tbuckley/cabot-search huggingface dataset:
Association of allele frequency of <i>EGFR</i> mutation with efficacy of <i>EGFR</i> TKIs in advanced non-small cell lung cancer.
Authors: Xiang-Meng Li, Jin-Ji Yang, Yi-Long Wu
Journal: Journal of Clinical Oncology (2019)

e20678 Background: Next-generation sequencing (NGS) is beneficial to precision medicine. However, it remains elusive whether the epidermal growth factor receptor ( EGFR) mutant allele frequency (MAF) tested by NGS is predictive for tyrosine kinase inhibitors (TKIs) therapy in advanced non-small-cell lung cancer (NSCLC). Methods: We enrolled 194 advanced NSCLC EGFR mutant patients receiving erlotinib or gefitinib orally. A total of 196 baseline tissue samples from a phase III clinical trial (CTONG 0901; clinicaltrials.gov No.NCT01024413) between July 2009 and 2014 were analyzed by a panel of 168 lung cancer-related genes NGS. The median EGFR MAF was 25.8% (range, 1.4%-86.2%). Patients were divided into MAF low group (1.4%-25.8%) and high group (25.8%-86.2%). We defined PFS as the time of randomization to confirmed disease progression or death from any cause. OS was calculated from randomization to the last visit or death from any cause. Tumor response was assessed by investigators according to RECIST version 1.1. Survival was estimated using the Kaplan-Meier method. The relationship between the response of TKIs and EGFR MAF were evaluated by Pearson Chi-square test or Fisher’s exact test. Results: The median age was 58.7 years (range,31.2- 85.1), 92 (47.4%) were male, 41(21.1%) were smokers,189 (97.4%) had adenocarcinoma, 105 (54.1%) patients were identified as carrying EGFR exon 19 deletion, while one patient with the co-existence of T790M mutation. 85 (43.8%) patients harbored EGFR exon 21 L858R mutation. After 5 weeks of treatment, the initial response was assessed. No significant difference was observed in initial response between the high and low groups ( P = 0.502). The difference in best response to EGFR-TKIs between the groups was not significant ( P = 0.557). Objective response rate (ORR) was 56.2% and 57.5% respectively. There was no significant difference in median PFS [11.2 (95% CI,10.0 -12.3) vs 12.4 (95% CI,10.3-14.5) months, P = 0.509] between the groups. The high group was not significantly superior to the low group in median OS[20.5 (95% CI,18.0-23.0) vs 23.1 (95% CI,19.3-27.0) months, P = 0.500]. Conclusions: EGFR mutant allele frequency tested by NGS is not associated with the efficacy of EGFR TKIs in advanced NSCLC.
Effectiveness of low-dose CT scan for lung cancer screening in the community setting.
Authors: Jason Aboudi Mouabbi, Tarik H. Hadid, Eugene Uh
Journal: Journal of Clinical Oncology (2019)

1543 Background: Lung cancer is the leading cause of cancer death in the United States (US) and worldwide. Chest X-ray (CXR) is ineffective in reducing lung cancer mortality. National Lung Cancer Screening Trail (NLST) reported 20% reduction in mortality with the use of low-dose computed tomography (LDCT) scan to screen high risk individuals. Therefore, major organizations including US Preventive Services Task Force has adopted LDCT for lung cancer screening in high risk populations. However, The generalizability of this approach in community setting is yet to be confirmed. Our objective is to assess the ability of LDCT in detection of lung nodules and lung cancer in the community setting and compare the results to those reported in the NLST. Methods: Charts of subjects who underwent LDCT screening between 2013 and 2016 at SJHMC were retrospectively reviewed. Demographic data, the results of the LDCT scans, interventions performed, complications of procedures and pathology findings were collected. All cancer cases found by LDCT and the stage of cancers were documented. The results of our study were statistically compared to the results of both arms of the NLST (CT and CXR arms). Since CXR is ineffective for lung cancer screening, CXR arm serves equivalently to no screening. Results: The baseline characteristics of the subjects are significantly different between this study and NLST. LDCT in our study detected significantly higher positive findings. There are more cancers detected in this study compared to NLST CT and CXR arms, which could reflect higher incidence of cancer in this community or higher proportion of current smokers in our study. In this study, LDCT detected cancers at higher stages compared to that of the NLST CT arm but similar stages to NLST CXR arm. This may indicate that LDCT when performed in the community is less effective in detecting cancer at early stages. Conclusions: The community population have different characteristics compared those enrolled in clinical trials. This may limit the generalizability of the results. Population-based studies are needed to confirm the results of the NLST. [Table: see text]
A phase III, randomized, double-blind, placebo (Pla)-controlled study of pertuzumab (P) + trastuzumab (H) + docetaxel (D) versus Pla + H+ D in previously untreated HER2-positive locally recurrent/metastatic breast cancer (LR/MBC) (PUFFIN).
Authors: Binghe Xu, Wei Li, Qingyuan Zhang, Shao Zhimin, Wang Xiao Jia, Huiping Li, Tao Sun, Yongmei Yin, Hong Zheng, Hong Zhang, Tiffanie Chan, Guiyuan Lei, Eleonora Restuccia
Journal: Journal of Clinical Oncology (2019)

