Publications by authors named "Philip E Lammers"

21 Publications

  • Page 1 of 1

Trilaciclib prior to chemotherapy reduces the usage of supportive care interventions for chemotherapy-induced myelosuppression in patients with small cell lung cancer: Pooled analysis of three randomized phase 2 trials.

Cancer Med 2021 09 18;10(17):5748-5756. Epub 2021 Aug 18.

Hetenyi Geza Korhaz, Szolnok, Hungary.

Background: Supportive care interventions used to manage chemotherapy-induced myelosuppression (CIM), including granulocyte colony-stimulating factors (G-CSFs), erythropoiesis-stimulating agents (ESAs), and red blood cell (RBC) transfusions, are burdensome to patients and associated with greater costs to health care systems. We evaluated the utilization of supportive care interventions and their relationship with the myeloprotective agent, trilaciclib.

Methods: Data were pooled from three independent randomized phase 2 clinical trials of trilaciclib or placebo administered prior to chemotherapy in patients with extensive-stage small cell lung cancer (ES-SCLC). The impact of supportive care on the duration of severe neutropenia (DSN), occurrence of severe neutropenia (SN), and occurrence of RBC transfusions on/after week 5 was analyzed across cycles 1-4. Concordance and association between grade 3/4 anemia, RBC transfusions on/after week 5, and ESA administration was also evaluated.

Results: The use of G-CSFs, ESAs, or RBC transfusions on/after week 5 was significantly lower among patients receiving trilaciclib versus placebo (28.5% vs. 56.3%, p < 0.0001; 3.3% vs. 11.8%, p = 0.0254; and 14.6% vs. 26.1%, p = 0.0252, respectively). Compared with placebo, trilaciclib significantly reduced DSN and SN, irrespective of G-CSF administration. RBC transfusions and ESAs were most often administered in patients with grade 3/4 anemia; however, patients typically received RBC transfusions over ESA administration.

Conclusions: By improving CIM and reducing the need for associated supportive care, trilaciclib has the potential to reduce the burden of myelosuppression on patients receiving myelosuppressive chemotherapy for the treatment of ES-SCLC.

Trial Registration: ClinicalTrials.gov (NCT02499770; NCT03041311; NCT02514447).
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http://dx.doi.org/10.1002/cam4.4089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419768PMC
September 2021

Increased ease of access to genetic counseling for low-income women with breast cancer using a point of care screening tool.

J Community Genet 2021 Jan 3;12(1):129-136. Epub 2021 Jan 3.

Vanderbilt Clinical and Translational Hereditary Cancer Program, Vanderbilt University Medical Center, Nashville, TN, USA.

Increased access to genetic counseling services is of prime importance in minority and underserved populations where genetic testing is currently underutilized. Our study tested a point of care screening tool to identify high-risk low-income patients for genetic counseling in a busy county hospital oncology clinic. Eligible breast patients treated at a "safety-net" hospital, were scored into 'high-risk' (> or = 6) or 'low-risk' (< 6) groups using a screening tool on personal and family history of cancer. Genetic counseling and testing were provided at the Vanderbilt Hereditary Cancer Program (VHCP) to all 'high-risk' and some 'low-risk' participants considered to need genetic counseling by their oncologist. Ninety-nine women with a history of breast cancer were enrolled onto the study over a period of 26 months. 53.5% (53/99) had a 'high-risk' score and ethnic predominance of African-American (60.4%). Of these, 67.9% (36/53) were counseled, and 91.6% (33/36) tested with a 9% (3/33) mutation positive rate. In the 'low-risk' group, 28.2% (13/46) still met current NCCN guidelines and were referred by their oncologist. 69.2% (9/13) were counseled and tested. The 'low-risk' group of predominantly Caucasian (41.3%) participants carried a 20% (2/10) mutation positive rate; which was later adjusted to 10% to exclude a mutation not conferring a strong breast cancer risk. The screening tool was well accepted by patients; and increased access to genetic counseling. There was a subset of breast cancer affected women under 45 with no reported family history that failed to be identified. Minor alterations to the tool would enhance concordance with current NCCN guidelines.
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http://dx.doi.org/10.1007/s12687-020-00499-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846634PMC
January 2021

Participant choices for return of genomic results in the eMERGE Network.

