tbuckley/cabot-search huggingface dataset:
Detection, frequency and actionability of recurrent copy number gains detected by non-invasive liquid biopsy of 3,942 lung and breast cancer samples.
Authors: Diana Abdueva, Darya Chudova, Richard Burnham Lanman, Kimberly C. Banks, Rebecca J Nagy, Stefanie Mortimer, AmirAli Talasaz, Helmy Eltoukhy, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2016)

11541 Background: Circulating tumor DNA (ctDNA) testing must include detection of single nucleotide variants (SNVs), indels, fusions, and copy number amplifications (CNAs) to identify all NCCN-recommended genomic targets. We examined CNA landscape in a large clinical cohort of breast and lung cancer ctDNA samples analyzed with Guardant360 (G360) test, classifying recurrent gene-level copy number changes across distinct oncogenic pathways and disease subtypes. Methods: We developed an improved CNA detection pipeline and evaluated its analytical and clinical performance on a set of cell-line spike-ins with known amplifications and 72 clinical plasma samples from patients with stage IV breast cancer with known ERBB2 amplification/overexpression. We then examined 1,935 lung adenocarcinoma and 2,007 breast carcinoma clinical cases: CNA patterns in samples with and without known driver mutations were compared using Fisher’s exact test to identify candidate driver amplification events. Results: Analytical sensitivity, specificity, and precision of the new CNA pipeline improved significantly - average coefficient of variation (CV) of copy number estimates across 18 genes on the panel was 1.2% for spike-in replicates, all spike-ins and copy number neutral samples were detected correctly, and signal-to-noise ratio increased 4.3-fold. We observed high concordance between tissue-verified amplification events in breast carcinoma subset when the mutant allele fraction of the driver mutation exceeded 0.5%. In the lung adenocarcinoma cohort, CNA-driver mutations were identified in ~7% of 1,935 samples, excluding cases known functional driver events. Focal amplification events in MET, CCND1, and ERBB2 were enriched in samples lacking other driver oncogene mutations (p-value < 0.001). Conclusions: Copy number variation is an important mechanism of oncogene activation in lung and breast cancers. Highly accurate quantification of copy number state in ctDNA allows for clinically meaningful identification of amplified therapeutic targets with otherwise wildtype DNA sequence.
Primary peritoneal hepatoid adenocarcinoma: Response to platin based chemotherapy.
Authors: Basak Oyan, Ozlem Sonmez, Onder Orhan Eren, Ferda Ozkan, Ali Ozgen
Journal: Journal of Clinical Oncology (2016)

e15667 Background: Hepatoid adenocarcinoma (HAC) is a rare alpha-fetoprotein (AFP) producing carcinoma arising in extrahepatic organs, morphologically resembling hepatocellular carcinoma. HAC arises mostly in gastrointestinal tract. HAC originating from peritoneum is extremely rare and there is no standard treatment. Methods: We report a 54-year-old man with HAC originating from peritoneal cavity who presented with massive ascites. CT scan of thorax and abdomen revealed massive ascites, multiple mass lesions of peritoneum and omentum, with the largest diameter of 71x51 mm. There was no obvious sign of tumor mass in other organs and liver. Upper gastrointestinal endoscopy and colonoscopy showed no abnormal findings. Serum AFP level was 161.230 ng/ml. Biopsy from the peritoneal tumor mass was done. The tumor was morphologically similar to hepatocellular carcinoma. Staining with AFP proved positive; staining with cytokeratin (CK)7, CK20, CK19, Beta-HCG, placental alkaline phosphatase (PLAP), calretinin, mesothelin, CEA were negative. The radiological and histopathological findings were consistent with HAP originating from peritoneal cavity. Results: Therapy with cisplatin and etoposide was initiated. After the fourth cycle, ascites was totally regressed, and a partial response achieved. Patient received 8 cycles of cisplatin and etoposide and serum AFP level reduced to 21.736 ng/ml. After the eight cycle, maintenance therapy with oral etoposide (50 mg/day, d1-14, q21 d) was started. The patient is still in partial remission at 7thmonth of follow-up. Conclusions: This is the seventh documented case of primary peritoneal HAC in the literature. Due to rarity and heterogeneity of HAC, no standard treatment exists. They are usually treated similar to the adenocarcinomas of the organ they arise. Cisplatin and etoposide can be a good treatment choice of primary peritoneal HAC.
Population pharmacokinetics (PopPK) and exposure-response (ER) analyses to confirm the global alectinib (ALC) 600mg BID dose in the Chinese treatment-naïve population.
Authors: Joy Hsu, Felix Jaminion, Alice Shaw, Caicun Zhou, Tony Mok, Tomohide Tamura, Tomohiro Tanaka, Emmanuel Mitry, Elena Guerini, Eveline Nüesch, Bogdana Balas, Ali Hassan Zeaiter, Peter N. Morcos, Nicolas Frey
Journal: Journal of Clinical Oncology (2018)