1026 Background: In CLEOPATRA (NCT00567190), adding P to H + D significantly improved progression-free and overall survival (PFS/OS) v Pla + H + D in patients (pts) with previously untreated HER2-positive LR/MBC. PUFFIN (NCT02896855) is a China bridging study; the objective being to assess consistency of efficacy with CLEOPATRA. Methods: Pts with previously untreated HER2-positive LR/MBC were randomized 1:1 to P + H + D or Pla + H + D, stratified by visceral v non-visceral disease and hormone receptor status. The primary endpoint was investigator-assessed PFS. Secondary endpoints included objective response rate (ORR in pts with measurable baseline disease), OS, and safety. The target sample size (240) was determined based on the consistency threshold for PFS, defined as hazard ratio (HR) &lt; 0.81, which maintains ≥ 50% of the risk reduction determined in CLEOPATRA (HR 0.62). Results: Two hundred forty-three pts were randomized. Baseline/disease characteristics and prior therapies were generally balanced between arms. For PFS, the HR was 0.69 (95% CI 0.49, 0.99) in the ITT population. No cases of heart failure or symptomatic left ventricular ejection fraction decline were reported. Efficacy/safety are shown in the table. Conclusions: PUFFIN met its primary endpoint. Overall, efficacy data were consistent with CLEOPATRA (ITT population and Asian subgroup). Safety was also consistent and in line with the known P safety profile, with no new or unexpected signals reported. PUFFIN adds to the totality of data with P in previously untreated HER2-positive LR/MBC, and supports the favorable benefit–risk profile of P in Chinese pts. Clinical trial information: NCT02896855. [Table: see text]
Performance and validation of a tumor mutation profiling, based on artificial intelligence annotation, to assist oncology decision making.
Authors: Miguel Mitne Neto, Alexandre Ricardo Fornari, Luciana Peniche Moreira, Matheus Burger, Andre Oku, Luciana Guilhermino Pereira, Raquel Stabellini, Gabriela Rampazzo Valim, Otavio Jose Eulalio, Gisele Wally Colleoni, Ilka Lopes Santoro, Maria Carolina Pintão, Monica Maria Agata Stiepcich, Aloisio Souza Felipe-Silva, Rodrigo Fernandes Ramalho, David Santos Marco Antonio, Ana Maria Fraga, Elisa Napolitano Ferreira
Journal: Journal of Clinical Oncology (2019)

