Publications by authors named "Cynthia Timmers"

40 Publications

Pediatric Gliosarcoma With and Without Neurofibromatosis Type 1: A Whole-exome Comparison of 2 Patients.

J Pediatr Hematol Oncol 2020 Nov 23. Epub 2020 Nov 23.

Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute.

Gliosarcoma is rare among pediatric patients and among individuals with Neurofibromatosis Type 1 (NF1). Here we compare 2 pediatric gliosarcoma patients, one of whom has NF1. We performed whole-exome sequencing, methylation, and copy number analysis on tumor and blood for both patients. Whole-exome sequencing showed higher mutational burden in the tumor of the patient without NF1. Copy number analysis showed differences in chromosomal losses/gains between the tumors. Neither tumor showed O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. The NF1 patient survived without progression while the other expired. This is the first reported case of gliosarcoma in a child with NF1.
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http://dx.doi.org/10.1097/MPH.0000000000002020DOI Listing
November 2020

Prospective Decision Analysis Study of Clinical Genomic Testing in Metastatic Breast Cancer: Impact on Outcomes and Patient Perceptions.

JCO Precis Oncol 2019 18;3. Epub 2019 Nov 18.

The Ohio State University College of Medicine, Columbus, OH.

Purpose: To evaluate the impact of targeted DNA sequencing on selection of cancer therapy for patients with metastatic breast cancer (MBC).

Patients And Methods: In this prospective, single-center, single-arm trial, patients with MBC were enrolled within 10 weeks of starting a new therapy. At enrollment, tumor samples underwent next-generation sequencing for any of 315 cancer-related genes to high depth (> 500×) using FoundationOne CDx. Sequencing results were released to providers at the time of disease progression, and physician treatment recommendations were assessed via questionnaire. We evaluated three prespecified questions to assess patients' perceptions of genomic testing.

Results: In all, 100 patients underwent genomic testing, with a median of five mutations (range, 0 to 13 mutations) detected per patient. Genomic testing revealed one or more potential therapies in 98% of patients (98 of 100), and 60% of patients (60 of 100) had one or more recommended treatments with level I/II evidence for actionability. Among the 94 genomic text reports that were released, there was physician questionnaire data for 87 patients (response rate, 92.6%) and 31.0% of patients (27 of 87) had treatment change recommended by their physician. Of these, 37.0% (10 of 27) received the treatment supported by genomic testing. We did not detect a statistically significant difference in time-to-treatment failure (log-rank = .87) or overall survival ( = .71) among patients who had treatment change supported by genomic testing versus those who had no treatment change. For patients who completed surveys before and after genomic testing, there was a significant decrease in confidence of treatment success, specifically among patients who did not have treatment change supported by genomic testing (McNemar's test of agreement = .001).

Conclusion: In this prospective study, genomic profiling of tumors in patients with MBC frequently identified potential treatments and resulted in treatment change in a minority of patients. Patients whose therapy was not changed on the basis of genomic testing seemed to have a decrease in confidence of treatment success.
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http://dx.doi.org/10.1200/PO.19.00090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446448PMC
November 2019

Comprehensive Genomic Analysis in NRG Oncology/RTOG 9802: A Phase III Trial of Radiation Versus Radiation Plus Procarbazine, Lomustine (CCNU), and Vincristine in High-Risk Low-Grade Glioma.

J Clin Oncol 2020 10 24;38(29):3407-3417. Epub 2020 Jul 24.

The Ohio State University, Columbus, OH.

Purpose: NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802.

Methods: mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates.

Results: Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were wild type, 43 (41%) were mutant/non-codeleted, and 37(35%) were mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; = .003; HR, 0.13; < .001) and OS (HR, 0.38; = .013; HR, 0.21; = .029) in the mutant/non-codeleted and mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the wild-type subgroup.

Conclusion: This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with -mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.
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http://dx.doi.org/10.1200/JCO.19.02983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527157PMC
October 2020

Predominant Distribution of the RNAi Machinery at Apical Adherens Junctions in Colonic Epithelia Is Disrupted in Cancer.

Int J Mol Sci 2020 Apr 7;21(7). Epub 2020 Apr 7.

Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA.

The RNA interference (RNAi) machinery is an essential component of the cell, regulating miRNA biogenesis and function. RNAi complexes were thought to localize either in the nucleus, such as the microprocessor, or in the cytoplasm, such as the RNA-induced silencing complex (RISC). We recently revealed that the core microprocessor components DROSHA and DGCR8, as well as the main components of RISC, including Ago2, also associate with the apical adherens junctions of well-differentiated cultured epithelial cells. Here, we demonstrate that the localization of the core RNAi components is specific and predominant at apical areas of cell-cell contact of human normal colon epithelial tissues and normal primary colon epithelial cells. Importantly, the apical junctional localization of RNAi proteins is disrupted or lost in human colon tumors and in poorly differentiated colon cancer cell lines, correlating with the dysregulation of the adherens junction component PLEKHA7. We show that the restoration of PLEKHA7 expression at adherens junctions of aggressively tumorigenic colon cancer cells restores the junctional localization of RNAi components and suppresses cancer cell growth in vitro and in vivo. In summary, this work identifies the apical junctional localization of the RNAi machinery as a key feature of the differentiated colonic epithelium, with a putative tumor suppressing function.
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http://dx.doi.org/10.3390/ijms21072559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177752PMC
April 2020

Phase I Trial of Trametinib with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer.

Clin Cancer Res 2020 07 6;26(13):3117-3125. Epub 2020 Apr 6.

Moffitt Cancer Center, Tampa, Florida.

Purpose: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and , , and mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC).

Patients And Methods: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples.

Results: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses.

Conclusions: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a -mutant selected population.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334091PMC
July 2020

Modeling rectal cancer to advance neoadjuvant precision therapy.

Int J Cancer 2020 Sep 3;147(5):1405-1418. Epub 2020 Feb 3.

Department of Surgery, Medical University of South Carolina, Charleston, SC.

