bluuebunny/crossref_metadata_2025 huggingface dataset:
PIK3 mutation as a predictor of immune checkpoint inhibitor response.
Authors: Jacob Aasems , Wu Jianrong , Chauhan Aman
Published: May 2020

e15257

Background: Although several biomarkers predicting response to immune checkpoint inhibitor (ICI) therapy have been evaluated, the emerging data is conflicting. There is a lack of real-world data that might help identify biomarkers in diverse populations. Methods: Patients with solid tumors who received ICI and underwent tumor tissue next generation sequencing (NGS) in our institution between 2016-2019 were included in the study. Response to ICI was assessed based on RECIST 1.1 and median progression free survival (mPFS), radiologic response and immune-related adverse events (IRAEs) were analyzed in relation to various molecular biomarkers. Results: 69 patients had complete NGS and RECIST 1.1 data required for analysis. Study cohort included 14 different cancer types. 78% of the patients were smokers. TP53 (62%), CDKN2A (44%), NOTCH1/2 and PIK3 (33%) were the most common mutations identified. 42% patients had CR/PR with ICI and mPFS was 38 weeks (w). A statistically significant improvement in PFS was observed in patients with PIK3 mutated cancers (mPFS 123 weeks vs. 23 weeks, p = 0.012). These patients also had a higher percentage of response (60.9% vs 39.1%, p = 0.5), and were also associated with increased risk of immune related adverse events (IRAEs) (73.9% vs. 37%, p = 0.004). PIK3 mutation had no association with PDL1 status or tumor mutational burden (TMB). Mean TMB was 12.59, and 29% patients had positive PDL1 expression. There was significant difference in mPFS between high (≥20mut/Mb) and low/intermediate TMB (0-19mut/Mb) (mPFS 18w vs. 65 w, p = 0.049) as well as PDL1 positive and negative tumors (40w vs. 18w, p = 0.059). BRAF mutation was associated with early progression in all cancers (mPFS 17w vs 39w, p = 0.033). Conclusions: Conventionally, a marker of poor survival and chemotherapy response, PIK3 mutation was associated with positive ICI response in our study. High incidence of IRAEs in PIK3 mutants also point towards increased ICI activity. High TMB, as expected was associated with ICI response.
T-cell inflamed gene expression to predict prognosis and response to immune checkpoint inhibitors.
Authors: Yu Yao , Ma Jingjiao , Chen Jie , He Ning , Xu Xiaohong , Wang Lingyu , Lin Rongbo
Published: May 2020

e15264

Background: To prove that T-cell-inflamed gene-expression profile (GEP) can predict prognosis and response to immune checkpoint inhibitors (ICIs) in the real-world study. Methods: 36 patients admitted from January 2018 to December 2018 were enrolled, including 15 patients with advanced NSCLC, 12 with advanced bladder cancer and 9 with advanced liver cancer. All patients were treated with nivolumab or pembrolizumab and provided informed written consent for analysis. Tumor total RNA was isolated from pretreatment FFPE samples and RNA-seq was performed on the Illumina NovaSeq 6000 system. GEP was calculated as a weighted sum of normalized expression values for 18 genes, as described in the article written by Ayer M, et al. in 2017. The data cutoff date was July 30, 2019. Primary end points were objective response rate (ORR) and disease control rate (DCR). Secondary end point was progression-free survival (PFS) assessed per RECIST v1.1. 95% CIs and P values for ORR and DCR were evaluated by the binomial exact method. Correlation between GEP and ORR, DCR and PFS was assessed by Wilcoxon rank sum test and Cox regression model, respectively. Survival curves were estimated by Kaplan-Meier methods. Cut-off value of GEP was confirmed by the Youden Index. The comparisons of DCR and PFS were performed by Fisher’s exact test and log-rank test, respectively. Results: ORR was 30.6% (95% CI, 16.3%-48.1%) and DCR was 50.0% (95% CI, 32.9%-67.1%). Median PFS was 3.9 months (95% CI, 0.8-NR). We found that GEP was higher in patients who achieved DCR and had longer PFS. And then GEP was significantly associated with DCR (p = 0.019) and PFS (p = 0.005), but not significantly with ORR (p = 0.42). Based on Youden Index, cut-off value of GEP was confirmed as -0.368, with 94.4% of sensitivity and 66.7% of specificity. According to cut-off value, 23 patients were evaluated as GEP-H. GEP-H group had higher DCR and longer PFS (DCR: 73.9% vs 7.69%, p = 0.0003; mPFS: 7.0m vs 2.1m, p = 0.00049). Conclusions: GEP can predict prognosis and response to ICIs in multiple cancers in our real-world study. Interpretation of these data may be limited by small sample sizes. Further studies are being conducted.
An open-label phase Ib study to determine safety and preliminary efficacy of oral Lucitanib (AL3810) in patients with locally advanced or metastatic gastric, hepatocellular, nasopharyngeal carcinoma, malignant biliary, and thymic tumors.
Authors: Pan Hongming , Qin Shukui , Zhang Li , Li Jin , Xu Jianming , Xu Ruihua
Published: May 2020