e13148 Background: Tumor mutation profiling has become a key component for orienteering the treatment of oncologic patients. A crucial step for this is the correct identification and classification of pathogenic and actionable variants. In the present work we aimed at the development and validation of a tumor mutation profiling panel, based on NGS, which uses artificial intelligence for variant annotation. Methods: We designed a hybrid capture panel, containing 366 genes to evaluate somatic SNVs, INDELs and CNVs, and to calculate TMB, using a customized bioinformatics pipeline. MSI status was determined by fragment analysis using capillary electrophoresis. Analytical performance was determined using reference cell lines. FFPE samples from 70 tumors were accessed and 53 were sequenced. Variant annotation was performed by IBM Watson for Genomics (WfG) platform. Assay performance on clinical samples was defined based on orthogonal assays using Agilent CGH+SNParray 400K (for CNVs only) and Foundation One test (Foundation Medicine) (F1). Results: Breast, colon and lung were the most common tumor origins. Fifty-three samples were successfully sequenced, while 41 of them could also be analyzed by F1 test. A summary of the assay performance is presented in Table 1. Our pipeline detected 1219 variants and 290 (23%) were classified as Pathogenic, Likely Pathogenic or Actionable, according to WfG. Thirty-five samples (66%) presented a variant that could drive the treatment, with 37.7% of samples being sensitive to targeted therapies, while 22.6% were resistant; additionally, 86% had an indication for a clinical trial. Conclusions: The developed assay presented a good overall sensitivity and allele frequency correlation, with TMB and MSI having the best rates. Comparisons with F1 had reduced values of concordance; however, SNVs and INDELs presented a similar frequency. Differences on CNVs identification may rely on distinct thresholds established by the different groups. The high percentage of samples that could benefit from mutational profiling highlights the importance of such approach in the clinical routine. Additionally, the high number of variants features the need for updated information for annotation. [Table: see text]
Tumor mutation burden and PD-L1 expression in SDH/FH mutated solid tumors.
Authors: Leylah Drusbosky, Christopher Szeto, Sandeep K. Reddy, Maninderjit Ghotra, Amir A. Toor, Steven Smith, Anthony Faber, Sosipatros Alexandros Boikos
Journal: Journal of Clinical Oncology (2019)

1524 Background: Succinate Dehydrogenases and Fumarate Hydratase (SDH/FH) deficient tumors are characterized by succinate/fumarate accumulation and resultant pesudohypoxia that drives malignant transformation. This state of pseudohypoxia leads to dysregulation of PD-1 receptor-ligand signaling. In this study, we explored tumor mutation burden (TMB), gene expression of PD-L1, and expression of other immune checkpoint- associated genes in a diverse cohort of human tumors harboring SDH A, B, C, D and FH mutations. Methods: Retrospective analysis was performed on whole exome sequencing (WES; ~150x coverage) and whole transcriptomic RNAseq (~200x106 reads per tumor) data from NantHealth to identify tumors harboring SDHx and/or FH mutations. WES was performed on tumor tissue and matched normal for each patient to assess TMB. TMB was measured by counting all somatic-specific non-synonymous exonic mutations, with &gt; 200 mutations qualified as TMB-high. Immune checkpoint therapy-related gene expression was evaluated for PDL1, CTLA4 , IDO, LAG3, FOXP3, PDL2, TIGIT, TIM3 and OX40 . Results: Among tumor samples from 3377 patients analyzed, 42 patients were found to harbor potentially-pathogenic &amp; pathogenic mutations in the SDHA, B, C, D and FH genes. The most common tumor types with SDH/FH mutations were lung (n = 7), breast (n = 6), and colon cancer (n = 6). Our analysis revealed that TMB was positively correlated with the presence of SDH/FH mutations (p &lt; 0.001). High PD-L1 expression was also significantly correlated with the presence of SDH/FH mutation (p &lt; 0.05), while CTLA4, IDO, LAG3, FOXP3, and OX40 expression was significantly higher in SDH/FH mutated samples (p &lt; 0.05). Conclusions: We report for the first time an association between increased TMB and increased PD-L1 expression in a variety of SDH/FH mutated tumors. These key parameters, imply that a higher TMB may drive the evolutionary pressure to select clones with a PDL1 high phenotype. This observation supports a potential therapeutic role for inhibition of PD-1/PD-L1 pathway in these tumors.
Emergency department visits for prescription and synthetic opioid overdoses among patients with cancer.
Authors: Vikram Jairam, Daniel X. Yang, James B. Yu, Henry S. Park
Journal: Journal of Clinical Oncology (2019)

