bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a unique anti-CD137 therapeutic antibody: Efficacy and safety profiles in mono and combination therapy.
Authors: Liu Guizhong , Cheung Peter , Chen Jun , She Xiaohong , Du Felix Fangyong , Luo Peter
Published: September 2018

e23079

Background: Abstract: CD137 (4-1BB), a member of the TNFR super family, is expressed on several subsets of activated immune cells and acts as co-stimulatory receptor for T-cells to promote cellular proliferation, survival and cytokine production. Agonist antibodies against human CD137 in early clinical trials show strikingly different toxicology profiles, ranging from severe liver toxicity at low doses, to manageable adverse effects at modest doses. Whereas preclinical studies in mouse show intense liver T-cell infiltration and toxicity by surrogate agonist mAb. The preclinical efficacy and pharmacology of anti-CD137 were extensively tested and validated in various tumor models with intact immune system. Since none of the available anti-CD137 agonist antibodies display multiple species cross reactivity including rodent, the translational significance of these mAbs is limited concerning their efficacy and safety profile. Methods: Through our proprietary Dynamic Precision Library (DPL) technology, we have discovered multiple agonistic antibodies that exhibit high affinity and broad species cross-reactivity against a unique epitope shared among human, monkey and rodent CD137. Results: These mAbs, after crosslinking, strongly activate CD137 mediated cellular NFkB signaling, as well as stimulate T-cell proliferation and IFNg release in the presence of suboptimal concentrations of anti-CD3 antibodies. The broad species cross-reactivity by a single therapeutic agent enabled us to evaluate their potentiation of host immune responses that gives rise to the anti-tumor efficacy and potential toxicity in relevant rodent and monkey models. Our lead anti-CD137 agonist mAb has demonstrated robust anti-tumor activities in multiple mouse syngeneic tumor models, with durable antigen specific protective memory T-cell responses. Conclusions: In sharp contrast to surrogate anti-mouse CD137 mAbs, no toxicities including liver inflammation or other adverse effects were observed. These preclinical results warrant further clinical development of our lead as a novel immunotherapeutic anti-cancer agent.
Stratification of tumors based on mTOR-pathway biomarkers.
Authors: Laes Jean-Francois , Sauvage S Bastien , Ghitti Gregori
Published: September 2018

e23097

Background: The mTOR pathway is often activated in human cancers. In this study, a total of 538 samples representing 40 different cancer types were analysed to evaluate the relationship between mTOR pathway activity and mutations in the upstream genes PIK3CA and PTEN. Methods: FFPE samples were analysed both by NGS (PIK3CA, PTEN, mTOR, TSC1, TSC2) and IHC (PTEN, 4pEBP1). Results: Overall, mTOR-pathway activation was identified in 83% of the samples, functional mutations were found in either or both PIK3CA and PTEN genes in 32% of the samples but there was no signification association between them. However when separating samples by cancer types, potential associations were identified. One example is the combination of PIK3CA activating mutation and PTEN loss of function which was associated with mTOR-pathway activation, most notably in the breast-cancer samples. Such combination has been associated with poor outcomes to some treatments (trastuzumab). Conclusions: In conclusion, our results show that stratification of tumors using the combination of mTOR-pathway biomarkers (and combined NGS and IHC technologies in their assessment) is potentially more informative than using a single biomarker to select the best treatment.
Secretary leukocyte peptide inhibitor (SLPI) in pleural fluid is useful as a diagnostic marker of malignant pleural mesothelioma.
Authors: Fujimoto Nobukazu , Kojima Yoko , Kishimoto Takumi
Published: September 2018

e23098

Background: There is no established diagnostic marker for malignant pleural mesothelioma (MPM). In particular, the differentiation from benign asbestos pleural effusion (BAPE) is challenging. Secretary leukocyte peptide inhibitor (SLPI) is an enzyme encoded by SLPI gene. SLPI gene is reported to be overexpressed in MPM cells. Methods: SLPI in pleural fluid was determined using Quantikine ELISA Human SLPI kit (R&D Systems). Results: Exploratory research revealed that SLPI value in pleural fluid of patients with MPM (n = 52) were significantly higher than those in lung cancer (LC) (n = 69) and BAPE (n = 50) ( P= 0.000). Prospective validation study included 12 pts of MPM, 24 pts of LC, 26 pts of BAPE. Median values of SLPI in MPM, LC, and BAPE were 159 .6 ng/ml, 90.5 ng/ml, and 43.2 ng/ml, respectively. SLPI value in patients with MPM were significantly higher than those in other groups ( P= 0.000). Receiver operating characteristics ROC) analysis was performed to examine the usefulness of differentiation of MPM and other diseases, and demonstrated that area under the curve (AUC) value was 0.758. With the cut of value of 88.6 ng/ml, the sensitivity was 83.3% and the specificity was 59.8%. Concerning the differentiation between MPM and BAPE, AUC value was 0.904 and with the cut of value of 81.8 ng/ml, the sensitivity was 83.3% and the specificity was 92.3%. Conclusions: Pleural fluid SLPI is a useful biomarker for the diagnosis of MPM, in particular, for the differentiation from BAPE.
Ranolazine and TDM1 treatment: Cardioprotective effects in vitro and in vivo.
Authors: Maurea Nicola , Coppola Carmela , Piscopo Giovanna , Riccio Gennaro , Rea Domenica , De Vecchis Renato , Maurea Carlo , Sorrentino Giorgia , De Lorenzo Claudia , De Laurentiis Michele
Published: September 2018