Progress in rectal cancer therapy has been hindered by the lack of effective disease-specific preclinical models that account for the unique molecular profile and biology of rectal cancer. Thus, we developed complementary patient-derived xenograft (PDX) and subsequent in vitro tumor organoid (PDTO) platforms established from preneoadjuvant therapy rectal cancer specimens to advance personalized care for rectal cancer patients. Multiple endoscopic samples were obtained from 26 Stages 2 and 3 rectal cancer patients prior to receiving 5FU/RT and implanted subcutaneously into NSG mice to generate 15 subcutaneous PDXs. Second passaged xenografts demonstrated 100% correlation with the corresponding human cancer histology with maintained mutational profiles. Individual rectal cancer PDXs reproduced the 5FU/RT response observed in the corresponding human cancers. Similarly, rectal cancer PDTOs reproduced significant heterogeneity in cellular morphology and architecture. PDTO in vitro 5FU/RT treatment response replicated the clinical 5FU/RT neoadjuvant therapy pathologic response observed in the corresponding patient tumors (p < 0.05). The addition of cetuximab to the 5FU/RT regiment was significantly more sensitive in the rectal cancer PDX and PDTOs with wild-type KRAS compared to mutated KRAS (p < 0.05). Considering the close relationship between the patient's cancer and the corresponding PDX/PDTO, rectal cancer patient-derived research platforms represent powerful translational research resources as population-based tools for biomarker discovery and experimental therapy testing. In addition, our findings suggest that cetuximab may enhance RT effectiveness by improved patient selection based on mutational profile in addition to KRAS or by developing a protocol using PDTOs to identify sensitive patients.
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http://dx.doi.org/10.1002/ijc.32876DOI Listing
September 2020

Modeling Human Cancer-induced Cachexia.

Cell Rep 2019 08;28(6):1612-1622.e4

Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University, Columbus, OH 43210, USA; Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address:

Cachexia is a wasting syndrome characterized by pronounced skeletal muscle loss. In cancer, cachexia is associated with increased morbidity and mortality and decreased treatment tolerance. Although advances have been made in understanding the mechanisms of cachexia, translating these advances to the clinic has been challenging. One reason for this shortcoming may be the current animal models, which fail to fully recapitulate the etiology of human cancer-induced tissue wasting. Because pancreatic ductal adenocarcinoma (PDA) presents with a high incidence of cachexia, we engineered a mouse model of PDA that we named KPP. KPP mice, similar to PDA patients, progressively lose skeletal and adipose mass as a consequence of their tumors. In addition, KPP muscles exhibit a similar gene ontology as cachectic patients. We envision that the KPP model will be a useful resource for advancing our mechanistic understanding and ability to treat cancer cachexia.
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http://dx.doi.org/10.1016/j.celrep.2019.07.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733019PMC
August 2019

Tumor heterogeneity and acquired drug resistance in FGFR2-fusion-positive cholangiocarcinoma through rapid research autopsy.

Cold Spring Harb Mol Case Stud 2019 08 1;5(4). Epub 2019 Aug 1.

Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA.

Cholangiocarcinoma is a highly aggressive and lethal malignancy, with limited treatment options available. Recently, FGFR inhibitors have been developed and utilized in FGFR-mutant cholangiocarcinoma; however, resistance often develops and the genomic determinants of resistance are not fully characterized. We completed whole-exome sequencing (WES) of 11 unique tumor samples obtained from a rapid research autopsy on a patient with FGFR-fusion-positive cholangiocarcinoma who initially responded to the pan-FGFR inhibitor, INCB054828. In vitro studies were carried out to characterize the novel FGFR alteration and secondary mutation identified. Multisite WES and analysis of tumor heterogeneity through subclonal inference identified four genetically distinct cancer cell populations, two of which were only observed after treatment. Additionally, WES revealed an N549H mutation hypothesized to confer resistance to the FGFR inhibitor INCB054828 in a single tumor sample. This hypothesis was corroborated with in vitro cell-based studies in which cells expressing fusion were sensitive to INCB054828 (IC value of 10.16 nM), whereas cells with the addition of the N549H mutation were resistant to INCB054828 (IC value of 1527.57 nM). Furthermore, the N549H secondary mutation displayed cross-resistance to other selective FGFR inhibitors, but remained sensitive to the nonselective inhibitor, ponatinib. Rapid research autopsy has the potential to provide unprecedented insights into the clonal evolution of cancer throughout the course of the disease. In this study, we demonstrate the emergence of a drug resistance mutation and characterize the evolution of tumor subclones within a cholangiocarcinoma disease course.
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http://dx.doi.org/10.1101/mcs.a004002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672025PMC
August 2019

Cutting Edge: Targeting Thrombocytes to Rewire Anticancer Immunity in the Tumor Microenvironment and Potentiate Efficacy of PD-1 Blockade.

J Immunol 2019 09 29;203(5):1105-1110. Epub 2019 Jul 29.

Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425;

Aside from their roles in hemostasis and thrombosis, thrombocytes or platelets also promote tumor growth via immune suppression. However, the extent to which platelet activation shapes the immunosuppressive tumor microenvironment (TME) and whether platelet inhibition can be leveraged to improve checkpoint blockade are unknown. We show in this study that platelet function in mice mediates suppression of CD8 T cell function within the TME but not in the draining lymph nodes. Tempering platelet activation genetically reduced TGF-β signaling in both immune and nonimmune cells in the TME, enhanced T cell frequency and function, and decreased CD11b myeloid cell infiltration in the tumor. Targeting platelet function pharmacologically in tumor-bearing mice with aspirin and clopidogrel in combination with PD-1 blockade improved tumor control. These results suggest that platelet function represents a continuous, supplemental mechanism of immune evasion co-opted by tumors to evade antitumor immunity and offers an attractive target for combination with immunotherapy.
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http://dx.doi.org/10.4049/jimmunol.1900594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304159PMC
September 2019

Homologous recombination and DNA repair mutations in patients treated with carboplatin and nab-paclitaxel for metastatic non-small cell lung cancer.

Lung Cancer 2019 08 17;134:167-173. Epub 2019 Jun 17.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States.

