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      A prospective pilot study of genome-wide exome and transcriptome profiling in patients with small cell lung cancer progressing after first-line therapy

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          Abstract

          Background

          Small cell lung cancer (SCLC) that has progressed after first-line therapy is an aggressive disease with few effective therapeutic strategies. In this prospective study, we employed next-generation sequencing (NGS) to identify therapeutically actionable alterations to guide treatment for advanced SCLC patients.

          Methods

          Twelve patients with SCLC were enrolled after failing platinum-based chemotherapy. Following informed consent, genome-wide exome and RNA-sequencing was performed in a CLIA-certified, CAP-accredited environment. Actionable targets were identified and therapeutic recommendations made from a pharmacopeia of FDA-approved drugs. Clinical response to genomically-guided treatment was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

          Results

          The study completed its accrual goal of 12 evaluable patients. The minimum tumor content for successful NGS was 20%, with a median turnaround time from sample collection to genomics-based treatment recommendation of 27 days. At least two clinically actionable targets were identified in each patient, and six patients (50%) received treatment identified by NGS. Two had partial responses by RECIST 1.1 on a clinical trial involving a PD-1 inhibitor + irinotecan (indicated by MLH1 alteration). The remaining patients had clinical deterioration before NGS recommended therapy could be initiated.

          Conclusions

          Comprehensive genomic profiling using NGS identified clinically-actionable alterations in SCLC patients who progressed on initial therapy. Recommended PD-1 therapy generated partial responses in two patients. Earlier access to NGS guided therapy, along with improved understanding of those SCLC patients likely to respond to immune-based therapies, should help to extend survival in these cases with poor outcomes.

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          Most cited references15

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          Pilot study using molecular profiling of patients' tumors to find potential targets and select treatments for their refractory cancers.

          To compare the progression-free survival (PFS) using a treatment regimen selected by molecular profiling (MP) of a patient's tumor with the PFS for the most recent regimen on which the patient had experienced progression (ie, patient as his own control). Patients with refractory metastatic cancer had tissue samples submitted for MP in two formats including formalin-fixed tissue for immunohistochemistry and fluorescent in situ hybridization assays and immediately frozen tissue for oligonucleotide microarray (MA) gene expression assays (all performed in a Clinical Laboratory Improvement Amendments [CLIA]-certified laboratory). The MP approach was deemed of clinical benefit for the individual patient who had a PFS ratio (PFS on MP-selected therapy/PFS on prior therapy) of ≥ 1.3. In 86 patients who had MP attempted, there was a molecular target detected in 84 (98%). Sixty-six of the 84 patients were treated according to MP results. Eighteen (27%) of 66 patients had a PFS ratio of ≥ 1.3 (95% CI, 17% to 38%; one-sided, one-sample P = .007). Therefore, the null hypothesis (that ≤ 15% of this patient population would have a PFS ratio of ≥ 1.3) was rejected. It is possible to identify molecular targets in patients' tumors from nine different centers across the United States. In 27% of patients, the MP approach resulted in a longer PFS on an MP-suggested regimen than on the regimen on which the patient had just experienced progression. Issues to be considered in interpretation of this study include limited prior experience with patients as their own controls as a study end point and overall patient attrition.
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            Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.

            Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV) were evaluated in a randomized, multicenter study of patients with small-cell lung cancer (SCLC) who had relapsed at least 60 days after completion of first-line therapy. Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 107) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) infused on day 1 every 21 days (n = 104). Eligibility included the following: bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of less than or equal to 2, and adequate marrow, liver, and renal function. Response was confirmed by blinded independent radiologic review. Response rate was 26 of 107 patients (24.3%) treated with topotecan and 19 of 104 patients (18.3%) treated with CAV (P = .285). Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .552). Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for four of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P< or =.043). Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P<.001). Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P<.001 for both). Nonhematologic toxicities were generally grade 1 to 2 for both regimens. Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms.
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              Randomized phase III trial of amrubicin versus topotecan as second-line treatment for patients with small-cell lung cancer.