e23102

Background: Ado trastuzumab emtansine (TDM1) is a novel antibody–drug conjugate consisting of trastuzumab (TRAS) covalently linked to the highly potent microtubule inhibitory agent DM1 via a stable thioether linker. TDM1 is used in metastatic ErbB2 positive breast cancer patients. Although, the potential cardiotoxic effects of TDM1 have not yet been fully elucidated, they can include changes in Ca2+ regulation related to blockade of ErbB2, PI3K-Akt and MAPK pathways. Here, we aim to elucidate whether Ranolazine (R), administered after TDM1 treatment, blunts or not cardiotoxicity in vivo and in vitro. Methods: In vitro, human fetal cardiomyocytes (HFC) were treated with TDM1 for 3 days and then treated in the absence or presence of R for 3 days. Cell viability was assessed by cell counting and MTT assay. To evaluate cardiac function in vivo, C57/BL6 mice, 2-4 months old, were daily treated with TDM1 (44.4 mg/kg/day). At day 0 and after 7 days, fractional shortening (FS) and ejection fraction (EF) were measured, by M/B mode echocardiography, and radial and longitudinal strain (RS and LS) were evaluated using 2D speckle-stracking. These measurements were repeated after 5 days of R treatment (305 mg/Kg/day), started at the end of TDM1 treatment. Results: R reduces TDM1 toxicity in HFC, as evidenced by the higher percentage of viable cells treated with TDM1+ R with respect to the cells treated with TDM1 alone (p < 0.01). In in vivo studies: after 7 days with TDM1 administration, FS decreased to 53.6±0.9%, versus 61.0±0.8 % (sham), (p < 0.01), and EF decreased to 85.5±3.5 % versus 91.0±0.8% (sham), (p < 0.01). Moreover, RS decreased to 20.92±3.2 % versus 42.2±10.1% (sham) (p < 0.01), and LS decreased to -15.5±2.8 % versus -23.6±6.7% (sham), (p < 0.01).In mice treated with TDM1 and, successively treated with R for 5 days, the indices of cardiac function partially recovered: FS 58±2.4 % (p < 0.05), EF 88.8±1.7 %, (p < 0.05), RS (35.7±8.2 %, p > 0.05), whereas the alteration of LS persists even after treatment with R (-17.3±3.7 %, p > 0.05) Conclusions: Here we show that in vivo R post-treatment reduces cardiotoxic effects due to TDM1, as demonstrated by the recovery of FS, EF and RS values. As expected, R increases cell viability of HFC treated with TDM1.
Clinical and radiological features of advanced RET-rearranged lung cancer.
Authors: Saiki Masafumi , Ohyanagi Fumiyoshi , Ariyasu Ryo , Koyama Junji , Sonoda Tomoaki , Kawashima Yosuke , Takano Natsuki , Oguri Tomoyo , Nishikawa Shingo , Kitazono Satoru , Yanagitani Noriko , Horiike Atsushi , Ninomiya Hironori , Takeuchi Kengo , Ishikawa Yuichi , Oikado Katsunori , Nishio Makoto
Published: September 2018

e23104

Background: RET fusion gene was found in 1–2% of non-small cell lung cancer (NSCLC). Most of the reports published so far investigated only surgical specimens, and details of advanced tumors were unknown. This study explored the clinical and radiological characteristics of RET-rearranged lung cancers in advanced stages. Methods: Among 1,074 advanced NSCLC patients who were treated at The Cancer Institute Hospital, Tokyo, from 2012 to 2016, 14 cases (14/1,074 = 1.3%) were treated as RET- rearranged lung cancer. The cases were identified by FISH and / or by RT-PCR (FISH 3, RT-PCR 2, FISH and RT-PCR 8, unknown 1). The fusion partner genes included KIF5B (n = 10), CCDC6 (n = 1). Three were unknown. The tumor size, location, and shape/margins of the primary tumor as well as lymphadenopathy and site of metastasis were recorded based on computed tomography (CT) images taken right before the initial chemotherapy. Results: The median age of the 14 patients was 64 years (range, 34–79), with 10 patients (71%) over 60 years old. Nine patients (64%) were women, whereas 10 patients (71%) were never smokers. Eight patients were classified as stage IV and 6 underwent recurrence after surgery. We successfully evaluated CT images at the initial chemotherapy of 12 patients. Of the 7 patients whose primary lesions were detectable, all were located peripherally and were of a solid tumor type without ground-glass, air bronchograms, or cavitation. The median size of the primary lesion was 3.0 cm (range, 1.2–6.8), and 3 lesions were less than 3.0 cm. Only 5 patients had lymphadenopathy (4 were of Stage IV, 1 was a recurrence), most of which were isolated with a median size of 1.5 cm (range, 1.2–3.5). The sites of distant metastases included 8 pleural disseminations, 5 lungs, 5 bones, 3 livers, 2 brains, and 0 adrenals. Conclusions: Advanced RET-rearranged lung cancer manifested as a relatively small and peripherally located solid primary lesion with isolated lymphadenopathy. Pleural dissemination was frequently observed, whereas brain metastasis was less frequent. These features differ from EGFR-mutated or ALK-fused lung cancers.
Next generation sequencing to reveal potentially actionable alterations in the majority of patients with hematologic malignancies.
Authors: Galanina Natalie , Goodman Aaron , Tran Lisa , Bejar Rafael , Choi Michael Y. , Kurzrock Razelle
Published: September 2018

