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Quantitative high-throughput efficacy profiling of approved oncology drugs in inflammatory breast cancer models of acquired drug resistance and re-sensitization.

ABSTRACT: Although there is no standard treatment protocol for inflammatory breast cancer (IBC), multi-modality treatment has improved survival. In this study we profiled the NCI approved oncology drug set in a qHTS format to identify those that are efficacious in basal type and ErbB2 overexpressing IBC models. Further, we characterized the sensitivity of an acquired therapeutic resistance model to the oncology drugs. We observed that lapatinib-induced acquired resistance in SUM149 cells led to cross-resistance to other targeted- and chemotherapeutic drugs. Removal of the primary drug to which the model was developed led to re-sensitization to multiple drugs to a degree comparable to the parental cell line; this coincided with the cells regaining the ability to accumulate ROS and reduced expression of anti-apoptotic factors and the antioxidant SOD2. We suggest that our findings provide a unique IBC model system for gaining an understanding of acquired therapeutic resistance and the effect of redox adaptation on anti-cancer drug efficacy.

SUBMITTER: Williams KP

PROVIDER: S-EPMC3763836 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Quantitative high-throughput efficacy profiling of approved oncology drugs in inflammatory breast cancer models of acquired drug resistance and re-sensitization.

Williams Kevin P KP Allensworth Jennifer L JL Ingram Shalonda M SM Smith Ginger R GR Aldrich Amy J AJ Sexton Jonathan Z JZ Devi Gayathri R GR

Cancer letters 20130517 1

Although there is no standard treatment protocol for inflammatory breast cancer (IBC), multi-modality treatment has improved survival. In this study we profiled the NCI approved oncology drug set in a qHTS format to identify those that are efficacious in basal type and ErbB2 overexpressing IBC models. Further, we characterized the sensitivity of an acquired therapeutic resistance model to the oncology drugs. We observed that lapatinib-induced acquired resistance in SUM149 cells led to cross-resi ...[more]

PMID: 23689139

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Project description:ImportanceA lack of generalizability of pivotal cancer clinical trial data to treatment of older adults with Medicare could affect therapeutic decision-making in clinical practice.ObjectiveTo evaluate the differences in survival, duration of therapy, and treatment patterns between clinical trial patients and older adults with Medicare receiving cancer drugs for metastatic solid cancers in usual practice.Design, setting, and participantsThis retrospective cohort study, performed from May 1, 2018, to August 30, 2020, used the linked Surveillance, Epidemiology, and End Results (SEER) program and Medicare database to examine sequential US Food and Drug Administration (FDA)-approved cancer drug indications (2008-2013) for locally advanced or metastatic solid tumors to assess whether pivotal trials reflect the outcomes of Medicare patients with cancer treated in usual practice.ExposuresTreatment with FDA-approved cancer drugs for metastatic solid cancers in pivotal clinical trials and in the SEER-Medicare database.Main outcomes and measuresOverall survival, duration of treatment, and dose reductions among trial participants and treated Medicare patients.ResultsA total of 11 828 trial participants (mean age, 61.8 years; 6718 [56.8%] male; and 7605 [64.3%] White) and 9178 SEER-Medicare patients (mean age, 72.7 years; 4800 [52.3%] male; and 7437 [81.0% White]) were compared. Twenty-nine indications for 22 cancer drugs were included. Median overall survival among Medicare patients was shorter than among patients in the clinical trial intervention arm for 28 of 29 indications (median difference, -6.3 months; range, -28.7 to 2.7 months). Median duration of therapy among Medicare patients was shorter for 23 of the 27 indications with data available (median difference, -1.9 months; range, -12.4 to 1.4 months). For 9 indications, there was information available regarding dose reductions in the package insert or trial publication. In all but 1 instance, dose reductions or single prescriptions were more common in the Medicare population compared with dose reductions among the clinical trial patients; for example, in the Medicare patients, 600 of 1032 (58.1%) received dose reduction or a single prescription and 172 of 1032 (16.7%) received a single prescription vs 734 of 3416 (21.5%) in the trial intervention arm. The exception was afatinib for non-small cell lung cancer: 34 of 71 (47.9%) received dose reduction or a single prescription and 15 of 71 (21.1%) received a single prescription among the Medicare patients vs 120 of 230 (52.2%) receiving dose reductions among the trial intervention group.Conclusions and relevanceIn this cohort study, patients receiving Medicare who were treated with FDA-approved cancer drugs did not live as long as treated clinical trial participants and commonly received treatment modifications. This study suggests that cancer clinical data relevant to newly approved drugs lack generalizability to Medicare beneficiaries with cancer; therefore, these agents should be used with caution.

Dataset Information

Quantitative high-throughput efficacy profiling of approved oncology drugs in inflammatory breast cancer models of acquired drug resistance and re-sensitization.

Publications

Quantitative high-throughput efficacy profiling of approved oncology drugs in inflammatory breast cancer models of acquired drug resistance and re-sensitization.

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