bluuebunny/crossref_metadata_2025 huggingface dataset:
MET amplification and exon 14 skipping in treatment naïve patients in lung cancer.
Authors: Han Yaqian , Xu Ying , Liu Chunling , Zhao Jun , Zhu Lingjun , Li Liren , Gen Lin , Liu Lianke , Cheng Yong , Ye Ke , Chen Likun , Zhang Longbo , Yu Fenglei , Du Kaiqi , Miao Liyun , Chen Rongrong , Xia Xuefeng
Published: May 2019

e14543

Background: Somatic mutations in MET are diverse and include MET amplification, exon 14 skipping and also some functional point mutations (H1094Y, Y1230H, D1228N, etc). Generally, amplification and ex14 skipping are the two main mutation types. Methods: MET mutation profiles were analyzed using hybridization capture based next-generation sequencing (NGS), which enables the simultaneous detection of multi-mutation types of at least 59 genes (range 59-1021 genes). Results: Screening tens of thousands treatment naive patients, we found 319 patients with MET mutations, 56 patients (18%) with MET amplification, 55 patients (17%) with MET ex14 skipping, and 214 patients with other unknown functional point mutations. 39 cases with MET amplification and 52 cases with MET ex14 skipping in lung cancer. Patients with MET amplification or ex14 skipping had fewer mutations compared with patients with other MET mutations ( P < 0.0001), while there were no differences in ctDNA abundance between two groups ( P = 0.58). Further compared the MET amplification and ex14 skipping groups, we found mutation numbers and ctDNA abundance were both significant lower in ex14 skipping group (mutation numbers: P = 0.0134; ctDNA abundance: P < 0.0001). MET amplification range from 2 to 7 copies in these 39 patients, and patients with more than 3 copies had a higher ctDNA abundance than = < 3 copies patients ( P < 0.0005). Six patients with both amplification and ex 14 skipping, all of them with advanced age ( > 70 years). Of the MET amplification group, 11 patients (28%) developed EGFR driver mutation concurrently, four patients with L858R, three with ex19 del, one with G719A, one with both L858R and EGFR amplification, one with both ex19 del and amplification and one with only amplification, while no patients were found to have any EGFR driver mutation in MET ex14 skipping group. Conclusions: The cfDNA from patients with EGFR amplification or ex14 skipping was only 18% or 17% in MET mutations. Both of these two mutation types were mainly found in lung cancer. Furthermore, MET amplification group patients had fewer mutations and lower ctDNA abundance. In treatment naïve patients, MET amplification concurrent with other EGFR drive mutations, rather than ex14 skipping.
Longitudinal monitoring of cell-free DNA to predict for transarterial chemo-embolization failure in hepatocellular carcinoma.
Authors: Evans Joanne , Ward Caroline , Pai Madhava , Sharma Rohini
Published: May 2019

e14544

Background: Transarterial chemo-embolization (TACE) is the standard of care for patients with intermediate stage hepatocellular carcinoma (HCC) with adequate synthetic function, and as bridging treatment in early stage disease. Survival outcomes are heterogeneous, and improved biomarkers are needed for detection of early relapse. Current practice relies on monitoring of alpha-foetoprotein (AFP) and serial imaging. Circulating cell-free DNA (cfDNA) is a compelling emergent biomarker. Here, we describe the first study of cfDNA as prognostic biomarker in HCC following TACE. Methods: 34 patients treated with TACE (2012-2018) who had full demographic information and longitudinal stored plasma available were identified. Samples were retrieved and cfDNA extracted using the QIAamp Circulating Nucleic Acid Kit. cfDNA yields were quantified by high-sensitivity Qubit analysis. Results: 74% of patients were male, 66% had Childs Pugh A disease, and 56% of patients secreted AFP ( > 10ng/mL). Aetiologies of liver diseases were varied: viral hepatitis (44%), alcoholic or non-alcoholic steatohepatitis/cirrhosis (29%), hereditary or auto-immune (12%), and unexplained (15%). 79% of patients saw a fall in cfDNA titre following TACE. Where no reduction was seen, patients had a poorer median overall survival than those who did: 20 months (range 5.13 – 66.7 months) compared to 37 months (9.9 – 79.3 months). Of note, 44% of patients were AFP non-secretors. Here, cfDNA had a clear advantage in disease monitoring, with mean cfDNA titres in this group falling post treatment: from 1605.1 (range 185.9 – 6830) ng/mL to 693.7 (range undetectable - 2300) ng/mL and rising again with subsequent progression (mean of 1329.2 - range 616 – 3341 - ng/mL). Conclusions: These findings support a cost-effective monitoring role for plasma cfDNA analysis following treatment with TACE, with an added advantage in AFP non-secretors. Prospective validation is suggested to fully assess clinical utility.
Identify driver mutants in lung cancer by supernatants of pleural effusion and monitor resistance to targeted therapy.
Authors: Wang Yuehong , Wang Tao , Xiao Shanshan , Mao Ruifang , Lin Rui
Published: May 2019