e15502

Background: Angiogenesis is an essential prerequisite for tumor growth, invasion and metastasis. Targeting tumor angiogenesis has become a common therapeutic target in clinical work. Lucitanib, an oral tyrosine kinase inhibitor, precisely targets FGFR/VEGFR/PDFGR. In this study, we evaluated the safety profile and preliminary anti-tumor effects of lucitanib in patients with locally advanced or metastatic gastric (GC), hepatocellular (HCC), nasopharyngeal carcinoma (NPC), malignant biliary (MBT) and thymic tumors (TT). Methods: Patients (Pts) with locally advanced or metastatic GC, HCC, NPC, BTC and TT, standard therapy failed, ECOG status ≤1, were enrolled. Total 44 subjects (6 GC, 4 HCC, 10 BTC, 4 TT, 20 NPC) were recruited, then randomized into two groups with lucitanib 10 mg QD given continuously (CON) or intermittently (INT) lucitanib 10 mg QD three weeks on and one week off. Results: 22 pts were included in CON and INT group respectively. The most common drug-related treatment emergent adverse events (TEAEs) for CON (AE≥10%, Grade≥3 ): proteinuria (19 [86.4%], 4 [18.2%]), hypertension (18 [81.8%], 7 [31.8%]), haematuria (3 [13.6%], 0), aspartate aminotransferase increased (8 [36.4%], 1 [4.5%]), hypothyroidism (7 [31.8%], 0), blood creatinine increased (5 [22.7%], 0), platelet count decreased (5 [22.7%], 1[4.5%]), white blood cell count decreased (3 [13.6%], 0), weight decreased (4 [18.2%], 0), diarrhea (4 [18.2%], 0) and rash(6 [27.3%], 0). For INT: proteinuria (8 [36.4%], 1[4.5%]), hypertension (9 [40.9%], 4 [18.2%]), hypothyroidism (6 [27.3%], 0), platelet count decreased (3 [13.6%], 0), white blood cell count decreased (4 [18.2%], 0). Treatment discontinuation due to drug-related TEAEs were 3 pts (13.6%) and 1 pt (4.5%) in CON and INT respectively. Preliminary efficacy for CON: ORR: 13.6%, DCR: 72.7%, median PFS: 3.8 months; for INT: ORR: 4.5%, DCR: 40.9%, median PFS: 1.9 months. Conclusions: Although CON exhibited higher incidence, drug-related TEAEs at both groups were expected and manageable. Lucitanib exhibited better efficacy profile when administrated 10mg QD continuously. Further safety and efficacy of lucitanib is being evaluated in phase II/III studies. Clinical trial information: 03260179.
Effect of general anesthetics on the tumor micro-environment in mouse models of breast cancers of spontaneous metastasis.
Authors: Lin Jun , Li Ru , Huang Yujie
Published: May 2020

e15503

Background: Metastatic breast cancer is a pressing health concern worldwide. Various treatments have been developed but no significant long-term changes in overall survival are observed. Therefore, there is a demand to improve current therapies to treat this disease. Surgical resection of the primary tumors is essential in the treatment. However, accumulating evidence alludes to a role for volatile anesthetics which are used during the surgery in metastatic tumor development, but the mechanism remains largely unknown. We have shown anesthetics exert different effects on lung metastasis in mouse models of breast cancers. This study analyses the effect of general anesthetics in lung microenvironment associated with the increased metastases. Methods: Balb/c mice and NOD-SCID mice were orthotopically implanted with 4T1 cells and MDA-MB-231 cells respectively, in the mammary fat pad to generate primary tumors. Mice were subjected to the tested anesthetic during implantation and/or before and after surgery. Surgical dissection of primary tumor was performed under anesthesia with sevoflurane or an intravenous anesthetic propofol. Survival curve was constructed and analysed. Mice were euthanized to harvest tissues for histology and cell analysis. Results: As we previously reported, surgical dissection of primary tumor in mice under anesthesia with sevoflurane led to significantly more lung metastasis than with propofol in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. Sevoflurane was associated with increased IL6(Li, Huang, & Lin, 2020). Here we show that anesthesia with sevoflurane resulted in changes of stroma composition in the lung, which was reversed by IL6 pathway interruption. Conclusions: Those results contribute to our understanding of effects of sevoflurane on cancer metastasis and suggest a potential therapeutic approach to overcome the risk of general anesthesia. Li, R., Huang, Y., & Lin, J. (2020). Distinct effects of general anesthetics on lung metastasis mediated by IL-6/JAK/STAT3 pathway in mouse models. Nat Commun, 11, 642.
Efficacy and safety of apatinib combined with TACE in patients with hepatocellular carcinoma refractory to transcatheter arterial chemoembolization.
Authors: Zhang Wei , Yan Zhiping
Published: May 2020

e15504

Background: Effective options for patients with advanced hepatocellular carcinoma (HCC) are urgently needed. Studies have shown that combination of sorafenib with TACE could imorove survival for the treatment of locoregional HCCs. Apatinib is a novel and highly selective inhibitor of VEGFR2 tyrosine kinase. We were aiming to explore the efficacy and safety of apatinib combined with TACE in patients with hepatocellular carcinoma refractory to transcatheter arterial chemoembolization. Methods: This was a single-center single-arm phase 2 study. The key inclusion criteria included: (1) Histologicaly and cytologicaly diagnosed as Hepatocellular carcinoma of the liver ( HCC ) and with at least one imaging examination of measurable lesions, CT or MR scan long diameter of tumor ≥ 10 mm. (2) BCLC B / C; (3) Progressed after at least twice TACE. Eligible pts received apatinib at 500 mg/day for a maximum after TACE 4-7 days, and TACE treatment was performed after 4 days of discontinuation of apatinib until unacceptable toxicity or tumor recurrence. The primary endpoint was time to progression (TTP), which was defined as the time from enrollment to disease progression. The secondary endpoint was overall survival (OS) and treatment safety. Results: From May 27, 2018 to Oct 12, 2019, 22 pts wereenrolled. 5 pts received TACE more than 5 times, and 17 pts received TACE within 4 times. For 20 evaluable pts, two pts achieved partial response (10%), and 13 patients achieved stable disease. The ORR and DCR were 10% and 75%, respectively. At the cutoff data of Nov 4, 2019, 5 pts were still on treatment. 16 recurrenced and 5 death occurred. The mTTP was 5.09 months (95% CI, 3.48-7.16), and the mOS was not reached. Treatment-related adverse events occurred in 12 pts (60%). Seven grade 3 or 4 adverse events were reported (35%), respectively wereascites (2), platelet count decrease (1), elevated ALT/AST (1), hypertension (1), proteinuria (1) and nausea (1). None of the treatment related AEs was fatal. Conclusions: Apatinib combined with TACE might be effective and tolerant in patients with hepatocellular carcinoma refractory to transcatheter arterial chemoembolization. Clinical trial information: NCT03510416.
Preclinical study of oncolytic adenovirus-mediated cytotoxic gene therapy with gemcitabine for chemoresistance of desmoplastic tumor.
Authors: Jung Bo-Kyeong , Li Yan , Hong JinWoo , Oh Eonju , Yun Chae-Ok
Published: May 2020

