tbuckley/cabot-search huggingface dataset:
Germline <i>EGFR</i> mutation and cancer predisposition in adolescent and young adult (AYA) females with adrenocortical carcinoma.
Authors: Sara Akhavanfard, Lamis Yehia, Roshan Padmanabhan, Todd Romigh, Ying Ni, Charis Eng
Journal: Journal of Clinical Oncology (2019)

e13014 Background: Adrenocortical Carcinoma (ACC) is a rare endocrine tumor with poor overall prognosis and slight overrepresentation in females. In children, ACC is associated with inherited cancers, predominantly Li-Fraumeni syndrome, with 50-80% of childhood ACC harboring TP53 germline mutations. ACC in AYA are rarely due to germline TP53 mutations; IGF2, PRKAR1A and MEN1 are other less common germline mutated genes in this age group. Methods: We analyzed exome sequencing data from 21 children (C, &lt; 15y), 32 AYA (15-39y), and 60 adult patients ( &gt; 39y) with ACC, originating from the Cleveland Clinic, and TCGA and St. Jude’s datasets. We utilized the Integrative Variant Analysis platform to classify variants based on the American College of Medical Genetics guidelines. We retained all pathogenic, likely pathogenic, and highly-prioritized Variants of Uncertain Significance. Results: Pathway analysis on prioritized variants showed EGFR and p53 pathways as the two top pathways among our C-AYA patients. We found that 4.8% of children and 6.2% of AYA, all female patients, harbored a non-kinase-domain germline EGFR mutation, compared to only 1.7% of adult patients with ACC. As proof-of-principle functional validation, we engineered a lentiviral-mutant stable ACC-cell line, harboring an EGFR variant from a 21 y/o female with aggressive bilateral ACC (p.Asp1080Asn), without germline TP53 mutation. We showed that mutant cells grow slower, yet migrate faster and are characterized by a stem-like phenotype compared to wildtype cells. Osimertinib, among all tested EGFR inhibitors, resulted in the highest growth inhibition of mutant cells. While EGFR inhibitors had no effect on the stemness of mutant cells, Sunitinib, a multi-receptor tyrosine kinase inhibitor, significantly reduced the stem-like behavior. Conclusions: Our data suggest that EGFR is a novel underlying germline predisposition factor for ACC, especially in the female C-AYA population. Although our pre-clinical observations need to be further validated, identifying a targetable gene for ACC has the potential to improve precision oncology management of this disease, which is known to have limited therapeutic options.
Prognostic value and clinicopathological significance of programmed cell death ligand 1 (PD-L1) expression in resected gastric cancer: A meta-analysis.
Authors: Shuixiu Yu, Jing Ning, Wei Ouyang, Lingzhi Ding, Kaisu Lin, Martin Qi, Hong Zhu
Journal: Journal of Clinical Oncology (2019)

e15512 Background: Programmed death ligand 1 (PD-L1) expression has become a promising biomarker in predicting the efficacy of immune checkpoint inhibitors in various advanced cancers, including gastric cancer (GC). However, the prognostic value and clinicopathological significance of PD-L1 in GC is still not clearly identified. Hence, we carried out a meta-analysis to investigate the potential role of PD-L1 in GC, expecting to provide new clues for the judgement of prognosis in resected gastric cancer. Methods: A literature search strategy was performed from the PubMed, Web of Science, EMBASE, and the Cochrane Library database as of December 1, 2018. Relevant data was rigorously extracted from the included literatures. Hazard ratios (HRs) and Odds ratios (ORs) along with 95% confidence intervals (95% CIs) were used to evaluate the prognostic value or clinicopathological significance of PD-L1 expression in GC. Results: A total of 21 studies containing 6021 patients fitted into our meta-analysis. The pooled HRs indicated that PD-L1 high-expression accompanied with a worse overall survival (OS) (HR=1.28, 95% CI: 1.01-1.62, P=0.04) in GC, while no correlation with disease-free survival (DFS) (HR=0.88, 95%CI: 0.53-1.45, P=0.61). Subgroup analysis showed that PD-L1 high-expression was negatively associated with distant metastasis groups (OR=0.66, 95%CI:0.48-0.89, P=0.01), but was positively related to elderly(OR=1.19, 95%CI: 1.01-1.40, P=0.04), lymph-node metastasis(OR=1.63, 95%CI: 1.08-2.46, P=0.02), deeper tumor infiltration(OR=1.73, 95%CI: 1.08-2.79, P=0.02), Epstein-Barr virus infection positive (EBV+) (OR=8.01, 95%CI: 3.10-20.72, P&lt;0.0001), and MET positive (MET+) groups (OR=1.78, 95%CI: 1.05-3.00, P=0.03). Conclusions: Our meta-analysis found that the high-expression of PD-L1 accompanied with a poor OS. Moreover, PD-L1 high-expression was related to age, lymph-node metastasis, depth of infiltration, distant metastasis, EBV infection, and MET status.