e21133 Background: Phase III studies conducted in Japanese (J-ALEX; JapicCTI-132316) and global (ALEX; NCT02075840) patients with treatment-naïve ALK+ NSCLC demonstrated superiority of ALC 300 and 600mg BID, respectively, versus crizotinib 250mg BID. PopPK and ER analyses established the appropriateness of ALC 600mg BID dose in the global population to achieve exposures above an optimal exposure threshold (Hsu et al. ASCPT 2018; abstract 824). Analyses were updated with emerging PK data from the ongoing phase III study ALESIA (NCT02838420) in Chinese treatment-naïve ALK+ NSCLC patients. Methods: A previously developed PopPK model (Hsu et al, ASCO 2016; abstract e20598) was applied to the collected PK data from ALESIA (n = 95). Using methods previously described, the model was then used to conduct PK simulations in Chinese patients for ALC 300mg and 600mg BID doses to determine the proportion of patients falling above and below the previously identified optimal PK exposure for PFS from Cox proportional hazards analysis. Results: The PopPK models adequately describe the PK of ALC in Chinese treatment-naïve ALK+ NSCLC patients. Body weight remained the only significant covariate for ALC PK with lower exposure at increasing body weight. No effect of race or ethnicity were confirmed in popPK analyses. PK simulations indicate 51% and 4% of alectinib treated Chinese patients would fall below the identified optimal exposure threshold for 300 and 600mg BID, respectively. ALC 600mg BID maximizes the expected PFS benefit while lower ALC doses could result in reduced efficacy. No significant exposure-safety relationships were seen from previous ALC PopPK and ER analyses. Conclusions: The Global ALC 600mg BID is the recommended dose in the Chinese ALK TKI treatment-naive population. Clinical trial information: JapicCTI-132316; NCT02075840.
Evolution of neurocognitive function in long-term survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only.
Authors: Wei Liu, Yin Ting Cheung, Heather M. Conklin, Lisa M Jacola, Ching-Hon Pui, Deokumar Srivastava, Vikki G Nolan, Hongmei Zhang, James G Gurney, Leslie L. Robison, Melissa M. Hudson, Kevin R. Krull
Journal: Journal of Clinical Oncology (2016)

10505 Background: Long-term survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for neurocognitive problems, whether these problems evolve over time is not well delineated. Methods: At the end of a chemotherapy only protocol, 158 survivors (48% male; mean [SD] age 9.2 [4.5] yrs) completed tests of sustained attention, and parents rated survivor behavior on standard scales. At follow-up, these survivors (age 13.7 [4.6] yrs; 7.6 [1.7] yrs post-diagnosis) completed neurocognitive testing, including sustained attention. General linear modeling (GLM) was used to test associations between neurocognitive outcomes and high dose IV methotrexate (MTX) plasma concentration (area under curve [AUC]) during consolidation and number of triple intrathecal therapies (TIT’s: cytarabine, MTX, and hydrocortisone). Mediation analysis was conducted to assess treatment effect on long-term outcomes, mediated by end of therapy function. Results: Survivors performed worse than national norms (10% expected) on sustained attention (39% observed) and rated learning problems (20%) at end of therapy (p’s<0.0001). Parent-rated learning problems were associated with higher MTX AUC (p=0.009) and higher TIT’s (p=0.002). At long-term follow-up, higher than expected problems were noted in flexibility (24%), fluency (21%), attention (15%), and processing speed (15%), all of which were associated with MTX AUC and TIT’s. Sustained attention at end of therapy was associated with lower processing speed (p=0.01) and attention (p=0.0004) at follow-up, but end of therapy measures were not associated with flexibility or fluency (indices of executive function). End of therapy learning problems was a weak mediator (p=0.05) of long-term processing speed, but direct effect of MTX AUC and TIT was predictive of executive function at long-term follow-up. Conclusions: The impact of chemotherapy on sustained attention and behavioral functioning at end of therapy predicts long-term attention and processing speed outcomes. In contrast, only chemotherapy, and not end of therapy function, predicts survivors who experience poor executive function at long-term follow-up.
Efficacy, safety, and immune activation with pegylated human IL-10 (AM0010) plus FOLFOX in metastatic pancreatic adenocarcinoma (PDAC).
Authors: J. Randolph Hecht, Gerald Steven Falchook, Manish R. Patel, Raid Aljumaily, Jeffrey R. Infante, Aung Naing, Deborah Jean Lee Wong, Karen A. Autio, Navneet Ratti, Zev A. Wainberg, Johanna C. Bendell, Shubham Pant, Gail Linda Brown, Peter Van Vlasselaer, Martin Oft, Kyriakos P. Papadopoulos
Journal: Journal of Clinical Oncology (2017)