e15507

Background: Pancreatic cancer is a highly lethal disease. Excessive accumulation of tumor extracellular matrix (ECM) and epithelial-to-mesenchymal transition (EMT) phenotype are two main contributors to drug resistance in desmoplastic pancreatic tumors. Methods: To overcome the limitations of various conventional therapeutics against desmoplastic pancreatic cancer, we utilized an oncolytic adenovirus (oAd) for combination therapy with gemcitabine, a standard chemotherapeutic for pancreatic cancer treatment. Here, we report the results of preclinical pharmacology and efficology studies conducted in pancreatic cancer model. Results: Efficacy studies in orthotopic pancreatic xenograft tumor model demonstrated that oAd effectively attenuated tumor cell proliferation. oAd further prevented metastasis of pancreatic cancer and sensitized pancreatic tumor to gemcitabine treatment. Furthermore, oAd augmented drug penetration and dispersion within pancreatic tumor xenografts and patient-derived pancreatic tumor spheroids. These results suggest that oAd enhance the therapeutic effect of chemotherapeutic agent in chemo-resistant and desmoplastic pancreatic tumor, thus overcoming the preexisting limitations of standard treatments. Conclusions: Overall, these results demonstrate that local administration of an oncolytic adenovirus with gemcitabine is well tolerated and support moving this investigational approach into human trials.
The KRAS mutation status and resistance to cetuximab in patients with squamous cell carcinoma of oral cavity.
Authors: Lyanova Aza A. , Vladimirova Liubov Yu , Engibaryan Marina A. , Abramova Natalia A. , Popova Irina L. , Ryadinskaya Ludmila A. , Tikhanovskaya Natalia M. , Teplyakova Maria A. , Novoselova Kristina A. , Myagkova Valeriya S , Kutilin Denis S.
Published: May 2020

e15514

Background: The standard treatment of squamous cell carcinoma of the tongue and the mucosa of the bottom of the oral cavity (SCCTOM) is chemotherapy (CT) in combination with cetuximab (mC, anti-EGFR antibody). However, not all patients manage to achieve positive results. A common cause of resistance to anti-EGFR antibodies is the constitutive activation of mediators of the underlying signaling pathways. Therefore, the aim of the study was to analyze mutations in the KRAS using the Digital Droplet PCR method in patients with SCCTOM on the background of CT in combination with targeted therapy or standard CT. Methods: The study used the QX200 system (Bio-Rad) and the ddPCRtm KRAS Screening Multiplex Kit (7 mutations). The study included 60 patients with T3-4N0-1M0 SCCTOM. The main group consisted of 30 patients (cisplatin, 5-fluorouracil+cetuximab). The control group consisted of 30 patients (CT). For research, cfDNA from blood plasma was used. Analysis of the data was performed using QuantaSoft v1.7.4. Results: The frequency of the KRAS mutant type (mtKRAS) is 43% before treatment and 32% after treatment (n = 60). In the group of patients CT+mC the incidence of mtKRAS before treatment was 40%, after treatment - 20%. In the group of patients CT without mC the incidence of mtKRAS before treatment was 47%, after treatment - 43%. Decrease of 20% (p = 0.00089) in the frequency of mtKRAS after CT+mC was found, while it was 23% (p = 0.00009) lower than the frequency of mtKRAS after CT without mC. After treatment, in the CT+mC group of patients, the number of mtKRAS DNA copies increased 1.5 times (p = 0.048). Analysis of clinical response to therapy allowed us to divide the main and control groups of patients into 2: sensitive and resistant to therapy. After treatment, a change in the mtKRAS ratio was not found in the subgroup sensitive to mC compared with the period before treatment, while the frequency of mtKRAS was reduced by 3 times (p = 0.009). In the mC-resistant subgroup, the mtKRAS ratio increased 1.9 times compared to the period before treatment (p = 0.009), while the frequency of mtKRAS increased 3.5 times compared with the mC-sensitive group (p = 0.0045). Conclusions: Prior to treatment, patients resistant to CT+mC were characterized by an increased occurrence of mutations in the KRAS and an apparently large number of tumor cells carrying mutations. The use of mCs caused a change in the direction of the clonal evolution of tumor cells - leading to an increase in the number of cells carrying mtKRAS (conditions were created for the elimination of cells with mutation in EGFR and KRAS wild type).
A new desensitization protocol, overcoming hypersensitivity reactions to chemotherapy.
Authors: Havasi Andrei Dan , Cainap Calin Ioan , Vlad Ioan-Cătălin , Achimaş-Cadariu Patriciu , Sur Daniel Genel , Meşter (Piciu) Andra , Heputiu-Pater Ana Teodora , Bochis Ovidiu , Balacescu Ovidiu , Crisan Ovidiu , Coza Ovidiu , Balacescu Loredana , Burz Claudia Cristina , Cainap Simona Sorana
Published: May 2020