A novel noninvasive biomarker based on peripheral PD-1<sup>posi</sup> CD8 T-cell receptor repertoire correlated with clinical outcomes to immunotherapy in non-small cell lung cancer.
Authors: Jie-Fei Han, Zhijie Wang, Hua Bai, Si Chen, Yuqi Wang, Jianchun Duan, Jie Wang
Journal: Journal of Clinical Oncology (2019)

e14174 Background: Although advances on exploration of biomarkers personalized the immune checkpoint blockades (ICBs) delivery, non-invasive blood-based approach remainsan intriguing area for further investigation.This study investigated the feasibility of peripheral isolated PD-1 posi CD8T cell receptor (TCR) repertoire profiling in predicting the clinical outcomes of ICBs treatment for non-small cell lung cancer (NSCLC) patients. Methods: The study comprised two independent cohorts (A and B), ultimately recruiting total 40 from 51 patients with stage IIIB-IV NSCLCs who received anti-PD-1/PD-L1 therapy between March 14, 2017 and May 2, 2018. Peripheral blood samples of pre- and post-ICBs (the timepoint of first imaging evaluation) were prospectively collected, and PD-1 posi CD8 T cells were isolated by flow cytometry for TCR sequencing. The diversity and clonality of the TCR repertoire were calculated for biomarker profiling. Cohort A (n = 25) was used as a training set for discovery of TCR diversity in the prediction of response to ICBs, and cohort B (n = 15) as a validation set. Progression-free survival (PFS) and response to ICBs treatment were correlated with TCR diversity and clonality. Results: In cohort A, patients with high pre-ICBs PD-1 posi CD8 TCR diversity had longer PFS than those with low diversity (6.5 vs. 2.6 months, p = .045), which were substantially validated in cohort B. By using the incorporated set, pre-ICBs PD-1 posi CD8 TCR diversity exhibited an optimal Youden's index of 0.81 with a sensitivity of 0.87 and a specificity of 0.94 in clarifying clinical response of ICBs (PR+SD vs. PD). Patients with increased PD-1 posi CD8 TCR clonality demonstrated significantly improved PFS (7.3 vs. 2.7 months, p = .005) compared to those with decreased TCR clonality. Interestingly, two patients with initial pseudo-PD exhibited similar change of TCR clonality and expansion of dominant TCR clones with those with PR, but not PD. Conclusions: Peripheral PD-1 posi CD8 TCR repertoire sequencing might be a promising non-invasive approach for selecting patients who could benefit from ICBs treatment, which guaranteed the further investigation and validation by larger cohorts.
Oral paclitaxel in the treatment of metastatic breast cancer (MBC) patients.