e23133

Background: Next generation sequencing (NGS) permits identification of genomic alterations that inform disease classification and prognosis and may also guide therapy selection. Methods: Using NGS (406 genes), we analyzed the clinical characteristics, genomic alterations, and potential actionability of 235 patients (pts) with diverse hematologic malignancies. Results: A total of 227 pts (96.5%) (59% men; median age 59 yrs) had adequate tissue for analysis. Most common diagnoses included myelodysplastic syndrome (22.9%), chronic lymphocytic leukemia (17.2%), non-Hodgkin lymphoma (13.2%), myeloproliferative neoplasm (9.2%), acute myeloid (11%) / lymphoid (8.8%) leukemia and multiple myeloma (7.5%). The majority of pts (N = 197/227 (86.8%)) harbored ≥1 genomic alteration(s); 164 pts (72%) had ≥1 potentially actionable alteration(s) targetable by an existing FDA-approved drug (mostly off label) or an investigational agent. A total of 551 distinct alteration s were seen with the most common involving TP53 (9.3%), TET2 (4.2%), DNMT3A (3.3%), ASXL1 (2.5%), MLL (2.5%), KRAS (2.2%). The vast majority of pts had unique molecular profile. Conclusions: About 96.5% of pts with hematologic malignancies have adequate tissue for NGS. Most pts had unique molecular signatures, and 72% had alterations that may be pharmacologically tractable. [Table: see text]
Clinical and therapeutic impact of family with sequence similarity 83, member B in EGFR gene wild type-lung adenocarcinoma.
Authors: Yamaura Takumi , Okabe Naoyuki , Takagi Hironori , Owada Yuki , Inoue Takuya , Watanabe Yuzuru , Fukuhara Mitsuro , Muto Satoshi , Matsumura Yuki , Hasegawa Takeo , Hoshino Mika , Osugi Jun , Shio Yutaka , Ezaki Junji , Watanabe Shinya , Suzuki Hiroyuki
Published: September 2018

e23136

Background: We have reported the usefulness of Family with sequence similarity 83, member B (FAM83B) as a novel biomarker for diagnosis and prognosis of lung squamous cell carcinoma. FAM83B expresses not only in lung cancer but also in several types of solid cancer. More recently, novel finding showing FAM83B involve to tumor growth, oncogenesis, and resistance of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in breast cancer cell lines has been shown. EGFR signaling pathway also plays an important role in lung adenocarcinoma, therefore, we hypothesize that FAM83B associates with tumor proliferation in lung adenocarcinoma (ADC), results in resistance to EGFR-TKI and in a novel therapeutic target in a part of lung ADC. Here we show that correlation between FAM83B expression and clinicopathological features. Methods: This study was conducted with approval of ethics committee in our institute, and informed consent was obtained from all the participants. We identified 216 participants underwent for primary lung ADC between 2008 and 2015. Paired tumor and corresponding normal tissue samples obtained from patients were subjected. FAM83B mRNA expression were examined by cDNA microarray, and analyzed relationship between the level of FAM83B and clinicopathological variables including survival analysis. Further, FAM83B knock down study was performed in several types of cancer cell lines (H1975, HLC-1, H2347) to validate whether FAM83B involve to cell proliferation. Results: FAM83B highly expressed in male (p = 0.007), or smoker (p = 0.007), or EGFR wild type tumor (p<0.001). Multivariate analyses also showed that EGFR wild type-tumor correlate with FAM83B expression. In survival analysis, multivariate analysis showed FAM83B correlated with poor outcome in both disease free survival and overall survival (p = 0.011 and p = 0.001), especially stratified by EGFR wild type-tumor (p = 0.017, p = 0.008). Gene silencing with FAM83B siRNA showed growth suppression of HLC-1 and H1975 cell lines. Conclusions: FAM83B could involve to tumor proliferation of lung ADC in part, and expected to be the novel therapeutic target of EGFR wild type-ADC.
Copper chelation as targeted therapy in a genetic mouse model of oncogenic BRAF-driven thyroid cancer.
Authors: Xu Mengmeng , Range Danielle , Sosa Julie Ann , Counter Christopher
Published: September 2018

e23148

Background: Over half of papillary thyroid cancers (PTC) contain the MAPK pathway activating, oncogenic BRAF V600E mutation. Early clinical trials using inhibitors to this mutant protein or its substrates, the MEK1/2 kinases, prolonged progression-free survival or stabilized disease in patients with advanced PTC. However, the toxicities of these inhibitors are uniquely highlighted in an indolent disease like PTC, which would require patients to endure toxicities long-term. Our goal was to determine if tetrathimoybdate (TM), a well-tolerated copper chelator we have previously shown to inhibit BRAF-mutated melanoma via MEK inhibition, can inhibit BRAF-driven PTC growth. Methods: We assessed TM in comparison to current standard of care (SOC), Lenvatinib and Sorafenib, and mutant BRAF inhibitor, Vemurafenib. Anchorage independent growth assays were used to test the inhibitory effect of these drugs on human BRAF-mutated PTC cell lines. We then confirmed these findings by treating a genetically engineered mouse model (GEMM) of aggressive BRAF-driven PTC. Results: TM inhibited 57.5% of colony growth in vitro, which was not significantly different from the 42.4% and 32.2% inhibition by Sorafenib and Lenvatinib, respectively. TM inhibition was less effective than the 70.3% inhibition by Vemurafenib ( p =0.04). We confirmed these results in vivo, where mice on the TM arm, on average, were observed to have 14.8% of their thyroid glands occupied by tumor, a statistically significant reduction from the mice in the control arm, whose tumor load averaged 23.6% ( p= 0.008). This 37.4% reduction in tumor burden was not statistically different from the 35.2% reduction measured in the Vemurafenib arm, where mice on average had 15.3% of their thyroid glands replaced by tumor. Conclusions: The copper chelator, TM, was as effective as the SOCs, Lenvatinib and Sorafenib, at inhibiting the growth of human PTC in vitro. Although TM was slightly less effective than Vemurafenib in vitro, TM was as effective as Vemurafenib at reducing tumor load in a GEMM of BRAF-driven PTC. Success of TTM in these PTC models may next inform a Phase I trial assessing TM in patients with advanced PTC.
Antitumor activity against GPR87-expressing non-small cell lung cancer cells in GPR87-suppressing adenoviral vector.
Authors: Nakano Takayuki , Liu Dage , Kita Yusuke , Tokunaga Yoshimasa , Nii Kazuhito , Matsuura Natsumi , Nakashima Nariyasu , Tarumi Shintaro , Zhang Xia , Go Tetsuhiko , Kakehi Yoshiyuki , Yokomise Hiroyasu
Published: September 2018