Genet Med 2020 11 16;22(11):1821-1829. Epub 2020 Jul 16.

Divisions of Human Genetics and Patient Services, Cincinnati Children's Hospital, Cincinnati, OH, USA.

Purpose: Secondary findings are typically offered in an all or none fashion when sequencing is used for clinical purposes. This study aims to describe the process of offering categorical and granular choices for results in a large research consortium.

Methods: Within the third phase of the electronic MEdical Records and GEnomics (eMERGE) Network, several sites implemented studies that allowed participants to choose the type of results they wanted to receive from a multigene sequencing panel. Sites were surveyed to capture the details of the implementation protocols and results of these choices.

Results: Across the ten eMERGE sites, 4664 participants including adolescents and adults were offered some type of choice. Categories of choices offered and methods for selecting categories varied. Most participants (94.5%) chose to learn all genetic results, while 5.5% chose subsets of results. Several sites allowed participants to change their choices at various time points, and 0.5% of participants made changes.

Conclusion: Offering choices that include learning some results is important and should be a dynamic process to allow for changes in scientific knowledge, participant age group, and individual preference.
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http://dx.doi.org/10.1038/s41436-020-0905-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477450PMC
November 2020

Returning Results in the Genomic Era: Initial Experiences of the eMERGE Network.

J Pers Med 2020 Apr 27;10(2). Epub 2020 Apr 27.

Genomic Medicine Institute, Geisinger, Danville, PA 17822, USA.

A goal of the 3rd phase of the Electronic Medical Records and Genomics (eMERGE3) Network was to examine the return of results (RoR) of actionable variants in more than 100 genes to consenting participants and their healthcare providers. Each of the 10 eMERGE sites developed plans for three essential elements of the RoR process: Disclosure to the participant, notification of the health care provider, and integration of results into the electronic health record (EHR). Procedures and protocols around these three elements were adapted as appropriate to individual site requirements and limitations. Detailed information about the RoR procedures at each site was obtained through structured telephone interviews and follow-up surveys with the clinical investigator leading or participating in the RoR process at each eMERGE3 institution. Because RoR processes at each of the 10 sites allowed for taking into account differences in population, disease focus and institutional requirements, significant heterogeneity of process was identified, including variability in the order in which patients and clinicians were notified and results were placed in the EHR. This heterogeneity in the process flow for eMERGE3 RoR reflects the "real world" of genomic medicine in which RoR procedures must be shaped by the needs of the patients and institutional environments.
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http://dx.doi.org/10.3390/jpm10020030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354592PMC
April 2020

Assessment of Treatment With Sorafenib Plus Doxorubicin vs Sorafenib Alone in Patients With Advanced Hepatocellular Carcinoma: Phase 3 CALGB 80802 Randomized Clinical Trial.

JAMA Oncol 2019 Nov;5(11):1582-1588

Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco.

Importance: Previous communication has reported significant improvement in overall survival (OS) when using doxorubicin plus sorafenib in the treatment of advanced hepatocellular cancer (HCC).

Objective: To determine if doxorubicin added to sorafenib therapy improves OS, with stratification for locally advanced and metastatic disease.

Design, Setting, And Participants: This unblinded randomized phase 3 clinical trial was led by Alliance in collaboration with Eastern Cooperative Oncology Group-American College of Radiology Imaging Network, Canadian Cancer Trials Group, and Southwest Oncology Group. It was launched in February 2010 and completed in May 2015; data were also analyzed during this time frame. Patients with histologically proven advanced HCC, no prior systemic therapy, Child-Pugh grade A score, Eastern Cooperative Oncology Group performance status of 0 to 2 (later amended to 0-1), and adequate hematologic, hepatic, renal, and cardiac function were eligible. The OS primary end point had a final analysis planned with 364 events observed among 480 total patients with 90% power to detect a 37% increase in median OS.

Interventions Or Exposures: Patients received either 60 mg/m2 of doxorubicin every 21 days plus 400 mg of sorafenib orally twice daily or the sorafenib alone, adjusted to half doses for patients with bilirubin levels of 1.3 to 3.0 mg/dL.

Main Outcomes And Measures: The primary end point was OS, and progression-free survival (PFS) was a secondary end point.