Authors: Ming-Shen Dai, Ta-Chong Chao, Chang-Fan Chiu, Yen-Shen Lu, Her-Shyongi Shiah, Yi-Yin Wu, Wei-Hong Cheng, Wing Kai Chan, Tak Hung, Noelyn Hung, David Cutler, Rudolf Kwan, Douglas Kramer, Tsu-Yi Chao
Journal: Journal of Clinical Oncology (2019)

1084 Background: Intravenous (IV) paclitaxel is an effective treatment for breast cancer. Oral administration paclitaxel is preferable to IV regarding minimizing IV injections, anaphylactic reactions to cremaphor, steroid pre-medications, hospital visits, and relevant costs. However, paclitaxel has poor oral absorption due to active excretion by P-glycoprotein (P-gp) in the intestinal cells. Oraxol (Athenex, USA) is an oral paclitaxel and HM30181, a novel oral inhibitor of intestinal P-gp which enables the oral administration of paclitaxel. We report the final results of a pharmacokinetics (PK) study, including clinical response and tolerability of Oraxol in treatment of metastatic breast cancer patients. Methods: Multicenter, single-arm, open-label, PK study of Oraxol (HM30181A at 15mg, plus oral paclitaxel 205mg/m 2 ) administered orally for 3 consecutive days weekly for up to 16 weeks. Paclitaxel PK was assessed at week-1 and week-4. Tumor Response was measured at weeks 8 and 16 using RECIST criteria 1.1. Toxicity was assessed using CTCAE v4.03. Results: Twenty-eight MBC patient were studied with a mean age of 56.6 years (range: 38 - 79 yrs). 26 patients had failed mutiple previous chemotherapies. There were 11 (42.3%) partial response, 12 (46.2%) stable disease and 3 (11.5%) progressive disease in 26 evaluable patients. Three patients had treatment-related SAEs (grade ≥3 neutropenia) and all patients recovered completely. PK results showed that the AUC of oral paclitaxel at week-1 was reproducible at week-4 (3050 to 3594 ng-hr/mL). Conclusions: Oral paclitaxel showed very encouraging anti-cancer activity in MBC patients who failed previous chemotherapies with acceptable toxicity. Weekly oral paclitaxel can achieve paclitaxel exposure similar to that of weekly IV paclitaxel (80mg/m 2 ) reported previously. PK of oral paclitaxel is reproducible. Clinical trial information: NCT03165955.
Safety and efficacy of docetaxel combined with cisplatin as induction chemotherapy followed by cisplatin concurrent chemoradiotherapy plus gemcitabine as adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma: A prospective and multicenter phase II trial.
Authors: Zhi Hui Wang, Peijian Peng, Siyang Wang, Yumeng Liu, Zhong Lin
Journal: Journal of Clinical Oncology (2019)

6064 Background: Radiation therapy is the only curative treatment modality for nonmetastatic nasopharyngeal cancer (NPC). Concurrent chemoradiation (CCRT) is the standard treatment strategy for NPC in locally advanced stages. However, the results after such treatment are suboptimal. Clearly, novel treatment strategies are needed to further improve patients’ survival rates. This trial aimed to determine the safety and efficacy of a new treatment strategy. Methods: Patients with stage III – IVa-b NPC received TP (docetaxel 75 mg/m2, cisplatin 75 mg/m2 every 3 weeks for 2-3 cycles) followed by cisplatin chemotherapy concurrently with either 3-dimentional conformal radiation therapy or intensity-modulated radiation therapy plus gemcitabine (1000mg/m2 every 2 weeks for 2 cycles) as adjuvant chemotherapy. Objective response rates and acute toxicity were assessed based on RECIST (1.1) and CTCAE v.4.0, respectively. Kaplan-Meier analysis was used to calculate survival rates. This trial is registered with the Chinese Clinical Trials Registry, number ChiCTR-OIC-17011464. Results: From July 2010 to July 2017, 20 eligible patients with nonmetastatic stage III-IVb NPC were enrolled. The objective response rates were 90% (3 complete responses [CRs] and 15 partial responses [PRs]) after two or three cycles of induction chemotherapy (ICT) and 100% (17 CRs and three PRs) after CCRT plus gemcitabine adjuvant chemotherapy, respectively. With a median follow-up time of 41 months, the 3-year overall survival rates were 90% (18/20,95% confidence interval [CI], 76.9%-100%).The 3-year progression-free survival, distant metastasis-free survival, and local progression-free survival rates were 80% (16/20,95% CI, 62.5%-97.5%), 85% (17/20,95% CI, 69.4%-100%),95% (19/20,95% CI, 85,4%-100%), respectively. The most frequent grade 3–4 toxicities were neutropenia (3/20,15%) and nausea (2/20,10%) after ICT and thrombocytopenia (6/20,30%) and leukopenia (6/20,30%) after CCRT plus gemcitabine adjuvant chemotherapy. Conclusions: Neoadjuvant TP followed by concurrent chemoradiation plus gemcitabine as adjuvant chemotherapy was well tolerated and produced promising outcomes in patients with LA-NPC in this hypothesis-generating study. The authors concluded that randomized controlled trials are warranted to definitively confirm this aggressive and potentially efficacious strategy. Clinical trial information: ChiCTR-OIC-17011464.
