bluuebunny/crossref_metadata_2025 huggingface dataset:
The clinical impact of performing routine next generation sequencing (NGS) in gastrointestinal stromal tumors (GIST).
Authors: Kelly Ciara Marie , Bowler Timothy Geoffrey , D'Angelo Sandra P. , Dickson Mark Andrew , Gounder Mrinal M. , Keohan Mary Louise , Vonya Taylor , Yoon Sam S. , Singer Samuel , DeMatteo Ronald P. , Antonescu Cristina R. , Zehir Ahmet , Ladanyi Marc , Solit David B. , Chi Ping , Tap William D.
Published: September 2018

11010

Background: The majority of GISTs harbor activating mutations in KIT or PDGFRα but the clinical relevance of other genomic alterations is unknown. We sought to determine the clinical impact of performing routine NGS and to describe the molecular landscape in GIST. Methods: From April 2014 to August 2016, 177 patients (pts) consented to an IRB-approved protocol. Tumor and matched normal samples were prospectively analyzed in a CLIA-compliant laboratory, with MSK-IMPACT, a NGS assay of up to 468 cancer-associated genes. Results: 191 samples were analyzed. NGS was most often performed in the setting of advanced disease (n = 108 (57%)). The primary tumor was most commonly tested (n = 120 (63%)). NGS guided clinical management in 79% (n = 150) of cases [matched therapy (MT) offered, n = 120/150 (80%); MT not offered, n = 24/150 (16%)]. In 25/41 cases (61%) where NGS did not influence management, treatment was not indicated because the GISTs were low risk. Most samples had ≤ 3 mutations (muts) (range: 0-17). Actionable muts were identified in 155/191 samples (81%). These included muts in KIT, PDGFRα and BRAF [oncoKB stratification: level 1 (84%), 2A (13%), 2B (2%), 3A(1%)]. 33/177 pts did not have a KIT/ PDGFRα mut [SDH deficiency, n = 15 (45%), NF1, n = 10 (30%), BRAF, n = 1(3%), NF1&BRAF, n = 1 (3%)]. 5pts had quadruple wild type GIST. Most GISTs had at least one genetic alteration in a non-driver allele (74%, n = 141/191)[frequently mutated genes in KIT exon 11 driven i) primary tumors include TP53, MAX, MLL2, SETD2, PIK3CA, TSC1; and ii) metastatic tumors include RB1, SETD2, PTEN, ANKRD11, TP53, TSC1]. CDKN2A deletion was the most common copy number alteration identified in KIT driven GIST and occurred most often in metastatic samples (with and without co-occurring, secondary KIT muts) and those with high mitotic rate. Conclusions: NGS of GIST informs clinical management in the majority of pts through the identification of muts in canonical driver genes. NGS also identifies a high prevalence of tumor-specific genetic alterations in non-canonical driver genes. These genes function in multiple pathways including intracellular signaling, chromatin remodeling, proteasomal degradation and cell cycle regulation.
Cost effectiveness of surveillance for distant recurrence in extremity soft tissue sarcoma.
Authors: Royce Trevor Joseph , Punglia Rinaa S. , Patel Sagar Anil , Thornton Katherine Anne , Raut Chandrajit P. , Baldini Elizabeth H.
Published: September 2018

11021

Background: Optimal surveillance strategies for extremity soft tissue sarcoma (STS) are unknown. We performed a cost-effectiveness analysis of competing imaging modalities performed at National Cancer Comprehensive Network guideline-specified intervals. Methods: We developed a Markov model simulating lifetime outcomes for 54-year-old patients after definitive treatment for Stage II-III extremity STS using four surveillance strategies: watchful waiting (WW), chest x-ray (CXR), chest computed tomography (CCT) and positron emission tomography-computed tomography (PET/CT) performed every 3-6 months for the first 3 years, every 6 months until year 5, and then annually. We used probabilities, utilities and costs extracted from the literature and Medicare claims to determine incremental cost-effectiveness ratios (ICER). Results: While the model showed that CCT is the most effective strategy, CXR is the most cost-effective strategy at a societal willing-to-pay (WTP) of $100,000/quality-adjusted life year (QALY). The ICER is $14,306/QALY for CXR versus $117,683/QALY for CCT while PET/CT is never cost effective (Table). Sensitivity analyses demonstrated CCT becomes the preferred imaging modality as the lifetime risk of DR increases beyond 38% or as the societal WTP increases beyond $130,000/QALY. Conclusions: Optimal DR surveillance imaging for Stage II-III extremity STS should be individualized based on patients’ risks for DR. CXR, or CCT at more protracted intervals, may be preferred for lower risk patients (i.e. DR risk less than 38%), whereas CCT may be preferred for higher risk patients (i.e. DR risk greater than 38%). These findings can help refine guidelines to reduce resource overutilization during surveillance of sarcoma patients. [Table: see text]
Association of genomically unstable Ewing sarcoma tumors with HOTAIR overexpression and clinical outcome.
Authors: Gardiner Jamie D. , Huang Xiaomeng , Lazaris Evangelia , Jones Kevin , Yap Jeffrey T. , Randall R Lor , Abegglen Lisa , Amatruda James , Schiffman Joshua David
Published: September 2018

