Bromodomain and extraterminal domain (BET) proteins are epigenetic molecules that regulate the expression of multiple genes involved in carcinogenesis. Breast cancer is an heterogenous disease ...emerging from aberrant gene expression and epigenetic alteration patterns. Amplification or overexpression of BET proteins has been identified in breast tumors highlighting their clinical significance. Development of BET inhibitors that disrupt BET protein binding to acetylated lysine residues of chromatin and suppress transcription of various oncogenes has shown promising results in breast cancer cells and xenograft models. Currently, Phase I/II clinical trials explore safety and efficacy of BET inhibitors in solid tumors and breast cancer. Treatment-emergent toxicities have been reported, including thrombocytopenia and gastrointestinal disorders. Preliminary results demonstrated greater response rates to BET inhibitors in combination with already approved anticancer agents. Consistently, BET inhibition sensitized breast tumors to chemotherapy drugs, hormone therapy and PI3K inhibitors in vitro. This article aims to review all existing preclinical and clinical evidence regarding BET inhibitors in breast cancer.
•BET proteins are epigenetic readers that regulate transcription of multiple cancer-associated genes.•BET inhibitors attenuate BET protein association to chromatin suppressing oncogene pathways.•Preclinical studies have shown promising efficacy of BET inhibitors in breast cancer murine xenografts and cell lines.•BET inhibitors provided an additive effect to widely used anticancer agents, including chemotherapy drugs, hormone therapy and tyrosine kinase inhibitors.•Ongoing Phase I/II trials revealed a potent BETi antitumor efficacy and safety limitations due to hematologic and gastrointestinal toxicity.
Osteonecrosis of the jaw (ONJ) has been associated with the use of pamidronate and zoledronic acid. ONJ was assessed prospectively since July 2003 in 202 patients with multiple myeloma (MM) who ...received bisphosphonates since April 1995. Fifteen patients (7.4%) developed ONJ. The median time of exposure to bisphosphonates was 39 months for patients with ONJ compared to 28 months (p=0.048) for patients with no ONJ. The cumulative hazard of developing ONJ was significantly higher in patients treated with zoledronic acid alone than in those treated with pamidronate alone/pamidronate+zoledronic acid/zoledronic acid+ibandronate sequentially (1% at 1 year and 15% at 4 years vs. 0% and 5%, p=0.003). In conclusion, the risk of ONJ is increased with time of exposure and probably with the use of zoledronic acid.
Thalidomide in cancer medicine Eleutherakis-Papaiakovou, V.; Bamias, A.; Dimopoulos, M. A.
Annals of oncology,
08/2004, Letnik:
15, Številka:
8
Journal Article
Recenzirano
Odprti dostop
Thalidomide, an oral agent with antiangiogenic and immunomodulatory properties, is being investigated extensively in the management of advanced cancer. Multiple studies with large numbers of patients ...have confirmed that this drug has significant activity in multiple myeloma. Some patients with myelofibrosis or myeodysplatic syndromes may reduce their need for transfusions after thalidomide treatment. The activity of thalidomide in solid tumors is less prominent. Studies in Kaposi's sarcoma, malignant melanoma, renal cell carcinoma and prostate cancer appear more promising especially when thalidomide is combined with biological agents or with chemotherapy. Limited activity was demonstrated in patients with glioma, while thalidomide appears to be inactive in patients with head and neck cancer, breast or ovarian cancer.
Thalidomide, a glutamic acid derivative, was withdrawn from clinical use in 1962 due to its severe teratogenic effects. Its recent reinstitution in clinical practice was related to its benefits in ...leprosy and multiple myeloma. Moreover, the antiangiogenic and immunomodulatory properties of thalidomide have led to its evaluation in several malignant diseases, including myelofibrosis, renal cell cancer, prostate cancer, and Kaposi sarcoma. However, thalidomide use is associated with several side effects: somnolence and constipation are the most common, while deep vein thrombosis and peripheral neuropathy are the most serious. A combination of thalidomide with steroids or chemotherapy is being evaluated in several phase 2 studies. While it is not yet clear whether these combinations will enhance efficacy, they appear to increase the toxicity of thalidomide, and thalidomide analogs are being developed to minimize this toxicity. Ongoing studies will clarify the potential advantages of these agents in the treatment of neoplastic diseases.