Factors associated with metastatic presentation in HPV-related squamous cell carcinoma of the head and neck (SCCHN): A National Cancer Database (NCDB) analysis.
Authors: Marta Brygida Bean, Jeffrey M. Switchenko, Conor Ernst Steuer, Mihir Patel, Mark El-Deiry, Kristin Ann Higgins, Mark William McDonald, Zhuo Georgia Chen, Jonathan Jay Beitler, Dong Moon Shin, Theresa Wicklin Gillespie, Nabil F. Saba
Journal: Journal of Clinical Oncology (2019)

e18213 Background: Metastasis is an ominous sign in SCCHN. Human papillomavirus (HPV) infection-associated SCCHN cancers tend to have a distinct prognosis. Factors that are associated with metastatic disease at the time of presentation and diagnosis in patients with HPV-related SCCHN tumors were examined. Methods: NCDB was queried to assess 12,857 patients with HPV-related oropharyngeal carcinomas (HPVOPCA) and 952 patients with HPV related non-oropharyngeal carcinomas (HPVNOPCA) diagnosed between between 2010-2014 with non-missing survival or M stage. Rate of metastases at presentation was analyzed using clinical M stage. Multivariable analysis was performed evaluating race, ethnicity, sex, age, facility location, facility type, insurance status, income, education, urban/rural location, surgery, radiation, and chemotherapy using logistic regression. Results: In both HPVOPCA and HPVNOPCA, over 90% of patients were white. Private insurance was carried by 64% and 47% of patients with HPVOPCA and HPVNOPCA, respectively. HPVOPCA cancer was located in the tonsil in 47% of cases. Patients with HPVOPCA were more likely to present with advanced nodal disease than patients with HPVNOPCA. For both HPVOPCA and HPVNOPCA, there was no meaningful difference in the rate of distant metastasis at presentation in facility type or location, sex, race, Hispanic ethnicity, or urban rural location. For HPVOPCA, there were significantly lower odds of metastasis in privately insured patients vs. uninsured patients (HR: 0.35, 95% CI: 0.21-0.59, p &lt; 0.001), and higher odds of metastasis for those living in census tracts with the lowest rates of high school graduates vs. those living in census tracts with the highest rates of high school graduates (HR: 1.82, 95% CI: 1.07-3.09, p = 0.026). For HPVNOPCA, patients living in census tracts with the lowest rates of high school graduates were less likely to develop metastasis compared to those living in census tracts with the highest rates of high school graduates (p = 0.031). Conclusions: This large retrospective analysis identifies likely modifiable risk factors for metastatic presentation in HPV-related SCCHN. Health policies and educational interventions may result in modifications of these patterns.
Evolution of androgen receptor variant (ARV) profiles in serial metastatic solid and liquid biopsies in metastatic castrate resistant prostate cancer (mCRPC) treated with abiraterone acetate/ prednisone (AA/P).
