tbuckley/cabot-search huggingface dataset:
Platinum based chemotherapy in elderly patients with non-small cell lung carcinoma (NSCLC): Experience from an Indian tertiary cancer center.
Authors: Aparna Sharma, Sachin Khurana, Raja Pramanik, Sunil Kumar, Sushmita Pathy, Prabhat Singh Malik
Journal: Journal of Clinical Oncology (2019)

e20528 Background: Instituting platinum based chemotherapy in elderly population is often associated with poor tolerance and attending toxicities. We present our limited center experience of chemotherapy in the geriatric population group. Methods: This is a retrospective single center experience of all registered patients in lung cancer clinic (LCC) in the department of medical oncology, Dr. B.R.A. IRCH, AIIMS. All histopathologically proven cases of NSCLC with age more than 70 years who received platinum based chemotherapy (single/doublet) with complete patient records were analysed. The study was carried out between November 2016 and August 2018.Data was analysed using STATA v13. Results: The cohort consisted of 25 patients who satisfied the inclusion criteria. Males comprised 84%(n = 21) of the cohort. Median age of study population was 72.7 years years (Range 70-84). 36%(n = 9) of the study population had one comorbidity while 8% (n = 2) had multiple comorbidities. 68% (n = 17) of the cohort were smokers. ECOG(Eastern cooperative oncology group) PS (performance status) 1 was seen in 48% (n = 12) and PS 2 in 32% (n = 8) and PS 3 in 16% (n = 4) respectively of the patients. Histopathologically, 48% (n = 12) of the population constituted squamous cell carcinoma while 40%(n = 10) had adenocarcinoma. 76%(n = 19) patients had Stage 4 NSCLC. Most common chemotherapy regimes used were weekly Paclitaxel carboplatin (n = 11, 44%), three weekly paclitaxel carboplatin (n = 8 , 32%) Pemetrexed carboplatin (n = 5, 20%) and gemcitabine carboplatin (n = 1, 4%). Only 12% (n = 3) could complete more than 4 cycles of chemotherapy and 3 could receive maintenance chemotherapy. Best responses according to RECIST (Response Evaluation Criteria In Solid Tumors) criteria v1.1 achieved were complete response in 12%(n = 3), partial response in 16% (n = 4), stable disease 24%(n = 6) and progressive disease in 48%(n = 12). Most common grade 3 and 4 adverse events according to CTCAE (common terminology criteria for adverse events) v4.03 were mucositis 29.17%(n = 7), diarrhea 12% (n = 3), peripheral neuropathy 12.5 (n = 3) and hematological toxicity 16%(n = 4). Conclusions: The patient number in this study cohort is limited.However, our experience demonstrates that abbreviated therapy in elderly subgroup is fairly well tolerated. Various tools like comprehensive geriatric assessment need to be utilized to provided tailored therapy in the elderly subgroup. A prospective study is required to address the efficacy and toxicity profile of chemotherapy in this select population.
Development and feasibility of virtual molecular tumor board.
Authors: Amit Verma, Jatinder Kaur, Amit Gupta, Aakriti Aggarwal, Arpana Kushwaha, Pramod Kumar Julka, Prashant Mehta, Randeep Singh, Vandana Lal
Journal: Journal of Clinical Oncology (2019)