e14554

Background: Malignant pleural effusion (MPE) from lung cancer is an attractive alternative for molecular testing due to advantages of non-invasiveness and less heterogeneity. Previously, cell pellet blocks of MPE are widely used. This study is to further address whether supernatants of MPE is a suitable source to identify key oncogenic mutants in lung cancer and provide more information for clinical molecular testing. Methods: MPE samples from 12 lung cancer patients were centrifuged to obtain supernatants and cell pellets, and DNA were extracted. The DNA samples were analyzed by a targeted next generation sequencing (NGS) panel using Illumina HiSeq platform. Results: In a pilot study, paired cancer tissue and MPE samples were obtained from 3 lung cancer patients and analyzed using a comprehensive 500-gene cancer panel. Nine mutants were identified both in the tissue samples and MPE samples. We then analyzed another 9 lung cancer patient samples to detect oncogenic mutants using an 18-gene panel. In total, 8 mutants including EGFR L858R, exon 19 deletion, or T790M mutants were identified in MPE samples. For the total 17 mutants from the 12 MPE samples, 10 mutants were observed in both matched supernatant and cell pellet of MPE, of which more pairs (6 out of 10) had supernatants with higher abundance of mutants than cell pellets. More importantly, 7 of the 17 mutants were only detected in the supernatants of the matched MPE. Taken together, these results suggest that supernatant of MPE is a more suitable source to detect key driver mutants of lung cancer. Interestingly, 2 patients had both tyrosine kinase inhibitor (TKI) resistant mutant T790M and TKI sensitive mutants detected in supernatants of MPE; both patients had prior treatment of EGFR TKI, consistent with the development of TKI resistant mutant and supporting the utility of supernatants of MPE in monitoring TKI resistance. Conclusions: This study suggest supernatant of MPE is a more suitable source for identifying key driver mutants for lung cancer and can also be used to monitor response to targeted therapy. The study provides evidence of using supernatant of MPE as alternative source for molecular testing and thus direct precise targeted therapy and effect surveillance.
cfDNA analysis to reveal association of genomic features with chemotherapy response and survival in patients with pulmonary large-cell neuroendocrine carcinoma.
Authors: Zhuo Minglei , Guan Yan-Fang , Yang Xue , Hong Lingzhi , Wang Yuqi , Li Zhongwu , Chen Runzhe , Abbas Hussein , Zhong Jia , Chen Hanxiao , Dong Zhi , Zhu Xiang , Li Jianjie , Roarty Emily , Rinsurongkawong Waree , Lewis Jeff , Futreal Andrew , Xia Xuefeng , Zhang Jianjun , Zhao Jun
Published: May 2019

e14555

Background: The optimal systemic treatment for pulmonary large-cell neuroendocrine carcinoma (LCNEC) is still under debate. Previous studies showed that LCNEC with different genomic characteristics might respond differently to different chemotherapy regimens suggesting the potential role of genomic profiling in therapeutic decision-making. Tumor biopsies are often inadequate for genomic profiling, while cell-free DNA (cfDNA) analysis has demonstrated great potential in genomic profiling. Methods: A total of 63 patients with LCNEC treated with different chemotherapy regimens (etoposide-platinum doublets, pemetrexed with platinum and gemcitabine, docetaxel, or paclitaxel with platinum, hereafter referred to as SCLC-PE, NSCLC-PEM and NSCLC-GEM/TAX) were enrolled in this study. Samples were collected and included tumor DNA only from 22 patients, cfDNA only from 18 patients and paired tumor DNA and plasma cfDNA from 23 patients. Tumor DNA and cfDNA were sequenced by target-captured 179 genes from Geneplus-Beijing or Oncomine Cancer Panel v3 or 70 genes panel from Guardant 360. Survival and response analyses were only applied to 54 patients who received first line chemotherapy. Results: The mutation landscape of frequently mutated cancer genes in LCNEC from cfDNA closely resembled that from tumor DNA, which led to a 90% concordance in genomic subtyping. We classified LCNEC harboring any of these alterations: RB1 mutation/loss, PTEN mutation/loss, FGFR1/FGFR4 mutation/amplification, TP53 loss, as “SCLC-like” tumors, otherwise as NSCLC-like. Overall, patients with SCLC-like LCNEC had a shorter overall survival (OS) than those with NSCLC-like LCNEC (10.3 vs 14.4 months, p = 0.32) despite higher response rate (RR) (41% vs 22%) to chemotherapy. Furthermore, treatment with SCLC-PE was associated with longer PFS in SCLC-like LCNEC compared to NSCLC-PEM and NSCLC-GEM/TAX (median 8.3 vs 2.3 months, p = 0.0002; median 8.3 vs 5.9 months, p = 0.05), while treatment with NSCLC-GEM/TAX led to a shorter survival compared to SCLC-PE (median 1.9 vs 4.1 months, p = 0.03) or NSCLC-PEM in NSCLC-like LCNEC patients (median 1.9 vs 4 months, p = 0.07). Conclusions: Genomic subtyping has potentials in prognostication and therapeutic decision-making for patients with LCNEC and cfDNA analysis is a reliable alternative for genomic profiling of LCNEC.
Circulating tumor DNA (ctDNA) mutation and epigenomic patterns in early-stage lung cancer patients and its utility in identifying patients at high risk for early recurrence.
Authors: Cho Jong Ho , Kim Il-Jin , Lee Junghee , Kim Hong Kwan , Lee Jinseon , Lee Se-Hoon , Shultz Matthew , Jaimovich Ariel , Odegaard Justin , Talasaz AmirAli , Kim Jhingook
Published: May 2019