Objectives: Chemotherapy remains a cornerstone treatment in non-small cell lung cancer either in combination with checkpoint inhibitors or as subsequent therapy. Identifying molecular predictors of response allows for optimal treatment selection. We performed genomic analysis on tumor samples of patients treated with carboplatin and nab-paclitaxel as part of a phase II trial to evaluate the prognostic and predictive value of mutations in DNA repair pathway in patients treated with this regimen.

Materials And Methods: Next-generation sequencing libraries were produced using a capture-based targeted panel covering the coding exons of 278 genes on patients treated on clinical trial NCT00729612. Overall survival (OS) and progression-free survival (PFS) were assessed as part of the clinical outcomes and correlated with mutation analysis.

Results: Of 63 patients enrolled, 25 patients had sufficient and acceptable DNA isolated from archival tumor samples for targeted sequencing. The most commonly altered pathways included DNA repair (DR) including Fanconi anemia and homologous recombination, JAK-STAT signaling, IGF-1, mTOR, and MAPK-ERK. Four patients with mutations in homologous recombination mutations had a shorter PFS (hazard ratio [HR] = 4.54, 95% CI 1.2, 17.1, p = 0.026) and OS (HR = 6.3, 95% CI 1.8, 21.3, p = 0.003).

Conclusion: In this analysis of patients with predominantly squamous cell non-small cell lung cancer treated with carboplatin and nab-paclitaxel in a phase II trial, patients with mutations in homologous recombination pathways had shorter overall and progression-free survival. Validation on additional datasets of patients treated with platinum-based chemotherapy and immunotherapy combinations is warranted.
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http://dx.doi.org/10.1016/j.lungcan.2019.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194132PMC
August 2019

Two Distinct E2F Transcriptional Modules Drive Cell Cycles and Differentiation.

Cell Rep 2019 06 23;27(12):3547-3560.e5. Epub 2019 May 23.

Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA. Electronic address:

Orchestrating cell-cycle-dependent mRNA oscillations is critical to cell proliferation in multicellular organisms. Even though our understanding of cell-cycle-regulated transcription has improved significantly over the last three decades, the mechanisms remain untested in vivo. Unbiased transcriptomic profiling of G, G-S, and S-G-M sorted cells from FUCCI mouse embryos suggested a central role for E2Fs in the control of cell-cycle-dependent gene expression. The analysis of gene expression and E2F-tagged knockin mice with tissue imaging and deep-learning tools suggested that post-transcriptional mechanisms universally coordinate the nuclear accumulation of E2F activators (E2F3A) and canonical (E2F4) and atypical (E2F8) repressors during the cell cycle in vivo. In summary, we mapped the spatiotemporal expression of sentinel E2F activators and canonical and atypical repressors at the single-cell level in vivo and propose that two distinct E2F modules relay the control of gene expression in cells actively cycling (E2F3A-8-4) and exiting the cycle (E2F3A-4) during mammalian development.
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http://dx.doi.org/10.1016/j.celrep.2019.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6673649PMC
June 2019

KRAS G12V Mutation in Acquired Resistance to Combined BRAF and MEK Inhibition in Papillary Thyroid Cancer.

J Natl Compr Canc Netw 2019 05;17(5):409-413

Division of Medical Oncology.

BRAF V600E mutations occur in approximately 40% of all patients with papillary thyroid cancer (PTC) and are associated with a worse prognosis in population studies. Treatment with single-agent BRAF inhibitors can result in nondurable partial responses (PRs) in clinical trials, but resistance inevitably develops. The mechanisms of resistance are not completely understood, but in non-thyroid tumors harboring BRAF V600E mutations, resistance has been ascribed to concurrent or acquired mutations in MEK1/2, RAC1, KRAS, and NRAS. This case report describes a patient with radioactive iodine-refractory metastatic PTC treated in a clinical trial with combination BRAF and MEK inhibition who achieved a durable PR. At time of progression, biopsy revealed an acquired KRAS G12V-activating mutation. The patient subsequently went on to have a PR to cabozantinib therapy in the clinical trial. This is the first reported case of an acquired KRAS-activating mutation that developed during treatment with BRAF and MEK inhibition in a patient with BRAF-mutated PTC. The KRAS mutation was also detected in peripheral blood samples taken as part of the trial, indicating that resistant mutations may be identified through noninvasive means. The identification of resistant mutations in patients at time of progression is necessary to identify possible therapeutic options including potential clinical trials.ClinicalTrials.gov identifier: NCT01723202.
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http://dx.doi.org/10.6004/jnccn.2019.7292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6673655PMC
May 2019

Degree of Amplification Affects Clinical Outcomes in Dedifferentiated Liposarcoma.

Oncologist 2019 07 24;24(7):989-996. Epub 2019 Apr 24.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA

Background: Dedifferentiated liposarcomas (DDLPS) are mesenchymal tumors associated with universally poor response to treatment. Genomic amplification of murine double minute 2 () is used as a diagnostic biomarker; however, no established biomarkers exist to guide DDLPS treatment. In the largest study of its kind, we report that the extent of amplification, not simply the presence of amplification, may be biologically important to the actions of DDLPS.

Patients And Methods: The distribution of amplification in DDLPS was assessed using data from a commercial sequencing laboratory ( = 642) and The Cancer Genome Atlas ( = 57). Data from two retrospective clinical trials ( = 15, = 16) and one prospective clinical trial ( = 25) were used to test 's utility as a clinical biomarker. in vitro and in vivo assessments were conducted in DDLPS cell lines.

Results: Genomic amplification follows a highly reproducible log-normal distribution. In patients with DDLPS treated with complete tumor resection, elevated was associated with shortened time to recurrence as measured by genomic amplification ( = .003) and mRNA expression ( = .04). In patients requiring systemic therapy, higher amplification was associated with reduced overall survival ( = .04). Doxorubicin treatment of DDLPS cells in vitro demonstrated variable sensitivity based on baseline levels, and doxorubicin treatment elevated MDM2 expression. In vivo, treatment with doxorubicin followed by an MDM2 inhibitor improved doxorubicin sensitivity.

Conclusion: amplification levels in DDLPS follow a reproducible distribution and are associated with clinical outcomes and drug sensitivity. These results suggest that a prospective study of as a predictive biomarker in DDLPS is warranted.