11035

Background: Ewing sarcoma (ES) is the second most common bone cancer in children, characterized by the EWS-FLI1 fusion protein. Like most translocation-driven pediatric cancers, ES is a genomically “quiet” cancer with a low mutational burden and strong epigenetic regulation. However, recurring copy number alterations (CNAs) still arise in some ES tumors (e.g., chromosome 1q gain, 8 gain, 12 gain, and 16q loss) while other ES tumors completely lack genomic CNAs. We hypothesized that clinical, molecular, and epigenetic differences exist between these two unstable vs. stable genomic subtypes of ES. Methods: We performed CNA analysis on over 200 ES FFPE tumors. 30% of ES tumors had stable genomes while 60% had one or more CNAs across the genome. We performed gene expression and methylation microarray analyses on 24 ES FFPE tumors (11 stable, 13 unstable). Expression and methylation signatures were compared between stable vs. unstable ES and combined with clinical outcome. Results: Patients with unstable vs. stable ES tumors revealed worse 5-year overall (OS) and event-free survival (EFS) (38% vs. 67% EFS, p = 0.005; 58% vs. 84% OS, p = 0.0016). The subtypes had distinct expression and methylation signatures and clustered by methylation patterns. We identified differentially expressed and methylated genes, including upregulation (p = 0.0005) and unmethylation (p = 0.0009) of the long non-coding RNA HOTAIR in unstable vs. stable ES tumors. HOTAIR expression is higher in metastatic ES tumors compared to primary ES tumors (p = 0.02). Per the Cancer Cell Line Encyclopedia (Broad), ES cell lines have increased HOTAIR expression compared to 36 other cancers. Conclusions: ES genomic profiling through copy number, gene expression, and methylation identified at least two subtypes of ES (stable and unstable) that differ in outcome, gene expression and methylation. This data suggests HOTAIR’s involvement in ES pathogenesis, particularly in unstable tumors that have worse prognosis. Investigation is ongoing for HOTAIR expression as a prognostic and therapeutic target for ES, including a marker for LSD-inhibitor response.
LMTK3 as a novel regulator of oncogenic KIT in KIT-mutant cancers.
Authors: Klug Lillian Rose , Tyner Jeffrey , Heinrich Michael C.
Published: September 2018

11044

Background: Multiple cancers, such as gastrointestinal stromal tumors (GIST) and melanoma, have been shown to be caused by somatic activating mutations in the receptor tyrosine kinase KIT. The major cause of death in patients with advanced KIT -mutant cancers is due to the development of KIT tyrosine kinase inhibitor-resistant (TKI-resistant) metastatic disease. Drug resistance arises almost exclusively from secondary mutations within KIT, highlighting the importance of KIT in the proliferation and survival of these tumors. Methods: We performed a human kinase siRNA screen in multiple KIT -mutant cancer cell lines using viability as a read out. We defined candidate targets as those whose knockdown decreased viability in all cell lines. Validation and mechanistic studies were done using a library of KIT-mutant GIST and melanoma cells. Results: We identified lemur tyrosine kinase 3 (LMTK3) as candidate target in three KIT -mutant cell lines. LMTK3 silencing reduced the viability of all KIT -mutant GIST and melanoma cells tested to date, including cell lines with KIT TKI-resistance mutations. Importantly, LMTK3 silencing decreased the viability of KIT -mutant cells specifically, but not that of KIT-independent GIST and melanoma cells. Further, we found that decreased cell viability was due to induction of apoptosis, as assessed by measuring caspase 3 and 7 activity within 96 hours of LMTK3 silencing. LMTK3 knockdown also reduced tumor growth in vivo in a GIST xenograft model. Because these cells depend so heavily on KIT and the loss of KIT signaling results in cell death, we hypothesized that LMTK3 silencing may affect this pathway. Indeed, LMTK3 silencing decreased levels of autophosphorylated KIT. We also observed a significant decrease in total KIT protein expression. This phenotype and corresponding viability was rescued with exogenous expression of full length LMTK3. Conclusions: LMTK3 is an important regulator of oncogenic KIT expression and activity in KIT-mutant GIST and melanoma and represents a novel, tractable target.
Elevated preoperative peripheral blood neutrophil-to-lymphocyte ratio to predict clinical outcome in patients with localized soft tissue sarcoma.
Authors: Chan Jason Yongsheng , Zhang Zewen , Chew Winston , Tan Grace Fangmin , Lim Chloe Liwen , Zhou Lingyue , Goh Wei Lin , Selvarajan Sathiyamoorthy , Sittampalam Kesavan , Chin Francis , Teh Jonathan Yi Hui , Tan Mann Hong , Soo Khee Chee , Teo Melissa , Mohamad Farid , Quek Richard Hong Hui
Published: September 2018

11049

Background: Recent studies suggest that markers of systemic inflammation such as blood neutrophil-to-lymphocyte ratio (NLR) may be prognostic for various cancers, though its clinical utility has not been widely accepted. This study aims to investigate its clinical relevance in patients (pts) with soft tissue sarcoma (STS). Methods: Five hundred and twenty-nine pts with localized STS who had available pre-operative blood counts at the time of diagnosis were retrospectively examined. An optimal cutoff for high NLR ( > 2.5) in predicting overall survival (OS) and relapse-free survival (RFS) in pts who underwent curative surgery (n = 473) was determined using receiver operating curve analyses. Cutoffs for platelet-lymphocyte ratios (PLR, > 180) and lymphocyte-monocyte ratios (LMR, < 3.6) were similarly obtained. Survival analysis was performed using the Kaplan-Meier method and multivariate Cox proportional models. Median follow-up was 40 months. Results: A high NLR was present in 311 (58.8%) pts, which was significantly associated with tumor grade ( p< 0.0001), depth ( p= 0.003) and size > 5 cm ( p= 0.0242), but not with age at diagnosis, sex or ethnicity. High NLR was associated with both worse OS (HR 1.78; 95%CI 1.28-2.47; p= 0.0005) and RFS (HR 1.54; 95%CI 1.17-2.03; p= 0.0019), as were age at diagnosis, tumor grade, size, PLR and LMR. In multivariate models adjusted for clinicopathological predictors of survival, only NLR, in addition to tumor grade and size, were independently associated with worse OS (HR 1.52; 95%CI 1.09-2.11; p= 0.0131) and RFS (HR 1.42; 95%CI 1.08-1.85; p= 0.0114). Analysis of survival according to American Joint Committee on Cancer (AJCC) stages subdivided as NLR-high and NLR-low revealed a significant worse prognosis for NLR-high subgroups ( p< 0.0001), with a 2.2-fold and 1.5-fold higher risk of death within stages II (HR 2.20; 95%CI 1.20-4.01; p= 0.0103) and III (HR 1.55; 95%CI 1.01-2.37; p= 0.0459), respectively. Conclusions: High NLR is an independent marker of poor prognosis among pts with localized STS. Inclusion of NLR as a classifier into the AJCC staging of STS may improve estimation of survival.
Phase 2 multicenter study of the EZH2 inhibitor tazemetostat in adults with synovial sarcoma (NCT02601950).
Authors: Schoffski Patrick , Agulnik Mark , Stacchiotti Silvia , Davis Lara Emily , Villalobos Victor Manuel , Italiano Antoine , George Suzanne , Cote Gregory Michael , Blakemore Stephen , Clawson Alicia , Daigle Scott , Ribich Scott , Roche Maria , Rodstrom Jill , Ho Peter T.C. , Gounder Mrinal M.
Published: September 2018