e14557

Background: Circulating tumor DNA (ctDNA) analysis has been successfully applied to therapy selection and treatment monitoring in advanced cancer patients. However, it is not yet established whether ctDNA can be used clinically for early cancer detection or predicting tumor recurrence in early stage lung cancer patients. Methods: We analyzed pre-operative plasma samples from 55 early stage NSCLC patients (stages I-IIIA) using next-generation sequencing to detect somatic mutations and differential epigenomics patterns, including methylation signatures. Results: Using somatic mutation analysis alone, ctDNA was detected in 42% (23/55) of patients, whereas combined mutational and epigenomic analysis detected ctDNA in 71%. ctDNA detection rate also varied markedly between lung squamous cell carcinoma (SCC) and adenocarcinoma (ADC);using combined analysis of somatic mutations and epigenomic patterns, ctDNA was detected in all SCC patients, while only 55% of ADC (12/22) were ctDNA-positive (p= 0.006). Within the ADC subgroup, ctDNA detection rates using the combined approach were dependent on disease stage: 47% (8/17) in stage I, 100% (2/2) in stage II, and 100% (2/2) in stage IIIA. Importantly, pre-operative ctDNA status was correlated with tumor recurrence post-resection; three of eight (38%) ctDNA-positive stage I ADC patients recurred within 2 years of resection, while only one of nine (11%) ctDNA-negative stage I ADC patients recurred (p= 0.29). Conclusions: Taken together, we show that the combination of somatic mutation detection and epigenomic analysis outperforms each individual biomarker in the detection of ctDNA in early stage lung cancer. Importantly, we also demonstrate that pre-operative ctDNA detection may identify a high-risk population of early stage lung cancer patients that may benefit from (neo)adjuvant therapy.
Dynamic change of PD-L1 expression on circulating tumor cells in advanced breast cancer undergoing PD-1 blockade therapy.
Authors: Wang Tao , Zhou Jinmei , Zhang Shaohua , Bian Li , Hu Zhiyuan , Jiang Zefei
Published: May 2019

e14558

Background: PD-1/PD-L1 checkpoint blockade immunotherapy is revolution- izing the therapeutic strategy of malignancies. Tumor PD-L1 levels have predictive value in PD-1/PD-L1 checkpoint blockade therapies. Whether PD-L1 expression on circulating tumor cells (CTCs) could serve as an alternative biomarker is of great interest, especially in breast cancer. Methods: We established an immunofluorescence assay for semi-quantitative assessment of the PD-L1 expression levels on CTCs with four categories (PD-L1negative, PD-L1low, PD-L1medium and PD-L1high). 20patients with advanced breast cancerwere enrolled who took PD-1 inhibitortherapy. The CTC numeration and the PD-L1 expression levels were analyzedat the begining and ending of treatment . Results: 20 patients were enrolled, 85%(17/20) were triple-negative breast cancer. 65% of patients had visceral metastases, 60% of patients had ≥3 lines of treatment. Prior the treatment of PD-1 inhibitor, 95% (19/20) patients had CTCs, ranging from1 to 53(median 5). 90% (18/20) had PD-L1positive CTCs, and 75% (15/20) had at least one PD-L1high CTCs. The clinical benefit rate(CBR) rate in PD-L1high patients (26.7%) is much higher than the others (0%). we examined the proportion of PD-L1high CTCs relative to total CTCs. The median proportion of PD-L1high CTCs was 33.3%. Patients with ≥33% PD-L1high CTCs had a significantly longer PFS (median 2.6 vs. 1.4 months( P = 0.027). 100% patients with CBR had PD-L1highCTCs decreased and 46.7% of patients without CBR decreased. Further analysis showed that the mean proportion of PD-L1highCTCs at baseline and after treatment was 56.8±20.7%, 19.0±23.7%, p = 0.005. There was no significant difference in the mean proportion of PD-L1highCTCs before and after treatment in the non-CBR group (28.0±26.2%, 30.3±31.5%, p = 0.846). Conclusions: We revealed that the abundance of PD-L1high CTCs at baseline might serve as a predictor to screen patients for PD-1/PD-L1 blockade therapies and measuring the dynamic changes of PD-L1high CTCscould indicate the therapeutic response at early time.
Clinical significance of circulating tumor cells identified by cell-surface vimentin in pancreatic cancer.
Authors: Wei Tao , Zhang Qi , Liang Tingbo , Bai Xueli
Published: May 2019

e14562

Background: Identification of circulating tumor cells (CTCs) largely rely on epithelial tumor cell marker. Here we sought to interrogate whether cell-surface vimentin could be a biomarker for isolating CTCs potentially with mesenchymal phenotype in pancreatic ductal adenocarcinoma (PDAC). Methods: In total, 100 PDAC patients, 16 patients with intraductal papillary mucinous neoplasm (IPMN), and 30 healthy individuals were enrolled between December 2016 and November 2017. Potential CTCs were captured in 4 ml blood samples by vimentin antibody-coated microfluidic chip. CTCs were defined as vimentin+CD45-Hoechst+. Results: In vitro experiment showed that vimentin was highly expressed on the surface of pancreatic tumor cells with mesenchymal phenotype. Overall, vimentin+ CTCs were detected in 76% of patients with PDAC, but only in 2 out 30 healthy donors. Besides, five patients (31.3%) with IPMN had vimentin+ CTCs, and 10 CTCs were identified in one case. Using a cut-off value of two cells/4 ml of blood, 65% PDAC patients were positive for vimentin+ CTCs , while the positivity rates for the patients with IPMN and the healthy controls were 25% and 0%, respectively. Combined vimentin+ CTCs and CA19-9 offered a favorable diagnostic potency with area under curve of 0.968. Vimentin+ CTCs counts correlated with change of tumor burden for patients undergoing resection ( P < 0.01). Significant reduction of CTCs counts was observed after chemotherapy for subjects responding to treatment ( P < 0.05). The paired analysis showed that CTC counts was higher in portal vein blood than peripheral blood for 10 patients with available samples ( P < 0.05). Patients with 2 or more CTCs detected had more advanced disease and poorer differentiated tumor. In addition, preoperative higher CTCs counts correlated with shortened recurrence-free survival (Log-rank test: P = 0.02). Conclusions: Vimentin+ CTCs serves as a reliable biomarker in pancreatic cancer. The enrichment of potential mesenchymal CTCs could complement the strategy capturing epithelial CTCs, and provides a way to more thoroughly interrogate the biology and clinical significance of CTCs in PDAC.
Analysis of circulating tumor DNA to monitor metastatic breast cancer patients treated with first-line chemotherapy (CAMELLIA study).
Authors: Yi Zongbi , Ma Fei , Rong Guohua , Li Jin , Chang Lianpeng , Guan Yanfang , Liu Binliang , Guan Xiuwen , Li Lixi , Li Chunxiao , Zhai Jingtong , Qian Haili , Xu Binghe
Published: May 2019