e15523

Background: Despite the progress for cancer treatment, some drugs remain a cornerstone for an optimal approach. Hypersensitivity reactions to chemotherapy may render these essential chemotherapeutic agents useless and for some types of cancer continuing the therapeutic scheme could be crucial. Various regimens for desensitization to allow chemotherapy administration through the time were conceived, with different dilutions, time and settings of administration. Methods: A prospective study of patients with systemic treatment for histopathologically confirmed cancer in our Oncological Institute „Prof. Ion Chiricuta” Cluj-Napoca, with an allergic reaction during treatment being the keys inclusion criteria in the analysis. Patients were administered a three days desensitization regimen from the following cycle of treatment with blood samples that were taken to observe the predictive value of biological markers. Results: Eighty-two patients were the initial pool, with a median age of 56 years. Platin derivates containing regiments were responsible for an allergic reaction for 75 out of 82 patients. Four of them were known with a previous allergic reaction for chemotherapy in their personal medical history, and 56 of them had more than one chemotherapy line in their treatment. More than 688 desensitization cycles were administrated during our study with a rate of failure of 1.3 %. The main reason for discontinuation was disease progression or adjuvant character (limited duration) of the chemotherapy administration. Conclusions: Allergic reaction does not impede the administration of the responsible drug. A 3-day inpatient regimen could be a valuable option with a successful rate of administration without the need for ICU monitoring.
Circulating tumor DNA is capable of monitoring the therapeutic response and resistance in advanced colorectal cancer patients undergoing combined target and chemotherapy.
Authors: Cao Hua , Liu Xinyi , Chen Yixin , Yang Pan , Huang Tanxiao , Song Lele , Xu Ruilian
Published: May 2020

e15524

Background: Colorectal cancer (CRC) is a highly lethal disease worldwide. The majority of patients receiving targeted therapy or chemotherapy develop drug resistance, while its molecular mechanism remains to be elucidated. The plasma circulating tumor DNA (ctDNA) exhibited the potential in identifying gene variations and monitoring drug resistance in CRC treatment. Methods: In this study, we monitored the ctDNA mutational changes in advanced CRC patients underwent first-line therapy with bevacizumab and cetuximab combined with chemotherapy. The mutation spectrum of 43 patients was established by a 605-gene next-generation sequencing (NGS) panel. Results: The baseline measurement shows that genes with the highest mutation frequency were TP53 (74%), APC (58%), KRAS (40%), SYNE1 (33%), LRP1B (23%), TOP1 (23%) and PIK3CA (21%). Mutations in TP53, APC and KRAS were detected in 29 paired plasma and tissue samples with the consistency of 81%, 67% and 42%, respectively. Clinically targetable gene mutations, such as APC, RNF43, SMAD4, BRAD1, KRAS, RAF1, and TP53, were also identified in ctDNA. The overall consistency between ctDNA and tissue samples was 54.6%. Alleviation of mutational burden in BRAF, KRAS, AMER1 and other major driving genes was observed following the first-line therapy. Patients with KRAS and TP53 mutations in tissues appeared to benefit more than the wild-type counterpart. The dynamic change of plasma mutation status was consistent with the tissue tumor burden and was closely correlated with disease progression. Conclusions: ctDNA monitoring is a useful method for molecular genotyping of colorectal cancer patients. Dynamic changes in resistance can be sensitively monitored by gene variation status, which potentially helps to develop treatment strategy.
Effect of local activation via SQ3370 on the safety of chemotherapy with concomitant anti-tumor immune response.
Authors: Srinivasan Sangeetha , Yee Nathan A. , Mahmoodi Amir , Zakharian Michael , Mejia Oneto Jose Manuel
Published: May 2020

e15525

Background: With systemic chemotherapy, only 1-2% of the dose given reaches a local tumor, while the remaining leads to off-target toxicities. Hence, there is a critical need to locally deliver cytotoxics directly to the tumor. Our approach (SQ3370) consists of: 1. SQL70 - drug-activating biomaterial carrying 2. SQP33 - chemically-modified prodrug of doxorubicin (Dox) with attenuated activity. Methods: SQL70 is injected at the tumor site followed by SQP33 given systemically. The prodrug is captured by the biomaterial due to their complementary chemical reactivities. The active drug is then spontaneously released, providing local delivery directly to the tumor region while reducing systemic side effects. Results: We have shown that the greater safety of SQ3370 allows significantly higher doses to be administered compared to conventional Dox. PK studies in rodents and dogs show highly efficient capture and activation of the prodrug, likely due to the rapid reaction of SQP33 with SQL70. Without SQL70, SQP33 shows minimal spontaneous conversion to active Dox. A single SQL70 injection selectively activated multiple doses of SQP33 at the target site, maximizing the local therapeutic index. Additionally, SQP33 was capable of being activated by SQL70 injected in various regions in the body, including peri/intratumoral, intraperitoneal, subcutaneous and intramuscular sites. SQ3370 treatment also enhances efficacy in tumor-bearing mice: In a syngeneic MC38 colorectal cancer model, SQ3370 significantly improved anti-tumor response and overall survival compared to conventional Dox. In mice bearing two tumors, SQL70 injection at one tumor site followed by systemic SQP33 treatment induced an anti-tumor response in both the injected and non-injected tumors. This technology also enabled a sustained anti-tumor response upon rechallenge with MC38 tumor cells, without additional treatment. Furthermore, SQ3370 increased CD4 and CD8 TILs and decreased regulatory T-cells in both injected and non-injected tumors, suggesting that SQ3370 can induce an immune-mediated anti-tumor effect, thus expanding potential treatment options in the clinic and highlighting the advantages of immune-sparing cytotoxic therapy. Conclusions: SQ3370 enables delivery of cytotoxic drugs to multiple target sites while limiting off-target exposure, leading to improved safety and efficacy. A multicenter, first-in-human, Phase 1 dose-escalation clinical trial (NCT04106492) in patients with advanced solid tumor malignancies is planned to commence enrollment in April, 2020.
Assessment of mutation burden after clinical intervention in pancreatic ductal adenocarcinomas (PDAC), and biliary tract cancers (BTC) via profiling circulating tumor DNA (ctDNA).
Authors: Pittella-Silva Fabio , Motoya Masayo , Kimura Yasutoshi , Nakamura Toru , Low Siew-Kee Kee , Nakamura Yusuke
Published: May 2020