Results: Of 356 patients included in the study, the mean (SD) age was 62 (10.1) years, and 306 (86.0%) were men. Although it was planned to include 480 patients, the study was halted after accrual of 356 patients (180 patients treated with doxorubicin plus sorafenib and 176 with sorafenib alone) with a futility boundary crossed at a planned interim analysis. Median OS was 9.3 months (95% CI, 7.3-10.8 months) in the doxorubicin plus sorafenib arm and 9.4 months (95% CI, 7.3-12.9 months) in the sorafenib alone arm (hazard ratio, 1.05; 95% CI, 0.83-1.31). The median PFS was 4.0 months (95% CI, 3.4-4.9 months) in the doxorubicin plus sorafenib arm and 3.7 months (95% CI, 2.9-4.5 months) in the sorafenib alone arm (hazard ratio, 0.93; 95% CI, 0.75-1.16). Grade 3 or 4 neutropenia and thrombocytopenia adverse events occurred in 61 (36.8%) and 29 (17.5%) patients, respectively, being treated with doxorubicin plus sorafenib vs 1 (0.6%) and 4 (2.4%) patients treated with sorafenib.

Conclusions And Relevance: This multigroup study of the addition of doxorubicin to sorafenib therapy did not show improvement of OS or PFS in patients with HCC.

Trial Registration: ClinicalTrials.gov identifier: NCT01015833.
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http://dx.doi.org/10.1001/jamaoncol.2019.2792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6735405PMC
November 2019

Bispecific Antibodies in the Treatment of Hematologic Malignancies.

Clin Pharmacol Ther 2019 10 29;106(4):781-791. Epub 2019 Mar 29.

Blood and Marrow Transplantation Program, Abramson Cancer Center and the Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Monoclonal antibody therapies are an important approach for the treatment of hematologic malignancies, but typically show low single-agent activity. Bispecific antibodies, however, redirect immune cells to the tumor for subsequent lysis, and preclinical and accruing clinical data support single-agent efficacy of these agents in hematologic malignancies, presaging an exciting era in the development of novel bispecific formats. This review discusses recent developments in this area, highlighting the challenges in delivering effective immunotherapies for patients.
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http://dx.doi.org/10.1002/cpt.1396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766786PMC
October 2019

Neoadjuvant PF-05280014 (a potential trastuzumab biosimilar) versus trastuzumab for operable HER2+ breast cancer.

Br J Cancer 2018 08 13;119(3):266-273. Epub 2018 Jul 13.

Pfizer Inc., 235 and 219 East 42nd Street, New York, NY, 10017-5755, USA.

Background: This randomised, double-blind study compared pharmacokinetics, efficacy, safety and immunogenicity of PF-05280014 (potential trastuzumab biosimilar) and trastuzumab reference product (Herceptin) sourced from the European Union (trastuzumab-EU) as neoadjuvant treatment for operable human epidermal growth factor receptor 2 (HER2)-positive breast cancer.

Methods: Patients (N = 226), stratified by primary tumour size and hormone receptor status, were randomised 1:1 to PF-05280014 or trastuzumab-EU (8 mg/kg loading dose; 6 mg/kg thereafter), each with docetaxel and carboplatin, every 3 weeks for six treatment cycles. Primary endpoint was percentage of patients with trough plasma concentration (C) >20 μg/ml at Cycle 5 (Cycle 6 predose). Efficacy endpoints included pathological complete response and objective response rate. Non-inferiority of PF-05280014 to trastuzumab-EU was declared if the lower limit of the 95% confidence interval for the stratified difference between groups in the percentage of patients with Cycle 5 C >20 μg/ml was above the prespecified non-inferiority margin of - 12.5%.

Results: For PF-05280014 vs trastuzumab-EU patients, respectively, 92.1% vs 93.3% had Cycle 5 C >20 μg/ml; the lower limit of the 95% confidence interval (- 8.02%, 6.49%) for the stratified difference between groups was above the non-inferiority margin (- 12.5%). Pathological complete response (47.0% vs 50.0%) and central radiology review-assessed objective response (88.1% vs 82.0%) rates were comparable. Incidence of all-causality, grade 3-4 treatment-emergent adverse events was 38.1% vs 45.5%; antidrug antibody rates were 0% vs 0.89%.