e23152

Background: GPR87 is a newly deorphanized member of the G protein-coupled receptor family, it was suggested to contribute to the viability of human tumor cells, and overexpression of GPR87 was found in many malignant tumors including lung cancer. To explore effective gene therapies, we previously reported that adenoviral vector expressing short hairpin RNA targeting GPR87 (Ad-shGPR87) exerts a strong anti-proliferation activity against GPR87-overexprssing human bladder cancer cells. Here, the effect of Ad-shGPR87 was further examined in lung cancer cells. Methods: Human lung cancer cells of EBC, H358, LUDLU, MAC10 and RERF were investigated. Two cell of adenocarcinoma cell H358 (Ad) and squamous cell carcinoma cell LUDLU with an overexpression of GPR87 were selected for experiment. An adenoviral vector expressing short hairpin siRNA targeting GPR87 gene (Ad-shGPR87) was constructed by the COS-TPC method with Adenovirus Expression Vector kit (Takara Biomedicals). Real-time RT-PCR was performed to evaluate gene expressions. MTT assay was used to evaluate the cell viability. A human tumor xenograft model in nude mice was prepared by subcutaneously implanting tumors derived from H358 cells. Results: Transfection with Ad-shGPR87 effectively downregulated the GPR87 expression in both cells (more than 90% 3 days after transfection). MTT assay demonstrated the transfection of Ad-shGPR87 strongly suppressed the cell viability (less than 6.6 % for LUDLU cell and 20.0% for H358 cell at nine days after transfection). Furthermore, the treatment with Ad-shGPR87 exerted a significant antitumor effect against the GPR87-overexpressing H358 xenografts. Conclusions: The cancer gene therapy using Ad-shGPR87 has a strong anti-tumor effect both in vitro and in vivo against the GPR87-overexpressing lung cancer cells. GPR87 appear to be a promising target for cancer therapy.
Next-generation sequencing (NGS) for personalized therapy in metastatic breast cancer: Selection of therapy and outcomes.
Authors: Gomes Jessica Ribeiro , Moreira Raphael Brandao , Alessandretti Matheus Bongers , Cruz Marcelo Rocha De Sousa
Published: September 2018

e23166

Background: Treatment for metastatic breast cancer (MBC) has been driven by hormone receptors, HER2 expressions or their absence. Resistance to therapy and progressive disease will occur and empirical chemotherapy lines usually are the next steps. We aim to analyze the role of next-generation sequencing (NGS) for a personalized therapy in metastatic breast cancer and its potential clinical benefit. Methods: We included patients diagnosed with MBC treated at Centro Oncologico Antonio Ermirio de Moraes – Brazil from April 2013 to December 2016. All patients had metastasis accessible for biopsy. The tumor tissue was stored in paraffin and then analyzed by NGS-based assay that identifies genomic alterations within 236 genes. Results: 19 patients with MBC were evaluated (10 triple-negative; 4 HER2-positive; 5 hormonal receptor positive/HER2-negative). The most frequent and relevant genomic alterations identified by NGS assay were in the following genes: 13 TP53 (68.4%); 4 ERBB2 (21%); 4 PTEN (21%); 4 FGFR (21%); 3 PIK3CA (15.8%); 2 BRCA (10.5%); 2 ATM (10.5%); 2 AKT (10.5%); 2 MYC (10.5%); 1 CCND1 (5.3%); and 1 KRAS (5.3%). The NGS assay was able to suggest further therapy in 16/19 patients (84%). The suggested therapies would not be an empirical option according to the cancer’s subtype in 12/16 patients (75%). Therapy could be personalized in nine patients, across multiple lines of therapies (median of 5th line, with a range of 1-14). Median PFS was 6 months, and 8/9 patients (90%) achieved an objective response with the treatment indicated by NGS. Therefore, the assay provided clinical benefit in 42% of patients. Conclusions: NGS panel identified potentially actionable alterations in the majority of patients with MBC (84%). The overall clinical benefit with use of NGS-based assay was 42%. Further studies are necessary to better evaluate the role of NGS for a personalized therapy in MBC.
Clinical applications of genetic sequencing in lymphoma: A retrospective review.
Authors: Shango Maryann , Devata Sumana , Wilcox Ryan A. , Phillips Tycel Jovelle
Published: September 2018