Authors: Karthik Giridhar, Carlos Sosa, Hugues Sicotte, Liewei Wang, Liguo Wang, Jason P. Sinnwell, Winston Tan, Brian Addis Costello, Fernando Quevedo, Henry C. Pitot, Alan Haruo Bryce, Rafael E. Jimenez, Richard M. Weinshilboum, Scott Dehm, Krishna R. Kalari, Manish Kohli
Journal: Journal of Clinical Oncology (2019)

e16559 Background: ARVs that develop early during treatment with abiraterone acetate/ prednisone (AA/P) may play a role in treatment resistance. We evaluated metastatic site and whole blood mRNA expression of full-length AR (AR-FL) and ARVs to characterize treatment-emergent ARVs (TE-ARVs) from men with mCRPC pre- and post- 12 weeks of AA/P collected in a prospective clinical trial (NCT#01953640). Methods: RNAseq performed on paired metastatic site biopsy (n = 40) and whole blood (n = 25) passed quality control. Reads were aligned to the GRCh38 reference genome with the spliced-alignment TopHat2 package. AR-FL or ARVs were detected if ≥ 2 splice reads aligned to unique splice junctions for AR-FL, AR-8, AR-45, AR-23, AR-V3, AR-V5V6, AR-V7, AR-V8, AR-V9, AR-V10, AR-V12, AR-V13, and AR-V14, and normalized to splice reads per million (SRPM). Cox proportional hazard regression analysis was performed on AR-FL and AR-Vs with ≥1 SRPM for association with time to treatment change (TTTC). Results: In metastatic site biopsies post-AA/P, the average number of splice reads was 27,376,541 (range 7,753,998 to 62,456,773). The median number of ARVs detected was 2 (range 0-8), with a total of total of 110 ARVs identified (Table). Dynamic shifts in ARV profiles were observed post-AAP, with 41 TE-ARVs identified in 17 unique patients. The most common TE-ARV was AR-8 (n = 8), followed by AR-45 (n = 5), AR-23 (n = 5), and AR-V7 (n = 4). The presence of AR-V7 post-AAP was adversely associated with TTTC (hazard ratio 2.46, p = 0.013). The identification of early TE- ARV was not associated with TTTC. In whole blood samples, post-AA/P detection of AR-FL was low (n = 3) and no ARVs were detected. Conclusions: No specific patterns were observed in ARV profiles obtained in the metastatic biopsies after 12 weeks of treatment with AA/P. Clinical trial information: 01953640. [Table: see text]
Emerging therapies for non-small cell lung cancer
Authors: Chao Zhang, Natasha B. Leighl, Yi-Long Wu, Wen-Zhao Zhong
Journal: Journal of Hematology & Oncology (2019)

Recent advances in the field of novel anticancer agents prolong patients' survival and show a promising future. Tyrosine kinase inhibitors and immunotherapy for lung cancer are the two major areas undergoing rapid development. Although increasing novel anticancer agents were innovated, how to translate and optimize these novel agents into clinical practice remains to be explored. Besides, toxicities and availability of these drugs in specific regions should also be considered during clinical determination. Herein, we summarize emerging agents including tyrosine kinase inhibitors, checkpoint inhibitors, and other potential immunotherapy such as chimeric antigen receptor T cell for non-small cell lung cancer attempting to provide insights and perspectives of the future in anticancer treatment.
Clinicopathological features of Epstein–Barr virus associated gastric carcinoma with submucosal invasion.
Authors: Hiroki Osumi, Hiroshi Kawachi, Toshiyuki Yoshio, Satoshi Ida, Yusuke Horiuchi, Akiyoshi Ishiyama, Toshiaki Hirasawa, Tomohiro Tsuchida, Noriko Yamamoto, Kensei Yamaguchi, Souya Nunobe, Kengo Takeuchi, Junko Fujisaki
Journal: Journal of Clinical Oncology (2019)

4029 Background: The incidence of lymph node metastasis (LNM) in pathological T1b (pT1b) gastric cancer (GC) is around 20% and the majority of them have no LNM. The Cancer Genome Atlas Research Network proposed the concept of molecular phenotype classifying GC into 4 phenotypes including Epstein-Barr virus-CIMP (EBV). EBV positive gastric cancer (EBVGC) is associated with a low prevalence of LNM; however, EBV status is not considered in the present indication of endoscopic resection (ER). We aimed to clarify the implication of EBV status for ER of pT1b GC. Methods: Consecutive cases of pT1b GCs treated with curative surgery between 2005 and 2014 were retrospectively analyzed. Tissue microarray was made and EBV-encoded RNA in situ hybridization was performed for evaluation of EBV status. Clinicopathological factors and LNM status were compared between EBVGC and non-EBVGC groups. Results: Among the 1221 pT1b GCs that underwent gastrectomy with regional lymph node dissection, 898 pT1bGCs were eligible in this study. EBVGC accounted for 7.9% (71 of 898) cases. Compared to non-EBVGC, EBVGC was more frequent in males (p = 0.0055), the upper third region (p &lt; 0.0001), showed elevated growth features (p = 0.0059), and was associated with a lower frequency of accompanying ulceration (p = 0.002), greater depth of submucosal invasion (p = 0.017), and lower frequency of lymphatic invasion (p &lt; 0.0001). Frequency of LNM was significantly lower in EBVGC than in non-EBVGC (4.2% vs. 21.9%, p &lt; 0.0001). In EBVGC, tumors without lymphovascular invasion showed significantly lower frequency of LNM than those with lymphovascular invasion (0 of 50, 0%; vs 3 of 21, 14.3%; p = 0.023). Histologically, 84.5% (60 of 71) of EBVGC included carcinomas with lymphoid stroma and/or lace pattern components. Conclusions: pT1b EBVGC is a convincing candidate for ER, regardless of risk factors other than lymphovascular invasion.