Conclusions: PF-05280014 demonstrated non-inferior pharmacokinetics and comparable efficacy, safety and immunogenicity to trastuzumab-EU in patients with operable HER2-positive breast cancer receiving neoadjuvant chemotherapy.
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http://dx.doi.org/10.1038/s41416-018-0147-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068194PMC
August 2018

High salt induces P-glycoprotein mediated treatment resistance in breast cancer cells through store operated calcium influx.

Oncotarget 2018 May 18;9(38):25193-25205. Epub 2018 May 18.

Department of Biological Sciences, Tennessee State University, Nashville, TN, USA.

Recent evidence from our laboratory has demonstrated that high salt (Δ0.05 M NaCl) induced inflammatory response and cancer cell proliferation through salt inducible kinase-3 (SIK3) upregulation. As calcium influx is known to effect inflammatory response and drug resistance, we examined the impact of high salt on calcium influx in breast cancer cells. Treatment of MCF-7 and MDA-MB-231 cells with high salt induced an enhanced intracellular calcium intensity, which was significantly decreased by store operated calcium entry (SOCE) inhibitor co-treatment. Further, high salt induced P-glycoprotein (P-gp) mediated paclitaxel drug resistance in breast cancer cells. Murine tumor studies demonstrated that injection of MCF-7 cells cultured in high salt, exerted higher tumorigenicity compared to the basal cultured counterpart. Knock down of SIK3 by specific shRNA inhibited tumorigenicty, expression of SOCE regulators and P-gp activity, suggesting SIK3 is an upstream mediator of SOCE induced calcium influx. Furthermore, small molecule inhibitor, prostratin, exerted anti-tumor effect in murine models through SIK3 inhibition. Taken together, we conclude that SIK3 is an upstream regulator of store operated calcium entry proteins, Orai1 and STIM1, and mediates high salt induced inflammatory cytokine responses and P-gp mediated drug resistance. Therefore, small molecule inhibitors, such as prostratin, could offer novel anti-cancer approaches.
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http://dx.doi.org/10.18632/oncotarget.25391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5982760PMC
May 2018

A rapidly growing human papillomavirus-positive oral tongue squamous cell carcinoma in a 21-year old female: A case report.

Oncol Lett 2018 May 23;15(5):7702-7706. Epub 2018 Mar 23.

Department of Pathology, Anatomy and Cell Biology, Meharry Medical College, Nashville, TN 37208, USA.

Oral tongue squamous cell carcinoma (OTSCC) has a median age at diagnosis of 62 years. The incidence of OTSCC in young adults has been increasing, and the reason is unclear. The present study describes a case, and molecular analysis, of OTSCC in a 21-year-old female. Clinical and pathological information were collected from medical records. Formalin-fixed paraffin-embedded biopsy tissue from the patient was reassessed using standard hematoxylin & eosin staining, and immunohistochemistry was used to assess the expression of cellular p16, MutL homolog (MLH)1, MLH2, MutS homolog 6 (MSH6) and PMS1 homolog 2 (PMS2). The human papilloma virus (HPV) genome was detected by PCR analysis of the extracted DNA. The young age of the patient with OTSCC was unusual. The original pathology report indicated , a cellular abnormality associated with HPV. Although HPV-positive oral cancer tends to occur in 'younger' individuals, 21 years is unusual. The confirmation of biologically active HPV in the tumor was obtained via the observation of strong positive staining for cellular p16. The patient described a maternal family cluster of rare cancer types, thus the possibility that this rapidly growing cancer resulted from HPV infection combined with an underlying genetic mutation causing decreased DNA-mismatch repair was explored. However, MSH1, MSH2, MSH6 and PSM2, proteins that are associated with Lynch Syndrome, were expressed at normal levels. A rapidly growing OTSCC of a 21-year-old female was determined to be HPV-positive. The patient underwent combination chemotherapy and radiation and has experienced long-term survival without recurrence. The reason this tumor grew so quickly in such a young individual remains unknown. These types of cases warrant additional genomic and proteomic studies to improve understanding of this phenomenon.
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http://dx.doi.org/10.3892/ol.2018.8339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962839PMC
May 2018

Barriers to the Access of Bevacizumab in Patients with Solid Tumors and the Potential Impact of Biosimilars: A Physician Survey.