e23169

Background: Personalized therapy through the identification of targetable mutations within individual tumors has increasingly become a focus in the management of patients (pts) with relapsed/refractory malignancy. To better understand how this is clinically applied, we reviewed 29 cases of B- and T-cell lymphomas that had genetic sequencing of their tumor. Methods: The electronic medical records of 29 pts who underwent Michigan Oncology Sequencing (MI-ONCOSEQ) testing at the University of Michigan from 2013-2016 were reviewed for disease and treatment history. Reports from whole-genome tumor sequencing were obtained for each patient to identify putative molecular targets. Results: Sixteen male and 13 female pts had a median age of 59 years (range 30-80 years) and median disease stage of IV at diagnosis. Five had CTCL, 5 PTCL, 11 follicular, 1 CLL/ mantle cell (MC), 1 MC, 1 marginal zone, 1 Waldenstrom’s (WM) and 4 DLBCL. Pts received a median of 2 therapies prior to MI-ONCOSEQ biopsy. Targetable mutations were identified in 15 pts and a total of 5 pts underwent MI-ONCOSEQ-based treatments. Bosutinib was given for FYB-FGR fusion, imatinib for FLI1-PDGFRB fusion, and everolimus for activating mTOR mutation with an avg. treatment duration of 3.6 weeks due to progressive disease. Bosutinib and imatinib were 3rd line therapies and everolimus was 5th. Another 2 pts were treated with ibrutinib for transformed WM with MYD88 mutation and bortezomib after classification of DLBCL as ABC-type based on MI-ONCOSEQ results, with CR in both. Other targetable mutations identified include BRAF, CDK, BCL2, EZH2 and NOTCH. Of the remaining 12 pts with targetable mutations, 8 pursued clinical trials, 2 responded to standard therapy, 1 died shortly after genetic analysis and 1 declined further therapy. About 50% of these pts remain alive. Conclusions: Our results demonstrate that targeted therapy is favored after standard therapy or clinical trial options are exhausted. Barriers to its use include the availability of clinical trials, off-label drug access and our incomplete knowledge of driver mutations. With further understanding of disease pathogenesis, we expect personalized therapy will be possible for all patients.
Association of hypoxia-induced centrosome amplification with clinical outcomes in triple-negative breast cancer.
Authors: Mittal Karuna , Choi Da Hoon , Ogden Angela , Melton Brian D , Gupta Meenakshi Vij , Reid Michelle D. , Jonsdottir Kristin , Janssen Emiel A. , Aleskandarany Mohammad A. , Ellis Ian O. , Rakha Emad A. , Rida Padmashree C.G. , Aneja Ritu
Published: September 2018

e23170

Background: Centrosome amplification (CA) which refers to presence of supernumerary or abnormally large centrosomes is believed to drive tumor progression by promoting chromosomal instability and the generation of aggressive tumor clones that are more capable of rapid metastasis. Not much is known about factors that drive CA within solid tumors. We have previously shown the existence of rampant CA in triple-negative breast cancers (TNBCs).We report here thatintratumoral hypoxia, which is one of the major contributors to tumor heterogeneity, induces CA in TNBCs via HIF-1α. Methods: We immunohistochemically labeled 24 TNBC and adjacent normal tissue samples for HIF-1α and derived weighted indices (WIs) for nuclear HIF-1α. Adjacent serial sections from the same tumors were immunofluorescently labeled for the centrosomal marker γ-tubulin and CA was determined. Using public microarray datasets (Kao dataset, n = 327), we investigated whether centrosomal gene expression is enriched in breast tumors characterized by a hypoxia gene expression signature. Finally, to test the role of hypoxia in CA induction we exposed cultured TNBC cells (MDA-MB-231 and MDA-MB-468) to hypoxia and overexpressed (OE) or knocked out (KO) HIF-1α and quantitated CA. Results: A strong positive correlation was found between nuclear HIF-1α WI and CA in TNBC samples (Spearman’s rho p = 0.722, p < 0.001), and higher nuclear HIF-1α was associated with worse overall survival (p = 0.041; HR = 1.03). Furthermore, breast tumors with high expression of hypoxia-associated genes exhibited higher expression of centrosomal genes than breast tumors with low expression of hypoxia-associated genes. TNBC cells cultured in hypoxic conditions exhibited ~1.5 fold higher (p < 0.05) CA compared to cells cultured in normoxic conditions. Interestingly, level of CA decreased when HIF-1α KO TNBC cells were exposed to hypoxia; conversely, CA increased when HIF-1α OE TNBC cells were cultured in normoxic conditions. Conclusions: Thus,intratumoral hypoxia drives CA in TNBC via HIF-1α and contributes to poor outcomes. Determination of CA may help identify TNBC patients who could benefit from centrosome declustering drugs and HIF-1α inhibitors.
Correlation between mutation burden of tumor and immunological/clinical parameters in considering biomarkers of immune checkpoint inhibitors for non-small cell lung cancer (NSCLC).
Authors: Owada Yuki , Muto Satoshi , Takagi Hironori , Inoue Takuya , Watanabe Yuzuru , Yamaura Takumi , Fukuhara Mitsuro , Okabe Naoyuki , Matsumura Yuki , Hasegawa Takeo , Ohsugi Jun , Tanaka Daisuke , Ito Emi , Nanamiya Hideaki , Imai Jun-ichi , Isogai Takao , Watanabe Shinya , Suzuki Hiroyuki
Published: September 2018

e23184

Background: There has been reported that mutation burden of solid tumor might probably be a predictive biomarker of efficacy of immune check point inhibitors, and the number of researches are still ongoing. Although the correlation of mutation burden between by whole exome sequence and by large targeted panel sequence has also been reported, neither method can be said to have solved technical and economical difficulty of using in clinical practice. Here we describe more convenient factors that can be used instead of mutation burden. Methods: 92 NSCLC patients with surgery during 2013-2015 in our institution were subjected for this study. Mutation burden in tumor samples was analyzed by whole exome sequence using Next Generation Sequencer. The major gene alteration was also analyzed by small targeted panel sequence. As immunological parameters, tumor infiltrating lymphocyte and PD-L1 expression in tumor were assessed by immunohistochemistry test using anti-CD8 antibody and anti-PD-L1 antibody. Statistical analysis was performed on mutation burden and the result of major gene alternation, immunohistochemistry, and clinical parameters. Results: There were 64 adenocarcinomas and 28 squamous cell carcinomas. The median value of mutation burden was 60 genes (10-502). The factors including squamous cell carcinoma, male, smoking history, EGFR-mutation negative, and TP53 alteration positive indicated close connection with higher mutation burden (p < 0.001) There were no significant difference in PD-L1 expression of tumor and tumor infiltrating lymphocyte. Multiple regression analysis showed that negative EGFR-mutation and positive TP53 alteration contribute to higher mutation burden (p < 0.05). Conclusions: Mutation burden in NSCLC tumor could be associated with EGFR-mutation and TP53 alteration status. These findings suggest that some major gene alteration make it possible to predict mutation burden, and could potentially be more simple predictive biomarkers of immune check point inhibitors.
Impact of 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines on HER2 fluorescent in situ hybridization (FISH) testing in breast cancers: Experience from a national reference laboratory.
Authors: Johnson Eric , Gulbahce Evin H
Published: September 2018