Relationship of <i>MET</i> exon 14 splicing variants and <i>MET</i> exon 14 skipping expression in NSCLC FFPE samples.
Authors: John B. Williamson, Xia Li, Guang Liu, Haigang Gu, Janet Orton, David Seidman, Tabetha Sundin, Suzanne Salazar, Seth Sadis, Tommie Lincecum, Thomas Ha, Christine Chin
Journal: Journal of Clinical Oncology (2019)

e14603 Background: MET is the target of recurrent somatic alterations in approximately 7% of non-small cell lung carcinomas (NSCLC). A key class of therapeutically relevant MET mutations results in aberrant mRNA splicing, deletion of exon 14 from the mRNA transcript (METex14 skipping), and MET overexpression. METex14 skipping assays routinely use next-generation sequencing (NGS). However, because most NGS assays are DNA based, the relationship between METex14 DNA alterations and METex14 skipping mRNA expression is not well understood. Furthermore, because METex14 skipping may have low background levels, setting a threshold for calling METex14 skipping based on RNA levels alone is challenging. To investigate these relationships, we initiated a research study in 3 CLIA/CAP laboratories using an NGS panel (OCAv3, for research use only, not for use in diagnostic procedures) that includes 161 cancer genes and detects METex14 splicing variants and METex14 skipping mRNA isoforms. Methods: OCAv3 libraries were prepared following kit instructions with templating and sequencing performed on the Ion Chef and S5 XL systems. Reads were aligned to hg19 using Torrent Suite Software and variant calling was performed using Ion Reporter software. Two cell lines (HS746T and NCI-H596) known to contain METex14 splice site mutations were used as controls. Results: Of the first 28 NSCLC FFPE specimens selected having a range of METex14 RNA expression, we detected METex14 skipping alterations in 9 cases: 6 cases with variants at exon 14 canonical splice sites and 3 cases of novel deletions in the intron 13 poly-pyrimidine tract. METex14 skipping alterations were exclusive to other oncogenic driver variants but occasionally associated with MDM2 amplification. All cases with splice site variants showed elevated METex14 skipping expression. Cases without splicing variants had no or lower METex14 skipping expression and commonly harbor activating mutations in other oncogenes (6 KRAS, 5 EGFR, 1 ERBB2, 1 MYC and 1 CD74-NRG1 fusion). Conclusions: We demonstrate a framework for interpreting MET alterations that considers both MET splice site variants and METex14 skipping transcript expression in the context of additional oncogenic mutations. An update will be presented as additional cases accrue.
Lack of clinical relevance of the type of chimeric mRNA in chronic myelogenous leukemia: a study of 90 patients
Authors: R. A. M. Melo, F. C. B. C. Melo, D. F. Lima, M. H. S. Scaffo, R. C. Fernandes, G. F. V. Ismael, J. P. M. Bighetti, Marco Antônio Zago, Belinda Pinto Simões
Journal: Blood (1997)