patients divided into two groups in dependence on the treatment: group A – 21 patients who did not receive neoadjuvant chemotherapy before surgery; group B – 24 patients who received neoadjuvant chemoimmunotherapy with intraperitoneal administration of interferon-gamma (ingaron) and the following surgery. The groups were identical in terms of the disease stages, age and general condition of patients. DNAs were analyzed in fresh tumor tissues using CycleTEST Plus DNA Reagent Kit (Becton Dickinson, USA). The data were processed using the ModFit LT program allowing analysis of ploidy and distribution of tumor cells in phases of the cell cycle. The proportion of cells with different DNA content in the histogram was calculated as a percentage of the total number of studied cells. Proliferation index (PI) was calculated as the total amount of tumor cells in S and G2+М phases of the cell cycle. Results: Full-volume surgery (panhysterectomy+omentectomy) was performed in 52.4% in group A and in 92% in group B, adnexectomy only – in 38.1% and 8%, respectively; exploratory surgeries were performed in group A only – 9.5%. During 2 years of the observation, recurrence in group A was found in 38% of patients, in group B – in 12.5%. Analysis of DNA cytometric parameters showed the minimal proliferation rates (percentage of cells in S phase) in group B – 12.6±2.3%, compared with 20.7±3.4% in group A. PI was lowest in group B – 13±2.7%, compared with group A – 22.4±3.3% (p≤0.05). Significant decrease in the DNA index by 1.3 times was noted in patients in group B in comparison with group A (1.11±0.01% and 1.4±0.05%, respectively) (p≤ 0.05). Conclusions: Thus,DNA cytometric parameters reflect the effectiveness of chemoimmunotherapy and can be used as prognostic factors.
Analysis of AR-driven resistance mechanisms in a phase 1/2 study of EPI-506, a novel AR N-terminal domain inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC) with progression after enzalutamide or abiraterone.
Authors: Kim N. Chi, Ulka N. Vaishampayan, Michael S. Gordon, David C. Smith, Emmanuel S. Antonarakis, Ryan Vance Dittamore, Chan Chandhasin, Frank Perabo, Robert B. Montgomery
Journal: Journal of Clinical Oncology (2016)

TPS5030 Background: Androgen receptor (AR) signaling remains essential for CRPC progression and current inhibitors, such as abiraterone and enzalutamide, focus on blocking androgen synthesis and/or preventing androgen binding to the receptor. Eventually, tumor escape mechanisms enable AR signaling to become reactivated despite these interventions and represent a challenge to treatment of these tumors. Known AR-driven resistance mechanisms include AR copy number increase, gain-of-function mutations, and constitutively active AR splice variants. EPI-506 is a first-in-class, highly specific small molecule AR N-terminal domain (NTD) inhibitor that has potential to overcome shortcomings of current hormone therapies by targeting AR transcriptional activity. By targeting the NTD, EPI-506 can affect a broader AR population, including variants implicated in resistant mCRPC tumors. Methods: This is an ongoing Phase I study (3+3 design) which will be followed by a 3-arm Phase II study in CRPC patients that are progressing after abiraterone and/or enzalutamide. Biomarkers of AR driven resistance will be explored using circulating tumor cell (CTC) and plasma derived cell free DNA (cfDNA). CTCs and cfDNA samples will be collected at serial timepoints (baseline, 12-weeks, and progression). Presence of AR splice variants, including AR-V7, will be analyzed using the Epic Sciences CTC platform to detect AR C-terminal loss followed by immunofluorescence or RT-PCR detection of AR-V7. cfDNA will be subjected to targeted sequencing of AR and 74 other prostate cancer related genes using an Ion Ampliseq Custom DNA panel for mutations and copy number changes. Information gathered will be used to evaluate the clinical activity of EPI-506 in the context of known AR resistance mechanisms. The clinical study will be the first to evaluate the novel NTD inhibitor EPI-506 in men with enzalutamide- and/or abiraterone-failure mCRPC, and is the first agent with the potential to inhibit both canonical and variant-mediated AR signaling. Clinical trial information: NCT02606123.
Germline variants and family history in caucasian and African-American prostate cancer.
Authors: Elisa M. Ledet, Emma M. Ernst, Joshua Schiff, Shuwen Lin, Brian E. Lewis, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2017)