              Amrubicin, a third-generation anthracycline and potent topoisomerase II inhibitor, showed promising activity in small-cell lung cancer (SCLC) in phase II trials. This phase III trial compared the safety and efficacy of amrubicin versus topotecan as second-line treatment for SCLC.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                6 June 2017
                2017
                : 12
                : 6
                : e0179170
                Affiliations
                [1 ]Western Regional Medical Center, Cancer Treatment Centers of America, Goodyear, Arizona, United States of America
                [2 ]Translational Genomics Research Institute, Phoenix, Arizona, United States of America
                Universita Campus Bio-Medico di Roma, ITALY
                Author notes

                Competing Interests: TGW holds patents (US Patent No.9,404,927 B2) and provisional patents (US Provisional Patent Application no. PCT/US2015/062785)-unrelated to this work and SAB holds patents (US Patent No. 9,140,689) or provisional patents (US Provisional Patent Application no. PCT/US2016/037292)-unrelated to this work. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                • Conceptualization: GJW JDC DWC.

                • Data curation: GJW SAB JA AS HB TGW.

                • Formal analysis: GJW SAB JK JA JDC DWC TGW.

                • Funding acquisition: GJW JDC DWC.

                • Investigation: GJW SAB JA AS HB JK JDC DWC TGW.

                • Methodology: GJW SAB JA JK JDC DWC TGW.

                • Project administration: GJW DWC TGW.

                • Resources: GJW SAB JA AS HB JK JDC DWC TGW.

                • Supervision: GJW DWC TGW.

                • Validation: GJW SAB JA JK JDC DWC TGW.

                • Visualization: GJW SAB JA JDC DWC TGW.

                • Writing – original draft: GJW SAB JA JK JDC DWC TGW.

                • Writing – review & editing: GJW SAB JA AS HB JK JDC DWC TGW.

                [¤a]

                Current address: Systems Oncology, Scottsdale, Arizona, United States of America

                [¤b]

                Current address: Department of Translational Genomics, Keck School of Medicine, University of Southern California, Los Angeles, California, United Stated of America

                [¤c]

                Current address: Norton Thoracic Institute, St. Joseph’s Hospital and Medical Center, Dignity Health, Phoenix, Arizona, United States of America

                ‡ DWC and TGW are Joint Senior Authors.

                Author information
                http://orcid.org/0000-0002-6067-597X
                Article
                PONE-D-17-08076
                10.1371/journal.pone.0179170
                5460863
                28586388
                7f761ec3-7df6-4d63-9b2b-db01636b5180
                © 2017 Weiss et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 1 March 2017
                : 19 May 2017
                Page count
                Figures: 4, Tables: 4, Pages: 13
                Funding
                Funded by: Stand Up 2 Cancer
                This work was supported by Stand Up to Cancer (SU2C). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. One or more of the authors received consulting fees from a commercial company: Blend Therapeutics, Pharmatech, Viomics, and Paradigm; speakers' bureau: Medscape, Merck, Novartis; Travel: NantWorks, Arbutus Biopharma and GE Global Research, Dell Inc., and Strategia Therapeutics, Inc. These funders provided support in the form of salaries for authors [GJW, TGW, SAB], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.
                Categories
                Research Article
                Medicine and Health Sciences
                Oncology
                Cancers and Neoplasms
                Lung and Intrathoracic Tumors
                Small Cell Lung Cancer
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Biology and life sciences
                Molecular biology
                Molecular biology techniques
                Sequencing techniques
                DNA sequencing
                Next-Generation Sequencing
                Research and analysis methods
                Molecular biology techniques
                Sequencing techniques
                DNA sequencing
                Next-Generation Sequencing
                Biology and Life Sciences
                Computational Biology
                Genome Analysis
                Transcriptome Analysis
                Next-Generation Sequencing
                Biology and Life Sciences
                Genetics
                Genomics
                Genome Analysis
                Transcriptome Analysis
                Next-Generation Sequencing
                Biology and life sciences
                Molecular biology
                Molecular biology techniques
                Sequencing techniques
                RNA sequencing
                Research and analysis methods
                Molecular biology techniques
                Sequencing techniques
                RNA sequencing
                Biology and Life Sciences
                Immunology
                Immune Response
                Medicine and Health Sciences
                Immunology
                Immune Response
                Research and Analysis Methods
                Research Design
                Pilot Studies
                Medicine and Health Sciences
                Surgical and Invasive Medical Procedures
                Biopsy
                Research and Analysis Methods
                Database and Informatics Methods
                Bioinformatics
                Sequence Analysis
                Sequence Alignment
                Custom metadata
                All NGS files are available from dbGaP under accession, phs001366.v1.p1 ( https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001366.v1.p1).

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