Pharmaceuticals (Basel) 2017 Jan 28;10(1). Epub 2017 Jan 28.

Pfizer Inc, 235 East 42nd Street, New York, NY 10017-5755, USA.

Access to bevacizumab, an important component of oncology treatment regimens, may be limited. This survey of oncologists in the US ( = 150), Europe ( = 230), and emerging markets (EM: Brazil, Mexico, and Turkey; = 130) examined use of and barriers to accessing bevacizumab as treatment of advanced solid tumors. We also assessed the likelihood that physicians would prescribe a bevacizumab biosimilar, if available. Bevacizumab was frequently used as early-line therapy in metastatic colorectal cancer, metastatic non-squamous non-small-cell lung cancer, and metastatic ovarian cancer (all markets), and as a second-line therapy in glioblastoma multiforme (US, EM). A greater percentage of EM-based physicians cited access-related issues as a barrier to prescribing bevacizumab versus US and EU physicians. Lack of reimbursement and high out-of-pocket costs were cited as predominant barriers to prescribing and common reasons for reducing the number of planned cycles. Overall, ~50% of physicians reported they "definitely" or "probably" would prescribe a bevacizumab biosimilar, if available. Efficacy and safety data in specific tumor types and lower cost were factors cited that would increase likelihood to prescribe a bevacizumab biosimilar. A lower cost bevacizumab biosimilar could address the unmet needs of patients and physicians worldwide, and may have the greatest impact on patient outcomes in EM.
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http://dx.doi.org/10.3390/ph10010019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374423PMC
January 2017

Fetuin-A (alpha 2HS glycoprotein) modulates growth, motility, invasion, and senescence in high-grade astrocytomas.

Cancer Med 2016 12 23;5(12):3532-3543. Epub 2016 Nov 23.

Department of Biochemistry and Cancer Biology, Meharry Medical College, 1005 D.B. Todd Blvd., Nashville, 37208, Tennessee.

Glioblastomas (high-grade astrocytomas) are highly aggressive brain tumors with poor prognosis and limited treatment options. In the present studies, we have defined the role of fetuin-A, a liver-derived multifunctional serum protein, in the growth of an established glioblastoma cell line, LN229. We hereby demonstrate that these cells synthesize ectopic fetuin-A which supports their growth in culture in the absence of serum. We have demonstrated that a panel of tissue microarray (TMA) of glioblastomas also express ectopic fetuin-A. Knocking down fetuin-A using shRNA approach in LN229, significantly reduced their in vitro growth as well as growth and invasion in vivo. The fetuin-A knockdown subclones of LN229 (A and D) also had reduced motility and invasive capacity. Treatment of LN229 cells with asialofetuin (ASF), attenuated their uptake of labeled fetuin-A, and induced senescence in them. Interestingly, the D subclone that had ~90% reduction in ectopic fetuin-A, underwent senescence in serum-free medium which was blunted in the presence of purified fetuin-A. Uptake of labeled exosomes was attenuated in fetuin-A knockdown subclones A and D. Taken together, the studies demonstrate the impact of fetuin-A as significant node of growth, motility, and invasion signaling in glioblastomas that can be targeted for therapy.
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http://dx.doi.org/10.1002/cam4.940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5224863PMC
December 2016

Inhibition of the Biosynthesis of Prostaglandin E2 By Low-Dose Aspirin: Implications for Adenocarcinoma Metastasis.

Cancer Prev Res (Phila) 2016 Nov 23;9(11):855-865. Epub 2016 Aug 23.

Department of Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee.