e14568

Background: Our precious study indicated that the dynamic changes in circulating tumor DNA (ctDNA) could reflect changes in tumor burden. We conduct this study to validate the role of ctDNA as a therapeutic response biomarker in a larger cohort prospective phase III randomized multicenter study. Methods: In this study, we collected 292 serial ctDNA samples from 125 metastatic breast cancer patients treated with first line chemotherapy. Target-capture deep sequencing of 1021 genes was performed to detect somatic variants in ctDNA. Results: 81.4% patients had detectable ctDNA at baseline. An undetectable ctDNA at baseline was associated with a lower disease volume (p < 0.05). The commonly mutated genes were PIK3CA (35.0%), TP53 (34.2%), MLL3 (9.4%) and ESR1 (9.4%). Kaplan–Meier analysis showed that TP53 gene mutations and remaining C2 (detected at base line and remaining at the second cycle of chemotherapy) were significantly associated with poor PFS. Longitudinal monitoring of 27 patients during treatment showed that the molecular tumor burden index ([mTBI] a measure of the percentage of ctDNA in samples) was positively correlated with tumor size as evaluated by computed tomography (P < 0.05). The evaluations based on mTBI values were consistent with those based on CT scans in 87.5% of cases at the endpoint of clinical observation. Conclusions: ctDNA could be used to predict treatment outcomes and the mTBI is a potential method to assess therapeutic response in metastatic breast cancer. Clinical trial information: NCT01917279.
PDL1 landscape in checkpoint inhibitor ineligible patients by IHC and cfRNA.
Authors: Kato Shumei , Khalid Noor , Jimenez Rebecca , Lee Suzanna , Drusbosky Leylah , Szeto Christopher , Garner Chad , Reddy Sandeep K. , Kurzrock Razelle
Published: May 2019

e14570

Background: Immune checkpoint inhibitors (ICT) are indicated in patients with PDL1+ IHC and restricted to certain histologies . Other tumor histologies express PDL1 at various frequencies with no established threshold for therapeutic efficacy. We evaluated traditionally ICT non-indicated histologies by IHC and cfRNA to determine potential therapeutic thresholds. Methods: A total of 97 pts (cancer of unknown primary [N = 10], appendix [N = 6], bile duct [N = 4], colorectal cancer [N = 25], esophageal [N = 6], ovary [N = 7], pancreas [N = 15], other [N = 24]) with IHC (Dako 76 22C3, 21 SP142) and cfRNA for PDL1 were available for analysis. cfRNA was a random draw not matched with the time of tissue collection and performed by qPCR. A cutoff of > 1.5x for PDL1 normalized to beta actin was defined as PDL1+ in cfRNA. IHC > 10% was used as the threshold for IHC+. Results: Most patients were PDL1- by IHC: 90/97 (93%), PDL1 TPS: 0% (N = 72), 1% (N = 7), 5% (N = 8), 10% (N = 3), > 10% (N = 3), > 50% (N = 4). No difference was seen between 22C3 and SP142 antibodies. PDL1+ cfRNA (N = 59), PDL1- cfRNA (N = 38). Positive concordance for cfRNA PDL1+ and IHC PDL1+ was 10.2% (6/59). Negative concordance for cfRNA PDL1 - and IHC PDL1- was 97.4% (37/38) (p = 0.079). Conclusions: In ICIs ineligible patients a > 50% IHC threshold is rarely met (4%). Random draw qPCR PDL1 is poorly correlated with IHC, with higher rates of PDL1+ in cfRNA in setting of IHC PDL1-. In the other hand, cfRNA PDL1- is strongly associated with an IHC negative result. Further investigation incorporating both cfRNA and IHC result to predict the response from ICIs are warranted.
Genetic mutation analysis of plasma circulating tumor DNA by ultra-deep sequencing in breast benign lesions and cancers.
Authors: Wu Qian , Jian Wenjing , Yao Xumei , Xie Xintong , Fang Hanjie , Geng Shengkai , Song Shufeng , Sheng Haiyan , Liu Xia , Cheng Fangsheng , Xie Wenling , Lu Shixin , Wang Yanhui , Deng Longhui , Li Xiaohua , Wang Xianming , Zhang HW , Xu Chuanbo
Published: May 2019