Implications For Practice: No validated biomarkers exist for treatment selection in dedifferentiated liposarcoma (DDLPS). Although murine double minute 2 () is currently used for diagnosis, the clinical relevance of amplification has yet to be fully assessed. This study found that amplification follows a predictable distribution in DDLPS and correlates with clinical and biological outcomes. These data suggests that amplification may be a useful biomarker in DDLPS.
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http://dx.doi.org/10.1634/theoncologist.2019-0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656442PMC
July 2019

Genomic risk prediction of aromatase inhibitor-related arthralgia in patients with breast cancer using a novel machine-learning algorithm.

Cancer Med 2018 01 23;7(1):240-253. Epub 2017 Nov 23.

The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Many breast cancer (BC) patients treated with aromatase inhibitors (AIs) develop aromatase inhibitor-related arthralgia (AIA). Candidate gene studies to identify AIA risk are limited in scope. We evaluated the potential of a novel analytic algorithm (NAA) to predict AIA using germline single nucleotide polymorphisms (SNP) data obtained before treatment initiation. Systematic chart review of 700 AI-treated patients with stage I-III BC identified asymptomatic patients (n = 39) and those with clinically significant AIA resulting in AI termination or therapy switch (n = 123). Germline DNA was obtained and SNP genotyping performed using the Affymetrix UK BioBank Axiom Array to yield 695,277 SNPs. SNP clusters that most closely defined AIA risk were discovered using an NAA that sequentially combined statistical filtering and a machine-learning algorithm. NCBI PhenGenI and Ensemble databases defined gene attribution of the most discriminating SNPs. Phenotype, pathway, and ontologic analyses assessed functional and mechanistic validity. Demographics were similar in cases and controls. A cluster of 70 SNPs, correlating to 57 genes, was identified. This SNP group predicted AIA occurrence with a maximum accuracy of 75.93%. Strong associations with arthralgia, breast cancer, and estrogen phenotypes were seen in 19/57 genes (33%) and were functionally consistent. Using a NAA, we identified a 70 SNP cluster that predicted AIA risk with fair accuracy. Phenotype, functional, and pathway analysis of attributed genes was consistent with clinical phenotypes. This study is the first to link a specific SNP/gene cluster to AIA risk independent of candidate gene bias.
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http://dx.doi.org/10.1002/cam4.1256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773952PMC
January 2018

An NRG Oncology/GOG study of molecular classification for risk prediction in endometrioid endometrial cancer.

Gynecol Oncol 2018 01 11;148(1):174-180. Epub 2017 Nov 11.

The Ohio State University, Columbus, OH, United States. Electronic address:

Objectives: The purpose of this study was to assess the prognostic significance of a simplified, clinically accessible classification system for endometrioid endometrial cancers combining Lynch syndrome screening and molecular risk stratification.

Methods: Tumors from NRG/GOG GOG210 were evaluated for mismatch repair defects (MSI, MMR IHC, and MLH1 methylation), POLE mutations, and loss of heterozygosity. TP53 was evaluated in a subset of cases. Tumors were assigned to four molecular classes. Relationships between molecular classes and clinicopathologic variables were assessed using contingency tests and Cox proportional methods.

Results: Molecular classification was successful for 982 tumors. Based on the NCI consensus MSI panel assessing MSI and loss of heterozygosity combined with POLE testing, 49% of tumors were classified copy number stable (CNS), 39% MMR deficient, 8% copy number altered (CNA) and 4% POLE mutant. Cancer-specific mortality occurred in 5% of patients with CNS tumors; 2.6% with POLE tumors; 7.6% with MMR deficient tumors and 19% with CNA tumors. The CNA group had worse progression-free (HR 2.31, 95%CI 1.53-3.49) and cancer-specific survival (HR 3.95; 95%CI 2.10-7.44). The POLE group had improved outcomes, but the differences were not statistically significant. CNA class remained significant for cancer-specific survival (HR 2.11; 95%CI 1.04-4.26) in multivariable analysis. The CNA molecular class was associated with TP53 mutation and expression status.

Conclusions: A simple molecular classification for endometrioid endometrial cancers that can be easily combined with Lynch syndrome screening provides important prognostic information. These findings support prospective clinical validation and further studies on the predictive value of a simplified molecular classification system.
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http://dx.doi.org/10.1016/j.ygyno.2017.10.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756518PMC
January 2018

Histone Deacetylase Inhibition Enhances the Antitumor Activity of a MEK Inhibitor in Lung Cancer Cells Harboring Mutations.

Mol Cancer Ther 2018 01 27;17(1):17-25. Epub 2017 Oct 27.

The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Non-small cell lung cancer (NSCLC) can be identified by precise molecular subsets based on genomic alterations that drive tumorigenesis and include mutations in , and various fusions. However, despite effective treatments for EGFR and ALK, promising therapeutics have not been developed for patients with mutations. It has been reported that one way the RAS-ERK pathway contributes to tumorigenesis is by affecting stability and localization of FOXO3a protein, an important regulator of cell death and the cell cycle. This is through regulation of apoptotic proteins BIM and FASL and cell-cycle regulators p21 and p27 We now show that an HDAC inhibitor affects the expression and localization of FOXO proteins and wanted to determine whether the combination of a MEK inhibitor with an HDAC inhibitor would increase the sensitivity of NSCLC with mutation. Combined treatment with a MEK inhibitor and an HDAC inhibitor showed synergistic effects on cell metabolic activity of -mutated lung cancer cells through activation of FOXOs, with a subsequent increase in BIM and cell-cycle inhibitors. Moreover, in a mouse xenograft model, the combination of belinostat and trametinib significantly decreases tumor formation through FOXOs by increasing BIM and the cell-cycle inhibitors p21 and p27 These results demonstrate that control of FOXOs localization and expression is critical in -driven lung cancer cells, suggesting that the dual molecular-targeted therapy for MEK and HDACs may be promising as novel therapeutic strategy in NSCLC with specific populations of mutations. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6430197PMC
January 2018

A Transcriptional Signature Identifies LKB1 Functional Status as a Novel Determinant of MEK Sensitivity in Lung Adenocarcinoma.