Meta-analyses have demonstrated that low-dose aspirin reduces the risk of developing adenocarcinoma metastasis, and when colon cancer is detected during aspirin treatment, there is a remarkable 83% reduction in risk of metastasis. As platelets participate in the metastatic process, the antiplatelet action of low-dose aspirin likely contributes to its antimetastatic effect. Cycloxooxygenase-2 (COX-2)-derived prostaglandin E (PGE) also contributes to metastasis, and we addressed the hypothesis that low-dose aspirin also inhibits PGE biosynthesis. We show that low-dose aspirin inhibits systemic PGE biosynthesis by 45% in healthy volunteers (P < 0.0001). Aspirin is found to be more potent in colon adenocarcinoma cells than in the platelet, and in lung adenocarcinoma cells, its inhibition is equivalent to that in the platelet. Inhibition of COX by aspirin in colon cancer cells is in the context of the metastasis of colon cancer primarily to the liver, the organ exposed to the same high concentrations of aspirin as the platelet. We find that the interaction of activated platelets with lung adenocarcinoma cells upregulates COX-2 expression and PGE biosynthesis, and inhibition of platelet COX-1 by aspirin inhibits PGE production by the platelet-tumor cell aggregates. In conclusion, low-dose aspirin has a significant effect on extraplatelet cyclooxygenase and potently inhibits COX-2 in lung and colon adenocarcinoma cells. This supports a hypothesis that the remarkable prevention of metastasis from adenocarcinomas, and particularly from colon adenocarcinomas, by low-dose aspirin results from its effect on platelet COX-1 combined with inhibition of PGE biosynthesis in metastasizing tumor cells. Cancer Prev Res; 9(11); 855-65. ©2016 AACR.
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http://dx.doi.org/10.1158/1940-6207.CAPR-16-0094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093073PMC
November 2016

Role of Rituximab and Rituximab Biosimilars in Diffuse Large B-Cell Lymphoma.

Clin Lymphoma Myeloma Leuk 2016 Apr 30;16(4):175-81. Epub 2016 Jan 30.

Global Medical Affairs, Pfizer Inc, New York, NY. Electronic address:

Diffuse large B-cell lymphoma (DLBCL), an aggressive non-Hodgkin lymphoma (NHL), is the most-common subtype of NHL. DLBCL can be classified into at least 3 major immunologically distinct types, which contributes to considerable variation in disease prognosis and response to treatment. DLBCL potentially is curable, even when diagnosed at advanced stages. The current standard of care for most patients with untreated or relapsed/refractory DLBCL is chemoimmunotherapy containing rituximab, an anti-CD20 monoclonal antibody. With advanced understanding of the molecular mechanisms involved in the pathogenesis of DLBCL and specific signaling pathways that are activated in different subtypes, potential new therapeutic targets have been identified, some of which are at the late stages of clinical development. This review summarizes the critical role of rituximab in the current standard of care treatment for DLBCL and discusses why rituximab is likely to remain an important component of treatment options for DLBCL in the foreseeable future. In addition, current and emerging therapeutic agents, including potential benefits of rituximab biosimilars, for patients with DLBCL are discussed. The advent of rituximab biosimilars may facilitate accessibility of rituximab-based chemotherapies to patients with DLBCL and has potential cost-saving benefits for healthcare systems globally.
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http://dx.doi.org/10.1016/j.clml.2016.01.004DOI Listing
April 2016

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

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

Phase II study of bendamustine in relapsed chemotherapy sensitive or resistant small-cell lung cancer.

J Thorac Oncol 2014 Apr;9(4):559-62

*Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee; †Department of Biostatistics, Center for Quantitative Science, Vanderbilt University Medical Center, Nashville, Tennessee; ‡South Carolina Oncology Associates, Columbia, South Carolina; §Department of Medicine, Division of Hematology and Medical Oncology, Oregon Health and Science University, OHSU Knight Cancer Institute, Portland, Oregon; ‖Department of Medicine, Division of Medical Oncology, The Ohio State University Medical Center, Arthur G. James Cancer Hospital, Columbus, Ohio; ¶Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas; and #Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.

Introduction: To determine the time to progression (TTP), response rate (RR), and toxicity for North American patients with relapsed small-cell lung cancer (SCLC) treated with bendamustine in the second- or third-line setting.

Methods: Patients with relapsed, histologically confirmed SCLC were eligible for enrollment on study. The study population included patients with both chemotherapy-sensitive and chemotherapy-resistant disease treated with up to two prior lines of chemotherapy. Patients were treated with 120 mg/m of bendamustine on days 1 and 2 of a 21-day cycle for up to six cycles. Primary end point was TTP; secondary end points included toxicity, RR, and overall survival.

