ABSTRACT
BACKGROUND: Bladder cancer (BC) is the 10th most common cancer in the world. BC with muscle invasion results in a poor prognosis and is usually fatal. Cancer cell metabolism has an essential role in the development and progression of tumors. Expression of tryptophan 2,3-dioxygenase (TDO2) is associated with tumor progression and worse survival in some other cancers. However, no studies have been performed to uncover the biofunctional roles of TDO2 in BC. AIM: This study aim to investigate the clinicopathologic significance of TDO2 in BC. METHODS AND RESULTS: TDO2 expression was evaluated by qRT-PCR and immunohistochemistry in an integrated analysis with the Cancer Genome Atlas (TCGA) and other published datasets. TDO2 overexpression was significantly associated with T classification, N classification, and M classification, tumor stage, recurrence, and basal type, and with the expression of CD44 and aldehyde dehydrogenase 1 (ALDH1) in BC. High TDO2 expression correlated with poor outcome of BC patients. Using BC cell lines with knockdown and forced expression of TDO2, we found that TDO2 was involved in the growth, migration, and invasiveness of BC cells. Moreover, TDO2 was found to be crucial for spheroid formation in BC cells. Importantly, TDO2 promoted BC cells resistance to cetuximab through integration of the EGFR pathway. CONCLUSION: Our results indicate that TDO2 might take an essential part in BC progression and could be a potential marker for targeted therapy in BC.
Subject(s)
Cetuximab/pharmacology , Drug Resistance, Neoplasm , Neoplasm Recurrence, Local/pathology , Neoplastic Stem Cells/pathology , Tryptophan Oxygenase/metabolism , Urinary Bladder Neoplasms/pathology , Antineoplastic Agents, Immunological/pharmacology , Biomarkers, Tumor , Case-Control Studies , Follow-Up Studies , Humans , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/enzymology , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/enzymology , Prognosis , Survival Rate , Tryptophan Oxygenase/genetics , Tumor Cells, Cultured , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/enzymologyABSTRACT
RATIONALE: Anaplastic lymphoma kinase (ALK) + anaplastic large cell lymphoma (ALCL) is considered as a good prognosis lymphoma. However, in an extremely rare subset of patients, ALK+ ALCL with leukemic presentations is known to be chemotherapy-resistant. Although several novel therapies have been tested, the standard therapy for relapsed/refractory ALK+ ALCL has not been established yet. PATIENT CONCERNS: An 18-year-old female patient who had conventional chemotherapy- and Brentuximab Vedotin (BV)-resistant ALK+ ALCL with leukemic presentation. She was successfully treated with an ALK inhibitor, crizotinib. Crizotinib induced complete remission (CR) and bridged to allogeneic bone marrow transplantation (BMT). DIAGNOSIS: However, her ALCL relapsed on day 60 after BMT and she developed high grade fever and lymphadenopathy. INTERVENTION: Although crizotinib was given to the patient immediately after relapse, she developed grade 3 nausea and could not continue to take it. Then, we gave alectinib to the patient, which promptly induced sustained CR without any further chemotherapy. The patient received second stem cell transplantation using umbilical cord blood with myeloablative regimen in 2nd CR. OUTCOMES: The patient has been in CR under maintenance therapy of alectinib for more than 16âmonths. LESSONS: Both ALK inhibitors demonstrated drastic efficacy for our patient who had chemotherapy- and BV-resistant ALK+ ALCL with leukemic presentation. Alectinib showed less gastro-intestinal toxicity than crizotinib and the patient was able to take it even at the relatively early phase of stem cell transplantation.
Subject(s)
Anaplastic Lymphoma Kinase/metabolism , Cord Blood Stem Cell Transplantation/methods , Lymphoma, Large-Cell, Anaplastic/therapy , Neoplasm Recurrence, Local/therapy , Protein Kinase Inhibitors/therapeutic use , Adolescent , Carbazoles/therapeutic use , Crizotinib/therapeutic use , Female , Humans , Lymphoma, Large-Cell, Anaplastic/enzymology , Medical Illustration , Neoplasm Recurrence, Local/enzymology , Piperidines/therapeutic use , Transplantation, HomologousABSTRACT
The tumor microenvironment plays an essential role in supporting glioma stemness and radioresistance. Following radiotherapy, recurrent gliomas form in an irradiated microenvironment. Here we report that astrocytes, when pre-irradiated, increase stemness and survival of cocultured glioma cells. Tumor-naïve brains increased reactive astrocytes in response to radiation, and mice subjected to radiation prior to implantation of glioma cells developed more aggressive tumors. Extracellular matrix derived from irradiated astrocytes were found to be a major driver of this phenotype and astrocyte-derived transglutaminase 2 (TGM2) was identified as a promoter of glioma stemness and radioresistance. TGM2 levels increased after radiation in vivo and in recurrent human glioma, and TGM2 inhibitors abrogated glioma stemness and survival. These data suggest that irradiation of the brain results in the formation of a tumor-supportive microenvironment. Therapeutic targeting of radiation-induced, astrocyte-derived extracellular matrix proteins may enhance the efficacy of standard-of-care radiotherapy by reducing stemness in glioma. SIGNIFICANCE: These findings presented here indicate that radiotherapy can result in a tumor-supportive microenvironment, the targeting of which may be necessary to overcome tumor cell therapeutic resistance and recurrence. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/8/2101/F1.large.jpg.
