tbuckley/cabot-search huggingface dataset:
Risk of pediatric malignancy in families known to carry <i>BRCA1</i>/<i>2</i> mutations.
Authors: Kevin Thomas Nead, Nandita Mitra, Wenting Zhou, Rhonda C Gillette, Dana Clark, Jessica E Ebrahimzadeh, Jessica M. Long, Danielle Mckenna, Jacquelyn Powers, Kara Noelle Maxwell, Payal Deepak Shah, Angela R. Bradbury, Katherine Nathanson, Susan M. Domchek
Journal: Journal of Clinical Oncology (2018)

1535 Background: Inherited mutations in cancer predisposition genes typically associated with adult-onset cancers, including BRCA1/2, have been found in children with cancer. However, it is unknown whether such mutations are causative. Our objective is to determine whether there is an increased risk of pediatric malignancy in families known to carry BRCA1/2 mutations. Methods: We utilized the Cancer Risk Evaluation Program (CREP), a registry of high-risk breast and ovarian cancer families undergoing BRCA1/2 testing. We compared the proportion of pediatric malignancies (age ≤ 18 years) among families tested positive vs negative for BRCA1/2 mutations in 1) the proband’s siblings and 2) other potential at risk relatives of the proband (siblings, children, nieces and nephews). We used generalized estimating equations to account for familial clustering. We compared pediatric malignancy rates in BRCA1/2 mutation positive families from CREP to the general population from SEER (Surveillance, Epidemiology and End-Results) using an incidence rate ratio (IRR). Results: We compared 1,313 BRCA1/2 mutation negative and 1,402 BRCA1/2 mutation positive families. 3,168 siblings had 10 pediatric malignancies (0.3%) in BRCA1/2 negative families and 3,185 siblings had 9 pediatric malignancies (0.3%) in BRCA1/2 positive families. When examining at-risk family members there were 30 BRCA1/2 negative families (2.3%) with a pediatric malignancy (31 malignancies) and 24 BRCA1/2 positive families (1.7%) with a pediatric malignancy (25 malignancies). We found no evidence for an increased risk of pediatric malignancy in BRCA1/2 positive vs BRCA1/2 negative families in the sibling (OR = 0.69, 95% CI, 0.25-1.92; p = 0.482) or family based (OR = 0.76; 95% CI, 0.42-1.35; p = 0.342) multivariable adjusted analyses. The pediatric malignancy rates (per 100,000 person-years) among BRCA1/2 positive families in CREP (incidence rate [IR] = 16.1, 95% CI, 10.9-23.9) and SEER (IR = 16.1, 95% CI, 16.0-16.3) were similar (IRR = 1.00; 95% CI, 0.65-1.48). Conclusions: We find no evidence for an increased risk of pediatric malignancy in BRCA1/2 mutation positive families. Our data supports delaying BRCA1/2 testing in BRCA1/2 mutation positive families until adulthood.
Determining barriers to effective data sharing in cancer genomic sequencing initiatives: A Global Alliance for Genomics and Health (GA4GH) survey.
Authors: Jeremy Howard Lewin, Daniel J Vis, Emile E. Voest, Rachel Liao, Petra M Nederlof, Barbara A. Conley, David B. Solit, Christopher L. Corless, Paulo V Campregher, Vanessa Tyrell, George Chong, Michael Watson, Sun Young Rha, Tim Maughan, Mark Caulfield, Vladimir Lazar, Laura Esserman, Charles L. Sawyers, Lillian L. Siu, Mark Lawler
Journal: Journal of Clinical Oncology (2016)