Results: Fifty-nine patients were accrued, 50 patients met eligibility for enrollment. The median age of patients was 62, and 56% were men. Twenty-nine patients (58%) had chemotherapy-sensitive disease. Median TTP was 4.0 months (95% confidence interval [CI], 3.3-5.4), median overall survival was 4.8 months (95% CI, 3.8-6.3), and the RR was 26% (95% CI, 13.3%-39.5%). Patients with chemosensitive disease had a median TTP of 4.2 months (95% CI, 3.3-6.0) compared with 3.4 months (95% CI, 2.7-∞) for chemotherapy-resistant disease. The RR was 33% (95% CI, 14.2%-51.8%) in patients with chemosensitive disease and 17% (95% CI, 0%-34.4%) in those with chemoresistant disease. The most common grade 3/4 adverse events were fatigue (20%), dyspnea (12%), and anemia (12%).

Conclusion: Bendamustine has modest activity in relapsed SCLC similar to other agents evaluated in this patient population.
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http://dx.doi.org/10.1097/JTO.0000000000000079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3990869PMC
April 2014

A patient with metastatic lung adenocarcinoma harboring concurrent EGFR L858R, EGFR germline T790M, and PIK3CA mutations: the challenge of interpreting results of comprehensive mutational testing in lung cancer.

J Natl Compr Canc Netw 2014 Jan;12(1):6-11; quiz 11

From the Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center and Vanderbilt Ingram Cancer Center, Nashville, Tennessee.

Mutational testing has moved to the forefront as an integral component in the management of patients with non-small cell lung cancer (NSCLC). Currently 3 targeted therapies (erlotinib, afatinib, and crizotinib) are approved by the FDA to treat patients with specific genetic abnormalities in NSCLC. As mutational screening expands to include a greater number of genes, the results will become more difficult to interpret, particularly if mutations are found in multiple genes or genes that are not actionable at the time of testing. This case report summarizes the diagnosis and treatment of a patient with NSCLC that harbored multiple potentially targetable driver mutations. It also discusses the current NCCN Clinical Practice Guidelines in Oncology for mutational testing in NSCLC and the inherent difficulties with interpreting mutational results when multiple mutations are found in a single gene or across multiple genes.
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http://dx.doi.org/10.6004/jnccn.2014.0002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151469PMC
January 2014

A randomized phase II trial investigating the effect of platelet function inhibition on circulating tumor cells in patients with metastatic breast cancer.

Clin Breast Cancer 2013 Dec;13(6):409-15

Department of Medicine, Division of Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO.

Background: Blockade of platelet activation and aggregation can inhibit metastasis in preclinical models and is associated with cancer prevention. To test whether disruption of platelet function with clopidogrel and aspirin would decrease the number of circulating tumor cells (CTCs) in patients with metastatic breast cancer, a randomized phase II study was performed.

Methods: Patients with metastatic breast cancer who were not currently receiving cytotoxic chemotherapy were eligible. Patients were randomized to receive either clopidogrel and aspirin or to a control group receiving no treatment. Phlebotomy was performed at baseline, at 2 and 4 weeks, and monthly thereafter to obtain specimens to assess CTC, platelet aggregation, and thrombin activity. The primary end point was the proportion of patients with detectable CTCs at 1 month.

Results: Forty-eight patients were enrolled and 42 were evaluable at 1 month. Baseline CTC numbers were ≥ 5 in 13% and ≥ 1 in 65% of patients. Despite adequate platelet function inhibition in the treatment group, the proportion of patients with detectable CTCs was similar between the clopidogrel/aspirin and control groups at baseline (P = .21) and 4 weeks (P = .75), showing no treatment effect. Measured endogenous thrombin potential did not correlate with CTC number. No bleeding-related serious adverse events (SAEs) occurred.

Conclusion: The baseline CTC numbers were lower than expected, decreasing the ability to detect an impact of platelet inhibition on CTCs. Clopidogrel and aspirin were well tolerated. Future studies evaluating the potential therapeutic role of antiplatelet therapy in breast cancer remain of interest, and they may be informed by these results.
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http://dx.doi.org/10.1016/j.clbc.2013.08.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3949605PMC
December 2013

Targeting angiogenesis in advanced non-small cell lung cancer.

J Natl Compr Canc Netw 2013 Oct;11(10):1235-47

From Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee.