4111 Background: Oxaliplatin or nal-irinotecan plus 5-FU are used as 2nd-line PDAC therapy (mOS 5-6 months (m)). PDAC also has been largely refractory to immune therapies which may depend on the expansion of activated, intratumoral, tumor specific cytotoxic CD8+ T cells that are low in most PDACs. AM0010 stimulates survival, expansion and cytotoxicity of intratumoral CD8+ T cells. Immune activation, durable stable disease and a 1yr survival of 22.5% was seen in salvage PDAC patients (pts) receiving AM0010 alone. Platins or 5-FU may activate immune responses to cancer and AM0010 has shown synergistic anti-tumor results with FOLFOX in preclinical models. In this phase 1b clinical study, the safety and efficacy of AM0010 +FOLFOX was studied in PDAC pts. Methods: PDAC pts progressing on a median of 1 prior therapy (range 1-3) were treated with AM0010 (5ug/kg SQ, qd) + FOLFOX (n = 21), an additional 4 pts with prior oxaliplatin and 5-FU were included in the safety population (n = 25). Tumor responses were assessed using irRC. Serum cytokines, activation of blood derived T cells and peripheral T cell clonality were analyzed. Pretreatment archival tissue samples were evaluated by IHC for tumor infiltration by CD8+ T cells. Results: On AM0010 + FOLFOX, G3/4 TrAEs included thrombocytopenia (52%), anemia (36%) and neutropenia (36%). A modified AM0010 dose schedule (5 days on 2 days off) avoided G3/4 thrombocytopenia. As of 01/31/2017, 2 patients remained on treatment for &gt; 1 year. 19 pts had objective tumor response assessment; 2 had irCR, 1 irPR, 11 irSD. ORR is 15.8%, DCR is 73.7%. With median follow-up of 11.0 m (range 5.8-16.3), mPFS was 3.5 m and mOS 10.0 m. Pts with more intra-tumoral CD8+ T cells had longer OS. AM0010 + FOLFOX increased serum Th1 cytokines and reduced mediators of chronic inflammation and TGFb. AM0010 induced de-novo oligoclonal expansion of T cell clones in patients with prolonged survival. Conclusions: AM0010 plus FOLFOX is well tolerated in patients with PDAC. The observed immune activation including clonal T cell expansion and prolonged objective tumor responses are encouraging in this advanced PDAC population. This regimen is currently being studied in a phase 3 trial. Clinical trial information: NCT02009449.
Abstract 14733: Reducing Heart Failure Readmissions Using a Multidisciplinary Approach
Authors: Alex Moseley, Micheal J Accavitti, Amar Bhakta, Monique Colbert, Barbara Hinch, Burhan Mohamedali
Journal: Circulation (2017)

Introduction: In 2015, Medicare and Medicaid beneficiaries readmitted within 30 days of hospital discharge cost $17 billion, with heart failure as the most common diagnosis. In an effort to improve...
NKG2D chimeric antigen receptor-T cells to target GBM.
Authors: Hong-jiu Dai, Dong Yang, Bin Sun, Lan Shi, Pei-xian Zhang, Xu-dong Zhao
Journal: Journal of Clinical Oncology (2018)