6579 Background: Patients with cancer may be at high risk of opioid dependence due to physical and psychosocial factors, although little data exists to inform providers and policymakers. Our aim is to examine overdoses from prescription and synthetic opiates leading to emergency department (ED) visits among patients with cancer in the United States. Methods: The Healthcare Cost and Utilization Project Nationwide Emergency Department Sample (HCUP-NEDS) was queried for all patient visits with a primary diagnosis of prescription or synthetic opioid overdose between 2006 and 2015. Baseline differences between patients with and without cancer were assessed using chi-square and ANOVA testing. Overdose rates by primary cancer site were normalized using prevalence data from the Surveillance, Epidemiology, and End Results (SEER) Program. Weighted frequencies were used to create national estimates for all data analyses. Results: There were 682,820 weighted ED visits for synthetic opioid overdose, among which 34,547 (5.1%) visits were also associated with a diagnosis of cancer. During this timeframe, ED visits for opioid overdose among patients with cancer increased 2.5-fold, compared to 1.7-fold among those without cancer. 16.5% of patients with cancer had metastatic disease. Patients with cancer presenting for opioid overdose had higher risk of hospital admission (74.8% vs 49.6%), respiratory intubation (13.2% vs 12.2%), mortality (2.1% vs 1.1%), and cost-of-hospital-stay ($32,665 vs $31,824) compared to their non-cancer counterparts (all P &lt; 0.05). Primary cancers with the highest normalized overdose rates (ED visits per 10,000 patients) were esophagus (134), liver &amp; intrahepatic bile duct (124), and cervical cancer (124). Other common cancers had the following normalized overdose rates: lung (105), head and neck (70), and breast (26). Conclusions: Approximately 5% of all ED visits due to prescription and synthetic opioid overdose are among patients with cancer. The rate of increase in ED visits due to opioid overdose from cancer patients was nearly 50% higher than that from non-cancer patients over the 10-year study period. Patients with esophageal, liver, and cervical cancer may be at highest risk.
A phase Ib trial of the cyclin-dependent kinase inhibitor dinaciclib (dina) in combination with pembrolizumab (P) in patients with advanced triple-negative breast cancer (TNBC).
Authors: Amy Jo Chien, Siti Rahmaputri, Heidi F Dittrich, Melanie Catherine Majure, Hope S. Rugo, Michelle E. Melisko, Andrei Goga
Journal: Journal of Clinical Oncology (2019)

1072 Background: Increased expression of the MYC transcriptional oncogene is found in 70% of TNBC and is associated with poor prognosis. In MYC-overexpressing TN xenografts, CDK1 inhibition with dina results in synthetic lethality, and attenuates distant metastasis. In syngeneic models, the combination of dina with anti-PD1 therapy is synergistic and increases immune cell tumor infiltration and activation. Methods: Patients (pts) with advanced TNBC were enrolled. Pts received intravenous dina day 1 and 8 in combination with fixed dose P 200 mg once every 21 days. Dina was dose escalated using a toxicity probability interval design targeting a dose limiting toxicity (DLT) rate of 25%. Evaluable disease and pre-treatment metastatic biopsies were required. After 17 pts were enrolled, eligibility was amended to require ≤2 lines of prior chemotherapy, and LDH ≤1.5x normal. Results: 22 pts were enrolled (median age 50, median 2 prior lines of therapy, 10 pts (45%) had disease which was previously ER+). Dina was dose escalated from 12 to 33 mg/m2 in 4 cohorts. No DLTs were observed. Of the first 5 patients in the 33 mg/m2 cohort, 2 pts required a dose reduction (1 pt due to recurrent grade (G) 3 fever and G2 chills; 1 pt due to recurrent G2 diarrhea, chills, fatigue), and 1 pt discontinued due to G3 hemolytic anemia. 4 additional pts were treated at 33 mg/m2 without DLT or dose reduction. G ≥3 adverse events (AEs) in all pts included neutropenia (ntp) (36.3%), febrile ntp (13.6%), and fatigue (13.6%). Most common all-grade AEs included fatigue (73%), diarrhea (59%), nausea (50%), ntp (45%), mucositis (32%), anorexia (23%). Immune-related AEs included sinusitis (3 pts), hemolytic anemia (1 pt), pneumonitis (1pt), and rash (2 pts). Of 21 pts evaluable for response, 1 pt had complete response (4.8%), 2 pts had partial response (9.5%), and 5 pts had stable disease (23.8%). Dose expansion and correlative biomarker studies are ongoing. Conclusions: The recommended phase 2 dose of dinaciclib given in combination with pembrolizumab is 33 mg/m2 on D1, 8 of 21-day cycle. Toxicities are generally manageable with dose reduction and dose delay. Clinical trial information: NCT01676753.
Investigation of an ethnic predisposition to developing brain metastases (BM) in Asian patients with colorectal cancer (CRC).
Authors: Kerri McGovern, Teresa Rodriguez, Melissa H Smith, Antonia Maloney, Wasif M. Saif
Journal: Journal of Clinical Oncology (2019)