11057

Background: Synovial sarcoma (SS) accounts for 5-10% of all soft tissue sarcomas (STS). Metastatic and/or locally advanced disease occurs in up to 70% of patients (pts), with reported median overall survival (OS) as short as 22 months. SS18-SSX translocations, a defining molecular feature of SS, generate a fusion protein that competes with native SS18 during SWI/SNF complex assembly disrupting complex function. SWI/SNF complexes containing the fusion protein lack INI1 and cellular INI1 expression levels are reduced to varying degrees in SS. This mechanism of INI1 reduction is distinct to that observed in malignant rhabdoid tumors, epithelioid sarcoma or other INI1 negative tumors. Tazemetostat, a potent and selective EZH2 inhibitor, has demonstrated activity in preclinical SS models with the proposed mechanism of sensitivity being via INI1 reduction inducing compromised SWI/SNF activity and tumor dependence on EZH2. Methods: This is a phase 2 multicenter open-label non-randomized study with 5 cohorts of different tumor types with INI1 loss/reduction or evidence of SS18 rearrangement. Adult pts in the SS cohort were treated with tazemetostat (800 mg po BID). Up to 30 pts were enrolled using a 2-stage Green-Dahlberg design. The primary endpoint is complete response, partial response or stable disease (SD) at 16 wks. Success at the end of stage 2 requires ≥9 of 30 treated pts meet this criterion. Key secondary endpoints include overall response rate, PFS, OS, safety/tolerability, PK and biomarkers of response. Results: In 33 treated SS pts with a median of 2 prior systemic treatments, best response of SD was observed in 11 pts (33%) with 5 pts (15%) having SD lasting ≥16 wks. No objective responses were observed. The protocol-defined success criterion at the end of study was not met. Tazemetostat was well-tolerated with grade 1/2 cough (36%), dyspnea (33%) and fatigue (33%) as the most frequently reported adverse events regardless of attribution. Conclusions: Tazemetostat was well tolerated with a favorable safety profile. Although there were no objective responses in heavily pretreated pts, the observation of SD in a subset of pts suggests further studies with tazemetostat in combination may be warranted in SS. Clinical trial information: NCT02601950.
Rates of survival throughout the years in soft tissue sarcoma with synchronous metastases: Results of a population-based study.
Authors: Vos Melissa , Ho Vincent K.Y. , Oosten Astrid W. , Verhoef Cornelis , Sleijfer Stefan
Published: September 2018

11068

Background: Roughly 10% of patients with soft tissue sarcoma (STS) present with synchronous metastases and generally cannot be cured anymore. With the registration of trabectedin, pazopanib and the identification of other agents exerting activity against STS, the treatment of these patients in the Netherlands has changed considerably in the last decade. The aim of this population-based study is to examine whether the overall survival (OS) of patients with STS and synchronous metastases has improved over the years. Methods: All patients diagnosed with adult-type STS and synchronous metastases between 1989 and 2014 were queried from the Netherlands Cancer Registry. Trends in OS were assessed by the Kaplan Meier method and log rank test in different timeframes based on year of registration of trabectedin ( < 2007 vs. ≥2007) and pazopanib ( < 2012 vs. ≥2012). A multivariable Cox regression analysis was performed to identify relevant characteristics prognostic for OS. Results: In total, 1,393 patients with adult-type STS and synchronous metastases were identified. Over the whole time period, median OS did not improve significantly (5.8 months in 1989-1994 to 8.1 months in 2010-2014, p = 0.095), but median OS < 2007 compared to ≥2007 did improve significantly (5.8 months to 7.3 months, p = 0.035). This was particularly apparent in the liposarcoma subgroup, where median OS doubled (5.2 months to 11.5 months, p = 0.020). Median OS < 2012 compared to ≥2012 did not increase significantly (6.1 months to 7.6 months, p = 0.062), though there was a relatively short follow-up of 2 years while the survival curve seems to reach a plateau phase. Aside from not receiving (any type of) treatment, elderly age, STS subtype other than lipo- or leiomyosarcoma, high or unknown grade and nodal involvement were significant negative predictors for OS, whereas primary tumor site in the extremity and surgery in an academic center had a favorable effect on OS. Conclusions: OS of STS patients with synchronous metastases has not improved significantly over the years, except for the subgroup of liposarcomas after 2007. A longer follow-up period is needed to clarify the impact of pazopanib on OS in patients with metastatic STS.
Clinical utility of routine surveillance CT/MRI imaging in patients with localized soft tissue sarcoma (STS) following curative resection.
Authors: Lim Chiew Woon , Harunal Rashid Mohamad Farid Rin , Goh Wei Lin , Tan Sze Huey , Wong Steven Bak Siew , Chan Lai Peng , Hennedige Tiffany Priyanthi , Selvarajan Sathiyamoorthy , Sittampalam Kesavan , Teh Jonathan Yi Hui , Chin Francis Kuok Choon , Tan Mann Hong , Soo Khee Chee , Teo Melissa Ching Ching , Quek Richard Hong Hui
Published: September 2018