Subject(s)
Astrocytes/enzymology , Brain Neoplasms/radiotherapy , Brain/radiation effects , GTP-Binding Proteins/metabolism , Glioblastoma/radiotherapy , Neoplastic Stem Cells , Transglutaminases/metabolism , Tumor Microenvironment/radiation effects , Animals , Astrocytes/radiation effects , Brain/cytology , Brain/physiology , Brain Neoplasms/pathology , Cell Survival/physiology , Enzyme Inhibitors/pharmacology , Extracellular Matrix/metabolism , Extracellular Matrix/radiation effects , Female , GTP-Binding Proteins/antagonists & inhibitors , Glioblastoma/pathology , Glioma/pathology , Glioma/radiotherapy , Humans , Male , Mice , Neoplasm Recurrence, Local/enzymology , Neoplasm Recurrence, Local/pathology , Neoplastic Stem Cells/physiology , Protein Glutamine gamma Glutamyltransferase 2 , Radiation Tolerance , Transglutaminases/antagonists & inhibitors , Tumor Microenvironment/physiologyABSTRACT
BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are a type of soft tissue sarcomas (STS) with recurrence and metastatic potential. We aimed to investigate the risk factors for developing distant metastases (DM) and to identify the prognostic factors in patients with DM. METHODS: Based on the Surveillance, Epidemiology, and End Result (SEER) database, MPNST patients diagnosed between 2010 and 2016 were extracted in our study. The logistic regression model was performed for predicting DM development while the Cox proportional hazard regression model was conducted for revealing the prognostic factors. RESULTS: Eventually, 764 patients diagnosed with MPNSTs were included with 109 cases presenting with metastases at initial diagnosis. Larger tumor size and lymph node metastases were independent risk factors for developing DM. The median overall survival (OS) for patients with metastases was 8.0 (95% CI: 6.1-9.9) months. Multiple metastatic sites and no surgical treatment were prognostic factors for worse survival. Tumors located in non-head and neck region were related with better survival. CONCLUSIONS: The incidence of DM was 14.3% with a dismal median OS of 8.0 months for metastatic MPNSTs. More evaluation should be applied for patients with large tumor size and lymph metastases. Tumors located in head and neck region and the presence of multiple metastases predicted worse survival outcome. Surgical treatment can significantly improve the survival of MPNST patients with distant metastasis.
Subject(s)
Head and Neck Neoplasms/epidemiology , Head and Neck Neoplasms/pathology , Neurofibrosarcoma/epidemiology , Neurofibrosarcoma/secondary , Soft Tissue Neoplasms/epidemiology , Soft Tissue Neoplasms/pathology , Adult , Female , Head and Neck Neoplasms/mortality , Humans , Incidence , Logistic Models , Male , Middle Aged , Neoplasm Recurrence, Local/enzymology , Neurofibrosarcoma/mortality , Prognosis , Risk Factors , SEER Program , Soft Tissue Neoplasms/mortality , United States/epidemiology , Young AdultABSTRACT
Malignant peripheral nerve sheath tumors often arise in patients with neurofibromatosis type 1 and are among the most treatment-refractory types of sarcoma. Overall survival in patients with relapsed disease remains poor, and thus novel therapeutic approaches are needed. NF1 is essential for negative regulation of RAS activity and is altered in about 90% of malignant peripheral nerve sheath tumors (MPNST). A complex interplay of upstream signaling and parallel RAS-driven pathways characterizes NF1-driven tumorigenesis, and inhibiting more than one RAS effector pathway is therefore necessary. To devise potential combination therapeutic strategies, we identified actionable alterations in signaling that underlie adaptive and acquired resistance to MEK inhibitor (MEKi). Using a series of proteomic, biochemical, and genetic approaches in an in vitro model of MEKi resistance provided a rationale for combination therapies. HGF/MET signaling was elevated in the MEKi-resistant model. HGF overexpression conferred resistance to MEKi in parental cells. Depletion of HGF or MET restored sensitivity of MEKi-resistant cells to MEKi. Finally, a combination of MEK and MET inhibition demonstrated activity in models of MPNST and may therefore be effective in patients with MPNST harboring genetic alterations in NF1. SIGNIFICANCE: This study demonstrates that MEKi plus MET inhibitor may delay or prevent a novel mechanism of acquired MEKi resistance, with clinical implications for MPNST patients harboring NF1 alterations.