e15529

Background: PDAC and BTC have very poor prognosis with limited treatment options. Blood-based monitoring of ctDNA may have great potential to improve early detection of relapse or failure to chemotherapy and to possibly identify actionable genetic alterations. Methods: We performed targeted sequencing using NGS with Ion S5 Oncomine PanCancer gene panel to investigate mutations in 52 genes in 42 PDAC and 24 BTC patients. Blood samples were obtained from PDAC and BTC cases before the first intervention (baseline) as well as 2-4 weeks later to evaluate cfDNA mutations after surgery or chemotherapy. Actionable alterations with potential therapeutic relevance was defined as those with possible treatments within OncoKB system. We also compared the amount of cfDNA and mutant allele detection rates in pre-, intra- and post-operative samples. Results: Overall detection of ctDNA alterations in baseline samples was 74% (31/42) in PDAC cases. Alterations including SNVs and CNVs were detected among 15 genes; mutations in TP53 (53%), KRAS (41%) and SMAD4 (10%) were most commonly identified. Overall detection rate in BTC patients was 83% (20/24) comprising 9 genes; frequent mutations were observed in TP53 (58%) and KRAS (33%). Decrease in MAF (mutant allele frequency) was observed in 64% (18/28) of PDAC cases after the treatment and that of CA19-9 was observed in 50% (14/28) of the cases. In BTC pts, reduction of MAF was observed in 60% of the cases after surgery. Potentially actionable mutations were observed in 38% of PDAC samples and in 25% of BTC samples. Interestingly, the amounts of cfDNA were 4-fold higher in intraoperative samples compared to pre- and post-operative samples indicating release of cfDNA during surgery, possibly by tissue damage. Conclusions: We have shown the feasibility to assess minimum residual tumor cells or drug response by liquid biopsy in both PDAC and BTC which may improve the clinical management.
Correlation of CTCs with disease progression in Indian oral cancer patients.
Authors: Khandare Jayant , Qayyumi Burhanuddin , Bharde Atul , Aland Gourishankar , Jayant Sreeja , Tripathi Swati , Singh Nitin , Badave Reecha , D'Souza Alain , Singh Balram , Arora Smriti , Kale Narendra , Vasudevan Aravindan , Ashturkar Amrut , Prabhash Kumar , Chaturvedi Pankaj ,   Actorius
Published: May 2020

e15541

Background: Head and neck squamous cell carcinoma is leading cancer in the India with Oral squamous cell carcinoma (OSCC) as the most frequent subtype. OSCC is classified as a locoregional disease and its increased frequency is attributed to lack of good biomarkers compared to other epithelial cancers. At the time of diagnosis, above 50% of cases present the manifestation of advanced-stage disease, and are predisposed to disease failure in spite of appropriate treatment. Thus, early diagnosis of OSCC can significantly reduce the disease burden. Here we describe regulatory approved method to establish Circulating tumor cells (CTCs) presence in OSCC Indian patients and its positive correlation with various clinicopathological parameters, suggesting the potential use of CTCs as a significant parameter to stratify oral cancer with respect to the disease advancement. Methods: In a cross-sectional observational study, 230 OSCC patients at the different pathological stage of the disease and treatment mode were enrolled. CTCs were isolated using approved OncoDiscover liquid biopsy technology (Drug controller general of India approved), platform technology based on immunomagnetic CTC enumeration. CTCs were detected for CK18 presence and well-defined, DAPI-stained nuclei. Enumerated CTC subsequently analyzed for various clinic-pathological parameters such as pstage, extra-capsular spread (ECS), lymphovascular emboli (LVE), perineural invasion (PNI) and depth of invasion (DOI). CTC cut off values were obtained to differentiate early vs advanced stages with respect to different clinical stages and parameters. Results: CTCs of OSCC patients correlated positively with the cancer stages (clinical as well as pathological) as well as aggressive pathological features. The presence of aggressive pathological features that often suggest the poor outcome of the disease, we observed a 25-50 % increase in CTC number. Early stage, treatment naïve patients had lower number of CTCs. Mean CTC number in advanced-stage patients was 50 % higher than early-stage OSCC patients. Conclusions: Considering a positive correlation of CTC number with various pathophysiological features, CTC can be contemplated as a reliable parameter to predict the disease outcome in oral cancer. The consistent presence of CTC across all disease stages also suggests a probable nature of OSCC as a biological systematic disease. Clinical trial information: CTRI/2018/03/012905.
Performance of a Nu.Q H3.1 assay for lung cancer detection.
Authors: Sibille Anne Louise Louise , Henket Monique , Herzog Marielle , Hardat Natalie , Corhay Jean-Louis , Louis Renaud , Duysinx Bernard
Published: May 2020