11069

Background: Guidelines recommend routine surveillance imaging in patients (pts) following curative resection of STS. However the benefit of such an approach is unclear. We sought to evaluate the utility of a surveillance imaging strategy in pts with localized STS treated with curative intent. Methods: Pts with localized non-indolent STS, seen between 2010 – 2016, who had undergone surgery with R0/R1 surgical margins were included. Epidemiology, treatment and relapse data were collected as was the mode of detection. We defined optimal surveillance as CT/ MRI performed at least 6-mthly following surgery; suboptimal surveillance was defined as CT/ MRI imaging performed less frequently than 6mthly. Results: Of 294 pts included, 31% (n = 92) vs 34% (n = 100) vs 35% (n = 102) had optimal, suboptimal and no routine CT/MRI surveillance imaging respectively. At a median follow-up of 27mths (range 0-79), 36% (n = 105) experienced a relapse; 43% (n = 45) local and 57% (n = 60) had metastatic relapse. More relapses were noted in the optimal surveillance group, 57% (n = 52) vs 28% (n = 28) and 25% (n = 25) in the suboptimal and no surveillance groups respectively (p < 0.001). Within each cohort, relapses detected directly by routine surveillance imaging vs outside of surveillance imaging were as follows: 35% (n = 32) / 22% (n = 20) in the optimal, 17% (n = 17) / 11% (n = 11) in the suboptimal and 0 / 25% (n = 25) in the no surveillance arms respectively. Comparing the 3 strategies, the proportion of pts who then went on to receive curative resection/ metastacectomy was not significantly different, 38% (n = 20), 57% (n = 16) and 32% (n = 8) of relapses, in the optimal vs suboptimal vs no surveillance cohorts respectively (p = 0.1). Notably, routine surveillance imaging directly leading to curative resection occurred only in 15% (n = 14) of pts in the optimal and 9% (n = 9) in the suboptimal surveillance groups. Conclusions: While an intensive routine CT/MRI surveillance imaging strategy detected more recurrences, the impact it has on subsequent resection is less certain. Optimal frequency of surveillance imaging remains unclear.
Sensitivity to chemotherapy of low-grade endometrial stromal sarcoma (LGESS) versus high-grade endometrial stromal sarcoma (HGESS).
Authors: Sanfilippo Roberta , Colia Vittoria , Fumagalli Elena , Bertulli Rossella , Morosi Carlo , Carcangiu Maria Luisa , Lorusso Domenica , Raspagliesi Francesco , Dei Tos Angelo Paolo , Casali Paolo Giovanni
Published: September 2018

11072

Background: LGESS and HGESS are rare uterine neoplasms of endometrial stromal origin. The activity of hormonal therapy in LGESS is reported, whilst no data are available in HGESS. The activity of chemotherapy is unknown in both. We focused on LGESS and HGESS to explore their sensibility to chemotherapy Methods: Cases diagnosed with LGHSS and HGESS from 1997 at Istituto Nazionale Tumori, Milan, or within the Italian Rare Cancer Network (RTR), were reviewed. Results: We identified 39 patients (pts), 28 with LGESS (median age:43) and 11 (median age: 54) with HGESS. Seventeen LGESS pts received systemic therapy for advanced disease (1-5 lines). Eight received an aromatase inhibitor, with 2 PR, 5 SD and 2 PD; 8 received oral progestins, with 4 PR, 5 SD and 2 PD. Nine patients (6/9 in first line, 1/9 in second line and 1/9 in third line) received antracyclines +/- ifosfamide and were evaluable for response: 2 had a CR, 4 a PR and 3 a SD. Median PFS was 7,6 months. Five patients received high-dose ifosfamide (HDIFX), obtaining 2 PR and 3 SD. Five pts received trabectedin, with 1 PR, 3 SD and 1 PD. All eleven pts with HGESS received systemic therapy for advanced disease (1-5 lines). Three patients received oral progestins, with PD. Ten pts received an antracycline-based combination chemotherapy and were evaluable for response: 5 had SD and 5 had PD. Median PFS was 3 months. Four pts received HDIFX and all progressed. Four pts received gemcitabine-based chemotherapy, obtaining 1 SD and 3 PD. Five pts received trabectedin, obtaining 1 SD and 4 PD. One pt received Pazopanib, with a PR lasting 5 months. Conclusions: In this series of endometrial stromal tumor pts treated with medical therapy, chemotherapy with antracycline-based combinations resulted in some objective responses in LGESS, while it was essentially inactive in HGESS. An observational clinical study is ongoing to expand this series.
Genomic profiling of resistant tumor samples following progression on EGF816, a third generation, mutant-selective EGFR tyrosine kinase inhibitor (TKI), in advanced non-small cell lung cancer (NSCLC).
Authors: Tan Daniel Shao-Weng , Kim Dong-Wan , Leighl Natasha B. , Riely Gregory J. , Yang James Chih-Hsin , Wolf Juergen , Seto Takashi , Felip Enriqueta , Ponce Aix Santiago , Jonnaert Maud , Pan Chun , Dolan Sinead , Barretina Jordi , Moody Susan Elizabeth , Sequist Lecia V.
Published: September 2018