e18334 Background: Practicing precision oncology is challenging due to the complex molecular interpretation and its implications in deciding pertinent treatment options. This is addressed by institutional Molecular Tumor Board (MTB) which is presided by all oncology sub-specialists including molecular biologist and bioinformatician, doing a meticulous job in untwining the intricacies but fail to obtain experiences across institutes. Further, meeting of all MTB members is neither always feasible nor accessible for the community oncologists. We hereby offer a virtual formation of MTB that is easily accessible and remotely attended by various experts across institutes, giving their opinion objectively at their ease that can be documented and archived. Methods: Virtual MTB (vMTB), a mobile cloud-based application was developed for both android and iOS platforms. The vMTB process involves submission and review of cases, whereby assigned members can opine blindly and rate different treatment options. Followed by averaging of rating score and then a final recommendation generated by the vMTB case-convener within 7 days, based on clinical context. A pilot study (2 months duration) was carried out where clinical cases bearing molecular information were invited from various oncology centers across India. Results: 21 cases were submitted (19 relapsed refractory, 3 treatment naïve) that included Breast (6), Lung (5), Leukemia/Lymphoma (3), Gall bladder (2), Uterine (2), Urinary bladder (1), GBM (1) and Sarcoma (1) cancers. The molecular query was based on 18 somatic (8 FoundationOne &amp; 10 Others) and 3 germline testing. Cases assigned to vMTB members (~7 members/case) had ~ 6 treatment options/case with a response turn-around time ~4 days. Therapeutic final recommendation(s) were given for all cases with 95% concordance among the members; 6 cases where multiple options were advised, discordance rate was 14%. Additional molecular diagnostic workup was advised in 3 cases. vMTB recommendations including 10 off label treatment options were accepted by majority of the submitting physicians (82%). Clinical benefit was observed in 5 (24%) cases within the stipulated analysis duration. Conclusions: vMTB is a user-friendly, feasible, acceptable mobile solution alternate to MTB for objectively generating clinically meaningful consensus document for complex molecular clinical case scenarios, where guidelines are limited. To best of our knowledge, this is a first smart mobile solution connecting various oncology experts and have an immediate utility for the practicing community oncologists globally.
Phase I dose escalation of H3B-6545, a first-in-class highly Selective ERα Covalent Antagonist (SERCA), in women with ER-positive, HER2-negative breast cancer (HR+ BC).
Authors: Erika Paige Hamilton, Elizabeth Claire Dees, Judy Sing-Zan Wang, Amy Kim, Manav Korpal, Vicki Rimkunas, Nathalie Rioux, Joanne Schindler, Dejan Juric
Journal: Journal of Clinical Oncology (2019)

1059 Background: H3B-6545 inactivates both wild-type and mutant ERα by targeting cysteine 530 and enforcing a unique antagonist conformation. Methods: Women with locally advanced or metastatic HR+ BC are treated (tx) with H3B-6545 administered once daily orally over a 28 day cycle after progression on at least one hormonal therapy and at least one additional therapy/regimen. Dose escalation uses a 3+3 design with the option to backfill previously cleared doses and allows for intrapatient dose escalation. This phase 1 explores the safety, pharmacokinetics and pharmacodynamics of H3B-6545 in women with HR+ BC to identify the recommended Phase 2 dose. Results: As of 10-Dec-2018, 32 pts have been tx with H3B-6545 at doses of 100 to 450 mg/day; 97% had prior tx with a CDK4/6 inhibitor and 56% had received ≥3 lines of prior anti-cancer therapy. No dose-limiting toxicities and only one Grade 3 treatment related adverse event (TRAE) have been observed (lymphocyte count decrease). The most common (≥10%) TRAEs include asymptomatic sinus bradycardia, diarrhea, nausea, fatigue, anemia, decreased appetite, and hot flush. H3B-6545 was rapidly absorbed with a t max of 2-4 h. Plasma concentration increased with dose from 100 to 450 mg, and was similar on C1D1 and C1D15. Consistent with the H3B-6545 mechanism of action and preclinical data, H3B-6545 inhibits ER target gene expression and shows a 50% decrease in Ki67 levels across all dose levels post-tx. ESR1 (60%) and PIK3CA (34%) mutations were detected in plasma at baseline and changes in mutant allele frequencies show correlation in response to tx. Stable disease was observed in 15 pts (47%) and 34% of pts completed at least 6 months of tx. Partial responses (PRs) were observed in 3 pts: 1 pt (mutant) received 2 prior lines of therapy and 2 pts (1 mutant and 1 wild-type) received &gt;5 prior lines of therapy including fulvestrant and capecitabine; all 3 pts received a prior CDK4/6 inhibitor. Conclusions: H3B-6545 has been well-tolerated up to the 450 mg dose level with early signs of single-agent anti-tumor activity in a post CDK4/6 setting. Dose escalation continues in pts with advanced HR+ BC. Clinical trial information: NCT03250676.
Chromosome 8q24 amplification predicts prognosis for patients with advanced hepatocellular carcinoma (HCC).
Authors: Yuan Cheng, Mengli Huang, Wenzhuan Xie, Chan Gao, Shangli Cai, Jing Ji, Mingxin Pan
Journal: Journal of Clinical Oncology (2019)