Subject(s)
Drug Resistance, Neoplasm , Neoplasm Recurrence, Local/enzymology , Nerve Sheath Neoplasms/enzymology , Receptor Protein-Tyrosine Kinases/metabolism , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Enzyme Activation , Female , Hepatocyte Growth Factor/metabolism , Humans , MAP Kinase Signaling System , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/mortality , Nerve Sheath Neoplasms/drug therapy , Nerve Sheath Neoplasms/genetics , Nerve Sheath Neoplasms/mortality , Neurofibromatosis 1/complications , Neurofibromatosis 1/metabolism , Neurofibromin 1/deficiency , Neurofibromin 1/genetics , Protein Kinase Inhibitors/therapeutic use , Protein Tyrosine Phosphatase, Non-Receptor Type 11/antagonists & inhibitors , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , Proteomics , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Proto-Oncogene Proteins c-met/metabolism , Proto-Oncogene Proteins c-raf/metabolism , Pyridones/pharmacology , Pyrimidinones/pharmacology , Random Allocation , Receptor, Platelet-Derived Growth Factor beta/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Up-Regulation , ras Proteins/antagonists & inhibitors , ras Proteins/metabolismABSTRACT
The landscape of uterine sarcomas has greatly expanded in recent years to include neoplasms with recurrent gene fusions, such as BCOR and YWHAE translocated high-grade endometrial stromal sarcomas. Sophisticated molecular techniques have also resulted in the description of "new" entities associated with recurrent kinase fusions involving NTRK and RET as well as COL1A1-PDGFB rearranged uterine sarcomas. These rare neoplasms will be discussed in this review, highlighting that some of the underlying molecular events are clinically actionable and potentially susceptible to targeted therapy. While relatively few of these neoplasms have been described to date, likely being previously lumped under the spectrum of undifferentiated uterine sarcoma, the number of cases will expand in the future given their recognition and the increasing availability of molecular testing. These neoplasms have overlapping morphology (often with a "fibrosarcoma-like" appearance) and immunohistochemical features, and are characterized by variable clinical outcomes. Although immunohistochemistry may assist in some cases, a definitive subclassification requires confirmatory molecular studies. As these molecular assays may not be routinely available in most laboratories, referral to reference centers may be needed. In order to assist the pathologist, we suggest a diagnostic algorithm for routine practice when dealing with a malignant or potentially malignant uterine spindle cell neoplasm.
Subject(s)
Receptor, trkA/metabolism , Sarcoma/metabolism , Uterine Neoplasms/metabolism , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Collagen Type I, alpha 1 Chain/genetics , Female , Gene Fusion/genetics , Gene Rearrangement , Genes, sis , Humans , Immunohistochemistry , Neoplasm Recurrence, Local/enzymology , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/metabolism , Proto-Oncogene Proteins c-ret/genetics , Proto-Oncogene Proteins c-ret/metabolism , Receptor, trkA/genetics , Sarcoma/enzymology , Sarcoma/genetics , Sarcoma, Endometrial Stromal/enzymology , Sarcoma, Endometrial Stromal/genetics , Sarcoma, Endometrial Stromal/metabolism , Soft Tissue Neoplasms/geneticsABSTRACT
Endometrial cancer is one of the three major malignant tumors of the female reproductive system. Although cyclindependent kinase 9 (CDK9) has a definitive pathogenic role in various types of cancer, little is known concerning its function in endometrial cancer. Our study was conducted to evaluate the expression and therapeutic potential of CDK9 in endometrial cancer. CDK9 expression was determined by immunohistochemistry in endometrial cancer tissues constructed with paired primary, metastatic, and recurrent tumor tissues from 32 endometrial cancer patients. Small interfering RNA (siRNA) and inhibitors of CDK9 were used to evaluate the effect of CDK9 inhibition on the antiapoptotic activity and proliferation in endometrial cancer cells. Colony formation assay and woundhealing assays were adopted to assess clonal formation and migratory capacity. The results of the immunohistochemistry demonstrated that CDK9 was highly expressed in the human endometrial cancer cell lines; moreover, it was elevated in metastatic and recurrent endometrial tumor tissue compared when compared with that in patientmatched primary endometrial tumor tissue. Knockdown of CDK9 with siRNA and inhibition of CDK9 activity with the inhibitor suppressed cell proliferation and promoted apoptosis in endometrial cancer. In conclusion, our results provide evidence that CDK9 may be a potential prognostic biomarker and a promising therapeutic target for the treatment of endometrial cancer in the future.
Subject(s)
Cyclin-Dependent Kinase 9/antagonists & inhibitors , Endometrial Neoplasms/enzymology , Endometrial Neoplasms/therapy , Neoplasm Recurrence, Local/enzymology , Neoplasm Recurrence, Local/therapy , Aged , Biomarkers, Tumor/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinase 9/genetics , Cyclin-Dependent Kinase 9/metabolism , Endometrial Neoplasms/genetics , Endometrial Neoplasms/pathology , Female , Humans , Immunohistochemistry , Middle Aged , Molecular Targeted Therapy , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , RNA, Small Interfering/genetics , Signal Transduction , Survival RateABSTRACT
Glioblastoma (GBM) is the most common primary brain tumor and is highly aggressive with a median survival of 15 months. We have previously shown that residual cells of GBM form multinucleated giant cells (MNGCs) showing a senescent phenotype, but eventually escape from therapy induced senescence (TIS), resulting in GBM recurrence. Here we demonstrate the role of PARP-1 in TIS and its recovery. We show that genetic and pharmacological inhibition of PARP-1 has an anti-proliferative effect on GBM cell lines and primary cultures derived from patient samples. Furthermore, the PARP-1 inhibitor olaparib, in combination with radiation increased MNGCs formation and senescence as assessed by ß-galactosidase activity, and macroH2A1 levels in residual cells. Additionally, we found that reduced PARP-1 activity and not protein levels in residual cells was crucial for MNGCs formation and their maintenance in the senescent state. PARP-1 activity was restored to higher levels in recurrent cells that escaped from TIS. Importantly, olaparib + radiation treatment significantly delayed recurrence in vitro as well in vivo in orthotopic GBM mouse models with a significant increase in overall survival of mice. Overall, this study demonstrates that sustained inhibition of PARP-1 activity during radiation treatment significantly delays GBM recurrence.