11506

Background: Up to 60% of patients (pts) with NSCLC harboring an activating EGFR mutation (mut) and treated with a 1st generation EGFR TKI develop a secondary gatekeeper T790M mut. EGF816 is an irreversible EGFR TKI that is highly potent against activating mut (L858R, ex19del) and T790M mut, while sparing wild-type EGFR. As previously reported, in a Phase I dose escalation study, the overall response rate to EGF816 in pts with advanced EGFR T790M mut NSCLC was 47% and the disease control rate was 87%. However, pts ultimately develop disease progression. Tumor biopsies were obtained from pts who had progressed on EGF816 to identify mechanisms of resistance. Methods: Pts with NSCLC with locally or centrally confirmed T790M status were enrolled in this multicenter, dose escalation study to determine the safety, tolerability and antitumor activity of EGF816 (NCT02108964). EGF816 was administered at 7 dose levels ranging from of 75-350 mg QD. Following disease progression, a tumor sample was obtained and was analyzed by the Foundation Medicine next-generation sequencing (NGS) T7 panel, which interrogates 395 cancer-related genes for base substitutions, insertion-deletions, and copy number changes, as well as introns of 31 genes involved in rearrangements. Results: Tumor samples taken following disease progression on EGF816 were analyzed from 9 pts. Of the 8 pts whose tumors were T790M+ at baseline, this was detected in only 3 pts’ post-EGF816 progression samples. One patient developed an EGFR C797S mut and concurrent deletion in mTOR. Other identified alterations include BRAF fusions (n = 2) and c-MET amplification (n = 1). Only one patient was found to have concurrent TP53 mutation and RB1 truncating mutation. Individual patient response data, including duration of response, will be presented along with detailed genomic parameters. Conclusions: NGS analysis of tumors that developed resistance to EGF816 revealed multiple potential mechanisms of resistance. These data are hypothesis-generating and could lead to rational combination studies with EGF816 to improve the depth and/or duration of response to EGF816. Clinical trial information: NCT02108964.
Characterization of tumor mutation load (TML) in solid tumors.
Authors: Salem Mohamed E. , Xiu Joanne , Lenz Heinz-Josef , Atkins Michael B. , Philip Philip Agop , Hwang Jimmy J. , Gatalica Zoran , Xiao Nianqing , Gibney Geoffrey Thomas , El-Deiry Wafik S. , Tan Antoinette R. , Kim Edward S. , Shields Anthony Frank , Raghavan Derek , Marshall John
Published: September 2018

11517

Background: Rapid advances in immunotherapy have created a need for biomarkers to improve patient treatment selection. TML is proposed as a potential predictive biomarker due to its association with tumor immunogenicity. Methods: TML was assessed in 8020 tumors from 14 different cancers using somatic nonsynonymous missense mutations sequenced with a 592-gene panel. High TML was set at ≥ 17 mutations per megabase (mt/MB) based on an established concordance ( > 99%) with MSI-High in colorectal cancer (CRC). Results: Mean TML was highest in melanoma (Mel; 21 mt/MB), NSCLC (11 mt/MB), and bladder cancer (BLC; 11 mt/MB), whereas prostate cancer (PC), pancreas adenocarcinoma (PA), and renal cell carcinoma (RCC) had the lowest levels (all 6 mt/MB). High TML was seen most frequently in Mel (36%), NSCLC (15%), BLC (15%), and anal cancer (SCCA; 9%); and least frequently in PA (1.6%) and RCC (0.5%). Primary NSCLC carried lower TML than its brain metastases (11 vs. 16 mt/MB, p < 0.001). Older age was associated with higher TML in Mel (p = 0.001), CRC (p = 0.009), breast cancer (BC; p = 0.01), and NSCLC (p = 0.02). Higher TML was seen in males than in females for Mel (p = 0.002) and NSCLC (p < 0.001). Presence of mutations in oncogenic driver genes such as EGFR, ALK, ROS1 RET fusions, cMET exon 14 skipping correlated with lower TML in NSCLC (6.9 vs. 12 mt/MB, p < 0.001), as did BRAF and NRAS mutations in Mel (17 vs. 26, p = 0.003). Conversely, mutations in tumor suppressor genes such as ARID1A (CRC, NSCLC, and BLC) and NF1 (BC, CRC, Mel, BLC, and NSCLC) were associated with higher TML (p < 0.05). MSI-high was correlated with high TML in CRC and gastric cancers (p < 0.05). Conclusions: TML varied significantly among different cancers. High TML was associated with older age, absence of oncogenic mutations and presence of tumor suppressor gene mutations. Future studies will assess the impact of TML on clinical outcome and establish its role in selecting patients for immunotherapy. [Table: see text]
Change in metabolic tumor activity on 18F-FDG PET after a single dose of cetuximab to predict for treatment benefit, PFS, and OS in patients with advanced colorectal cancer.
Authors: Van Helden Erik Jacobus , Menke Catharina Wilhelmina , Boon Eline , van Es Suzanne , Huisman Marc C. , De Groot Derk Jan , Boellaard Ronald , Van Herpen Carla M.L.- , De Vries Elisabeth , Hoekstra Otto S. , Verheul Henk M.W.
Published: September 2018

11519

Background: Despite RAS selection, one third of patients with metastatic RAS wild-type colorectal cancer (mCRC) do not benefit from anti-EGFR inhibitors. Therefore, an additional or more accurate predictive biomarker is needed to identify patients with primary resistant mCRC. Methods: In the IMPACT-CRC trial (NCT02117466) patients with chemotherapy refractory mCRC received 500 mg/m2 cetuximab every 2 weeks. Before the first dose and just before the second dose, patients underwent a 18F-FDG PET/CT (FDG PET). PET scans were quantitatively assessed by manual tumor delineation of ≤ 5 lesions, 2 per organ. Outcome is reported in total lesion glycolysis (TLG), defined as metabolic tumor volume times mean standard uptake value of the tumor. An optimal threshold to assess metabolic response was defined as decrease in TLG ≥15%. Quantitative data were correlated with CT evaluation after 8 weeks of treatment according to RECIST v1.1. Results: Out of 35 patients, 1 was excluded due to an infusion reaction. Median age was 64 years, 74% was male, 4 patients had a BRAF mutated tumor and 9 patients had right-sided primary tumors. 62% of patients had stable disease or partial response on CT after 8 weeks. At the time of this analysis, 88% of patients had progressive disease and 71% had died. Of the patients with right-sided tumors 11% had treatment benefit, compared to 80% in the left-sided group (p = 0.001). None of the 9 metabolic non-responders had treatment benefit, whereas 83% of the metabolic responders had treatment benefit according to RECIST v1.1. After adjustment for age, WHO score, BRAF mutation, sex and primary tumor site, FDG PET response remained correlated with PFS and OS (p = 0.002 and p = 0.014). Conclusions: Early evaluation of metabolic response after 1 dose of cetuximab is highly and independently predictive for treatment benefit with a 100% negative predictive value. Implementation of early FDG-PET evaluation in daily clinical practice can prevent unnecessary toxicity, costs of ineffective treatment and allows timely treatment adjustment for patients with mCRC undergoing anti-EGFR treatment. Clinical trial information: NCT02117466.
Correlation of cell-free circulating DNA, RNA, and PD-L1 from plasma with clinical response in patients with metastatic lung and breast cancers.
Authors: Raez Luis E. , Danenberg Kathleen , Castrellon Aurelio Bartolome , Usher Joshua L. , Jaimes Yolanda S , Hunis Brian , Velez Michel E. , Habaue Cheryl , Danenberg Peter
Published: September 2018