Cancer Res 2017 01 7;77(1):153-163. Epub 2016 Nov 7.

Department of Internal Medicine, James Thoracic Center, Ohio State University, Columbus, Ohio.

LKB1 is a commonly mutated tumor suppressor in non-small cell lung cancer that exerts complex effects on signal transduction and transcriptional regulation. To better understand the downstream impact of loss of functional LKB1, we developed a transcriptional fingerprint assay representing this phenotype. This assay was predictive of LKB1 functional loss in cell lines and clinical specimens, even those without detected sequence alterations in the gene. In silico screening of drug sensitivity data identified putative LKB1-selective drug candidates, revealing novel associations not apparent from analysis of LKB1 mutations alone. Among the candidates, MEK inhibitors showed robust association with signature expression in both training and testing datasets independent of RAS/RAF mutations. This susceptibility phenotype is directly altered by RNA interference-mediated LKB1 knockdown or by LKB1 re-expression into mutant cell lines and is readily observed in vivo using a xenograft model. MEK sensitivity is dependent on LKB1-induced changes in AKT and FOXO3 activation, consistent with genomic and proteomic analyses of LKB1-deficient lung adenocarcinomas. Our findings implicate the MEK pathway as a potential therapeutic target for LKB1-deficient cancers and define a practical NanoString biomarker to identify functional LKB1 loss. Cancer Res; 77(1); 153-63. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1639DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027166PMC
January 2017

Dual Inhibition of MEK and PI3K/Akt Rescues Cancer Cachexia through both Tumor-Extrinsic and -Intrinsic Activities.

Mol Cancer Ther 2017 02 3;16(2):344-356. Epub 2016 Nov 3.

Arthur G. James Comprehensive Cancer Center Cancer Cachexia Program, The Ohio State University Medical Center, Columbus, Ohio 43210, USA.

Involuntary weight loss, a part of the cachexia syndrome, is a debilitating comorbidity of cancer and currently has no treatment options. Results from a recent clinical trial at our institution showed that biliary tract cancer patients treated with a MEK inhibitor exhibited poor tumor responses but surprisingly gained weight and increased their skeletal muscle mass. This implied that MEK inhibition might be anticachectic. To test this potential effect of MEK inhibition, we utilized the established Colon-26 model of cancer cachexia and the MEK1/2 inhibitor MEK162. Results showed that MEK inhibition effectively prevented muscle wasting. Importantly, MEK162 retained its ability to spare muscle loss even in mice bearing a Colon-26 clone resistant to the MEK inhibitor, demonstrating that the effects of blocking MEK are at least in part independent of the tumor. Because single-agent MEK inhibitors have been limited as a first-line targeted therapy due to compensatory activation of other oncogenic signaling pathways, we combined MEK162 with the PI3K/Akt inhibitor buparlisib. Results showed that this combinatorial treatment significantly reduced tumor growth due to a direct activity on Colon-26 tumor cells in vitro and in vivo, while also preserving skeletal muscle mass. Together, our results suggest that as a monotherapy, MEK inhibition preserves muscle mass, but when combined with a PI3K/Akt inhibitor exhibits potent antitumor activity. Thus, combinatorial therapy might serve as a new approach for the treatment of cancer cachexia. Mol Cancer Ther; 16(2); 344-56. ©2016 AACRSee related article by Kobayashi et al., p. 357.
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5292063PMC
February 2017

Evaluation of frozen tissue-derived prognostic gene expression signatures in FFPE colorectal cancer samples.

Sci Rep 2016 09 14;6:33273. Epub 2016 Sep 14.

University of Miami Miller School of Medicine, Division of Biostatistics, Department of Public Health Sciences, Miami, 33136, USA.

Defining molecular features that can predict the recurrence of colorectal cancer (CRC) for stage II-III patients remains challenging in cancer research. Most available clinical samples are Formalin-Fixed, Paraffin-Embedded (FFPE). NanoString nCounter® and Affymetrix GeneChip® Human Transcriptome Array 2.0 (HTA) are the two platforms marketed for high-throughput gene expression profiling for FFPE samples. In this study, to evaluate the gene expression of frozen tissue-derived prognostic signatures in FFPE CRC samples, we evaluated the expression of 516 genes from published frozen tissue-derived prognostic signatures in 42 FFPE CRC samples measured by both platforms. Based on HTA platform-derived data, we identified both gene (99 individual genes, FDR < 0.05) and gene set (four of the six reported multi-gene signatures with sufficient information for evaluation, P < 0.05) expression differences associated with survival outcomes. Using nCounter platform-derived data, one of the six multi-gene signatures (P < 0.05) but no individual gene was associated with survival outcomes. Our study indicated that sufficiently high quality RNA could be obtained from FFPE tumor tissues to detect frozen tissue-derived prognostic gene expression signatures for CRC patients.
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http://dx.doi.org/10.1038/srep33273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021945PMC
September 2016

Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma.

Mol Ther 2016 Jun 4;24(6):1150-1158. Epub 2016 Apr 4.

Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, Ohio, USA. Electronic address:

Pelareorep causes oncolysis in tumor cells with activated Ras. We hypothesized that pelareorep would have efficacy and immunomodulatory activity in metastatic pancreatic adenocarcinoma (MPA) when combined with carboplatin and paclitaxel. A randomized phase 2 study (NCT01280058) was conducted in treatment-naive patients with MPA randomized to two treatment arms: paclitaxel/carboplatin + pelareorep (Arm A, n = 36 evaluable patients) versus paclitaxel/carboplatin (Arm B, n = 37 evaluable patients). There was no difference in progression-free survival (PFS) between the arms (Arm A PFS = 4.9 months, Arm B PFS = 5.2 months, P = 0.6), and Kirsten rat sarcoma viral oncogene (KRAS) status did not impact outcome. Quality-adjusted Time without Symptoms or Toxicity analysis revealed that the majority of PFS time was without toxicity or progression (4.3 months). Patient immunophenotype appeared important, as soluble immune biomarkers were associated with treatment outcome (fractalkine, interleukin (IL)-6, IL-8, regulated on activation, normal T cell expressed and secreted (RANTES), and vascular endothelial growth factor (VEGF)). Increased circulating T and natural killer (NK)-cell subsets were also significantly associated with treatment outcome. Addition of pelareorep was associated with higher levels of 14 proinflammatory plasma cytokines/chemokines and cells with an immunosuppressive phenotype (Tregs, cytotoxic T lymphocyte associated protein 4 (CTLA4)(+) T cells). Overall, pelareorep was safe but does not improve PFS when administered with carboplatin/paclitaxel, regardless of KRAS mutational status. Immunologic studies suggest that chemotherapy backbone improves immune reconstitution and that targeting remaining immunosuppressive mediators may improve oncolytic virotherapy.
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http://dx.doi.org/10.1038/mt.2016.66DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4923331PMC
June 2016

Veliparib Alone or in Combination with Mitomycin C in Patients with Solid Tumors With Functional Deficiency in Homologous Recombination Repair.