Subject(s)
Brain Neoplasms/pathology , Glioblastoma/pathology , Neoplasm Recurrence, Local/enzymology , Poly (ADP-Ribose) Polymerase-1/metabolism , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Animals , Brain Neoplasms/enzymology , Cellular Senescence/drug effects , Cellular Senescence/radiation effects , Glioblastoma/enzymology , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Neoplasm Recurrence, Local/pathology , Phthalazines/pharmacology , Piperazines/pharmacology , Poly (ADP-Ribose) Polymerase-1/drug effects , Poly (ADP-Ribose) Polymerase-1/radiation effects , Radiation Tolerance/drug effects , Radiotherapy , Xenograft Model Antitumor AssaysABSTRACT
Lung cancer has been recognized as the leading cause of cancer-related death worldwide. Despite the improvements of treatment, the distant metastasis and recurrence of lung cancer caused by therapy resistance is the biggest challenge in clinical management. Extracellular vesicles named exosomes play crucial roles in intercellular communication as signaling mediators and are involved in tumor development. In this study, we isolated exosomes from irradiated lung cancer cells and co-cultured the exosomes with other lung cancer cells. It was found that cellular growth and motility of recipient cells were facilitated. High-throughput LC-MS/MS assay of exosomal proteins and Gene Ontology enrichment analyses indicated that the metabolic enzymes ALDOA and ALDH3A1 had potential contribution in exosome-enhanced motility of recipient cells, and clinical survival analysis demonstrated the close correlations between ALDOA or ALDH3A1 expression and poor prognosis of lung cancer patients. After co-culturing with exosomes derived from irradiated cancer cells, the expressions of these metabolic enzymes were elevated and the glycolytic activity was promoted in recipient cancer cells. In conclusion, our data suggested that exosomes from irradiated lung cancer cells regulated the motility of recipient cells by accelerating glycolytic process, where exosomal ALDOA and ALDH3A1 proteins were important signaling factors.
Subject(s)
Aldehyde Dehydrogenase/metabolism , Cell Movement/genetics , Cell Proliferation/genetics , Exosomes/metabolism , Fructose-Bisphosphate Aldolase/metabolism , Glycolysis , Lung Neoplasms/metabolism , Neoplasm Recurrence, Local/metabolism , Aldehyde Dehydrogenase/genetics , Cell Communication/genetics , Cell Line, Tumor , Cell Movement/radiation effects , Cell Proliferation/radiation effects , Chromatography, Liquid , Coculture Techniques , Exosomes/enzymology , Exosomes/radiation effects , Exosomes/ultrastructure , Fructose-Bisphosphate Aldolase/genetics , Gene Expression Regulation, Neoplastic , Gene Ontology , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Microscopy, Electron, Transmission , Neoplasm Recurrence, Local/enzymology , Neoplasm Recurrence, Local/genetics , Prognosis , Proteomics , Radiation , Tandem Mass SpectrometryABSTRACT
BACKGROUND: The aim of the current study was to estimate two protocols for HER2-negative locally recurrent or metastatic breast cancer patients, bevacizumab combined with paclitaxel versus bevacizumab combined with capecitabine, from the economic view. METHODS: The process of HER2-negative locally recurrent or metastatic breast cancer treated with bevacizumab combined with paclitaxel or bevaciz-umab combined with capecitabine made up the decision model in our analysis. The primary objective was to show the incremental cost-effectiveness ratio (ICER). The critical parameters and the robustness of the model on the results of the analysis were assessed by univariate sensitivity analysis and probabilistic sensitivity analysis. RESULTS: In the analysis, quality-adjusted life year (QALY) increased by 0.4 with bevacizumab plus paclitaxel compared with bevacizumab plus capecitabine, and incremental cost of USD 4,340.46. Therefore, the ICER was USD 27,252.875. The ICER exceeded the commonly accepted willingness to pay on the recommendation of the World Health Organization, which is defined as 3 times of the gross domestic product per capita of China in the model (USD 25,840.88 per QALY). On univariate analysis, it is found that the most significant affecting factor is the cost of progression-free survival state in the bevacizumab plus paclitaxel group. Besides, bevacizumab plus paclitaxel had a 47.8% probability of being cost-effective versus bevacizu-mab plus capecitabine according to probabilistic sensitivity analysis. CONCLUSIONS: Based on the results of the analysis, bevacizumab plus paclitaxel is unlikely to be a cost-effective option for patients with HER2-negative locally recurrent or metastatic breast cancer compared with bevacizumab plus capecitabine.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/economics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/economics , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/economics , Receptor, ErbB-2/metabolism , Bevacizumab/administration & dosage , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Capecitabine/administration & dosage , Clinical Trials, Phase III as Topic , Cost-Benefit Analysis , Female , Follow-Up Studies , Humans , Markov Chains , Neoplasm Metastasis , Neoplasm Recurrence, Local/enzymology , Neoplasm Recurrence, Local/pathology , Paclitaxel/administration & dosage , Prognosis , Quality of Life , Randomized Controlled Trials as Topic , Survival RateABSTRACT
BACKGROUND: Indoleamine 2,3-dioxygenase (IDO1) is an enzyme that acts as an immunomodulatory molecule. It is found in several types of cancer where it seems to be associated with tumor escape due to its immunosuppressive mechanisms. However, the role of IDO1 expression in prostate cancer (PC) is unclear. The aim of our study was to evaluate the expression of IDO1 in localized PC and to correlate with the classic prognostic factor and recurrence after surgical treatment. METHODS: We retrospectively evaluated surgical specimens from 111 patients with localized PC, who underwent radical prostatectomy. Recurrence was defined as a prostate specific antigen (PSA) level exceeding 0.2 ng/mL postoperatively, and the follow-up was 123 months. IDO1 expression was evaluated by immunohistochemistry in 72 cases of which 42 (58%) had biochemical recurrence. RESULTS: Lower IDO1 expression was associated with higher Gleason score (p = 0.022) and PSA levels (p = 0.042). The multivariate analyses revealed that the loss of IDO1 and higher PSA were independently associated with biochemical recurrence. The chance of recurrence was increased by 85% in patients with lower IDO1 [OR = 0.15; p = 0.009 CI 95% (0.038-0.633)] and increased by 5.5 times in patients with higher PSA [OR = 5.51; p = 0.012 CI 95% (1.435-21.21)]. The recurrence-free survival curve also demonstrates that lower IDO1 was associated with lower time to biochemical recurrence (p = 0.0004). CONCLUSION: The loss of IDO1 expression was associated with increased chance of biochemical recurrence, higher PSA, and a Gleason score in localized PC.