e15542

Background: Lung cancer diagnosis relies on invasive methods and often occurs at a late stage of disease, explaining its poor outcome. Nucleosomes are DNA fragments wrapped around histones. They may constitute a non-invasive and early diagnostic method for lung cancer. We investigated the clinical and statistical performance of nucleosome assay levels alone and in combination with cytokines in plasma from untreated lung cancer (LC) patients and what their discriminant power was towards chronic obstructive pulmonary disease (COPD) and healthy (H) subjects. Methods: 142 plasma samples were prospectively collected: H, n = 45; LC, n = 44 and COPD, n = 53. The circulating level of intact nucleosomes containing the histone H3.1 isoform (Nu.Qª-H3.1) was individually tested and in combination with cytokines for its performance in discriminating subjects for their underlying condition. Then, statistical performance of each model was tested with binary logistic regression models for the best combination of biomarkers for the following groups: cancer vs control (group A), cancer vs COPD+control (group B) and for cancer vs COPD (group C). The best model for each group was then applied to two independent biobank cohorts for validation. Results: Results for Nu.Q-H3.1 was an area under the curve (AUC) of 0.79, for group A, B and C; a sensitivity of 68%, 66% and 66% for group A, B and C, respectively, for 80% specificity. For group A the H3.1+IL-10 model achieved a sensitivity of 77% for 80% specificity with an AUC of 0.88 (R² = 55.8%). For group B the H3.1+IL-6+IL-10 model achieved a sensitivity of 70% with an AUC of 0.85 (R² = 40.6%). For group C the H3.1+IL-6+IL-10 model achieved a sensitivity of 79% with an AUC of 0.85 (R² = 46.1%). The validation cohort performed similarly. Results for the 3 cohorts taken together were: AUC of 0.83, 0.87 and 0.90 for group A, B and C, respectively; sensitivity of 75%, 76 % and 84% for group A, B and C, respectively, for 80% specificity. Conclusions: Nucleosomes are detected in the plasma of H, LC and COPD patients. Combination with cytokines as described in these models allows for a good power ofdiscrimination between the three groups. Based on these encouraging results, we believe further studies with larger numbers of patients should be performed to confirm and validate the usefulness of these biomarkers and models.
Combined use of albumin and neutrophil-to-lymphocyte ratio as new prognostic and predictive factor in patients with poorly differentiated neuroendocrine carcinomas.
Authors: Colombo Elena , Manca Paolo , Bini Marta , Bottiglieri Achille , Massa Giacomo , Prinzi Natalie , Torchio Martina , Niger Monica , Corti Francesca , Prisciandaro Michele , Zattarin Emma , Proto Claudia , Garassino Marina Chiara , Milione Massimo , Cattaneo Laura , Di Bartolomeo Maria , Platania Marco , De Braud Filippo G. , Lo Russo Giuseppe , Pusceddu Sara
Published: May 2020

e15543

Background: Outcomes of patients affected by advanced neuroendocrine carcinomas (NEC) with Ki-67 labeling index > 55% are heterogeneous regardless of the primary tumor site. We explored baseline inflammatory indexes and serum albumin levels to identify markers of response to standard first line chemotherapy. Methods: We retrospectively identified patients with advanced NEC treated with cisplatin (CP) or carboplatin (CB) and etoposide between 2015 and 2019 at the National Cancer Institute of Milan. Linear and Cox regressions were used to investigate, respectively, numeric and time-to-event outcomes. Maximization of log-rank statistics was used for optimal cutoffs finding. An artificial intelligence algorithm, random forest, was used to rank the impact of different clinical features on OS and PFS. Results: A total of 81 consecutive patients with different primary tumors (53 small cell lung carcinoma, 12 large cell neuroendocrine carcinoma, 10 gastrointestinal neuroendocrine carcinoma and 6 Merkel cell carcinoma) either treated with CP (n = 39) or CB (n = 42) were analyzed. Overall response rate (ORR), median progression free survival (PFS) and median overall survival (OS) were, respectively, 50.6%, 5.5 months (m) and 9.1m. Considered together, high serum albumin (SA > 3.5 g/dl) and low neutrophile-to-lymphocyte ratio (NLR < 3.59) identified a group of patients (n = 42) with longer median PFS and OS compared to the rest of the cohort (8.3m vs 1.5m, HR 3.58, CI 2.14-6.02, p < 0.001 for PFS and 12.6m vs 4.4m, HR 3.11, CI 1.88-5.18, p < 0.001 for OS); within this group a higher ORR (74% vs 36%, OR 5.01, CI 1.83-14.64, p = 0.002) was observed. Two multivariate models showed statistically significant associations of SA and NLR with PFS ( p = 0.017 and p = 0.005) and OS ( p = 0.016 and p = 0.036), independent of baseline ECOG performance status, age, sex, body mass index, smoking status, stage, hepatic tumor burden, primary site, histology, lactate dehydrogenase (LDH) serum levels, type of platinating agent and number of cycles. Two random forest models ranked SA, NLR and LDH as the most important factors for PFS and OS prediction. Conclusions: In the setting of advanced NEC with Ki-67 > 55% the combined use of SA and NLR identified two groups of patients with remarkably different outcomes, suggesting that these serum markers at baseline may have prognostic implications and be predictive of response to platinating agents. Prospective studies should validate these preliminary findings.
Whole genome SNP arrays for best practice for detection of diagnostic, prognostic and therapy related copy number changes and copy neutral-loss of heterozygosity across solid tumors and hematologic malignancies.
Authors: Lennon Patrick Alan , Raca Gordana , Fang Min , Wolff Daynna , Li Marilyn M. , Iqbal Anwar M. , Levy Brynn , Schwartz Stuart , Dubuc Adrian M.
Published: May 2020