11502 Background: Harmonizing informatics in the era of next generation sequencing (NGS) is a precision medicine priority as unconnected data silos unacceptably stall advancement of genomic medicine. GA4GH is a not for profit organization that promotes responsible and effective sharing of genomic/clinical data. In this context, GA4GH conducted a survey of international cancer sequencing initiatives to catalog global activity and dissect perceived barriers to data sharing. Methods: A total of 108 genomic sequencing initiatives were invited to participate in a web based survey that assessed perceived barriers to data sharing. Responses were presented as Likert scales (minor barrier ( = 1); major barrier ( = 6)) and were analyzed by Chi-square testing. Results: Responses were obtained from 59 initiatives (55%) which were largely North American or European based (61%). Initiatives varied in samples analyzed/year ((1-1000 (small): 49%; > 1000 (large): 51%)) and were well distributed between Diagnostic (D) and Research (R) intent (D: 15%; R: 37%; D/R: 34%; Unknown:14%). Biggest perceived barriers to effective data sharing (Likert scales ≥ 4) were: A: lack of funding (75%); incompatible data systems (69%); insufficient clinical data capture (58%); B: lack of informatics expertise (49%); legal (36%) and privacy issues (34%); (A vs B, p < 0.001)). Informatics barriers did not differ between initiative size (p = NS) or intent (D v R, p = NS), but larger initiatives had greater difficulty in capturing clinical data (p < 0.001). Financial barriers did not differ according to size or initiative’s intent (D vs R). Data protection legislation barriers were more apparent in European initiatives (p = 0.04). Conclusions: In this survey, funding, informatics system, clinical data capture and European data protection legislation were perceived as the greatest hurdles to effective data sharing. This more granular definition of potential deficits is informing GA4GH’s efforts to promote system interoperability, collect and effectively share clinical outcome data and harmonize legal/ethics policies, thus maximizing the value of clinico-genomic data for improving patient care.
Efficacy and safety of denosumab from a phase III, randomized, active-controlled study compared with zoledronic acid in patients of Asian ancestry with bone metastases from solid tumors.
Authors: Zefei Jiang, Zhimin Shao, Qingyuan Zhang, Yang Yao, Jianxing He, Wangjun Liao, Shukui Qin, Ying Cheng, Yanmei Xu, Jie Dong, Li Zhang
Journal: Journal of Clinical Oncology (2016)

10116 Background: This phase III double-blind study was conducted to provide bridging data to the available efficacy and safety data of denosumab (DmAb) from global skeletal-related events (SRE)-prevention studies, by comparing DmAb with zoledronic acid (ZA). Methods: Patients aged ≥18 years who had a confirmed solid tumor, evidence of ≥1 bone metastasis and ECOG score 0-2 were enrolled. Patients were randomized (2:1) to receive either DmAb 120 mg subcutaneously every 4 weeks (Q4W) or ZA 4 mg intravenously Q4W for 49 weeks (wks) and are being followed up to Wk 73. The primary endpoint was percent change in urinary amino-terminal cross-linking telopeptide of type I collagen, corrected for urine creatinine (uNTx/uCr) from baseline (BL) to 13 wks. Other endpoints were percent change in bone-specific alkaline phosphatase (S-BALP) from BL to 13 wks and time to first on-study SRE. Safety and tolerability were assessed including collecting all adverse events (AEs) and performing vital signs measurement and a standard panel of laboratory tests. Results: A total of 485 (DmAb=326, ZA=159) pts were randomized; 90% of pts had either completed the study or withdrawn by planned data cut-off (29 February 2016). Mean (SD) age of pts was 53.9 (11.38) years; 67% pts were women, 93% Chinese, 50% had breast cancer and 27% had non-small cell lung cancer. The mean change in uNTx/uCr from BL to Wk 13 was -81.9% for DmAb and -75.2% for ZA (ANCOVA; p<0.0001). The median change in S-BALP from BL to Wk 13 was -36.8% (DmAb) and -30.3% (ZA) (p=0.027). Rate of developing any on-study SRE within the first year after initializing treatment was lower in pts receiving DmAb vs ZA (4.9% vs 6.3%) without statistical significance. Incidence of AEs was similar in DmAb and ZA groups (89% vs 91%), with most common AEs being anemia (25% vs 24%), white blood cell count decreased (21% vs 24%), and pyrexia (13% vs 21%); overall incidence of serious AEs: 14% vs 9%. One serious AE (muscular weakness) was reported as related to study treatment. Conclusions: DmAb was found to be superior than ZA in reducinguNTx/uCr in overall and Chinese pts. No new safety concerns were identified with DmAb. Clinical trial information: NCT01920568.
Metagenomic shotgun sequencing to identify specific human gut microbes associated with immune checkpoint therapy efficacy in melanoma patients.
Authors: Arthur E. Frankel, Thomas W. Froehlich, Jiwoong Kim, Laura A. Coughlin, Yang Xie, Eugene P. Frenkel, Andrew Y. Koh
Journal: Journal of Clinical Oncology (2017)