Subject(s)
Indoleamine-Pyrrole 2,3,-Dioxygenase/biosynthesis , Prostatic Neoplasms/enzymology , Adult , Aged , Correlation of Data , Disease-Free Survival , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/enzymology , Prognosis , Prostatectomy , Prostatic Neoplasms/surgery , Retrospective StudiesABSTRACT
PURPOSE: To determine the pharmacodynamic relationship between target occupancy of Bruton tyrosine kinase (BTK) and inhibition of downstream signaling. PATIENTS AND METHODS: Patients with chronic lymphocytic leukemia (CLL) enrolled in a phase II clinical trial (NCT02337829) with the covalent, selective BTK inhibitor acalabrutinib donated blood samples for pharmacodynamic analyses. Study design included randomization to acalabrutinib 100 mg twice daily or 200 mg once daily and dose interruptions on day 4 and 5 of the first week. BTK occupancy and readouts of intracellular signaling were assessed sequentially between 4 and 48 hours from last dose. RESULTS: Four hours from last dose, BTK occupancy exceeded 96% and at trough, was higher with twice daily, median 95.3%, than with once daily dosing, median 87.6% (P < 0.0001). By 48 hours from last dose, median free BTK increased to 25.6%. Due to covalent binding of acalabrutinib, free BTK is generated by de novo synthesis. The estimated rate of BTK synthesis varied widely between patients ranging from 3.6% to 31.4% per day. Acalabrutinib reduced phosphorylation of BTK and inhibited downstream B-cell receptor (BCR) and NFκB signaling. During dosing interruptions up to 48 hours, expression of BCR target genes rebounded, while phosphorylation of signaling molecules remained repressed. In vitro cross-linking of IgM on CLL cells obtained 36 to 48 hours from last dose upregulated CD69, with high correlation between cellular free BTK and response (R = 0.7, P ≤ 0.0001). CONCLUSIONS: Higher BTK occupancy was achieved with twice daily over once daily dosing, resulting in deeper and more sustained inhibition of BCR signaling.
Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Antineoplastic Agents/therapeutic use , Benzamides/therapeutic use , Biomarkers, Tumor/genetics , Gene Expression Regulation, Neoplastic/drug effects , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Neoplasm Recurrence, Local/drug therapy , Pyrazines/therapeutic use , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/enzymology , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Middle Aged , Neoplasm Recurrence, Local/enzymology , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , PrognosisABSTRACT
BACKGROUND/AIM: In estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, standard chemotherapies as well as adjuvant endocrine therapy might not be enough for prevention of early relapse. MATERIALS AND METHODS: We focused on ER-positive, HER2 immunohistochemistry (IHC) 0 or 1+ breast cancer, and retrospectively examined HER2 gene amplification and TP53 mutation in breast cancer tissues in patients with or without early recurrence. Post-relapse survival in patients with early recurrence was also analyzed by mutation status of HER2 and TP53. RESULTS: Surprisingly, amplification of the HER2 gene was found in 15% of patients with early recurrence. None of the patients without relapse had HER2-amplified tumors. Post-relapse survival in patients with HER2 gene amplification and/or TP53 mutation in primary tumors was shorter than that in patients without these mutations, especially among postmenopausal women. CONCLUSION: HER2 gene amplification exists in ER-positive, HER2 IHC 0 or 1+ breast cancer in patients who developed early distant metastasis.