Lung cancer is the leading cause of cancer-related mortality in the United States. Over the past 40 years, treatments with standard chemotherapy agents have not resulted in substantial improvements in long-term survival for patients with advanced lung cancer. Therefore, new targets have been sought, and angiogenesis is a promising target for non-small cell lung cancer (NSCLC). Bevacizumab, a monoclonal antibody targeted against the vascular endothelial growth factor, is the only antiangiogenic agent currently recommended by NCCN for the treatment of advanced NSCLC. However, several antibody-based therapies and multitargeted tyrosine kinase inhibitors are currently under investigation for the treatment of patients with NSCLC. This article summarizes the available clinical trial data on the efficacy and safety of these agents in patients with advanced lung cancer.
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http://dx.doi.org/10.6004/jnccn.2013.0146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628716PMC
October 2013

Membrane insertion of betaine/GABA transporter during hypertonic stress correlates with nuclear accumulation of TonEBP.

Biochim Biophys Acta 2005 Jun 7;1712(1):71-80. Epub 2005 Apr 7.

Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, 46202-5120, USA.

MDCK cells stably transfected with betaine/GABA transporter tagged with EGFP (EGFP-BGT) were used to study plasma membrane insertion of EGFP-BGT. Adaptive response to hypertonicity requires nuclear migration of TonEBP. Confocal microscopy showed that after 6 h hypertonicity, the nuclear/cytoplasmic ratio of TonEBP fluorescence was increased to 2.4 compared to 1.4 in isotonic controls (P<0.001). The ratio in hypertonic cells was reduced by the proteasome inhibitor MG-132 in a dose-dependent way. Inhibition was 50% at 3 microM. After 6 h, hypertonicity expressed EGFP-BGT was localized in the plasma membrane, but there was no change in total EGFP-BGT abundance compared to isotonic controls. In contrast, EGFP-BGT remained mostly intracellular when 3 microM MG-132 was included in the hypertonic medium. The transport function of EGFP-BGT was studied as Na(+)-dependent uptake of [(3)H]GABA. This was not changed by MG-132 in isotonic controls, but MG-132 produced dose-dependent inhibition of hypertonic upregulation of Na(+)/GABA cotransport. Inhibition was 80% at 3 muM MG-132. Transport likely reflects membrane insertion of EGFP-BGT and there was a positive correlation (P<0.05) between Na(+)/GABA cotransport and the N/C ratio of TonEBP. Results are consistent with a role for TonEBP-mediated transcription in synthesis of additional proteins required for membrane insertion of EGFP-BGT protein.
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http://dx.doi.org/10.1016/j.bbamem.2005.03.006DOI Listing
June 2005

Hypertonic upregulation of betaine transport in renal cells is blocked by a proteasome inhibitor.

Cell Biochem Funct 2005 Sep-Oct;23(5):315-24

Department of Cellular & Integrative Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

The renal betaine transporter (BGT1) protects cells in the hypertonic medulla by mediating uptake and accumulation of the osmolyte betaine. Transcription plays an essential role in upregulating BGT1 transport in MDCK cells subjected to hypertonic stress. During hypertonic stress, the abundance of the transcription factor TonEBP increases and it shifts from the cytoplasm to the nucleus where it activates transcription of the BGT1 gene. Little is known about post-transcriptional regulation of BGT1 protein. In the presence of the proteasome inhibitor MG-132, which blocked nuclear translocation of TonEBP, the hypertonic upregulation of BGT1 protein and transport was prevented and cell viability in hypertonic medium was impaired over 24 h. Urea also prevented the hypertonic upregulation of BGT1 protein and transport, but did not interfere with TonEBP translocation and cell viability. Shorter treatments of hypertonic cells with MG-132 avoided viability problems and produced dose-dependent inhibition of translocation and transport. When stably transfected MDCK cells that over-expressed BGT1 were treated for 6 h with hypertonic medium containing 3 microM MG-132, there was 43% inhibition of nuclear translocation, 83% inhibition of BGT1 transport, and no change in viability. While other proteasome functions may be involved, these data are consistent with a critical role for nuclear translocation of TonEBP in upregulation and membrane insertion of BGT1 protein.
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http://dx.doi.org/10.1002/cbf.1241DOI Listing
December 2005
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