e15575

Background: High resolution single nucleotide polymorphism (SNP) chromosomal microarrays (CMA) detect copy number changes and copy neutral-loss of heterozygosity (CN-LOH) across the entire genome, currently providing the best assessment for these types of genomic variants. Chromosomal microarrays are first tier tests utilized in the postnatal detection of microdeletions, microduplications and uniparental disomy/regions of homozygosity in constitutional disorders involving congenital abnormalities, developmental delay and intellectual disability. Methods: In the oncology setting, aberrations detected may be diagnostic, prognostic, and therapeutic. Because CMA assesses the entire genome and can readily detect aberrations as small as a single exon to as large as a whole chromosome, this is an important clinical tool to bridge the gap between low resolution of metaphase chromosome analysis and PCR-based short read sequencing-based assays. Results: No single genomic technique (metaphase chromosome analysis, FISH, CMA or Next Generation Sequencing, including large targeted gene panels) has the ability to detect all relevant information. Therefore, CMA should be considered an important clinical tool for solid and liquid tumors. Across a wide variety of solid tumors, whole genome assessment (including oncogene amplification, tumor suppressor loss, and copy number burden) leads not only to possible therapy targets but also to opportunities for participation in active clinical trials. Recently, the Cancer Genomics Consortium has published evidenced-based reviews on the clinical utility of CMA for copy number and CN-LOH assessment in a variety of hematologic malignancies, and similar papers in solid tumors are in review. Recognizing the growing evidence for CMA, the American Medical Association (AMA) CPT editorial board recently created a new Tier 1 test for cytogenomic arrays in neoplasia, and Centers for Medicare and Medicaid Services (CMS) approved crosswalking the price of the new code to the well-established constitutional cytogenomic array CPT code. Conclusions: For this presentation, examples of diagnostic, prognostic, and therapeutic utility and inclusion in clinical trials across many hematologic and solid tumor neoplasms will be presented to demonstrate the efficacy, cost effectiveness and sensitivity of whole genome assessment of copy number and copy neutral loss of heterozygosity
Targeted PCR vs NGS for molecular diagnostic in solid tumors and liquid biopsies. How to choose in real-life.
Authors: Merlin Jean-Louis , Gilson Pauline , Husson Marie , Harle Alexandre
Published: May 2020

e15576

Background: Molecular diagnostic is now part of routine diagnosis in many solid tumors and multiple technical options are available from extensive sequencing (NGS) to fully-automated targeted PCR (FAPCR). Tumor tissue testing is the gold standard, liquid biopsy is becoming a valuable option. Methods: 417 FFPE tumors, and 28 liquid biopsies were analyzed from 233 non small cell lung cancer (NSCLC), 177 colorectal cancer (CRC), 35 melanoma (MEL) in an ISO 15189 certified, French NCI molecular genetics platform. FAPCR analyses were performed individually, every day, using CE-IVD kits for the exclusive analysis of KRAS, NRAS, BRAF and EGFR mutations in NSCLC, CRC and MEL. NGS analyses were performed weekly as 12 or 24 sample runs using custom multiple gene panel capture sequencing. In all cases, prior to analysis, the specimens were macrodissected to warrant tumor cell content > 10% after examination of hematoxylin eosin stained slide by a pathologist. For liquid biopsy, cfDNA was extracted within 3 days from blood samples collected in cfDNA BCT tubes and analyzed using CE-IVD EGFR mutation kits. Time to results was recorded from registration of the specimen to validation of the results. Results: All FFPE tumors were analyzed using either FAPCR (N = 321) or NGS (N = 110) according to the clinician choice. Less than 2% of samples were not analyzable because of tumor cell content < 10% or degradated DNA. Median time to results was 6 days for FA-PCR (range 1-19) and 18 days for NGS (range 7-28). No significant difference was observed between NSCLC, CRC and MEL. Most cases of delay > median were related to pre-analytical defects and the need for a second specimen. For liquid biopsies, time to result was 6 days (range 1-18). The mutation rates were respectively, 13% for EGFR in NSCLC, 57% for KRAS/NRAS/BRAF in CRC and 69% for BRAF/NRAS in MEL. Using NGS led to the identification of additional molecular targetable alterations that were not analyzed by FAPCR in 44% of NSCLC, 22% of CRC and 14% of MEL. Among the 28 liquid biopsies analyzed mostly at progression under anti-EGFR TKI, EGFR mutations including T790M, were detected in 61% of the cases. Conclusions: Independently of cost-effectiveness, using PCR reduces time to results and can accelerate the initiation of targeted therapy but restricts the range of analysis, while extensive NGS delays time to results but identifies additional biomarkers that could be useful for therapeutic stratification. Using liquid biopsy testing could be an alternative and allow dynamic molecular diagnostic at 1st line and during follow-up.
NGSCUP: Phase II trial of site-specific treatment based on gene expression and mutation profiling by next generation sequencing (NGS) for patients (pts) with cancer of unknown primary site (CUP).
Authors: Hayashi Hidetoshi , Takiguchi Yuichi , Minami Hironobu , Akiyoshi Kohei , Segawa Yoshihiko , Ueda Hiroki , Iwamoto Yasuo , Kondoh Chihiro Nakayama , Matsumoto Koji , Takahashi Shin , Yasui Hisateru , Sawa Toshiyuki , Onozawa Yusuke , Chiba Yasutaka , Togashi Yosuke , Sakai Kazuko , Fujita Yoshihiko , Tomida Shuta , Nishio Kazuto , Nakagawa Kazuhiko
Published: May 2020