Subject(s)
Breast Neoplasms/genetics , Neoplasm Recurrence, Local/genetics , Receptor, ErbB-2/genetics , Receptors, Estrogen/metabolism , Adult , Aged , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Case-Control Studies , Female , Gene Amplification , Humans , Immunohistochemistry , Middle Aged , Mutation , Neoplasm Recurrence, Local/enzymology , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Receptor, ErbB-2/metabolism , Receptors, Estrogen/biosynthesis , Retrospective Studies , Tumor Suppressor Protein p53/geneticsABSTRACT
OBJECTIVE: To compare the combination of a MEK inhibitor (pimasertib) and a PI3K inhibitor (SAR245409) to pimasertib alone in recurrent unresectable borderline/low malignant potential (LMP) or low-grade serous ovarian carcinoma (LGSOC), determining whether combination is superior. METHODS: Patients with previously treated, recurrent LMP or LGSOC with measurable disease received either combination of pimasertib (60 mg daily) + SAR245409 (SAR) (70 mg daily) or pimasertib alone (60 mg BID) until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR) by RECIST 1.1, determining whether combination was superior to pimasertib alone. Secondary endpoints included progression free survival (PFS), disease control, and adverse events. RESULTS: Sixty-five patients were randomized between September 2012 and December 2014. ORR was 9.4% (80% CI, 3.5 to 19.7) in the combination arm and 12.1% (80% CI, 5.4 to 22.8) in the pimasertib alone arm. Median PFS was 7.23 months (80% CI, 5.06 to -) and 9.99 (80% CI, 7.39 to 10.35) for pimasertib alone and pimasertib + SAR, respectively. Six-month PFS was 63.5% (80% CI, 47.2% to 75.9%) and 70.8% (80% CI, 56.9% to 80.9%). Eighteen (56.3%) patients in the combination arm and 19 (57.6%) patients in the pimasertib alone arm discontinued the trial. The study was terminated early because of low ORR and high rate of discontinuation. CONCLUSIONS: Response to pimasertib alone (ORR 12%) suggests that MEK inhibition could be used as an alternative treatment method to cytotoxic chemotherapy in this population. The MEK inhibitor alone was as effective as the combination, although the trial was limited by small numbers. Additional studies investigating the role of single agent or combination MEK and PI3K inhibition are warranted to further evaluate the utility of these treatments and describe a standard of care for LGSOC.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Niacinamide/analogs & derivatives , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/enzymology , Adult , Aged , Double-Blind Method , Female , Humans , MAP Kinase Kinase 1/antagonists & inhibitors , MAP Kinase Kinase 1/metabolism , MAP Kinase Kinase 2/antagonists & inhibitors , MAP Kinase Kinase 2/metabolism , Middle Aged , Neoplasm Grading , Neoplasm Recurrence, Local/enzymology , Neoplasm Recurrence, Local/pathology , Neoplasm Staging , Niacinamide/administration & dosage , Niacinamide/therapeutic use , Ovarian Neoplasms/pathology , Phosphatidylinositol 3-Kinases/metabolism , Phosphoinositide-3 Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Quinoxalines/administration & dosage , Sulfonamides/administration & dosage , TOR Serine-Threonine Kinases/antagonists & inhibitors , TOR Serine-Threonine Kinases/metabolism , Young AdultABSTRACT
PURPOSE: The 21-gene recurrence score (RS) assay is prognostic among women with early-stage estrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer and is used to inform recommendations for chemotherapy. Women ≤ 40 years of age represent a minority of patients studied using gene expression profiles. METHODS: The Young Women's Breast Cancer Study is a prospective cohort of women diagnosed with breast cancer at age ≤ 40 years and enrolled patients between 2006 and 2016 (N = 1,302). We identified patients with stage I-III ER+/HER2- breast cancer. The RS assay was performed on banked specimens for patients who had not been tested clinically. Distant recurrence-free survival (DRFS) was assessed by TAILORx and traditional RS risk groups among patients with axillary node-negative (N0) and limited node-positive (N1) breast cancer. RESULTS: Among eligible women (N = 577), 189 (33%) had undergone RS testing, and 320 (56%) had banked specimens sufficient for testing. Median follow-up was 6.0 years. Median age at diagnosis was 37.2 years; 300 of 509 patients (59%) had N0 breast cancer, of whom 195 (65%) had an RS of 11-25 and fewer than half (86 of 195; 44%) received chemotherapy. Six-year DRFS rates were 94.4% and 92.3% (RS < 11), 96.9% and 85.2% (RS 11-25), and 85.1% and 71.3% (RS ≥ 26) among women with N0 and N1 disease, respectively. CONCLUSION: The RS assay is prognostic among young women with node-negative and limited node-positive breast cancer, representing a valuable tool for risk stratification. Disease outcomes with a median follow-up of 6 years among young women with N0 disease and an RS of 0-25, a minority of whom received chemotherapy, and node-positive disease with an RS < 11 were very good, whereas those with N0 disease and an RS ≥ 26 or N1 disease with an RS ≥ 11 experienced substantial risk of early distant recurrence.