2034 Background: GBM is the most common and the most lethal brain tumors with the 5-year survival rate of ~4% for patients over age 55. Recently people are exploring the potential of chimeric antigen receptor T (CAR-T) cell therapy in glioblastoma, yet the clinical outcome is limited. It’s reported that NKG2DLs are wildly expressed in glioma stem-like cells, which supports NKG2D system might play an important role in GBM therapy. Here we used NKG2D as antigen binding domain to construct a second generation of CAR (KD-025) for GBM treatment. Methods: U251 cell line as well as GBM cancer patient samples were evaluated for NKG2DLs expression. The KD-025 CAR T cells showed antigen-specific stimulation by cytokine secretion and target cell lysis. U251 were used to establish in vivo subcutaneous and xenograft models in NSG mice. Mice received a single treatment of 10 million KD-025 CAR-T cells intravenously. The main organs of mice were examined by hematoxylin and eosin (HE) staining after different doses of KD-025 administration. Results: NKG2DLs were detected on U251 cells and most of screened glioma patient samples. The KD-025 expression was > 50% on the surface of T cells confirmed by flow cytometry. Co-incubation of KD-025 CAR with U251 cell specifically upregulates TNFa, IFN-γ, IL-10 and IL-2 cytokines and strongly lysis tumor cells even at low E:T ratio (50-60% at 1:1, 70% at 10:1). Strikingly, KD-025 CAR demonstrate very potent anti-tumor activity in vivo. All the tumor cells are gone 14 days after single treatment of KD-025 CAR T cells. Regarding to T cell persistence, the CAR-T cells are barely detectable 24 days after injection, which is comparable with CD19 CAR in our experiments as well as published data. No obvious pathological changes were found in the tested organs. Conclusions: Our work with the KD-025 CAR contributes to the growing body of research committed to discovering a novel therapy for GBM. NKG2D ligands are highly expressed on human GBM samples. NKG2D based CAR T cells KD-025 potently respond to GBM and eliminate tumor in a xenograft mouse model with no obvious safety issue. The results support future clinical trial of KD-025 CAR in patients with GBM, where the need for effective treatment is great.
Interim results from a phase II study of CC-486 in previously treated patients (pts) with locally advanced/metastatic nasopharyngeal cancer (NPC).
Authors: Ricard Mesia, Paolo Bossi, Aaron Richard Hansen, Ching-Yun Hsieh, Lisa F. Licitra, Eng-Huat Tan, Damir Begic, Li Li, Abderrahim Fandi, Lillian L. Siu, Robert I. Haddad
Journal: Journal of Clinical Oncology (2016)

6029 Background: For pts with advanced NPC, no approved chemotherapy is available in the second-line setting or beyond, and treatment options are limited. Hypermethylation contributes to the initiation and progression of NPC; thus, epigenetic modifying agents may be a useful therapeutic strategy. Single-agent CC-486, an oral formulation of azacitidine, has shown promising results in pts with relapsed/refractory solid tumors, including NPC. Here we report interim results from the phase II study of CC-486 in previously treated pts with recurrent locally advanced/metastatic NPC. Methods: Pts with locally advanced/metastatic, progressive NPC and 1 to 2 previous treatments (including a platinum-containing regimen) received oral CC-486 300 mg/day (d) d 1-14 of a 21-d cycle. In addition, the first 6 Asian-Pacific (AP) pts received CC-486 200 mg/d d 1-14 of cycle 1; if well tolerated, subsequent AP pts received 300 mg/d as above. Pts were treated until disease progression or unacceptable toxicity. The primary endpoints were independently assessed overall response rate and progression-free survival. Secondary endpoints included overall survival, disease control rate, safety, and pharmacokinetic analyses in AP pts. Results: As of Nov 12, 2015, 36 pts were enrolled and received CC-486 (6 pts at 200 mg and 30 pts at 300 mg). The median age was 54 y, and most pts were men (78%) with an ECOG PS of 1 (58%); 36% were Asian. Of 10 pts evaluable for efficacy, 3 (30%) had an unconfirmed partial response, and 2 (20%) had stable disease by independent review ( ≥ 16 weeks). In 34 pts evaluable for safety, grade 3/4 adverse events (AEs) were hematologic and included mainly neutropenia (3 pts at 200 and 4 pts at 300 mg). Grade 2 nonhematologic AEs included vomiting (1 pt at 200 mg and 8 pts at 300 mg) and nausea (3 pts each at 200 and 300 mg). Dose reductions due to AEs occurred in 3 and 5 pts at the 200 and 300 mg dose levels, respectively. 26 pts remain on treatment. Conclusions: Single-agent CC-486 was well tolerated in pts with recurrent locally advanced/metastatic NPC; grade 3/4 AEs were mainly hematologic. Initial efficacy results are encouraging. More follow-up data will be presented at the meeting. Clinical trial information: NCT02269943.
Chemotherapy delivery for resected colorectal cancer liver metastases: Management and outcomes in routine clinical practice.
Authors: Anuradha Krishnamurthy, Janarthanan Kankesan, Xuejiao Wei, Sulaiman Nanji, James Joseph Biagi, Christopher M. Booth
Journal: Journal of Clinical Oncology (2016)