J Natl Cancer Inst 2016 Jul 4;108(7). Epub 2016 Feb 4.

Divisions of Medical Oncology (MAVC, WD, JR, ML, TBS) and Clinical Cancer Genetics (JAW), Department of Pathology (WZ, KS), Comprehensive Cancer Center (MAVC, WD, LJS, JT, TBS, CT), and Center for Biostatistics (LX), The Ohio State University , Columbus, OH ; Lombardi Cancer Center, Georgetown University , Washington, DC (JM); National Cancer Institute , Bethesda, MD (JJ, AC).

Background: BRCA germline mutations are being targeted for development of PARP inhibitors. BRCA genes collaborate with several others in the Fanconi Anemia (FA) pathway. We screened cancer patients' tumors for FA functional defects then aimed to establish the safety/feasibility of administering PARP inhibitors as monotherapy and combined with a DNA-breaking agent.

Methods: Patients underwent FA functional screening for the presence (or lack) of tumor FancD2 nuclear foci formation on their archival tumor material, utilizing a newly developed method (Fanconi Anemia triple-stain immunofluorescence [FATSI]), performed in a Clinical Laboratory Improvement Amendments-certified laboratory. FATSI-negative patients were selected for enrollment in a two-arm dose escalation trial of veliparib, or veliparib/mitomycin-C (MMC).

Results: One hundred eighty-five of 643 (28.7%) screened patients were FATSI-negative. Sixty-one received veliparib or veliparib/MMC through 14 dose levels. Moderate/severe toxicities included fatigue (DLT at veliparib 400mg BID), diarrhea, and thrombocytopenia. Recommended doses are 300mg BID veliparib and veliparib 200mg BID for 21 days following 10mg/m(2) MMC every 28 days. Six antitumor responses occurred, five in the combination arm (3 breast, 1 ovarian, 1 endometrial [uterine], and 1 non-small cell lung cancer). Two patients have received 36 and 60 cycles to date. BRCA germline analysis among 51 patients revealed five deleterious mutations while a targeted FA sequencing gene panel showed missense/nonsense mutations in 29 of 49 FATSI-negative tumor specimens.

Conclusions: FATSI screening showed that a substantial number of patients' tumors have FA functional deficiency, which led to germline alterations in several patients' tumors. Veliparib alone or with MMC was safely administered to these patients and produced clinical benefit in some. However, a better understanding of resistance mechanisms in this setting is needed.
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http://dx.doi.org/10.1093/jnci/djv437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4948564PMC
July 2016

Whole-exome tumor sequencing study in biliary cancer patients with a response to MEK inhibitors.

Oncotarget 2016 Feb;7(5):5306-12

Department of Internal Medicine, Divison of Medical Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.

We previously conducted a phase-II study with selumetinib (AZD6244), a small molecule inhibitor of MEK1/2, in advanced biliary tract cancers (BTC), where the primary endpoint was response rate. Several patients experienced objective response. These findings were confirmed with MEK162 in a similar patient population. To assess for tumor-specific genetic variants that mediate sensitivity to MEK inhibition in BTC, we performed whole-exome sequencing in patients with an objective response to selumetinib. Normal and tumor DNA from FFPE tissue from two patients who experienced an objective response underwent whole-exome sequencing. Raw sequence reads were processed with GATK workflow and tumor specific variants were identified using MuTect and VarScan2. Ensemble Variant Effect Predictor was used to determine functional consequences of these variants. Copy number changes and potential gene fusion events were also screened. Findings were compared to assess for any commonality between the two tumor samples, and whether the identified variants were intrinsic to the MAPK pathway. 1169 and 628 tumor-specific variants were identified in the two samples. Further analysis demonstrated 60 and 53 functional and novel variants, respectively. Of the identified tumor-specific variants, fusion events or copy number changes, no commonality was seen. Several variants in genes associated with ERK signaling were present in each tumor sample. Although there were no common tumor-specific variants in the two patients who exhibited an objective response to selumetinib, several genes associated with ERK signaling were identified. Confirmatory studies investigating the role of the identified genes and other potential tumor independent factors need further investigation.
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http://dx.doi.org/10.18632/oncotarget.6632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868687PMC
February 2016

Impact of Pre-Analytical Variables on Cancer Targeted Gene Sequencing Efficiency.

PLoS One 2015 25;10(11):e0143092. Epub 2015 Nov 25.

James Thoracic Center, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, 43210, United States of America.

Tumor specimens are often preserved as formalin-fixed paraffin-embedded (FFPE) tissue blocks, the most common clinical source for DNA sequencing. Herein, we evaluated the effect of pre-sequencing parameters to guide proper sample selection for targeted gene sequencing. Data from 113 FFPE lung tumor specimens were collected, and targeted gene sequencing was performed. Libraries were constructed using custom probes and were paired-end sequenced on a next generation sequencing platform. A PCR-based quality control (QC) assay was utilized to determine DNA quality, and a ratio was generated in comparison to control DNA. We observed that FFPE storage time, PCR/QC ratio, and DNA input in the library preparation were significantly correlated to most parameters of sequencing efficiency including depth of coverage, alignment rate, insert size, and read quality. A combined score using the three parameters was generated and proved highly accurate to predict sequencing metrics. We also showed wide read count variability within the genome, with worse coverage in regions of low GC content like in KRAS. Sample quality and GC content had independent effects on sequencing depth, and the worst results were observed in regions of low GC content in samples with poor quality. Our data confirm that FFPE samples are a reliable source for targeted gene sequencing in cancer, provided adequate sample quality controls are exercised. Tissue quality should be routinely assessed for pre-analytical factors, and sequencing depth may be limited in genomic regions of low GC content if suboptimal samples are utilized.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143092PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659597PMC
June 2016

Risk factors for anthracycline-associated cardiotoxicity.