e23188

Background: Accurate HER2 testing is expected to identify patients who will benefit from HER2 directed therapy (HDT) minimizing false positive and negatives. Like many biologic processes, HER2 protein expression and gene copy numbers are a continuum, however these tests are expected to be reported dichotomously. In 2013, ASCO/CAP revised the guidelines in an attempt to decrease false negative results and reverted to FDA approved ratio of ≥ 2.0 for HER2 positivity. We reviewed HER2 FISH testing results after the implementation of 2013 ASCO/CAP guidelines to determine the effects on HER2 reporting from our national reference laboratory. Methods: HER2 FISH testing performed between 5/2015-4/2016 at ARUP Labs following current 2013 ASCO/CAP guidelines was included. HER2 to control probe ratios, mean HER2 and control probe copy numbers were used to reassign HER2 status using 2007 ASCO/CAP, and FDA guidelines for each case. Results: HER2 FISH results were available in 2,017 cases. 342 (17.0%) cases were amplified, 301 (14.9%) were equivocal, and 1374 (68.1%) were non-amplified. After additional testing with alternate probe, 93 (31.2%) of the equivocal cases were reclassified as amplified increasing amplified cases to 21.6%. All of the equivocal cases which were reinterpreted as amplified with alternate probe showed low level amplification (range: 2.0-3.6; mean: 2.3). HER2 positivity rates following 2013 ASCO/CAP guidelines, both at initial testing and after additional testing to resolve equivocal results were significantly higher compared to 2007 ASCO/CAP guidelines and FDA criteria. Conclusions: 2013 ASCO/CAP guidelines lead to higher number of HER2 FISH positive and equivocal cases. In a reference laboratory setting where alternative control probe was used to resolves equivocal FISH cases, 31.2% of patients with initial equivocal results become HER2 positive. However, it is not known if these patients benefit from targeted therapies as they would not be included in the original adjuvant or metastatic trials.
Hyaluronan assessment in tumor microenvironment using new affinity histochemistry assay and scoring method.
Authors: Pu Jie , Aldrich Carrie , Zhu Junming , Jiang Ping , Wu Xionghua W. , Müller Thomas , Delgado Paco , Quiroz Michelle , Khelifa Sihem
Published: September 2018

e23196

Background: Enzymatic degradation of hyaluronan (HA) by PEGylated recombinant human hyaluronidase PH20 (PEGPH20) induces a remodeling of the tumor microenvironment that impacts tumor behavior and response to therapy. Ventana Medical Systems, Inc., (VMSI) and Halozyme Therapeutics co-developed the VENTANA HA RxDx Assay and a scoring method to evaluate HA in solid tumors to potentially predict which patients might better respond to the addition of PEGPH20 to cancer treatments. Methods: Using Halozyme’s novel recombinant HA binding probe altered to include a rabbit Fc region, VMSI developed a highly specific and sensitive affinity histochemistry assay that binds to HA in tissues. Histological features and staining patterns of 106 samples from Halozyme’s 109-202 Phase 2 study of PEGPH20 combined with nab-paclitaxel plus gemcitabine (AG) vs. AG alone in patients with previously untreated stage IV pancreatic ductal adenocarcinoma (PDA) with clinical outcome data were analyzed to develop a scoring method evaluating HA accumulation. Results: A novel scoring algorithm focused solely on the extracellular matrix (ECM) was developed. An ECM HA staining ≥ 50% of the entire tumor surface at any intensity defines an HA-High PDA. We recommend that a 0.05 cm x 0.2 cm uninterrupted fragment of tumor cells and associated stroma obtained using needle gauges of 16 to 20 G as the minimally required amount of tissue to assess HA in PDA. Based on verification studies performed by VMSI, including an inter-reader precision study with a 94% agreement rate, VMSI scoring method proved to be trainable, reproducible, and transferable to pathologists, supporting an IDE approval for selecting patients in the Phase 3 HALO 109-301 study. Conclusions: Performance of the VENTANA HA RxDx Assay, a robust affinity histochemical assay, has been successfully verified in PDA. Two Halozyme clinical studies in PDA (Phase 2 HALO 109-202 Stage 2 & ongoing Phase 3 HALO 109-301) are expected to validate the VMSI HA scoring method in selecting patients who might better respond to the addition of PEGPH20 to cancer treatments. Current Phase 1/2 studies are exploring the utility of the VENTANA HA RxDx Assay and the pantumor potential of PEGPH20.
Measuring functional HER2-driven signaling status ex vivo to predict response to HER2 therapy: Results from a mouse breast tumor xenograft study.
Authors: Laing Lance G. , Burns David J , Huang Yao , MacNeil Ian A. , Rich Benjamin E. , Soltani Sajjad , Myhre Samantha , Sullivan Brian
Published: September 2018