9516 Background: Immune checkpoint inhibitor therapy, ICT, achieves durable remissions in 30-50% of patients (pts) with metastatic melanoma (Larkin et al. NEJM 2015). It is still unclear what host factors modulate response to ICT. Preclinical mouse studies with B16 melanoma demonstrated that ICT response was dependent on the presence of specific commensal gut bacteria (Vetizou et al. Science 2015; Sivan et al. Science2015). These specific gut bacteria induced the maturation of dendritic cells (DCs) and T-cells needed for effective ICT. We sought to determine whether specific gut microbiota are associated with improved response to ICT in melanoma patients. Methods: 37 melanoma pts treated with ICT (nivolumab plus ipilimumab or pembrolizumab alone) at UTSW Medical Center were enrolled. Fecal samples were collected prior to ICT. Genomic DNA was extracted, and metagenomic shotgun sequencing (MSS) performed on an Illumina HiSeq 2500 PE-100. Taxonomic (MetaPhlAn) and functional (HUMAnN) analysis was performed on MSS data. Disease status was assessed by CT scans and physical exams every two months. Results: Among the 23 evaluable pts, 8 were classified as RECIST responders, 5 with stable disease and 10 with progression. RECIST responder microbiomes were significantly enriched with Methanobrevibacter smithii(p = 0.03; LDA coupled with effect size measurements, LEfSe; Kruskal-Wallis test) , Bacteroides thetaiotamicron(p = 0.03) , Lactobacillus plantarum(p = 0.04), and Eubacterium limosum(p = 0.01) compared to those with progressive disease. Conclusions: MSS identified 4 specific gut microbiota associated with improved response to ICT therapy in melanoma pts. All of these bacteria have been shown to modulate host immune response (Bang PLoS One 2014; Hickey Cell Host Microbe 2016; Rigaux Allergy 2009; Kaunachi World J Gastroentertol 2006). To gain mechanistic insight and confirm causality, shotgun metabolomics on the same fecal specimens used for MSS, in vitroimmune cell assays using the gut microbiota identified, and preclinical modeling in a mouse melanoma model with ICT are underway. These studies may lay the foundation for optimizing the host response to ICT.
Oncometabolite succinate to promote angiogenesis by upregulating VEGF expression through GPR91-mediated STAT3 and ERK activation.
Authors: Xianmin Mu, Ting Zhao, Che Xu, Wei Shi, Biao Geng, Jiajia Shen, Chen Zhang, Jinshun Pan, Jing Yang, Shi Hu, Yuanfang Lv, Hao Wen, Qiang You
Journal: Journal of Clinical Oncology (2017)

e23000 Background: Altered cellular metabolism is now generally acknowledged as a hallmark of cancer cells, the resultant abnormal oncometabolites cause both metabolic and nonmetabolic dysregulation and potential transformation to malignancy. A subset of cancers has been found to be associated with mutations in succinate dehydrogenase genes which result in the accumulation of succinate. However, the function of succinate in tumorigenesis remains unclear. In the present study, we aim to investigate the role of oncometabolite succinate in tumor angiogenesis. Methods: Succinate levels were measured in gastric cancer and paracancerous tissues as well as cell culture supernatants from normal cells and gastric cancer cells. Chemotactic motility, capillary structure formation and proliferation of primary human umbilical vascular endothelial cells (pHUVECs) were determined in the presence of succinate in vitro. Moreover, the vessel formation in zebrafish embryo was also used to examine the effect of succinate on angiogenesis. The activation of STAT3 and ERK signaling by succinate was checked by Western Blot. Results: Our data demonstrated the accumulation of markedly elevated succinate in gastric cancer tissues compared with that in paracancerous tissues. Moreover, succinate was able to increase the chemotactic motility, tube-like structure formation and proliferation of pHUVECs in vitro, as well as promote the blood vessel formation in transgenic zebrafish. Our mechanistic studies reveal that succinate upregulates vascular endothelial growth factor (VEGF) expression by activation of signal transducer and activator of transcription 3 (STAT3) and extracellular regulated kinase (ERK)1/2 via its receptor GPR91 in a HIF-1α independent mechanism. Conclusions: These data indicate an important role of the succinate-GPR91 axis in tumor angiogenesis, which may enable development of a novel therapeutic strategy that targets cancer metabolism.
Financial burden in adult cancer survivors: Care affordability and accessibility.
Authors: Ryan David Nipp, Amy Shui, Anne C. Kirchhoff, Giselle Katiria Perez, Beverly Moy, Elyse R. Park, Karen Kuhlthau
Journal: Journal of Clinical Oncology (2016)