Subject(s)
Breast Neoplasms/genetics , Neoplasm Recurrence, Local/genetics , Adolescent , Adult , Breast Neoplasms/enzymology , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Cohort Studies , Female , Gene Expression Profiling , Humans , Lymph Nodes/pathology , Lymphatic Metastasis , Multivariate Analysis , Neoplasm Recurrence, Local/enzymology , Neoplasm Recurrence, Local/pathology , Prognosis , Prospective Studies , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Young AdultABSTRACT
PURPOSE: Precision medicine trials in glioblastoma (GBM) are often conducted at tumor recurrence. However, second surgeries for recurrent GBM are not routinely performed, and therefore, molecular data for trial inclusion are predominantly derived from the primary sample. This study aims to establish whether molecular targets change during tumor progression and, if so, whether this affects precision medicine trial design. MATERIALS AND METHODS: We collected 186 pairs of primary-recurrent GBM samples from patients receiving chemoradiotherapy with temozolomide and sequenced approximately 300 cancer genes. MGMT, TERT, and EGFRvIII status was individually determined. RESULTS: The molecular profile of our cohort was identical to that of other GBM cohorts (IDH wild-type [WT], 95%; EGFR amplified, approximately 50%), indicating that patients amenable to second surgery do not represent a specific molecular subtype. Molecular events in IDH WT GBMs were stable in approximately 80% of events, but changes in mutation status were observed for all examined genes (range, approximately 90% and 60% for TERT and EGFR mutations, respectively), and such changes strongly affected targeted trial size and design. A similar pattern of GBM driver instability was observed within MGMT promoter-methylated tumors. MGMT promoter methylation status remained prognostic at tumor recurrence. The observation that hypermutation at GBM recurrence was rare (8%) and not correlated with outcome was relevant for immunotherapy-based treatments. CONCLUSION: This large cohort of matched primary and recurrent IDH WT tumors establishes the frequency of GBM driver instability after chemoradiotherapy with temozolomide. This allows per gene or pathway calculation of trial size at tumor recurrence, using molecular data of the primary tumor only. We also identify genes for which repeat surgery is necessary because of low mutation retention rate.
Subject(s)
Brain Neoplasms/therapy , Glioblastoma/genetics , Glioblastoma/therapy , Isocitrate Dehydrogenase/genetics , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/therapy , Precision Medicine/methods , Adolescent , Adult , Aged , Antineoplastic Agents, Alkylating/administration & dosage , Brain Neoplasms/enzymology , Brain Neoplasms/genetics , Case-Control Studies , Chemoradiotherapy , Clinical Protocols , Clinical Trials as Topic , DNA Methylation , DNA Modification Methylases/genetics , DNA Repair Enzymes/genetics , Evolution, Molecular , Female , Glioblastoma/enzymology , Humans , Male , Middle Aged , Neoplasm Recurrence, Local/enzymology , Promoter Regions, Genetic , Temozolomide/administration & dosage , Tumor Suppressor Proteins/genetics , Young AdultABSTRACT
PURPOSE: To evaluate whether preoperative biopsy affects the outcomes of patients undergoing at least lobectomy for stage I lung adenocarcinoma. METHODS: We reviewed the medical records of patients who underwent surgery for stage I lung adenocarcinoma between 2006 and 2013. Tumor recurrence and survival were compared between patients who underwent preoperative biopsy, including computed tomographic-guided needle biopsy and transbronchial biopsy, and those who underwent intraoperative frozen section. RESULTS: Among 509 patients, 229 patients (44.9%) underwent preoperative biopsy and 280 patients had lung adenocarcinoma diagnosed by intraoperative frozen section (reference group). Recurrence developed in 65 (12.8%) patients within a median follow-up period of 54.4 months. Multivariate analysis demonstrated that preoperative biopsy (OR 1.97, p = 0.045), radiological solid appearance (OR 5.43, p < 0.001), and angiolymphatic invasion (OR 2.48, p = 0.010) were independent predictors of recurrence. In the overall cohort, preoperative biopsy appeared to worsen 5-year disease-free and overall survival significantly (76.6% vs. 93.0%, p < 0.001; and 83.8% vs. 94.5%, p = 0.002, respectively) compared with the reference group. After propensity matching, multivariable logistic regression still identified preoperative biopsy as an independent predictor of overall recurrence (OR 2.21, p = 0.048) after adjusting for tumor characteristics. CONCLUSION: Preoperative biopsy might be considered a prognosticator of recurrence of stage I adenocarcinoma of the lungs in patients who undergo at least anatomic lobectomy without postoperative adjuvant chemotherapy.
Subject(s)
Adenocarcinoma/pathology , Biopsy , Lung Neoplasms/pathology , Neoplasm Recurrence, Local/enzymology , Adenocarcinoma/mortality , Adenocarcinoma/surgery , Adult , Aged , Aged, 80 and over , Biopsy/methods , Female , Humans , Lung Neoplasms/mortality , Lung Neoplasms/surgery , Male , Middle Aged , Neoplasm Recurrence, Local/epidemiology , Neoplasm Staging , Pneumonectomy , Predictive Value of Tests , Preoperative Period , Prognosis , Survival RateABSTRACT
BACKGROUND: Inositol polyphosphate-5-phosphatase (INPP5A) has been shown to play a role in the progression of actinic keratosis to cutaneous squamous cell carcinoma (cSCC) and the progression of localized disease to metastatic disease. Currently, no cSCC biomarkers are able to risk stratify recurrent and metastatic disease. OBJECTIVE: To determine the prognostic value of INPP5A expression in cSCC recurrent and metastatic disease. METHODS: We conducted a multicenter, single-institutional, retrospective cohort study within the Mayo Clinic Health System on the use of immunohistochemical staining to examine cSCC INPP5A protein expression in primary tumors and recurrent and metastatic disease. Dermatologists and dermatopathologists were blinded to outcome. RESULTS: Low staining expression of INPP5A in recurrent and metastatic disease tumors was associated with poor overall survival (OS) (31.0 months for low versus 62.0 months for high expression; P = .0272). A composite risk score (calculated as score of primary tumor + score of recurrent or metastatic disease tumor, with tumors with high expression scoring a zero and low expression a 1, score range 0-2) of 0 was predictive of improved OS compared with a composite risk score of ≥1 (hazard ratio 0.42, 95% confidence interval 0.21-0.84; P = .0113). LIMITATIONS: This is a multicenter but single institution study of a white population. CONCLUSION: Loss of INPP5A expression predicts poor OS in recurrent and metastatic disease of cSCC.