Support Care Cancer 2016 May 12;24(5):2173-2180. Epub 2015 Nov 12.

The Breast Program, The Ohio State University Comprehensive Cancer Center and the Stefanie Spielman Comprehensive Breast Center, B421 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH, 43210, USA.

Purpose: Carbonyl reductase (CBR) catalyzes anthracycline metabolism, and single nucleotide polymorphisms (SNPs) in CBR impact metabolic efficiency. In pediatric patients, homozygosity for the major allele (G) in the CBR3 gene was associated with increased risk of anthracycline cardiotoxicity. We hypothesized that CBR SNPs contribute to cardiotoxicity in adults.

Methods: We retrospectively identified female breast cancer patients in the Columbus Breast Tissue Bank Registry treated with adriamycin and cytoxan (AC) from 2003 to 2012. We selected patients who developed cardiomyopathy, defined as a drop in ejection fraction to <50 % or >15 % decrease from pre-therapy. Univariate and multivariate logistic regressions were performed to identify cardiotoxicity risk factors. SNPs were genotyped, and frequency of the major allele (G)/minor allele (A) of the CBR3 and CBR1 genes was calculated.

Results: We identified 52 cases of cardiotoxicity after AC and 110 controls. Multivariate analysis showed that trastuzumab (p = 0.009), diabetes (p = 0.05), and consumption of >8 alcoholic drinks/week (p = 0.024) were associated with higher cardiotoxicity risk. Moderate alcohol consumption (<8 drinks/week) was associated with lower risk (p = 0.009). No association was identified between CBR SNPs and cardiotoxicity (CBR1 p = 0.261; CBR3 p = 0.556).

Conclusions: This is the first study to evaluate SNPs in the CBR pathway as predictors of AC cardiotoxicity in adults. We did not observe any significant correlation between cardiotoxicity and SNPs within the CBR pathway. Further investigation into CBR SNPs in a larger adult sample is needed. Additional exploration into genomic predictors of anthracycline cardiotoxicity may allow for the development of preventative and therapeutic strategies for those at risk.
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http://dx.doi.org/10.1007/s00520-015-3008-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874738PMC
May 2016

Noncatalytic PTEN missense mutation predisposes to organ-selective cancer development in vivo.

Genes Dev 2015 Aug;29(16):1707-20

Solid Tumor Biology Program, James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Genetics, College of Arts and Sciences, The Ohio State University, Columbus, Ohio 43210, USA; Department of Molecular Virology, Immunology, and Medical Genetics, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA;

Inactivation of phosphatase and tensin homology deleted on chromosome 10 (PTEN) is linked to increased PI3K-AKT signaling, enhanced organismal growth, and cancer development. Here we generated and analyzed Pten knock-in mice harboring a C2 domain missense mutation at phenylalanine 341 (Pten(FV)), found in human cancer. Despite having reduced levels of PTEN protein, homozygous Pten(FV/FV) embryos have intact AKT signaling, develop normally, and are carried to term. Heterozygous Pten(FV/+) mice develop carcinoma in the thymus, stomach, adrenal medulla, and mammary gland but not in other organs typically sensitive to Pten deficiency, including the thyroid, prostate, and uterus. Progression to carcinoma in sensitive organs ensues in the absence of overt AKT activation. Carcinoma in the uterus, a cancer-resistant organ, requires a second clonal event associated with the spontaneous activation of AKT and downstream signaling. In summary, this PTEN noncatalytic missense mutation exposes a core tumor suppressor function distinct from inhibition of canonical AKT signaling that predisposes to organ-selective cancer development in vivo.
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http://dx.doi.org/10.1101/gad.262568.115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561480PMC
August 2015

Somatic Mutation Spectrum of Non-Small-Cell Lung Cancer in African Americans: A Pooled Analysis.

J Thorac Oncol 2015 Oct;10(10):1430-6

*Department of Internal Medicine, James Thoracic Center, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio; †Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee; ‡Department of Internal Medicine, Baptist Center for Cancer Care, Columbus, Mississippi; §Department of Pathology, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; ‖Pathology Associates of Saint Thomas, Nashville, Tennessee; ¶Department of Internal Medicine, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; #GenomOncology, Cleveland, Ohio; ††Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio; and ‡‡Department of Biomedical Informatics, Biomedical Informatics Shared Resource, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.

Introduction: The mutational profile of non-small-cell lung cancer (NSCLC) has become an important tool in tailoring therapy to patients, with clear differences according to the population of origin. African Americans (AAs) have higher lung cancer incidence and mortality than Caucasians, yet discrepant results have been reported regarding the frequency of somatic driver mutations. We hypothesized that NSCLC has a distinct mutational profile in this group.

Methods: We collected NSCLC samples resected from self-reported AAs in five sites from Tennessee, Michigan, and Ohio. Gene mutations were assessed by either SNaPshot or next generation sequencing, and ALK translocations were evaluated by fluorescence in situ hybridization.

Results: Two hundred sixty patients were included, mostly males (62.3%) and smokers (86.6%). Eighty-one samples (31.2%) were squamous cell carcinomas. The most frequently mutated genes were KRAS (15.4%), epidermal growth factor receptor (EGFR, 5.0%), PIK3CA (0.8%), BRAF, NRAS, ERBB2, and AKT1 (0.4% each). ALK translocations were detected in two nonsquamous tumors (1.7%), totaling 61 cases (23.5%) with driver oncogenic alterations. Among 179 nonsquamous samples, 54 (30.2%) presented a driver alteration. The frequency of driver alterations altogether was lower than that reported in Caucasians, whereas no difference was detected in either EGFR or KRAS mutations. Overall survival was longer among patients with EGFR mutations.