6535 Background: Cancer survivors represent a population that requires affordable and accessible long-term medical care, yet studies examining their financial burden and health care experience are lacking. We compared difficulties affording and accessing care in a national sample of adult cancer survivors (ACS) and matched control subjects (MCS). Methods: Using data from the 2010-2014 National Health Interview Survey, we examined self-reported problems with affordability (e.g. medical bills, prescriptions, follow-up care) and accessibility (e.g. delayed or forgone care) for ACS and a sample of MCS (matched 1:3 on age, sex, race, ethnicity). We compared difficulties affording and accessing care between groups using logistic regression, adjusted for age, region, sex, race, ethnicity, marital status, paid sick leave at current job, insurance, survey year, income, employment and education. Results: Among 6,169 ACS and 18,502 MCS, ACS were more likely to be insured (90% vs 87%, p<0.001). However, ACS were more likely to report problems affording medical bills (23% vs 18%), prescriptions (13% vs 9%) and follow-up care (7% vs 5%) (all p<0.001). For accessibility, ACS reported more problems with delayed (15% vs 13%) and foregone (11% vs 9%) care (all p<0.001). In multivariable models, we found decreased odds of affordability and accessibility issues over time, yet ACS remained more likely than MCS to report problems with these issues. Conclusions: Despite higher rates of insurance coverage, which may reflect insurance expansion in recent years, ACS are more likely to report difficulties affording and accessing care compared to MCS. Our results suggest ACS struggle to afford and access necessary medical care, underscoring the need to look beyond insurance coverage and examine the financial burden and barriers to care these patients experience. Comparing ACS vs MCS Odds Ratio 95% CI* Affordability issues Unable to afford prescriptions 1.65 1.38-1.98 Unable to afford at least one of six items# 1.42 1.24-1.62 Accessibility issues Delayed care 1.32 1.14-1.53 Forgone care 1.41 1.18-1.70 *=all P-values <0.001 #=cannot afford at least one of the following: medicines, follow-up care, specialist care, mental health care, dental care, eyeglasses.
Post-recurrence survival in triple negative breast cancer.
Authors: Zaida Morante, Gabriel Antonio De la Cruz Ku, Daniel Enriquez, Antonella Saavedra, Maria Luján, Renato Luque, Eduardo Eyzaguirre, David Guardamino, Bryan Valcárcel, Jhajaira M Araujo, Joseph Pinto, Hugo Alejandro Fuentes, Silvia P. Neciosup, Henry Leonidas Gomez
Journal: Journal of Clinical Oncology (2018)

e13120 Background: Prediction of clinical behavior of triple-negative breast cancer (TNBC) is difficult to achieve. Furthermore, it is characterized by a high rate of recurrences and worse outcomes, especially in patients who develop distant metastasis. Given the prognosis of this population, we analyze the pattern of metastasis and outcomes according to the site of metastasis. Methods: In this study, we included 534 triple negative breast cancer patients who developed recurrence. Metastasis was divided into bone, visceral and multiple sites (bone and/or visceral reported at the same date). Relapse-free survival (RFS) and overall survival (OS) rates were calculated by Kaplan-Meier method, while differences between metastasis were assessed by Log Rank test. Results: The median age was 48 years (range: 21-91). A total of 120 (27.4%) patients had obesity, and 49.4% were premenopausal. The majority of patients correspond to stage (S) III (74%) and 9 had bilateral breast cancer. Adjuvant chemotherapy (ACT) was administered in 53.2%, and 64.8% received radiotherapy (RT). Locoregional recurrence was reported in 268 (50.2%) cases and 420 (78.7%) presented distant metastasis. When we analyze the first place of metastasis, lung was the most frequent 130 (31%), followed by brain 72 (17.1%), bone 38 (9%), liver 26 (6.2%), leptomeningeal 6 (1.4%) and others 30 (7.1%), while multiple metastases were found in 114 (27.1%) patients. Indeed, we had 61% metastasis to a solid organ. In total, we reported 183, 146, 113 and 93 patients with lung, brain, bone and liver metastasis, respectively. At 3 and 5 years, RFS was 20% and 8%, respectively, and 44% and 26% for OS. However, on disease-free metastasis (DFM), no differences were shown between lung, brain, and liver (p = 0.20), as the same as between bone, organ and multiple metastases (p = 0.33). Otherwise, OS was lower in multiple sites of metastasis ( < 0.001). Results are on Table 1. Conclusions: Lung and brain are the most frequent sites of metastases in TNBC. Patients with bone lesions have better survival rates, while multiple metastases were related to shorter post-recurrence survival. Time/sites Bone Solid Multiple sites Total p value OS (%) 3-months 71 66 55 64 < 0.001 6-months 61 47 33 45 12-months 37 29 19 28
Molecular classification of cancers with an uncertain diagnosis as candidates for immunotherapy.
Authors: Afsaneh Barzi, Harris S Soifer, Mason Israel, Catherine A. Schnabel
Journal: Journal of Clinical Oncology (2017)