e15654 Background: China accounts for over 50% of global liver cancer burden and most patients have advanced disease at the time of diagnosis. Currently, very little is known about the mutational landscape of Chinese HCC patients because it is risky to perform tissue biopsy on late-stage patients. In this study, this problem was overcome by genetic profiling using circulating tumor DNA (ctDNA) and frequently mutated loci were evaluated as biomarkers for prognosis prediction. Methods: Targeted next generation sequencing (NGS) was performed on ctDNA obtained from patients with advanced HCC using a 150-gene panel. The relationship between overall survival (OS) and genetic alterations was analyzed using Kaplan-Meier method. The predictive value of frequently mutated genes was then validated using 607 western HCC cases of the cBioPortal (http://www.cbioportal.org,including TCGA and other two studies). Impact of 8q24 amplification on transcription of other genes was analyzed using mRNA data from TCGA database. Results: Fifty-eight Chinese advanced HCC patients were enrolled and ctDNA was detected in 89.7% of them. The most frequently mutated genes were TP53 (57.7%) and TERT (30.8%) and amplification of chromosome 8q24 occurred at a higher frequency (20.0%) than previously reported for western HCC patients. The 8q24 amplified patients showed significantly shorter OS compared to those without 8q24 amplification (4.9 months vs. Not Reached, p = 0.008). This was confirmed by the cBioPortal database, where 8q24 amplification, which was identified in 10.1% of the HCC cases, was also associated with decreased OS (55.6 months vs.102.7 months, p &lt; 0.001). Gene expression analysis using TCGA mRNA data revealed that upon 8q24 amplification, transcription of 56 genes was upregulated and 169 genes were downregulated, among which ABC transporters, RAS signaling and Hippo signaling pathways were significantly enriched in 8q24 amplified population (p = 0.001, 0.015, 0.027, respectively) as suggested by KEGG analysis. Conclusions: Amplification of chromosome 8q24 ocurred at a higher frequency in Chinese HCC patients and showed promise as a biomarker for prognosis prediction.
NET-02: A multi-center, randomised, phase II trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients (pts) with progressive poorly differentiated extra-pulmonary neuroendocrine carcinoma (PD-EP-NEC).
Authors: Mairead Geraldine McNamara, Jayne Swain, Zoe Craig, Jonathan Wadsley, Nicholas Reed, Olusola Olusesan Faluyi, Angela Lamarca, Richard Hubner, Wasat Mansoor, Debashis Sarker, Helen C Howard, David A. Cairns, Tim Meyer, Juan W. Valle
Journal: Journal of Clinical Oncology (2019)

TPS4158 Background: The prognosis for pts with PD-EP-NEC is poor. First-line treatment for advanced disease is etoposide/platinum-based chemotherapy, analogous to that of high grade lung NEC, with no standard second-line treatment, and is an area of unmet need. Methods: This is a multi-centre, randomised, phase II trial of nal-IRI; 80mg/m 2 intravenously (IV) over 90 mins, prior to 5-FU; 2400 mg/m 2 infusion over 46 hrs and folinic acid, Q14 days, or docetaxel; 75mg/m 2 IV over 60 mins, Q21 days, as second-line therapy in pts with progressive PD-EP-NEC (Ki-67 &gt; 20%), with the overall aim of selecting a treatment for continuation to a phase III trial. The standard arm is that used in high-grade lung NEC, of which docetaxel is a second-line therapy option (NCCN guidelines) and combination regimens such as Irinotecan/5-FU are a second-line therapy option currently used without trial evidence for this subset of pts. Pts must have had prior treatment with first-line platinum-based chemotherapy, have documented disease progression and have an ECOG performance status of ≤2. This study plans to recruit 102 pts from 16 UK centres (over 37 mths). Primary endpoint is 6-mth progression-free survival (PFS) rate; trial is designed to have an 80% chance of demonstrating that the one-sided 95% confidence interval of the 6 mth PFS rate excludes 15%, if the true rate is at least 30%, where 30% is the required level of efficacy, and a rate of &lt; 15% would give grounds for rejection. If both treatment arms exceed the required level of efficacy to warrant further evaluation in a phase III trial, treatment with the higher PFS rate at 6 mths will be selected. Secondary endpoints include overall survival, objective response rate, toxicity, quality of life, serum neuron-specific enolase. Exploratory endpoints include quantification of circulating tumour cells (CTCs), circulating tumour deoxyribonucleic acid (ctDNA) and molecular profiling of CTCs, ctDNA and tumour tissue, and generation of CTC-derived xenografts. This trial is open and has enrolled 6 pts at time of submission. Clinical trial information: 10996604.
Long non-coding RNA Linc00525 as a prognostic factor to regulate proliferation and apoptosis in colorectal cancer.
Authors: Peng Peng, Qin Zheng
Journal: Journal of Clinical Oncology (2019)