11550

Background: There is an unmet need to evaluate tumor response by other means than radiology tests. Changes in gene expression, allele-fractions of mutations, PDL-1 expression and levels of cell free DNA [DNA] or RNA [RNA] in plasma might be useful for monitoring disease state and predicting outcome to anti-tumoral therapy. Methods: We measured serial levels of plasma DNA/RNA in metastatic patients (pts) with NSCLC and breast cancers undergoing treatment and correlated them with response (CR/PR/SD/PD) seen by CT scans. We also monitored PD-L1 expression in NSCLC pts treated with immunotherapy. DNA/RNA were extracted from plasma. RNA was reverse transcribed with random primers to cDNA. Levels of DNA/RNA were determined by RT-qPCR. Results: 52 pts were enrolled (28 breast/24 NSCLC). Breast group: 39% (11/28) were Caucasian (NHW) and 36% (10/28) Hispanic (H). 20 pts completed first two cycles of therapy: 2 pts had PR and showed no change (NC) or decrease (DEC) in levels of DNA/RNA. 11pts achieved SD, 9 had NC levels of DNA/RNA. Pts with PD: 5/6 underwent significant increase (INC) in DNA/RNA levels. Overall, among breast pts, there was an 84% (16/19) agreement between response and levels of DNA/RNA. These were correlated with one another ( r = 0.7002, p< 0.0001). NSCLC group: 71% (16/24) were NHW and 25% (6/24) H. Non-SQCC were 87% (21/24). 20 pts had CT scans. One pt had PR with DEC levels of DNA/RNA. 10 pts achieved SD, all showed DEC or NC levels of DNA/RNA. 8 pts had PD, 6 of them had INC in DNA/RNA levels even 7 weeks prior to PD. Among NSCLC pts, there was a 90% (17/19) agreement in response and levels of DNA/RNA. These were correlated with one another ( r= 0.6231, p< 0.0001). In 5 pts PD-L1 expression remained stable when CT scans showed SD or PR. Conclusions: There is a strong correlation between clinical responses with changes in plasma levels of DNA/RNA in pts with NSCLC (90%) and breast cancer (84%). Some of these were documented weeks before imaging was done. cfRNA is as effective as cfDNA as predictive tool for response. Plasma PDL-1 expression is a new tool to monitor immunotherapy response.
Metabolic barriers to immunotherapy in renal cell carcinoma.
Authors: Beckermann Katy , Siska Peter , Mason Frank , Rathmell Kimryn , Rathmell Jeffrey C
Published: September 2018

11560

Background: Cancer cells can inhibit effector T cells through both immunomodulatory receptors and alteration of the tumor microenvironment as a result of cancer metabolism. A majority of patients treated with immune checkpoint inhibitors recently approved by the FDA fail to exhibit a clinical response. The extent to which metabolic conditions within the tumor impede T cell activation and anti-tumor effector function in renal cell carcinoma (RCC) are unknown. Methods: Under the IACUC protocol M1600005-00, BALB/c or Rag mice were subcutaneously injected with 100,000 Renca cells obtained from ATCC and growth monitored by caliper measurements in 3 dimensions every 3 days. In vivoPD-1 blockade was performed by 200 mcg/i.p. injection every 3 days using purified mPD-1 (BioXcell, J43). Deidentified tissue donations from patients with RCC were collected under the IRB protocol #151549 and processed into single cell suspensions following mechanical dissociation for the functional assays indicated below. Results: Through work with Rag deficient mice lacking functional B and T cells, we have established that tumor growth is regulated in a T cell dependent manner as evidenced by earlier formation and faster tumor growth. In a syngeneic mouse model of RCC (RenCa), we find that inhibition of PD-1 delays tumor growth and size. Tumor infiltrating lymphocytes (TILs) were abundant in patient-derived RCC, but are phenotypically distinct and are impaired both functionally and metabolically from healthy control. Instead of efficient use of aerobic glycolysis, TILs fail to increase glucose metabolism, and instead display increased reactive oxygen species (ROS) and mitochondrial dysfunction. CD8 effector cells found in tumors have notable differences in mitochondrial morphology compared to healthy control CD8 T cells by electron microscopy and immunofluorescence where CD8 TIL are punctate and dispersed throughout the cell while healthy control CD8 mitochondria are fused in networks. Thus bypassing metabolic defects may partially restore TIL activation. Conclusions: Preclinical data suggests that improved understanding of metabolic dysfunction in TILs of RCC may allow for combined therapies to improve response rates of checkpoint inhibition in this disease.
Baseline cell-free DNA (cfDNA) and metabolic tumor volume (MTV) independently predict outcome in metastatic chemorefractory colorectal cancer (mCRC).
Authors: Woff Erwin , Kehagias Pashalina , Vandeputte Caroline , Kamoun Tarek , Guiot Thomas , Ameye Lieveke , Geboes Karen Paula , Delaunoit Thierry , Demolin Gauthier , Peeters Marc , D'Hondt Lionel A. , Janssens Jos , Carrasco Javier , Holbrechts Stephane , Goeminne Jean-Charles , Van Laethem Jean-Luc , Vergauwe Philippe , Paesmans Marianne , Flamen Patrick , Hendlisz Alain
Published: September 2018