Subject(s)
Carcinoma, Squamous Cell/enzymology , Inositol Polyphosphate 5-Phosphatases/genetics , Neoplasm Recurrence, Local/enzymology , Skin Neoplasms/enzymology , Aged , Biomarkers/analysis , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Disease Progression , Female , Gene Expression , Humans , Immunohistochemistry , Inositol Polyphosphate 5-Phosphatases/analysis , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Prognosis , Retrospective Studies , Skin Neoplasms/genetics , Skin Neoplasms/pathologyABSTRACT
OBJECTIVE: Cyclin-dependent kinase 7 (CDK7) engages tumor growth by acting as a direct link between the regulation of transcription and the cell cycle. Here, we investigated the clinical significance of CDK7 expression and its potential as a therapeutic target in epithelial ovarian cancer (EOC). METHODS: CDK7 expression was examined in 436 ovarian tissues including normal to metastatic ovarian tumors using immunohistochemistry, and its clinical implications were analyzed. Furthermore, we performed in vitro and in vivo experiments using CDK7 siRNA or a covalent CDK7 inhibitor (THZ1) to elucidate the effect of CDK7 inhibition on tumorigenesis in EOC cells. RESULTS: The patient incidence of high CDK7 expression (CDK7High) gradually increased from normal ovarian epithelium to EOC (P < 0.001). Moreover, CDK7High was associated with an advanced stage and high-grade histology (P = 0.035 and P = 0.011, respectively) in EOC patients and had an independent prognostic significance in EOC recurrence (P = 0.034). CDK7 inhibition with siRNA or THZ1 decreased cell proliferation and migration, and increased apoptosis in EOC cells, and this anti-cancer mechanism is caused by G0/G1 cell cycle arrest. In in vivo therapeutic experiments using cell-line xenograft and PDX models, CDK7 inhibition significantly decreased the tumor weight, which was mediated by cell proliferation and apoptosis. CONCLUSION: Mechanistic interrogation of CDK7 revealed that it is significantly associated with an aggressive phenotype of EOC, and it has independent prognostic power for EOC recurrence. Furthermore, CDK7 may be a potential therapeutic target for patients with EOC, whether platinum sensitive or resistant.
Subject(s)
Carcinoma, Ovarian Epithelial/enzymology , Cyclin-Dependent Kinases/biosynthesis , Ovarian Neoplasms/enzymology , Animals , Biomarkers, Tumor/antagonists & inhibitors , Biomarkers, Tumor/biosynthesis , Carcinoma, Ovarian Epithelial/drug therapy , Carcinoma, Ovarian Epithelial/pathology , Cell Line, Tumor , Cell Proliferation/drug effects , Cyclin-Dependent Kinases/antagonists & inhibitors , Female , Heterografts , Humans , Immunohistochemistry , Mice , Mice, Inbred BALB C , Middle Aged , Neoplasm Recurrence, Local/enzymology , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Phenylenediamines/pharmacology , Prognosis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Cyclin-Dependent Kinase-Activating KinaseABSTRACT
BACKGROUND: The ETV6-NTRK3 gene fusion is present in the majority of cases of infantile fibrosarcoma (IFS) and acts as a potent oncogenic driver. We report the very rapid, complete, and sustained response of an advanced, chemotherapy-refractory, recurrent IFS to targeted treatment with the oral tropomyosin receptor kinase (TRK) inhibitor larotrectinib. PATIENT AND METHODS: A male infant born with a large congenital IFS of the tongue had the tumour surgically resected at age 4 days. Within 2 months, he developed extensive lymph node recurrence that progressed during two cycles of vincristine-doxorubicin-cyclophosphamide chemotherapy. At screening, a large right cervical mass was clinically visible. Magnetic resonance imaging (MRI) revealed bilateral cervical and axillary lymph node involvement as well as infiltration of the floor of the mouth. The largest lesion measured 5.5×4.5×4.4 cm (ca. 55 cm3). The patient started outpatient oral larotrectinib at 20 mg/kg twice daily at age 3.5 months. RESULTS: After 4 days on treatment, the parents noted that the index tumour was visibly smaller and softer. The rapid tumour regression continued over the following weeks. On day 56 of treatment, the first scheduled control MRI showed the target lesion had shrunk to 1.2×1.2×0.8 cm (ca. 0.6 cm3), corresponding to a complete response according to the Response Evaluation Criteria In Solid Tumors version 1.1. This response was maintained over subsequent follow-up visits, and on day 112 at the second control MRI the target lymph node was completely normal. At last follow-up, the disease remained in complete remission after 16 months on larotrectinib, with negligible toxicity and no safety concerns. CONCLUSION(S): Selective TRK inhibition by larotrectinib offers a novel, highly specific and highly effective therapeutic option for IFS carrying the characteristic ETV6-NTRK3 gene fusion. Its use should be considered when surgery is not feasible. (NCT02637687).