e14572

Background: Mammography screening for breast cancer results in large number of impalpable lesions without clear determination of the malignancy. Analysis of breast cancer related gene mutations in blood circulating tumor DNA (ctDNA) may provide clarification. This analysis aims to provide insights into the feasibility of the approach. Methods: The clinical trial was conducted at top tier teaching hospitals in China to recruit patients with breast diseases for surgery. Eligible patients were consented and the breast lesions were pathologically diagnosed. Peripheral blood was collected prior to surgical resection. For breast cancer patients, samples of resected tissue were also collected. The samples were analyzed using our proprietary NGS technique called systematic error correction sequencing (Sec-Seq) (detailed in Abstract ##e23057, ASCO 2018). Results: In total, 69 patients with breast lesions (57 malignant and 12 benign) were included in this analysis. Tumor gDNA and plasma ctDNA were analyzed by deep NGS sequencing using a panel of 62 breast cancer-associated genes. The average sequencing depth is 35000. After deduplication, the average number of unique reads is 1500. Detection limit for mutant allele frequency was set at 0.2% for ctDNA and 1% for tumor tissue. For ctDNA mutation detection, 2 out of 12 patients with benign diseases were found with mutations while 10 out of 55 breast cancer patients had no mutations, resulting in an overall sensitivity of 82% and specificity of 83%. By cancer stage, the two Stage 0 (carcinoma in situ) patients had no mutation, and the range of mutations detected is between 53% to 75% from Stage I to III. The tumor tissue samples have higher rate of mutations (only 2 cancer patients, 1 Stage 0 and 1 Stage 2, had no mutations). 15% patients have at least one common mutation detected in both the tumor tissue and ctDNA, and 27% patients have mutations in the same genes in the two matching samples. The concordance increases as the clinical stage advances. The most commonly mutated genes are previously reported breast cancer drivers of PIK3CA (79% of tumor and 18% of ctDNA samples), TP53 (56% and 39%), and BRCA1 (6% and 15%). Conclusions: In this hypothesis generating analysis, we showed the feasibility of plasma ctDNA sequencing for gene mutation detection in early stage breast cancer and differentiation from the benign breast diseases. Although with limited number of samples, the data encourage further improvement of the gene panel and the validation of ctDNA assay as a non-invasive approach to the cancer screening. Clinical trial information: ChiCTR1800017345.
#earlydetection: Leveraging social media to recruit individuals at increased-risk of pancreas cancer for an early detection study.
Authors: Klute Kelsey , Hoy Christina , Larson Luann , Yu Fang , Hollingsworth Michael A. , Eberle Kirsten , Blase Terri , Boerner Brian , Shivaswamy Vijay , Singh Shailender
Published: May 2019

e14577

Background: Social media (SM) could transform how individuals learn of clinical trials. In an ongoing, single-center cohort study to collect serial biospecimens and clinical data from high-risk individuals (HRIs) for pancreatic cancer (PC), we explored how HRIs learned of the study, surveyed relevant SM posts and compared those referred by SM vs. other means. Methods: Initial recruitment focused on HRIs with familial risk for PC. Referral method was self-reported. We identified relevant SM posts and compared those referred via SM vs. other means by ANOVA and t-test. Investigators did not create SM content but were featured in a relevant local news clip, institutional blog post and Project Purple podcast; study-related media was IRB-approved. Results: We enrolled 91 HRIs between Aug 2018 and Jan 2019. Over half self-referred; 55.0% of self-referrals came from SM. We identified 16 unique SM posts, all to Facebook. Authors were 2 administrators for local hereditary cancer organizations, Project Purple, UNMC and 2 study subjects (9,4, 3 and 2 posts). Content included links to a podcast, clinicaltrials.gov, local news story, blog post, live chat and anecdotes from subjects. Nine posts shared study contact information or clinicaltrials.gov link. The mean age of those referred via SM was younger than for other methods (mean 49.2 vs. 53.4y) but was not statistically significant (p = 0.19). SM was more likely to recruit HRIs with familial risk than other methods (100.0% vs. 76.3%; p < 0.01) Conclusions: SM effectively recruited HRIs with familial risk for PC; this group may be more likely to seek information online. Individuals may find studies via SM without investigator involvement. SM may be an effective tool to recruit HRIs to early detection research in PC and other conditions. Clinical trial information: NCT03568630. [Table: see text]
Business versus science: High drug prices conspire against oncological research.
Authors: Gercovich Felipe G. , Gil Deza Ernesto , Morgenfeld Eduardo L. , Muino Marcelo , Mizrahi Marvin Albert , Martin Reinas Gaston , Smolje Leonardo , Abal Mariana , Rivarola Edgardo G. J.
Published: May 2019

e14580

Background: It has been consistently proven that pivotal clinical trials (PCT) for drug registration or new drug indications (NDI), sponsored by the pharmaceutical industry, obtain better results than independent confirmatory studies (ICS). The interplay between PCT and ICS has supported better treatment selections and more realistic expectations: hope vs hype.The aim of this paper is to analyze the amount of ICS publications in Oncology within the last decade. Methods: All new FDA approved oncological drugs or NDI for solid tumors between 2005 and 2017 were taken into account. The PCT that led to their approval were identified, and between October and November 2019 a thorough search for related ICS (published or ongoing) was conducted on MEDLINE, ASCO Abstracts, NEJM, Lancet Oncology, JAMA, JCO, Cancer, PLOS ONE, PLOS Medicine and www.Clinicaltrials.gov. Results: Fifty-five new drugs or NDI were analyzed (Abemaciclib, Abiraterone, Ado-trastuzumab emtasine, Afatinib, Alectinib, Atezolizumab, Avelumab, Axitinib, Bendamustine, Bevacizumab, Brigatinib, Cabozantinib, Ceritinib, Cobimetinib, Crizotinib, Dabrafenib, Degarelix, Denosumab, Durvalumab, Eribuline mesylate, Everolimus, Ipilimumab, Irinotecan liposome, Ixabepilone, Lapatinib, Lenvatinib, Necitumumab, Neratinib, Nilotinib, Niraparib, Nivolumab, Olaparib, Osimertinib, Paclitaxel protein bound, Palbociclib, Panitumumab, Pazopanib, Pembrolizumab, Pertuzumab, Ramucirumab, Regorafenib, Ribociclib, Rucaparib, SipuleucelT, Sonidegib, Sorafenib, Sunitinib, Topotecan, Trabectedin, Trametinib, Trastuzumab, Vandetanib, Vemurafenib, Vismodegib, Ziv-afilbercept). Until November 30, 2019, no published or ongoing ICS were found in any of the cases. Conclusions: a) For the past decade, none of the PCT used for approval of new oncological drugs or NDI were replicated by ICS (without pharmaceutical industry sponsorship). b) We ignore the reasons for these approval methods but they raise suspicion and unnecessary discomfort. c) From an ethical point of view, patients’ Informed Consent must specify that expected results for the new drug or NDI are based exclusively on trials sponsored by the selling pharmaceutical company, unless other ICS are published. d) The current state of affairs can only be reverted if regulatory agencies and the scientific community demand ICS as part of the drug approval process or post-marketing duties.
Moving away from the boilerplate: Real-world evidence for clinical trial laboratory criteria.
Authors: Hadley David , Edenfield William Jeffery , Kientop Debra A.
Published: May 2019