e15023 Background: CRC, the third most common cancer in the United States, carries racial/ethnic disparities in both incidence and mortality. With availability of effective systemic therapies, the life of CRC patients can be prolonged which thereby increases the risk of metastases at uncommon sites, such as the brain. We report our investigation into the impact of race/ethnicity on the incidence of BM in CRC patients using retrospective data (2010 – 2018) at a single institution. Methods: We retrospectively reviewed patients diagnosed with CRC and collected data on age, race/ethnicity, stage, treatment modalities, metastatic sites, and survival. Race and ethnicity were defined in accordance with federal standards set by the U.S. Census. Following this, race/ethnicity was self-declared and/or based on the primary language declared and categorized as non-Hispanic White, Hispanic White, non–Hispanic Black, Asian, or Unknown/Other. CRC location was classified as right-sided, left-sided or rectal. Results: We identified 264 CRC patients (median age: 61; range: 38 - 99). Among them 123 identified as non-Hispanic white, 28 non-Hispanic black, 26 Hispanic white, and 9 declared Other. There were 76 (29%) who identified as Asian. Of those 76 patients, 5 (7%) developed BM. All 5 patients were male and stage IV at initial diagnosis. BM was a late stage phenomenon with rectal primary and lung metastases seemly associated with an increased risk in the specific cohort. Molecular markers such as KRAS were available in 3 patients without clear association. Median time to development of BM was 29 months (range: 26 - 33). Median overall survival after BM diagnosis was 5.5 months (range: 4 - 11). Overall survival was longest for the patient who had both radiation and surgery. Conclusions: Our study showed an incidence of BM of 7% in the Asian sub-population compared to the historical control of 0.6 – 3.2% in the overall population. These results at the least warrant further investigation in a larger patient population of BM in CRC patients with emphasis on molecular markers. Recognition of BM in CRC patients is clinically relevant secondary to multiple lines of therapy as mentioned earlier and its grave impact on outcome.
Analytical validation of a tumor-agnostic integrated multianalyte circulating tumor DNA (ctDNA) assay in early-stage cancer.
Authors: Anna Hartwig, Carlo Artieri, Ariel Jaimovich, Emily E. Van Seventer, Aparna Raj Parikh, Ryan Bruce Corcoran, Arthur Baca, AmirAli Talasaz
Journal: Journal of Clinical Oncology (2019)

3057 Background: ctDNA sequencing has been rapidly adopted for the identification of targetable somatic alterations (alts) in patients with advanced cancers. However, early stage disease detection has been hindered by low levels of ctDNA in circulation and the presence of confounding non-tumor-related somatic alts. We developed and validated a ctDNA assay that combines somatic and epigenomic signals to detect early stage tumors without tumor tissue or white blood cells (WBC). Methods: Using a single input sample, our assay integrates the sensitive detection of genomic alts with quantification of epigenomic signals associated with cancer. Non-tumor alts (e.g., clonal hematopoiesis of indeterminate potential; CHIP) are excluded using a newly developed bioinformatic classifier. To assess analytical sensitivity, specificity, and positive and negative reproducibility, we tested 337 clinical and contrived samples. Results: Clinical specificity was determined using 80 plasma samples from 50-75 year old presumptive cancer-free donors, and resulted in a single false positive (99% specificity). Analytical sensitivity (limit of detection) was established using a dilution series of 4 different late stage CRC pts tested in triplicate at a clinically relevant DNA input (30 ng) across multiple batches. 100% sensitivity was maintained even at the lowest tested level (estimated 0.1% tumor level). Positive/negative reproducibility was assessed by testing triplicates of diluted late stage samples and age-matched healthy donors, respectively, across different cfDNA inputs, and multiple reagent lots. Both positive and negative calls were 100% concordant across all replicates. Independent estimation of tumor levels from epigenomic or genomic signals produced highly concordant results (correlation r-value: 0.82, p-value: 3e-16). Conclusions: We designed and validated a highly specific ctDNA assay that integrates both genomic and epigenomic signals to allow for accurate and quantitative tumor level detection in early stages of the disease without requiring tumor tissue or WBC.