Dataset Information

Complete and Durable Response to Combined Chemo/Radiation Therapy in EGFR Wild-Type Lung Adenocarcinoma with Diffuse Brain Metastases.

ABSTRACT: Most non-small-cell lung cancer (NSCLC) patients are likely to develop brain metastases during the course of their illness. Currently, no consensus on NSCLC patients' treatment with brain metastasis has been established. Although whole brain radiotherapy prolongs the median survival time of approximately 4 months, a cisplatin-pemetrexed combination may also represent a potential option in the treatment of asymptomatic NSCLC patients with brain metastases. Herein, we report the case of a non-smoker male patient with multiple, large and diffuse brain metastases from an "epidermal growth factor receptor (EGFR) wild-type" lung adenocarcinoma who underwent an overly aggressive chemo/radiation therapy. This approach led to a complete and durable remission of the disease and to a long survival of up to 58 months from diagnosis of primary tumor. The uncommon course of this metastatic disease induced us to describe its oncological management and to investigate the molecular features of the tumor.

SUBMITTER: Santeufemia DA

PROVIDER: S-EPMC6627459 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Complete and Durable Response to Combined Chemo/Radiation Therapy in <i>EGFR</i> Wild-Type Lung Adenocarcinoma with Diffuse Brain Metastases.

Santeufemia Davide Adriano DA Palmieri Giuseppe G Cossu Antonio A De Re Valli V Caggiari Laura L De Zorzi Mariangela M Casula Milena M Sini Maria Cristina MC Baldino Giovanni G Dedola Maria Filomena MF Corona Giuseppe G Miolo Gianmaria G

Diagnostics (Basel, Switzerland) 20190411 2

Most non-small-cell lung cancer (NSCLC) patients are likely to develop brain metastases during the course of their illness. Currently, no consensus on NSCLC patients' treatment with brain metastasis has been established. Although whole brain radiotherapy prolongs the median survival time of approximately 4 months, a cisplatin-pemetrexed combination may also represent a potential option in the treatment of asymptomatic NSCLC patients with brain metastases. Herein, we report the case of a non-smok ...[more]

PMID: 30979070

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Project description:Background: Brain radiotherapy is the standard treatment option for multiple brain metastases (BMs) from non-small cell lung cancer (NSCLC), especially in the absence of a driver mutation. However, the prognosis for such patients remains poor. Apatinib is a potent antiangiogenic compound directed at the vascular endothelial growth factor receptor-2 (VEGFR-2); however, to date, there are no investigations of apatinib concurrent with brain radiotherapy for NSCLC patients with BMs. We report a case of EGFR wild-type and ALK-negative lung adenocarcinoma patient with multiple symptomatic BMs, who received apatinib together with brain radiation therapy. A favorable oncologic outcome was achieved for both brain metastatic lesions and the primary pulmonary tumor. Case Presentation: A 61-year-old female (never smoker) who initially presented with headache and dizziness was diagnosed with lung adenocarcinoma with multiple brain metastasis (cT2aN3M1b stage IV), and was negative for EGFR and ALK. The patient refused to receive chemotherapy and was only amenable to brain radiotherapy and targeted therapy. After approval from the institutional ethics committee, she underwent concurrent oral apatinib (500 mg/day) with whole brain radiation therapy (WBRT) (37.5Gy) with simultaneous in-field boost (49.5Gy) in 15 fractions with image guided intensity-modulated radiotherapy. Three weeks later, neurologic symptoms entirely ceased and a partial response (PR) for the BMs with near-complete resolution of peritumoral brain edema was achieved. Chest CT performed at the same time and showed shrinkage of the lung primary with a PR. The patient suffered grade III oral mucositis one week after brain radiotherapy and refused further apatinib. At 12 months after brain radiotherapy, the brain tumors remained well controlled. Conclusions: This is the first known documentation of a rapid clinical response of apatinib concurrent with brain radiotherapy in a lung adenocarcinoma patient with symptomatic multiple BMs. Apatinib combined with brain radiotherapy could be an alternative treatment option for BMs from NSCLC, especially for those without a driver mutation. Further clinical trials are required to corroborate this discovery.

Project description:BackgroundLung cancer is still the main cause of cancer death worldwide despite the availability of targeted therapies and immune-checkpoint inhibitors combined with chemotherapy. Cancer cell heterogeneity and primary or acquired resistance mechanisms cause the elusive behaviour of this cancer and new biomarkers and active drugs are urgently needed to overcome these limitations. p65BTK, a novel isoform of the Bruton Tyrosine Kinase may represent a new actionable target in non-small cell lung cancer (NSCLC).Methodsp65BTK expression was evaluated by immunohistochemistry in 382 NSCLC patients with complete clinico-pathological records including smoking habit, ALK and EGFR status, and in metastatic lymph nodes of 30 NSCLC patients. NSCLC cell lines mutated for p53 and/or a component of the RAS/MAPK pathway and primary lung cancer-derived cells from Kras/Trp53 null mice were used as a preclinical model. The effects of p65BTK inhibition by BTK Tyrosine Kinase Inhibitors (TKIs) (Ibrutinib, AVL-292, RN486) and first-generation EGFR-TKIs (Gefitinib, Erlotinib) on cell viability were evaluated by MTT. The effects of BTK-TKIs on cell growth and clonogenicity were assessed by crystal violet and colony assays, respectively. Cell toxicity assays were performed to study the effect of the combination of non-toxic concentrations of BTK-TKIs with EGFR-TKIs and standard-of-care (SOC) chemotherapy (Cisplatin, Gemcitabine, Pemetrexed).Resultsp65BTK was significantly over-expressed in EGFR-wild type (wt) adenocarcinomas (AdC) from non-smoker patients and its expression was also preserved at the metastatic site. p65BTK was also over-expressed in cell lines mutated for KRAS or for a component of the RAS/MAPK pathway and in tumors from Kras/Trp53 null mice. BTK-TKIs were more effective than EGFR-TKIs in decreasing cancer cell viability and significantly impaired cell proliferation and clonogenicity. Moreover, non-toxic doses of BTK-TKIs re-sensitized drug-resistant NSCLC cell lines to both target- and SOC therapy, independently from EGFR/KRAS status.Conclusionsp65BTK results as an emerging actionable target in non-smoking EGFR-wt AdC, also at advanced stages of disease. Notably, these patients are not eligible for EGFR-TKIs-based therapy due to a lack of EGFR mutation. The combination of BTK-TKIs with EGFR-TKIs is cytotoxic for EGFR-wt/KRAS-mutant/p53-null tumors and BTK-TKIs re-sensitizes drug-resistant NSCLC to SOC chemotherapy. Therefore, our data suggest that adding BTK-TKIs to SOC chemotherapy and EGFR-targeted therapy may open new avenues for clinical trials in currently untreatable NSCLC.

Dataset Information

Complete and Durable Response to Combined Chemo/Radiation Therapy in EGFR Wild-Type Lung Adenocarcinoma with Diffuse Brain Metastases.

Publications

Complete and Durable Response to Combined Chemo/Radiation Therapy in <i>EGFR</i> Wild-Type Lung Adenocarcinoma with Diffuse Brain Metastases.

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