e23203

Background: Clinical trials indicate a weak correlation between HER2 expression levels and HER2 targeted therapy benefit. Other biological factors, such as HER2 signaling activity, may be important to measure when identifying patients for treatment with HER2 therapies. To measure the HER2 signaling activity of a patient’s live tumor cells, a new assay using an impedance biosensor, the CELx HER2 Signaling Function (CELx HSF) Test, was developed. In this study, we evaluated whether functional HER2 signaling status was more predictive of response to a dual-HER2 kinase inhibitor than HER2 receptor or gene amplification status, using breast tumor xenograft in vivo models. Methods: Two breast cancer cell lines were studied: HCC1954, a HER2+ cell line with normal HER2 signaling according to the CELx HSF Test, and BT483, a HER2- cell line with abnormally high HER2 signaling according to the CELx HSF Test. Thus, the HER2 receptor status of each cell line was opposite its HER2 signaling status. For each cell line, twenty 4-5 week old female NSG mice were injected with two million cells. Mice were randomly assigned to either a control group that received Captisol or a treatment group that received lapatinib at a dose of 20mg/kg daily for 16 days. Results: There was no significant difference in tumor volume between the control and lapatinib-treated groups in the mice injected with the HCC1954 (HER2+, normal HER2 signaling) cells. Average tumor sizes reached 1028.7 ± 166.9 mm3 for the control group and 893.8 ± 111.5 mm3 for the lapatinib-treated group (P = 0.285) by the end of the study. With the BT483 (HER2-, abnormal HER2 signaling) cells, lapatinib treatment significantly slowed down the increase in tumor size. Average tumor sizes reached 328.3 ± 54.9 mm3 for the control group and 192.4 ± 19.4 mm3 for the lapatinib-treated group (P = 0.0049). Conclusions: The results demonstrate that functional HER2-driven signaling status in live tumor cells is more correlative to response to lapatinib in mouse xenograft tumors than HER2 expression level. These findings provide strong evidence that HER2- breast cancer patients with abnormal HER2 signaling may respond to anti-HER2 therapies.
Managing cancer and living meaningfully (CALM): A randomized controlled trial of a psychological intervention for patients with advanced cancer.
Authors: Rodin Gary , Lo Christopher , Rydall Anne , Nissim Rinat , Malfitano Carmine , Shnall Joanna , Zimmermann Camilla , Hales Sarah
Published: September 2018

LBA10001

The full, final text of this abstract will be available at abstracts.asco.org at 2:00 PM (EDT) on Friday, June 2, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
SCORAD III: Randomized noninferiority phase III trial of single-dose radiotherapy (RT) compared to multifraction RT in patients (pts) with metastatic spinal canal compression (SCC).
Authors: Hoskin Peter , Misra Vivek , Hopkins Kirsten , Holt Tanya , Brown Gillian , Arnott Seonaid , Shibu Thomas Sharon , Reczko Krystyna , Beare Sandy , Lopes Andre , Forsyth Sharon
Published: September 2018

LBA10004

The full, final text of this abstract will be available at abstracts.asco.org at 2:00 PM (EDT) on Friday, June 2, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Temporal trends in chronic disease among survivors of childhood cancer diagnosed across three decades: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Gibson Todd M. , Mostoufi-Moab Sogol , Stratton Kayla , Barnea Dana , Chow Eric Jessen , Donaldson Sarah S. , Howell Rebecca M. , Hudson Melissa M. , Leisenring Wendy M. , Mahajan Anita , Nathan Paul C. , Ness Kirsten K. , Sklar Charles A. , Tonorezos Emily S. , Weldon Christopher Bertero , Wells Elizabeth M. , Yasui Yutaka , Armstrong Gregory T. , Robison Leslie L. , Oeffinger Kevin C.
Published: September 2018

LBA10500

The full, final text of this abstract will be available at abstracts.asco.org at 2:00 PM (EDT) on Friday, June 2, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
Adding abiraterone for men with high-risk prostate cancer (PCa) starting long-term androgen deprivation therapy (ADT): Survival results from STAMPEDE (NCT00268476).
Authors: James Nicholas D. , De Bono Johann S. , Spears Melissa Ruth , Clarke Noel , Mason Malcolm David , Dearnaley David P. , Ritchie Alastair W S , Russell J. Martin , Gilson Clare , Jones Robert J. , Gillessen Silke , Matheson David , Aung San , Birtle Alison J. , Chowdhury Simon , Gale Joanna , Malik Zafar , O'Sullivan Joe M. , Parmar Mahesh K B , Sydes Matthew Robert
Published: September 2018

LBA5003

The full, final text of this abstract will be available at abstracts.asco.org at 7:30 AM (EDT) on Saturday, June 3, 2017, and in the Annual Meeting Proceedings online supplement to the June 20, 2017, issue of the Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Saturday edition of ASCO Daily News.
UNICANCER: Prospective cohort study of treatment related chronic toxicities in patients with localized breast cancer (CANTO).
Authors: Luis Ines Maria Vaz Duarte , Cottu Paul H. , Mesleard Christel , Martin Anne-Laure , Dumas Agnes , Dauchy Sarah , Tredan Olivier , Levy Christelle , Adnet Johan , Rousseau-Tsangaris Marina , Andre Fabrice , Arveux Patrick
Published: September 2018