Conclusions: We demonstrated that NSCLC from AAs has a different pattern of somatic driver mutations than from Caucasians. The majority of driver alterations in this group are yet to be described, which will require more comprehensive panels and assessment of noncanonical alterations.
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http://dx.doi.org/10.1097/JTO.0000000000000650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618391PMC
October 2015

Upfront molecular testing in patients with advanced gastro-esophageal cancer: Is it time yet?

Oncotarget 2015 Sep;6(26):22206-13

Department of Medicine, The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute, Columbus, Ohio 43221, USA.

Introduction: Targeting HER2 has improved outcomes in metastatic GE (mGE) cancer. In this study, we aim to explore the feasibility of molecular profiling in patients with refractory mGE cancer in routine clinical practice.

Methods: Archival formalin-fixed, paraffin-embedded (FFPE) samples for patients with mGE were analyzed with commercially available targeted next generation sequencing (NGS) and/or FISH for MET amplification. We also reviewed the patients' medical records for concurrent HER 2 testing.

Results: Tumor samples from 99 patients with mGE cancer were analyzed as follows: NGS (N = 56), FISH for MET amplification (N = 65), IHC and/or FISH for HER2 (N = 87). Of patients who underwent NGS, 50/56 (89%) had at least one actionable molecular alteration. The most notable actionable alterations included cell cycle abnormalities (58%), HER2 amplification (30%), PI3KCA mutation (14%), MCL1 amplification (11%), PTEN loss (9%), CDH1 mutation (2%) and MET amplification (5%). Ninety-two percent (12/13) of patients with HER2 amplification by NGS were positive for HER2 by IHC and/or FISH. In contrast, only 12/18 (66%) patients positive for HER2 by IHC and/or FISH demonstrated HER2 amplification by NGS.

Conclusion: Comprehensive molecular testing is feasible in clinical practice and provides a platform for screening patients for molecularly guided clinical trials and available targeted therapies.
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http://dx.doi.org/10.18632/oncotarget.4247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673157PMC
September 2015

Genomic Characterization of Non-Small-Cell Lung Cancer in African Americans by Targeted Massively Parallel Sequencing.

J Clin Oncol 2015 Jun 27;33(17):1966-73. Epub 2015 Apr 27.

Luiz H. Araujo, Cynthia Timmers, Erica Hlavin Bell, Konstantin Shilo, Weiqiang Zhao, Jianying Zhang, Ayse S. Yilmaz, Tom Liu, Kevin Coombes, Joseph Amann, and David P. Carbone, The Ohio State University Comprehensive Cancer Center, Columbus; Thanemozhi G. Natarajan and Clinton J. Miller, GenomOncology, Cleveland, OH; Philip E. Lammers, Meharry Medical College, Nashville, TN.

Purpose: Technologic advances have enabled the comprehensive analysis of genetic perturbations in non-small-cell lung cancer (NSCLC); however, African Americans have often been underrepresented in these studies. This ethnic group has higher lung cancer incidence and mortality rates, and some studies have suggested a lower incidence of epidermal growth factor receptor mutations. Herein, we report the most in-depth molecular profile of NSCLC in African Americans to date.

Methods: A custom panel was designed to cover the coding regions of 81 NSCLC-related genes and 40 ancestry-informative markers. Clinical samples were sequenced on a massively parallel sequencing instrument, and anaplastic lymphoma kinase translocation was evaluated by fluorescent in situ hybridization.

Results: The study cohort included 99 patients (61% males, 94% smokers) comprising 31 squamous and 68 nonsquamous cell carcinomas. We detected 227 nonsilent variants in the coding sequence, including 24 samples with nonoverlapping, classic driver alterations. The frequency of driver mutations was not significantly different from that of whites, and no association was found between genetic ancestry and the presence of somatic mutations. Copy number alteration analysis disclosed distinguishable amplifications in the 3q chromosome arm in squamous cell carcinomas and pointed toward a handful of targetable alterations. We also found frequent SMARCA4 mutations and protein loss, mostly in driver-negative tumors.

Conclusion: Our data suggest that African American ancestry may not be significantly different from European/white background for the presence of somatic driver mutations in NSCLC. Furthermore, we demonstrated that using a comprehensive genotyping approach could identify numerous targetable alterations, with potential impact on therapeutic decisions.
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http://dx.doi.org/10.1200/JCO.2014.59.2444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451177PMC
June 2015

Enhanced bioavailability of lycopene when consumed as cis-isomers from tangerine compared to red tomato juice, a randomized, cross-over clinical trial.

Mol Nutr Food Res 2015 Apr 10;59(4):658-69. Epub 2015 Mar 10.

Department of Food Science and Technology, The Ohio State University, Columbus, OH, USA.

Scope: Tangerine tomatoes (Solanum lycopersicum) are rich in tetra-cis-lycopene resulting from natural variation in carotenoid isomerase. Our objective was to compare the bioavailability of lycopene from tangerine to red tomato juice, and elucidate physical deposition forms of these isomers in tomatoes by light and electron microscopy.

Methods And Results: Following a randomized cross-over design, subjects (n = 11, 6 M/5 F) consumed two meals delivering 10 mg lycopene from tangerine (94% cis) or red tomato juice (10% cis). Blood was sampled over 12 h and triglyceride-rich lipoprotein fractions of plasma were isolated and analyzed using HPLC-DAD-MS/MS. Lycopene was crystalline in red tomato chromoplasts and globular in tangerine tomatoes. With tangerine tomato juice we observed a marked 8.5-fold increase in lycopene bioavailability compared to red tomato juice (p < 0.001). Fractional absorption was 47.70 ± 8.81% from tangerine and 4.98 ± 1.92% from red tomato juices. Large heterogeneity was observed among subjects.

Conclusion: Lycopene is markedly more bioavailable from tangerine than from red tomato juice, consistent with a predominance of cis-lycopene isomers and presence in chromoplasts in a lipid dissolved globular state. These results justify using tangerine tomatoes as a lycopene source in studies examining the potential health benefits of lycopene-rich foods.
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http://dx.doi.org/10.1002/mnfr.201400658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460827PMC
April 2015