e14581

Background: There is a need to enable as many suitable patients onto clinical trials in oncology, that are also representative of patients seen in clinical practice. Currently, oncology trials often require patients to have minimum laboratory tests for hematology and liver function amongst others. We compared the real-world laboratory results and clinical information in TransMed’s patient repository against the requirements of a set of clinical trials to assess patient eligibility retrospectively. Methods: Industry-sponsored clinical trials for follicular lymphoma which started in 2018 were retrieved from the U.S. National Library of Medicine’s clinical trials website. We aimed to find the most common set of diagnosis inclusion criteria and the range of platelet requirements to those observed from real-world data. TransMed’s patient data was collected from its consortium of 205 clinical sites, which includes a variety of source systems at each site, such as electronic medical record systems and laboratory information management systems among others. Results: There were 16 trials which matched our criteria. The most common trial inclusion criteria were for grades 1-3a, progression after at least one line of therapy, and a platelet count > 75 x10-9/L. We found 53 retrospectively-eligible patients who would have met the trial’s main criteria when the patient was between therapies in 2018. At some point within 90 days before starting another therapy, 9% (5/53) of patients failed the requirement for platelet count. Among those, 40% (2/5) were within a 10% drop in the required threshold. Conclusions: We have presented an exemplar combination of cancer diagnosis with a single laboratory test and found patients who could be considered for trials though are deemed ineligible due to a narrowly-missed requirement. Many such tests vary over time, by cancer type, prior treatment, comorbidities and should be considered in the context of other test results. By using real-world evidence at the time of trial design, clinical trials can be optimized to allow improved patient recruitment and expanded availability to patients while ensuring clinical suitability.
Trends in case-control allocation in phase III randomized cancer clinical trials.
Authors: Gupta Shruti , Gopishetty Swathi , Malhotra Srishti , Kota Vamsi , Jillella Anand P. , Guddati Achuta Kumar
Published: May 2019

e14582

Background: Patients enrollment in cancer clinical trials has traditionally been limited to an equal distribution between cases and controls. Some clinical trials have an unequal distribution between the case and control arm. Although such unequal allocation is uncommon it has certain advantages and disadvantages to it. The trend and proportion of cancer clinical trials that have an unequal allocation has not been studied. Methods: Data about cancer clinical trials was extracted from clinical trials.gov. The query included phase 3 trials which included adults and were conducted between 2010 to 2017. Only clinical trials that were either completed or active – but not recruiting were included. T test was used to determine statistical difference between different subgroups. Results: 601 clinical trials were identified of which 356 trials with two arms and 47 trials with 3+ arms were identified. Amongst the eligible 298 trials with two arms, there were 216 trials with equal allocation (1:1) and 82 trials with unequal allocation. Amongst the eligible 29 trials with 3+ arms; there were 21 trials with equal allocation (1:1:1) and 8 trials with unequal allocation. There was no significant difference in the proportion of trials with unequal allocation over the time period from 2010 to 2017. The categories of cancer which had the highest number of two arm clinical trials with unequal allotment were: genitourinary, breast and hematological malignancies (Table). Conclusions: Cancer clinical trials with unequal allocation between case and control arms have been common in the past decade. This may represent a new trend in clinical trial design to help enhance closer monitoring of adverse events despite higher costs attached to this method.[Table: see text]
The relationship between response and dose in published, contemporary phase 1 oncology trials.
Authors: Hazim Antonious Ziad , Chen Emerson Yu-sheng , Mills Gordon B. , Prasad Vinay
Published: May 2019

e14583

Background: Traditional dose-escalation trial designs have changed little even as diverse classes of oncology drugs have been developed. We aimed to examine whether the association of drug dose to preliminary clinical efficacy previously established in cytotoxic chemotherapies remains true in contemporary phase I dose-escalation oncology trials. Methods: We conducted a systematic review of recent early-phase, dose-finding clinical trials of oncology drugs from November 15, 2015 to November 15, 2018 to examine the relationship between the dose of the investigational drug and objective response rate. We searched PubMed using “cancer” or “oncology” search terms and selected studies that enrolled adults with advanced cancer, determined maximum tolerated dose (MTD) and/or recommended phase II dose, and reported efficacy results by drug dose level. Trials testing combination therapies, single dose level, and non-pharmacologic therapies were excluded. Information related to the study drug, study design, cancer type, dose levels, MTD, and recommended phase II dose were all collected. Treatment response for every dose level was categorized into: complete response, partial response, stable disease, and progressive disease. Dose level was categorized into four categories: < = 40%, 41-80%, 81-120%, and > 120% of the recommended phase II dose. Results: We identified 93 trials with 2506 participants having both dose and treatment response data. Of these trials, 71 (76%) were testing targeted agents, 7 (8%) were immunotherapy, and 6 (7%) were cytotoxic chemotherapy. Median response rate across trials was 5% (range 0-83%). Among the dose range of < = 40%, the response rate was 12% (57 of 491), 41-80% was 17% (95 of 562), 81-120% was 23% (272 of 1206), and > 120% was 29% (71 of 247). Conclusions: Observed treatment response across dose levels in recent phase I trials should cause us to re-examine the toxicity-benefit ratio and influence how we design phase I trials testing novel classes of oncology drugs.
Feasibility of a platform trial based on molecular analysis in rare gynecologic cancers.
Authors: Brown Jubilee , Farley John H. , Herzog Thomas J. , Crane Erin , Covens Al , Arguello David , Ramos Pilar , Chen Wangjuh , ElNaggar Adam
Published: May 2019