TPS10125

Background: Corresponding with improved survival among breast cancer patients an awareness of the long term effects of cancer treatments has increased. There is now a call for better coordination of care and management of these patients to focus on their survivorship. This study will identify factors associated with the development and persistence of long term toxicities in patients treated for Stage I-III breast cancer. In addition, it will characterize their incidence as well as, psychological, social and economic impacts. Methods: This is a prospective cohort study enrolling newly diagnosed invasive cT0-cT3, cN0-3, M0 breast cancer patients of 26 French comprehensive cancer centers. All patients will be followed for a minimum of 5 years. Patients will be assessed at diagnosis, 3-6 (M0), 12 (M12), 36 (M36), 48 (M48), 60 (M60), months after treatment completion. Treatment completion is defined as completion of primary surgery, chemotherapy or radiotherapy, whichever comes last. Adjuvant trastuzumab, endocrine therapy or participation in clinical trials can be ongoing. CANTO collects an extensive list of clinical, treatment, and toxicity data including validated patient reported outcomes questionnaires ( Hospital Anxiety and Depression scale [HADS], Scheier et Carver’s Questionnaire, Life Orientation Test-Revised [LOT-R], Beck Depression Inventory [BDI-SF], European Organization for Research and Treatment-QOL questionnaire for breast cancer [EORTC QLQC30-BR23], EORTC-FA13, 12 Item Short Form Survey [SF12], Global physical activity questionnaire [GPAQ]6, impact of cancer questionnaire [IOCv2], economic and social questionnaires). Blood collection is available for all patients at diagnosis, M0, M12, M36 and M60. Genotyping will be performed in all samples. Biologic substudies are ongoing (e.g, microbiotic and cognitive substudy). CANTO aggregates a multidisciplinary team of French investigators and created a dedicated national network. Enrolment started in 2012 and by December 2016, 10030 patients were already enrolled, with a goal of 12.000 patients. Clinical trial information: NCT01993498.
Testing a behavioral intervention to improve adherence to adjuvant endocrine therapy (AET).
Authors: Kimmick Gretchen Genevieve , Bosworth Hayden B , Keefe Francis J , Sutton Linda , Owen Lynda , Erkanli Alaattin , Reed Shelby D. , Staley Sarah A , Pak Sarah , Barrett Nadine , Huettel Scott , Shelby Rebecca A.
Published: September 2018

TPS10128

Background: Adjuvant endocrine therapy (AET) is a crucial component of treatment used to prevent recurrence and reduce mortality for women with hormone receptor positive breast cancer. Poor adherence to AET is a significant problem, with rates of non-adherence ranging from 28% to 59%. Non-adherence to AET contributes to increased medical costs and increased mortality. Symptoms (e.g., pain, hot flashes, sleep problems, vaginal dryness) associated with AET are related to non-adherence and early discontinuation of treatment. Our goal is to test the efficacy of a novel self-management intervention (SMAET) that teaches patients skills for enhancing adherence to AET and coping with AET-related symptoms. Methods: Trial participants will be recruited from a tertiary care medical center and community clinics that are located in medically underserved areas. Target enrollment is 400 patients. Prospective participants must meet the following criteria: diagnosis of Stage I to III breast cancer; hormone receptor positive tumor; local definitive cancer treatment complete; within 12 months of beginning AET; have at least 18 months of AET recommended; and at least 21 years of age. We will test the effects of the SMAET intervention (n = 200) by comparing it to a general health education intervention (n = 200; attention control). The SMAET protocol includes 7 sessions providing systematic training in coping skills for managing symptoms that interfere with adherence and 3 maintenance calls delivered over 6 months by a nurse via the phone. The intervention also includes interactive voice messaging that is tailored based on real-time adherence data. The primary study outcome, adherence to AET, will be assessed in real-time for 18 months using wireless smart pill bottles (i.e., bottle opening and percent of pills remaining). Symptom interference will be examined as a secondary outcome and will be assessed over 18 months. If effective, the intervention may reduce the burden of AET use. Clinical trial information: NCT02707471.
Phase 1 trial of lyso-thermosensitive liposomal doxorubicin (LTLD) and magnetic resonance guided high intensity focused ultrasound (MR-HIFU) for pediatric refractory solid tumors.
Authors: Kim AeRang , Sharma Karun , Yarmolenko Pavel , Celik Haydar , Kaplan Rosandra N. , Dome Jeffrey , Musso Lauren , Borys Nicholas , Partanen Ari , Warner Lizette , Kim Peter C W
Published: September 2018

TPS10579

Background: Prognosis for children and young adults with refractory solid tumors remains unacceptably poor. Current approaches have reached the limits of maximal dose intensification, and the acute and late side effects of therapy are substantial. MR-HIFU is an innovative therapy that uses an external applicator to focus ultrasound energy inside a tumor non-invasively and without radiation. The resulting heating is precisely controlled and accurately targeted with the aid of MR thermometry and anatomic imaging. The flexibility and control over local heating by MR-HIFU provide an ideal system to be used with LTLD, a novel formulation of liposomal doxorubicin with the unique property of rapid heat-activated release of doxorubicin, an active agent in most pediatric solid tumors. The potential synergistic effects include enhanced permeability of the tumor vasculature, enhanced extravasation of the drug and subsequent high local concentrations of doxorubicin in the targeted tumor, inhibition of DNA repair, and stimulation of immune responses. Methods: This is the first pediatric trial of LTLD with MR-HIFU in refractory solid tumors (NCT02536183). Part A is a phase 1 dose escalation study to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of LTLD combined with MR-HIFU ablation in children. Part B combines LTLD at the MTD/RP2D with MR-HIFU induced mild hyperthermia (MHT) in an expanded cohort. Patients ≤21 (Part A) and ≤30 (Part B) years of age with refractory solid tumors at sites accessible to MR-HIFU, adequate organ function including cardiac function, and prior anthracycline dose of ≤ 450 mg/m2 are eligible. LTLD is administered intravenously over 30 min followed immediately by MR-HIFU on day 1 of a 21-day cycle. Patients can receive a maximum of 6 cycles (or lifetime of 600 mg/m2 of cumulative anthracycline) provided treatment is tolerated and have at least stable disease. Secondary objectives evaluate changes in quality of life and pharmacodynamic immune markers in children treated with LTLD and MR-HIFU. Clinical trial information: NCT02536183.