e23183 Background: FDA approvals of immunotherapy checkpoint inhibitors (CPIs) are based on organ site and thus cancers of unknown primary or with uncertain tumor type diagnoses have limited access to these revolutionary treatments. The 92-gene assay (CancerTYPE ID) is a validated gene expression classifier of 50 tumor type/subtypes for metastatic patients, six of which (lung adenocarcinoma, lung squamous cell, head &amp; neck squamous cell, urinary bladder, kidney, and melanoma) have FDA-approved indications for CPIs. Study objectives were to analyze the distribution of the 6 tumor types with available CPIs in a large dataset of clinical cases and report patient and disease characteristics for this subset. Methods: A de-identified database was created under an IRB approved protocol that contains pathology and molecular information from consecutive cases submitted for clinical testing with the 92-gene assay. The distribution of molecular diagnoses was analyzed based on biopsy site, age, and gender. Chi-squared tests were used to compare between subgroups. Results: A total of 24,484 patients were available for analysis. Median age was 66y and 46% were male. The assay rendered a molecular diagnosis with an approved CPI in 27% (N = 6536) of cases. The most common biopsy sites were lymph node (23%), lung (15%) and liver (12%). Lung adenocarcinoma (31%) was the most common molecular diagnoses, followed by urinary bladder (20%), and head &amp; neck squamous (16%). The proportion of melanoma molecular diagnoses decreased with age (11% in &lt; 40y vs 4-6% across other age groups, p &lt; 0.001), whereas the proportion of urinary bladder molecular diagnoses increased from 15% in &lt; 40y to 23% in patients &gt; 65y (p &lt; 0.001). Women had a higher proportion of lung adenocarcinoma molecular diagnoses (36% vs 28% in men; p &lt; 0.001), while kidney molecular diagnoses were more common in men (14% vs 8% in women; p &lt; 0.001). Conclusions: These findings highlight the utility of molecular classification to identify metastatic cancers with unknown or uncertain tumor type diagnoses that are eligible for CPI. In addition, there was a significant difference in the distribution of 92-gene molecular diagnoses by age and gender among cancers susceptible to CPI.
Initial results of two phase I trials delivering mbIL-21 ex vivo expanded haploidentical NK cells after fludarabine/cytarabine for patients with relapsed/refractory myeloid leukemias.
Authors: Stefan O. Ciurea, Lucia Silla, Kai Cao, Katayoun Rezvani, Elizabeth J. Shpall, Doris Soebbing, Richard E. Champlin, Dean Anthony Lee
Journal: Journal of Clinical Oncology (2018)

7008 Background: NK cells play an important role in the control of malignancies but are ablated by high-dose chemotherapy. Thus, rapid recovery of NK cell number and function correlates with improved disease control. Haploidentical NK cells delivered after lymphodepleting chemotherapy can induce remission in patients with relapsed and/or refractory AML. Methods: We hypothesized that anti-leukemic activity could be increased without toxicity by adoptive transfer of expanded NK cells after reinduction with fludarabine, cytarabine, and G-CSF (FLAG), or mini-FLAG (4 days) for patients with low performance score. Haploidentical NK cell donors were selected by KIR ligand and/or KIR gene content. NK cells were expanded on feeder cells and cryopreserved in multiple aliquots. Patients received 3 NK-cell infusions per week for two weeks, beginning 3-10 days after chemotherapy. Response was assessed at day 30 after treatment. Parallel Phase I studies were opened using the same regimen and NK cell manufacturing platform at two centers (US and Brazil). Results: 13 patients have been treated to date, age 12-70 years (median 61y), with AML/MDS/CMML (11/1/1), having received 2-8 prior lines of therapy (median 4). 12 patients received 10^6 NK cells/kg/infusion, one received 5x10^6. One patient had no response and received other investigational therapy prior to formal disease assessment. One patient with pre-existing liver toxicity developed worsening hepatic dysfunction and died prior to day 30. Two patients achieved marrow remission but had residual CNS disease. The remaining 9 patients (69%) achieved < 5% blasts by morphology, with/without peripheral count recovery, for overall marrow remission rate of 85%. One patient progressively improved in MRD status by PCR over a 4-month period after treatment, suggesting ongoing immunologic anti-leukemic activity. Immune correlative studies will be presented at the meeting. Conclusions: Multiple infusions of cryopreserved expanded NK cells can be safely delivered after high-dose chemotherapy, with encouraging responses on this first dose level. Clinical trial information: NCT01787474.