11569

Background: No validated prognostic biomarker is currently available for mCRC. This trial assessed cfDNA and MTV before treatment with regorafenib as prognostic biomarkers for progression-free survival (PFS) and overall survival (OS) in mCRC. Methods: After signed informed consent, mCRC patients were enrolled in a prospective non-randomized trial aiming to define unlikelihood to benefit from regorafenib (EudraCT number: 2012-005655-16) and assessed for cfDNA and FDG PET/CT MTV at baseline. cfDNA was extracted from 3mL of plasma and quantified using the Qubit 2.0 fluorometer. All target lesions were delineated on FDG PET/CT using a PERCIST-based threshold and their volumes were summed to obtain total MTV. MTV and cfDNA optimal cutoffs for OS and PFS prediction were determined by the Contal and O’Quigley’s method. MTV, cfDNA, age, gender, Body Mass Index (low, normal, high, obese), ECOG PS, number of chemotherapy lines (NCL), previous use of bevacizumab and presence of a KRAS mutation were included in a multivariate analysis. Results: MTV and cfDNA of 132 evaluable/141 eligible patients were well correlated (Spearman’s correlation coefficient = 0.70; p < 0.001) and risk groups for both PFS and OS were identified on the basis of cfDNA (cfDNA < 1 µg/mL; cfDNA≥1 µg/mL) and MTV (MTV < 100 cm³; 100-300 cm³; > 300 cm³). The multivariate analysis retained cfDNA, MTV, NCL, and obesity as independent parameters for PFS prediction, and cfDNA, MTV, NCL, BMI, and previous use of bevacizumab as independent parameters for OS prediction. Prognostic scores for PFS and OS were developed based on regression coefficients from the final Cox proportional hazards models. Prognostic scores for PFS (1.8 vs 5.3 months, HR: 3.15 for score ≥-3 vs < -3, (95% CI, 2.08-4.76); p < 0.001) and for OS (4.2 vs 13.9 months, HR: 4.59 for score ≥-6 vs < -6: (95% CI, 2.92-7.21); p < 0.001) both identified patients with much contrasted outcomes. Conclusions: Baseline cfDNA and MTV along with BMI parameters predict outcome in patients with mCRC before regorafenib onset. These parameters not related to treatment should be considered, if validated in further studies, as stratification factors in future clinical trials. Clinical trial information: 2012-005655-16.
Contribution of microarrays of gene expression (MAGE) to the definition of PET/CT as a qualified biomarker of early response in metastatic patients.
Authors: Sureda Manuel , Crespo-Jara Aurora , Gonzalez Manzano Ramon , Redal Maria del Carmen , Garcia-Cases Francisco Javier , Martinez Navarro Elena Mª , Brugarolas Antonio
Published: September 2018

11573

Background: Proliferating cancer cells consume elevated quantity of glucose, converted into lactate regardless the presence of oxygen (Warburg effect). This effect has been useful for imaging metabolically active tumors with FDG-PET, although its use in early response is controversial. Molecular mechanisms of FDG uptake are not fully understood. We have used MAGE to determine the most relevant genes involved in FDG uptake. Methods: Fresh-frozen tumor biopsies and quantitative basal FDG-PET/CT were obtained from metastatic lesions in cancer patients. Total tumor RNA was hybridized to a whole human genome oligonucleotide microarray. Gene expression signature-based prediction, using the most relevant genes involved in FDG uptake measured by SUV, was finally determined by Partial Least Squares (PLS). The interpretation of biological phenomena (IBP) derived from the selected genes was made by means of different public statistical bioinformatics resources. Results: 71 patients with different histological diagnosis were included in the training cohort and 13 in the validation one. 909 probes correlated significantly with SUV: 333 positively and 576 negatively. A predictive signature based on these 909 probes was built using PLS-3, with an RMSE in the validation set of 0.645 (within the 95% CI of RMSE determined in the training set). In IBP, other biological processes were more relevant than glycolysis in FDG uptake: RNA processing, ribosome biogenesis, protein processing, cell adhesion, cytoskeleton organization, angiogenesis and autophagy. Conclusions: This PLS-3-built signature is the first reported one that can accurately predict SUV. FDG uptake is a complex phenomenon that involves multiple biological processes, confirming the value of PET/CT in early response.
The mutational landscape of gastrointestinal malignancies as reflected by circulating tumor DNA.
Authors: Riviere Paul , Fanta Paul T. , Ikeda Sadakatsu , Baumgartner Joel Micah , Heestand Gregory M. , Kurzrock Razelle
Published: September 2018

11574

Background: Liquid biopsy of circulating tumor DNA (ctDNA) is a novel method of detecting genetic alterations in cancer patients without tissue acquisition. Methods: Our analysis surveyed the genomic landscape of 213 patients with various gastrointestinal malignancies using next generation sequencing of plasma ctDNA across a 68 gene panel (www.guardanthealth.com/guardant360/). Data analysis was performed following UCSD IRB guidelines for de-identified database (NCT02478931). Results: The most common cancer types were colorectal adenocarcinoma (N = 55 (26%)), appendiceal adenocarcinoma (N = 46 (22%)), hepatocellular carcinoma (N = 31 (15%)), and pancreatic ductal adenocarcinoma (N = 25 (12%)). 70% of patients had discernible alteration(s), and 58% of patients had ≥1 characterized alterations. The median number of characterized alterations per patient was 1 (range 0-13). The number of detected alterations per patient varied between cancer types: in hepatocellular carcinoma, 74% of patients (23/31) had > 1 characterized alteration(s), whereas 76% of patients (35/46) with appendiceal adenocarcinoma had no characterized alterations. Overall, of 123 patients with characterized alterations, > 99% (122/123) had ≥1 hypothetical (experimental or approved) treatment options available. Potentially targetable alterations varied between cancer types, proportionally to the detection rate of characterized alterations. The median percent ctDNA of characterized alterations was 2.50% (IQR 0.76-8.96%). Of interest, 95% of patients (117/123) had distinct molecular portfolios. Altogether, there were 143 unique characterized alterations within 56 genes. Overall concordance rates of 96%, 94%, 95%, and 91%, respectively, were found between ctDNA and tissue biopsy (105 patients) (https://www.foundationmedicine.com/) in the four most common alterations ( KRAS amplification, MYC amplification, KRAS G12V, and EGFR amplification). Conclusions: Our observations suggest that many patients with gastrointestinal tumors have discernible and pharmacologically tractable ctDNA alterations. Hence, ctDNA assessment through non-invasive liquid biopsy may have an important role in clinical practice.
Rare tumor clinic: The UCSD Moores Cancer Center experience with a precision therapy approach.
Authors: Kato Shumei , Kurasaki Kellie , Ikeda Sadakatsu , Kurzrock Razelle
Published: September 2018