e14585

Background: Challenges in patient accrual limit successful conduct of clinical trials in rare gynecologic malignancies. A platform trial using molecular analysis to guide therapy choice would optimize enrollment but would require actionable mutations (AM) to be feasible. Therefore, we sought to determine if enough AMs exist in rare gynecologic cancers (CA) to justify the design of a platform trial. Methods: We compiled all molecular profiling data performed at Caris Life Sciences through February 2019. Non-epithelial ovarian cancer (OC), rare epithelial OC, non-endometrioid uterine, neuroendocrine gynecologic, and vulvar CA were compiled. AMs were identified. Results: Among 280 cases of non-epithelial OC, 228 malignant stromal tumors and 52 germ cell tumors were identified. AMs in stromal tumors included KMT2D (9.8%), PIK3CA (7.8%), and 16 other AMs ( < 1% each). AMs in germ cell tumors included PIK3CA (20%), KIT (10%), PTEN (10%), TMB (8.2%), CDKN2A (8%), ARID1A (6%), and 16 other AMs ( < 6% each). Among 702 rare epithelial OCs, 132 mucinous CAs, 91 low-grade serous/endometrioid, 367 clear cell, and 112 carcinosarcoma (CS) cases were identified. AMs in mucinous CAs included KRAS (61.8%), CDKN2A (15.3%), PIK3CA (12.7%), ARID1A (9.9%), GNAS (6.9%), and 20 other AMs ( < 5% each). AMs in low-grade serous/endometrioid included KRAS (28.9%), ARID1A (13.3%), PTEN (8.9%), PIK3CA (7.8%), MSI (6.2%), and 15 other AMs ( < 6% each). AMs in clear cell OCs included ARID1A (53.4%), PIK3CA (47.5%), KRAS (11.6%), PTEN (6.8%), and 36 other AMs ( < 6% each). AMs in ovarian CSs included PIK3CA (7.2%), ARID1A (6.2%), and 22 other AMs ( < 5% each). Among 4864 rare uterine CA, 4670 sarcomas, 173 serous CAs, and 21 clear cell CAs were identified. AMs in uterine sarcomas included PTEN (40.1%), PIK3CA (37.1%), ARID1A (31.6%), MSI (20.7%), KRAS (16.8%), TMB (14%), PIK3R1 (10%), and 41 other AMs ( < 10% each). Among 102 gynecologic neuroendocrine tumors, AMs included ARID1A (29.2%), PIK3CA (18%), PTEN (18%), MSI (6.5%), TMB (6%), and 4 other AMs ( < 6% each). Among 59 vulvar CAs, AMs included CDKN2A (28.7%), PIK3CA (17.8%), NOTCH1 (9.6%), TMB (6.8%), and 24 other AMs ( < 5% each). Conclusions: A variety of actionable mutations are present in every type of rare gynecologic cancer evaluated, but mutations specific to individual histologies are not reliably present. This supports the use of molecular profiling to identify potential targets and supports a platform trial strategy to study rare gynecologic cancers.
Efficacy and toxicity of CDK 4/6 inhibitors in breast cancer: Systematic review and meta-analysis of the phase III clinical trials.
Authors: Farooq Faheem , Cohen Jules A.
Published: May 2019

e14591

Background: Selective CDK4/6 inhibitors such as palbociclib, abemaciclib, and ribociclib have demonstrated efficacy in advanced HR+/HER2- breast cancer. Drug-related toxicity has been manageable, but variable amongst the drugs. This meta-analysis was conducted to guide CDK inhibitor choice based on efficacy and toxicity. Methods: A systematic literature review of Pubmed, Cochrane Library, and EMBASE was performed in December 2018. Efficacy was evaluated via reported progression free survival (PFS) and pooled hazard ratios (HR). Overall response rate (ORR), treatment discontinuation, and treatment-related adverse events (AEs) were measured via pooled odds ratios (OR). Meta-analyses were performed using random effects modeling and 95% confidence intervals (CI). Results: A pooled analysis of 7 phase III clinical trials (n = 4415) demonstrated a HR of 0.55 (CI: 0.51-0.60) for PFS and an OR of 1.93 (CI: 1.54-2.42) for ORR. First-line treatment trials (n = 3020) pairing CDK 4/6 inhibitors with NSAI/tamoxifen had a HR of 0.56 (CI: 0.51-0.60) for prolonged PFS and an OR of 1.64 (CI: 1.39-1.95) for ORR. Second-line treatment trials (n = 1916) pairing CDK 4/6 inhibitors with fulvestrant had an HR of 0.54 (CI: 0.48-0.61) for prolonged PFS and an OR of 2.48 (CI: 1.57-3.90) for ORR. Palbociclib and ribociclib had similar rates of grade 3/4 AEs, neutropenia, and treatment discontinuation. Abemaciclib had lower rates of grade 3/4 AEs overall, but significantly increased rates of diarrhea and treatment discontinuation due to AEs. Conclusions: Each drug demonstrated a significant improvement in PFS. However, there is no statistical difference in efficacy among the three CDK inhibitors. Treatment decisions can be guided by the tolerability of AEs amongst the medications. Further patient follow-up will illuminate whether there is an OS advantage in this novel drug class. [Table: see text]
Muscle wasting, visceral and subcutaneous adiposity, inflammation, nutritional deficiencies, and metastatic esophageal cancer (MEC) prognosis.
Authors: Bajwa Jaspreet K , Fares Aline Fusco , Dong George , Araujo Daniel Vilarim , Hueniken Katrina , Patel Devalben , Taylor Kirsty , Darling Gail Elizabeth , Wong Rebecca , Chen Eric Xueyu , Knox Jennifer J. , Jang Raymond Woo-Jun , Elimova Elena , Xu Wei , Liu Geoffrey , Rozenberg Dmitry , McInnis Micheal
Published: May 2019