e16548 Background: Family history (FH) is a well-documented risk factor for prostate cancer (PCa). Previously, germline pathogenic variants (PVs) have been identified in metastatic PCa. The goal of this study was to fully evaluate cancer FH and assess PVs detected in PCa patients undergoing both detailed FH ascertainment and germline genetic testing. Methods: FHs were collected from 535 PCa pts (Caucasian (Ca) n = 359, African American (AA) n = 85, Other n = 18) at Tulane from 2015-2016. Age at diagnosis, Gleasons, and the presence of metastases at any time were noted for these pts. Chi-square and the Mann-Whitney U tests were performed to identify relationships between clinical parameters and FH. 124 PCa pts including those with both localized and metastatic disease were identified with FHs that met guidelines for genetic testing. Genetic testing was done using a commercially available panel (Invitae, San Francisco, CA) of 25-79 cancer-related genes for mutations/selected exon deletions/duplications. Results: Of the 124 tested pts, 20 pts (16.1%) had ≥ 1 germline PV and 47 pts (37.9%) had ≥ 1 germline variant unknown significance. PVs included: BRCA2 (n = 4), BRCA1 (n = 3), CHEK2 (n = 3), MUTYH (n = 3), ATM (n = 2), TP53 (n = 1), MITF (n = 1), NBN (n = 1), PMS2 (n = 1), and RAD51D (n = 1). No PVs were detected in AA pts (n = 20). 435 of 535 PCa pts (81.3%) had a cancer FH with prostate (37.8%), breast (28.2%), lung (16.4%), colorectal (14.8%), and pancreatic (7.5%) cancer being most common. 281 pts (52.5%) had ≥ 2 relatives with cancer. Pts with PCa FH were more likely to be dx age ≤ 55 (p = 0.017). Median age was younger at dx for pts with PCa FH (p = 0.0005). PCa FH did not alter Gleason or metastatic rate. FH influenced age at dx for Ca men (p = 0.0009, 58 vs. 62.5 and Ca men with PCa FH) were 1.55x more likely to develop metastases (p = 0.035). In AA pts, there were no significant associations between FH, and metastases or age at dx. Conclusions: The most prevalent germline mutations in this cohort were in DNA repair pathway genes. Pts with PCa FH were younger at dx than those without PCa FH. Further studies are needed to understand the co-segregation of PCa with other cancers and genetic studies are needed to clarify the mechanisms of these trends which may differ between Ca and AA men.
Effect of APF530 on health-related quality of life (QOL) and other chemotherapy-induced nausea and vomiting (CINV) end points: Phase III MAGIC trial.
Authors: Ian Schnadig, Eduardo Braun, Michael Mosier, Robert B. Geller, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2016)

e21666 Background: Delayed (24-120 h) CINV after highly emetogenic chemotherapy (HEC) is a clinical challenge, negatively affecting QOL. APF530, a new extended-release granisetron formulation, maintains therapeutic concentrations ≥ 5 days after 1 SC dose. In MAGIC, the first pivotal phase 3 comparison of 5-HT3 receptor antagonists in the recommended 3-drug regimen, the APF530 arm had superior complete response (CR; no emesis, no rescue medication use [RMU]) vs ondansetron (Ond) arm (65 vs 57%; P = .014; 8% absolute improvement) in the delayed phase after HEC (Schnadig et al. ASCO Breast 2015, A68). Other CINV and QOL-related end points are reported here. Methods: MAGIC compared APF530 500 mg SC (granisetron 10 mg) (N = 450) vs Ond 0.15 mg/kg IV (N = 452), each + fosaprepitant 150 mg IV + dexamethasone (12 mg IV on day 1; 8 mg PO 1 × daily on day 2, 2 × daily on days 3, 4) (NCT02106494). On day 6, patients (pts) reported worst nausea severity over 5 days, Functional Living Index–Emesis (FLIE) score, and daily RMU. No impact on daily life (NIDL) = FLIE average > 6 of 7 or total > 108 of 126. On days 1-5, total response (TR; no nausea, vomiting or RMU) was measured. This study was not powered to detect differences in these end points. Results: Nausea severity numerically favored the APF530 vs Ond arm in the overall phase (0-120 h) (P = .145) (no/mild nausea, 80 vs 75%; moderate/severe nausea, 20 vs 25%). RMU was lower each day up to day 5 for APF530 vs Ond (Table). Median overall FLIE scores were similar across arms; more APF530 pts had CINV control achieving NIDL in the overall phase. TR, a stringent measure of CINV control, was numerically higher in the APF530 vs Ond arm in delayed and overall phases (Table). Conclusions: Though not statistically significant, trends favoring the APF530 vs Ond arm for reduced nausea severity, less RMU, CINV control reaching NIDL, and TR are interesting. Given APF530 vs Ond arm superiority in CR for delayed CINV, effects of APF530 on QOL-related end points warrant further study. Clinical trial information: NCT02106494. APF530 N = 450 Ond N = 452 P Value RMU, % pts Day 1 21 24 .185 Day 2 17 21 .102 Day 3 20 27 .011 Day 4 18 22 .142 Day 5 19 21 .375 Median overall FLIE score 119 118 .793 NIDL, % pts 64 60 .310 TR, % pts Delayed 44 39 .104 Overall 40 36 .211
OS3.3 Radiological characteristics and natural history of adult IDH wild type astrocytomas with TERT promoter mutations
Authors: C Izquierdo, M Barritault, D Poncet, S Cartalat, B Joubert, J Bruna, E Jouanneau, J Guyotat, A Vasiljevic, T Fenouil, Y Berthezène, J Honnorat, D Meyronet, F Ducray
Journal: Neuro-Oncology (2018)