e15085 Background: Colorectal cancer (CRC) is one of the most common digestive system tumors and poses a serious threat to human health. More and more studies have shown that long noncoding RNAs (lncRNAs) play an important role in the occurrence and development of various tumors. They regulate a variety of cancer biology, such as proliferation, apoptosis, invasion and metastasis. Abnormally expressed lncRNAs are closely related to colorectal cancer. The purpose of this study was to find lncRNAs associated with the development of colorectal cancer and to explore its function and mechanism. Methods: (1) By analyzing the expression profile of lncRNAs in colorectal cancer-normal tissues in GEO databases, the abnormal expression of lncRNA LINC00525 was screened. Colorectal cancer tissues, adjacent normal colon tissues and colorectal cancer cell lines (HCT116, DLD1, HT-29, SW480) were detected by qRT-PCR. We analyzed the relationship between expression of LINC00525 and clinical features. (2) The biological functions of LINC00525 in HCT116, DLD1 and SW480 were peformed in vitro by MTT, clone formation assay, EDU and flow cytometry. (3) The effect of LINC00525 on tumorigenesis in vivo was evaluated by nude mice model. (4) The expression of lncRNA LINC00525 was knocked down in colorectal cancer cell lines (HCT116, SW480), and the mRNA expression levels of P15, P21, P27 and KLF2 were detected by qRT-PCR. Results: (1) Microarray data and qRT-PCR verification showed that the expression of lncRNA LINC00525 in colorectal cancer tissues and colorectal cancer cell lines was significantly upregulated. The overexpression of LINC00525 was positively correlated with clinical stage and tumor size. (2) Knockdown of LINC00525 in colorectal cancer cell lines could inhibit cancer cell proliferation and induce apoptosis. In SW480 and HCT116 cell lines, cells were arrested in G0/G1 phase after knocking down LINC00525. (3) Subcutaneous xenograft experiments in nude mice further confirmed that knockdown of LINC00525 could inhibit the tumor growth. (4) After knocking down the expression of LINC00525 in HCT116 and SW480 cell lines, the expression of mRNAs of tumor suppressor genes P15, P21, P27 and KLF2 increased. Conclusions: Our studies suggested that LINC00525 was significantly upregulated in colorectal cancer tissues. Mechanism studies had shown that LINC00525 could regulate the expression of KLF2, P15, P21 and P27 in CRC cell lines, and then affect cell proliferation and apoptosis.
Effect of therapeutic GAS6/AXL inhibition of tumor and stromal cells on DNA damage and response to chemotherapy in ovarian cancer.
Authors: Mary M Mullen, Elena Lomonosova, Hollie M Noia, Lei Guo, Lindsay Midori Kuroki, Andrea M Hagemann, Carolyn K. McCourt, Premal H. Thaker, David Gardner Mutch, Matthew A. Powell, Katherine Cynthia Fuh
Journal: Journal of Clinical Oncology (2019)

e14676 Background: Ovarian cancer is the leading cause of death due to gynecologic malignancy. Biomarkers to predict chemoresponse and novel therapies to target these proteins would be practice changing. We aim to establish serum and tissue GAS6 as a predictive biomarker of chemoresponse and to determine if AXL inhibition through sequestration of its ligand, GAS6, with AVB-S6-500 (AVB) can improve chemoresponse. Methods: AVB was supplied by Aravive Biologics. High grade serous ovarian cancer (HGSOC) tumor samples were obtained pre- and post-neoadjuvant chemotherapy. AXL and GAS6 expression were evaluated by immunohistochemistry and serum concentration. In vitro viability and clonogenic assays were performed on chemoresistant tumor (OVCAR8, OVCAR5, COV62, and POV71-hTERT) and stromal cells (CAF86) treated with chemotherapy +/- AVB. Mouse models (OVCAR8, PDX, OVCAR5) were used to determine if the combination of chemotherapy + AVB reduced tumor burden. Immunofluorescent assays targeting ɣH2AX were used to evaluate DNA damage. Results: Patients with high pretreatment tumor GAS6 expression ( &gt; 85%, n = 7) or serum GAS6 concentrations ( &gt; 25ng/mL, n = 13) were more likely to be resistant to neoadjuvant chemotherapy than those with low tumor GAS6 expression ( &lt; 45%, n = 4) (P = 0.010) or low serum GAS6 concentrations ( &lt; 15ng/mL, n = 5) (P = 0.002). Carboplatin plus AVB (2µM, 5µM) and paclitaxel plus AVB (1µM) resulted in decreased cell viability and clonogenic growth compared to chemotherapy alone (p &lt; 0.05) in all tumor and stromal cell lines. Synergism was seen between carboplatin+AVB and paclitaxel+AVB with a weighted combination index &lt; 1. In vivo tumor mouse models treated with chemotherapy+AVB had significantly smaller subcutaneous and intraperitoneal (IP) tumors than those treated with chemotherapy alone (3.1mg vs 64mg, P = 0.003 OVCAR8; 62mg vs 157mg, P = 0.0108 PDX subcutaneous model; 0.05mg vs 0.3669mg, P &lt; 0.001 OVCAR5 IP model). Increased DNA damage was noted in tumor and stromal cells treated with carboplatin+AVB compared to carboplatin alone (OVCAR8, COV362, CAF86 P &lt; 0.001). Conclusions: High GAS6 is associated with lack of neoadjuvant chemoresponse in HGSOC patients. The combination of chemotherapy with AVB decreases tumor cell viability, tumor growth, and an increase in DNA damage response.
The Pro-Oncogenic Adaptor CIN85 Acts as an Inhibitory Binding Partner of Hypoxia-Inducible Factor Prolyl Hydroxylase 2
Authors: Nina Kozlova, Daniela Mennerich, Anatoly Samoylenko, Elitsa Y. Dimova, Peppi Koivunen, Ekaterina Biterova, Kati Richter, Antti Hassinen, Sakari Kellokumpu, Aki Manninen, Ilkka Miinalainen, Virpi Glumoff, Lloyd Ruddock, Lyudmyla Borysivna Drobot, Thomas Kietzmann
Journal: Cancer Research (2019)