e15577

Background: Although gene profiling is a promising diagnostic technique to determine the tissue of origin for pts with CUP, we reported that site-specific treatment based on gene profiling using microarray did not result in an improvement the survival compared with empirical therapy in the previous randomized phase 2 trial (Hayashi, et. al, JCO 2019). Recently, we have established new integrative diagnostic system combined the gene expression from RNA-sequencing and mutation/copy number variation data from targeted genomic-sequencing using NGS. We have performed a single-arm phase 2 study to assess the efficacy of site-specific therapy determined by this system in previously untreated pts with CUP. Methods: Comprehensive gene profiling was performed by NGS, and an established algorithm was applied to predict tumor origin. Pts with CUP was received site-specific chemotherapy determined by the predicted site. The primary endpoint was one-year survival rate. Results: A total of 111 pts was enrolled and all had sufficient biopsy tissue for gene profiling. Efficacy analysis was performed for 97 pts who received site-specific treatment. Cancer types most commonly predicted were lung (21%), liver (15%), kidney (15%), and colorectal cancer (12%). The one-year survival rate, median overall survival (OS), and progression free survival (PFS) was 53.1% (95%CI, 42.6-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Median OS (15.7 versus 11.0 months, P = .078) and PFS (5.5 versus 2.8 months, P = .019) were better for predicted tumor types categorized as more responsive types than for less responsive ones. Conclusions: Site-specific treatment based on NGS demonstrated promising efficacy. Pts with CUP predicted to have more responsive tumor types had longer survival compared with pts with less responsive tumor types, suggesting that molecular tumor profiling by both DNA and RNA testing contributes to the management of pts with CUP. Clinical trial information: UMIN051180009.
A new model to prognosticate man breast cancer in China.
Authors: Liu Yunjiang , Zhang Shuo , Liu Yueping , Song Chao , Wang Ning , Tang Jiyu , Zhou Meng-Li , Chen Ming-Shuo , Cheng Skye Hung-Chun
Published: May 2020

e15579

Background: Male breast cancer is rare, and much of our understandings in this disease is still extrapolated from data in women with breast cancer. However, it has been suggested that male breast cancer may exist different etiology and biology from female by comparing the results of 21-gene Breast Recurrence Score (RS). However, the patient cohorts of these studies involved mainly patients being identified as Caucasian. Racial and ethnic disparities exist in genetic and biological factors that could influence the disease. A new model RecurIndex, based on a genomic database from RNA expression of Asian patients predominantly, is mainly developed for predicting the distant metastasis (DM) in female Breast cancer patients. We aim to validate whether this model can prognosticate male breast cancer in China. Methods: A total of 23 male patients with breast cancer were enrolled in a retrospective study in the single medical center. Kaplan-Meier survival curves was used to calculate the survival rate. The primary endpoint was relapse free survival (RFS)。Differences between male and female patients in terms of individual mRNA expression level were also determined. Results: Among the 23 patients enrolled in this study, Recurindex classified 11 patients as low risk 12 patients as high risk in distant metastasis respectively. When the low- and high-risk groups according to the Recurindex results were compared, there were only significant different in lymph node stage among individual clinical factors. 16 Patients with follow-up information which were stratified in DM low risk group have higher survival probability than high risk group. Mean quantitative gene expression of Recurindex signatures comparison between 16 men and 267 women patients reveals gene expression differences in numbers of gene. Conclusions: Based on genetic profiling assay specific designed for Asian population, the current study exhibits some different genetic features of male breast cancer. Our multigene signatures may also be utilized by male patient.
A functional precision medicine 3D microtumor platform to identify and personalize novel indications.
Authors: Apfel Christian , Chen David , Baratta Juliana , Mishra Dhruva K.
Published: May 2020

e15588

Background: We have previously validated our 3D microtumor platform that captures the tumor heterogeneity of a patient's primary tumor biopsy using a patient-derived xenograft model (Nikolov et al. ASCO 2019, e17076). Here we describe its utility to identify FDA approved therapies that may be effective for tumors previously not considered. Methods: A fresh tumor sample of a liver metastasis of a 45-year-old colorectal cancer patient was shipped overnight and processed to create hundreds of live 3D microtumors. These microtumors were treated with a panel of 12 commonly used drugs including chemotherapies and targeted therapies. Treatment effects were quantified and validated on fresh and cryopreserved/thawed samples using our metabolic and proprietary multiplexed fluorescent staining technologies to quantify the ratio of live and dead cells in those microtumors. Results: None of the conventional treatments in the 12-panel drug test suggested any efficacy as determined by the log of efficacy concentrations (in µmol/l): Oxaliplatin 2.59, 5-FU 3.00 (upper cut-off value), paclitaxel 1.72, topotecan 3.00, irinotecan (SN-38) 2.33, gemcitabine 2.44, and bevacizumab 3.00. The microtumors also appeared resistant to several targeted therapies that are not commonly given, ranging from 1.85 to 2.44. However, abemaciclib had an efficacy of 0.49, which was confirmed on thawed samples with all drug efficacy concentrations again suggesting resistance, except for abemaciclib at 0.67. Conclusions: Our 3D microtumor platform may be a useful tool a) to identify rescue treatment options for metastatic patients that have multi-resistant tumors and b) to identify novel indications to personalize FDA-approved cytotoxic or targeted therapies as a companion diagnostic.