11578

Background: Rare tumors have an incidence of < 15/100,000 per year; utra-rare, prevalence < 2000 in the USA. Patients (pts) may lack approved treatments and clinical trial access. Although each rare tumor is uncommon, cumulatively they account for > 20% of cancers. We recently initiated a Rare Tumor Clinic that emphasized a precision medicine strategy (genomic and proteomic analysis and individualized therapy). We report our preliminary experience. Methods: We investigated outcome among the first 40 pts presenting to the Rare Tumor Clinic at UC San Diego Moores Center for Personalized Cancer Therapy. Whenever possible, next-generation sequencing (NGS) of tissue and plasma-derived circulating tumor DNA (ctDNA) as well as proteomic markers were assessed. Results: Median age was 58 (range, 31 – 78 yo); 70% (28/40) were women; median number of previous systemic therapies, 2 (range, 0-7). The most common diagnoses were sarcoma (N = 7) for solid tumors; Erdheim-Chester disease (N = 5), for hematologic malignancies. Twenty distinct diagnoses were seen. Examples of ultra-rare tumors included ameloblastoma, yolk sac liver tumor, ampullary cancer, Castleman's disease, and desmoid tumor. 82.5% of pts (33/40) had tissue NGS (182 to 405 genes); 7.5% (3/40), inadequate tissue. The median number of characterized tissue alterations was 3 (range, 0 to 24); 32 pts (80%) had ≥1 characterized genomic alteration. 33 pts (82.5%) had ctDNA analysis; 15 pts had ≥1 characterized alteration. Among those 15 pts, median number of characterized alterations was 3 (range, 1 to 14). 92.5% (37/40) of pts had ≥ 1 actionable target based on either genomic (32 pts) or proteomic markers (27 pts) (FDA-approved [mostly off-label] or investigational agent). 52.5% (21/40) received matched therapy; 52.4% (11/21) achieved SD≥6 months (N = 3)/CR (N = 2)/PR (N = 6). Matched therapy resulted in significantly longer PFS compared to last prior unmatched therapy (HR: 0.26, 95% CI: 0.10 – 0.71 [p = 0.008]). Conclusions: Identifying genomic and proteomic markers in pts with rare and ultra-rare tumors was feasible. When therapies were matched, > 50% of pts attained SD≥6 months/CR/PR. Further clinical investigations focusing on rare and ultra-rare tumors are urgently needed.
Role of ERBB signaling in RET-rearranged lung cancer and contribution of EGFR amplification to cabozantinib resistance.
Authors: Smith Roger , Drilon Alexander E. , Kunte Siddharth , Suzawa Ken , Hayashi Takuo , Delasos Lukas , Tai Huichun , Hitchman Tyler , Khodos Inna , Mattar Marissa , Kohsaka Shinji , de Stanchina Elisa , Lockwood William , Ladanyi Marc , Somwar Romel
Published: September 2018

11583

Background: Lung cancers driven by oncogenic RET fusions have lower response rates to targeted monotherapy such as cabozantinib (28%) relative to response rates typically observed in ALK- or ROS1- rearranged lung adenocarcinomas (60-80%). Methods: To identify targetable co-dependencies or cooperating pathways for RET fusion-positive lung cancers, we performed high-throughput chemical and genetic screens to find FDA-approved drugs or genes that when inhibited, would synergize with cabozantinib in RET fusion-positive lung cancer cell lines. In addition we performed NGS of a pair of pre-treatment and post-cabozantinib progression samples. Results: We identified EGFR siRNAs and anti-EGFR drugs as synergistic with cabozantinib. Combinations of drugs that target EGFR (cetuximab, afatinib, erlotinib, gefitinib, neratinib) and RET (cabozantinib, CEP-32496, lenvatinib, vandetanib) were more effective at reducing growth of RET cell lines than any single agent in vitro and in xenograft models. Cabozantinib treatment of RET fusion-positive cell lines inhibited EGFR and RET phosphorylation, an observation not seen in RET wild-type cell lines. Co-immunoprecipitation studies reveal that RET and EGFR interact. Ectopic expression of CCDC6-RET in NIH-3T3 or human bronchial epithelial cells resulted in upregulation of multiple ERBB receptors and ligands (not seen in a ROS1 fusion-positive cell line) and a concomitant increase in EGFR stability. Treatment with ERBB pathway ligands or overexpression of EGFR decreased sensitivity to cabozantinib in two RET fusion-positive cell lines. Finally, sequencing of a pair of pre-treatment and post-progression samples from a lung cancer patient treated with cabozantinib revealed acquired amplification of EGFR in the latter sample. Conclusions: Taken together, these results suggest that the tumorigenic potential of RET fusion oncogenes is dependent on deregulation of ERBB-activated pathways and that a combination of RET and EGFR drugs could be more effective in treating RET fusion-positive tumors. Moreover, amplification of EGFR is a potential driver of resistance to cabozantinib in RET-rearranged lung cancers.