e14595

Background: MEC, associated with fatigue and dysphagia, leads to loss of skeletal muscle mass, malnutrition, subcutaneous and visceral adiposity. Cancer inflammation mobilizes muscle and adipose tissue, potentially leading to cachexia and sarcopenia. Supportive management depends on understanding the cancer frailty determinants that lead to poor outcomes. Methods: We retrospectively identified de novo MEC patients pts treated in Toronto, Canada (2007-2014). Body composition including visceral (VA) and subcutaneous adiposity (SA) at L3 level were assessed with baseline CT scans using SliceOMatic software by two outcome-blinded radiologists (Intraclass correlation, 0.92-1.00). Sarcopenia was assessed using Skeletal Muscle Index (SMI) with cut-offs defined either by optimized-stratification (OpS) or gender-dependent consensus cutoffs (GdC). Cox proportional hazard models generated adjusted hazard ratios (aHR). Results: Of 101 patients, 82% were male; 96% Caucasian; median age at diagnosis 61y (29-88); mean body mass index (BMI) 25.4; 69%/31% adeno/squamous cell carcinoma; median overall and progression free survival were: 6.4 (OS) and 3.9 mos (PFS). Median follow-up time was 5.6 mos. SMI-OpS and SMI-GdC were correlated (Rho = 0.67). Nutritional risk index, BMI, neutrophil-to-lymphocyte and neutrophil-to-platelet ratios were not associated with outcome (p > 0.20, each comparison). However, univariable analyses identified serum albumin, LDH, and either SMI-OpS or SMI-GdC as being associated with OS. In multivariable models, sarcopenia was associated with worse OS (SMI-OpS aHR = 1.93 (1.0-3.7) p = 0.046; SMI-GdC aHR = 2.30 (1.3-4.1) p = 0.004), and worse PFS (SMI-OpS aHR = 2.16 (1.2-4.0) p = 0.01; SMI-GdC aHR = 1.66 (1.0-2.9) p = 0.07)). In 55 pts receiving chemotherapy at diagnosis, less VA (p = 0.01) and SA (p = 0.02), as continuous variables, were associated with worse OS. Conclusions: Though no associations were found between nutritional deficiencies or inflammatory markers and prognosis, there was approximately a two-fold worse prognosis in the presence of sarcopenia, and associations with loss of adiposity. (JB/AFF/DR/MM contributed equally).
Impact of precision medicine on clinical care: A single institution retrospective study.
Authors: Patel Rajvi , Quinn Ryann , Zhu Xinhua
Published: May 2019

e14601

Background: In Oncology, precision medicine (PM) looks at molecular characteristics of tumors instead of traditional histology to determine treatment strategies. Examples are EGFR, ALK, BRAF, ROS1 and PD-L1 in non-small cell lung cancer, HER2 in breast and gastric cancer, K-RAS, N-RAS in colon cancer, and MMR/MSI in all solid tumors. Genomic testing is commonly done for patients with advanced cancer resistant to standard treatment. FoundationOne-CDx (F1CDx) is expensive but only FDA approved test for somatic genomic profiling of tumors. It is necessary to review an expensive test and its impact on clinical care. At our institution, we have patients who have had F1CDx testing. Our aim was to determine proportion of tumors that have actionable mutation (AM) for which there are currently FDA or non-FDA approved targeted treatment(s) (TT) available, proportion of pts who received TT, and barriers to receiving TT. Methods: Retrospective study of 1000 patients treated at our institution who had F1CDx testing done between September 2012 and July 2018. Variables collected included primary tumor type, F1CDx results, treatments received, and any barriers. Descriptive statistics including frequencies and proportions were utilized. Results: Of 1000 pts, 652 had tumors harboring AM. Of the 652 pts: 42 went on a clinical trial, 165 received standard next line chemotherapy, 135 received TT (38 pts received currently non-FDA approved TT), 144 either went on hospice or died prior to receiving treatment, 142 were lost to follow up, 21 were treated with surgery only, and 3 had issues with insurance approval of TT. Conclusions: Of the 65% of pts with tumors harboring AM, only 20% received TT. 25% of pts received standard next line chemotherapy. Going on hospice and being lost to follow up largely accounted for patients not receiving TT. Therefore, treating physicians should strongly consider pts’ performance status and co-morbidities prior to sending expensive genomic testing as it may have limited impact on clinical outcome. Our next steps to further investigate will be to look at objective response rate, progression free survival, and overall survival in pts who received non-FDA approved TT.
Relationship of MET exon 14 splicing variants and MET exon 14 skipping expression in NSCLC FFPE samples.
Authors: Williamson John B. , Li Xia , Liu Guang , Gu Haigang , Orton Janet , Seidman David , Sundin Tabetha , Salazar Suzanne , Sadis Seth , Lincecum Tommie , Ha Thomas , Chin Christine
Published: May 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.