The EGFR adaptor protein, CIN85, has been shown to promote breast cancer malignancy and hypoxia-inducible factor (HIF) stability. However, the mechanisms underlying cancer promotion remain ill defined. Here we show that CIN85 is a novel binding partner of the main HIF-prolyl hydroxylase, PHD2, but not of PHD1 or PHD3. Mechanistically, the N-terminal SRC homology 3 domains of CIN85 interacted with the proline-arginine-rich region within the N-terminus of PHD2, thereby inhibiting PHD2 activity and HIF degradation. This activity is essential in vivo, as specific loss of the CIN85-PHD2 interaction in CRISPR/Cas9-edited cells affected growth and migration properties, as well as tumor growth in mice. Overall, we discovered a previously unrecognized tumor growth checkpoint that is regulated by CIN85-PHD2 and uncovered an essential survival function in tumor cells by linking growth factor adaptors with hypoxia signaling. SIGNIFICANCE: This study provides unprecedented evidence for an oxygen-independent mechanism of PHD2 regulation that has important implications in cancer cell survival. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/79/16/4042/F1.large.jpg.
A preliminary single institution experience with droplet digital polymerase chain reaction (dd-PCR) liquid biopsy (LB) for therapeutic decision in advanced solid tumors: Personal precision oncology clinic and genetic diagnostics, Brazil.
Authors: Andre Marcio Murad, Jose Claudio Casali Rocha
Journal: Journal of Clinical Oncology (2019)

e14613 Background: Droplet digital polymerase chain reaction (dd-PCR) is a promising method for analyzing minor amounts of cell-free circulating free nucleic acid (DNA and RNA) due to its high sensitivity, low cost, and fast reading, since it dispenses bioinformatics, making it an appropriate alternative to new generation sequencing (NGS) for the detection of biomarkers to guide molecularly targeted cancer therapy. The assay covers main actionable hotspot alterations across many actionable genes: EGFR(mutations), ALK (fusion, mutations), ROS1(fusion), BRAF(mutations), KRAS (mutations), NRAS(mutations), ERBB2(CNV), ESR1(mutations), KIT(CNV) and PDGFRA(CNV). Methods: We analyzed so far 38 patients with advanced NSCLC: 13(35%), breast: 9(24%), colorectal: 6(16%), pancreatic: 4(10%), ovary: 2(5%), salivary gland: 2(5%), melanoma 1(2.5%), and GIST: 1 (2.5%). ddPCR was performed using the QX200 system (BIO-RAD, Hercules). All samples were tested in duplicate. All assays were performed at Personal Precision Genetic Diagnostics. Belo Horizonte, MG. Brazil. Results: We detected meaningful genomic alterations in 7(18.5%) patients: 4(10.5%) KRAS G12V mutations (all in colorectal cancer), 1(2.6%) EGFR Del19 mutation, 1 EGFR L858R mutation(2.6%), both in NSCLC and 1(2.6%) ERBB2 amplification (in breast cancer). MAF (Mutant Allele Fraction) varied from 0.9% to 24%. In all cases the results were decisive for the indication or the change of a targeted therapy. Conclusions: Our preliminary results suggest that dd-PCR is a highly sensitive method and could be used for a routine laboratory detection of the important genomic variations to determine the targeted therapy in patients with varied advanced solid tumors.