e18089 Background: International guidelines recommend peri-operative chemotherapy for patients with resectable colorectal cancer liver metastases (CRCLM). Chemotherapy delivery in routine practice is not well described. Methods: All cases of CRC who underwent resection of LM in 2002-2009 were identified using the population-based Ontario Cancer Registry. Electronic treatment records identified chemotherapy delivered within 16 weeks before or after hepatectomy. All pathology reports were reviewed to describe extent of LM. Modified Poisson regression was used to evaluate factors associated with chemotherapy delivery. Cox proportional hazards model and propensity score analysis were used to explore the association between post-operative chemotherapy and cancer-specific (CSS) and overall (OS) survival. Results: We identified 1310 patients. Sixty-two percent of cases (815/1310) received peri-operative chemotherapy; 25% (200/815) pre-operative, 45% (366/815) post-operative, and 31% (249/815) pre- and post-operative. Utilization of chemotherapy increased over time from 51% in 2002 (57/112) to 73% in 2009 (157/216, p < 0.001). Fifty-four percent of patients received FOLFOX, 41% FOLFIRI, and 10% 5-FU monotherapy. Factors that were independently associated with greater utilization of post-operative chemotherapy included younger age (p < 0.001), female sex (p = 0.050), shorter disease-free interval (p = 0.006), and no prior adjuvant chemotherapy (p < 0.001). Utilization of chemotherapy varied substantially across geographic regions (from 24% to 71%, p = 0.001). Post-operative chemotherapy was associated with improved CSS (HR 0.58, 95%CI 0.44-0.76) and OS (HR 0.49, 95%CI 0.38-0.61); results were consistent in propensity score analysis. Conclusions: Utilization of chemotherapy for resected CRCLM in routine practice has evolved with emerging evidence. Post-operative chemotherapy is associated with improved survival in the general population.
Evaluation of pegaspargase (PEG-ASP) adverse events among adolescents and young adults (AYAs) and younger patients with lymphoid malignancies (LM) at the Children’s Hospital of Eastern Ontario (CHEO).
Authors: Nicole Mathies, Isabelle Laforest, Kenneth Tang, Genevieve Goulet, Lesleigh S. Abbott
Journal: Journal of Clinical Oncology (2018)

10531 Background: PEG-ASP is a common component of the chemotherapy regime for LM, but with significant side effects. The aim of this study was to determine the prevalence of major adverse events: allergic reactions, pancreatitis and thrombosis/hemorrhage among pediatric patients treated with PEG-ASP, and whether there is an association between age and a specific adverse event. Methods: Patients aged 0-18 years diagnosed with LM from January 1, 2007 to June 30, 2017 at CHEO, a tertiary care pediatric hospital, were eligible for this retrospective cohort study. A stratified, discrete-time, multivariable Cox regression model was fitted to elucidate the relationship between age at diagnosis and risk to adverse event. Model covariates included sex, body mass index and route of PEG-ASP administration (intravenous versus intramuscular). Results: Among 186 eligible patients, the median duration of follow-up was 2.0 years (IQR: 1.0-3.0). There were 34 allergic reactions, 8 cases of pancreatitis, and 32 cases of thrombosis/hemorrhage were observed. Estimates of 4-year cumulative incidence were 18.9% [95%CI:13.9, 25.4], 4.5% [95%CI:2.3, 8.7], and 19.4% [95%CI: 13.8, 26.9] for the three adverse events, respectively. Cox regression revealed a significant association between age at diagnosis and risk of allergic reaction (adjusted Hazards ratio (HR) = 2.18 [95%CI:1.45, 3.28], p < .001 for a 5-year increase in age) and risk of pancreatitis (adjusted HR = 1.93 [95%CI:1.02, 3.63], p = 0.04 for a 5-year increase in age), but not the risk of thrombosis/hemorrhage (adjusted HR = 1.25 [95%CI:0.84, 1.85], p = 0.28, for a 5-year increase in age). The Cox model concordance index was 0.58. Conclusions: Evidence of an association between age at diagnosis and 2 of 3 adverse events (allergic reaction and pancreatitis) was revealed among pediatrics patients treated with PEG-ASP. In light of the study results, cautious observation is further warranted when administering PEG-ASP particularly to AYAs with lymphoid malignancies.
Reply to Runqiang Yuan's Letter to the Editor re: James T. Kearns, Anna V. Faino, Lisa F. Newcomb, et al. Role of Surveillance Biopsy with No Cancer as a Prognostic Marker for Reclassification: Results from the Canary Prostate Active Surveillance Study. Eur Urol 2018;73:706–12
Authors: James T. Kearns, Lisa F. Newcomb, Daniel W. Lin
Journal: European Urology (2018)