BackgroundThalidomide is effective in approximately 30% of patients with refractory multiple myeloma. Dexarnethasone is active in 25%of patients with disease resistant to alkylating agents. We ...investigated the combination of thalidomide with dexarneth treatment for heavily pretreated patients with multiple myeloma, in order to assess its efficacy and toxicity. Patients and methods: Forty-four patients with refractory myelorna were treated with thalidomide, 200 mg p.o. daily at bededtime, with dose escalation to 400 rng after 14 days, and dexarnethasone, which was administered intermittently at a dose of 20 mg/m2 p.o. daily for four days on day 1–4, 9–12, 17–20, followed by monthly dexamethasone for four days. Patients' median age was 67 years. All patients were resistant to standard chemotherapy, 77% were resistant to dexamethasone based regimens and 32% had previously received high-dose therapy. Results: On an intention-to-treat basis twenty-four patients (55%) achieved a partial response with a median time to response of 1.3 months. The thalidomide and dexamethasone combination was equally effective in patients with or without prior resistance to dexamethasone-based regimens and in patients with or without prior high-dose therapy. Toxicities were mild or moderate and consisted primarily of constipation, morning somnolence, tremor, xerostomia and peripheral neuro pathy. The median time to progression for responding patients is expected to exceed 10 months and the median survival for all patients is 12.6 months. Conclusion: The combination of thalidomide with dexa methasone appears active in patients with refractory multiple myeloma. If this activity is confirmed, further studies of this combination as second-line treatment for patients resistant to conventional chemotherapy, and as primary treatment for patients with active rnyeloma. should be considered.
The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed ...myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. beta2-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio.
Background: High-dose chemotherapy with autologous stem cell transplantation after initial cytoreductive chemotherapy with the combination vincristine, doxorubicin and dexamethasone (VAD) is ...considered an effective therapy for many patients with newly diagnosed, symptomatic multiple myeloma. Response to initial cytoreductive chemotherapy is important for the long-term outcome of such patients. Thalidomide has recently shown significant antimyeloma activity. We studied the efficacy and toxicity of the combination of a liposomal doxorubicin-containing VAD regimen with thalidomide, administered on an outpatient basis, as initial cytoreductive treatment in previously untreated patients with symptomatic myeloma. Patients and methods: Thirty-nine myeloma patients were treated with vincristine 2 mg intravenously (i.v.), liposomal doxorubicin 40 mg/m2 i.v. administered as single dose on day 1, and dexamethasone 40 mg per os daily for 4 days. Dexamethasone was also given on days 15–18 of the first cycle of treatment. The regimen was administered every 4 weeks for four courses. Thalidomide was given daily at a dose of 200 mg at bedtime. Response to treatment was evaluated after four cycles of treatment. After completion of four cycles, the patients were allowed to proceed to high-dose chemotherapy or to receive two additional cycles of the same treatment. Results: On an intention-to-treat basis, 29 of the 39 patients (74%) responded to treatment. Four patients (10%) achieved complete and 25 (64%) partial response. Three patients (8%) showed minor response and seven (18%) were rated as non-responders. Major grade 3 or 4 toxicities consisted of neutropenia (15%), thrombocytopenia (15%), deep vein thrombosis (10%), constipation (10%), skin rash (5%) and peripheral neuropathy (5%). Two patients (5%) experienced early death due to infection. Conclusions: The combination of vincristine, liposomal doxorubicin, and dexamethasone (VAD doxil) with thalidomide is an effective and relatively well-tolerated initial cytoreductive treatment.Prospective randomized studies are required in order to assess the effect of this regimen on the long-term outcome of patients with multiple myeloma.
Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma.
In this phase 3 trial, we ...randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival.
At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients 18.5% in the daratumumab group vs. 116 of 283 41.0% in the control group; hazard ratio, 0.37; 95% confidence interval CI, 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 10
white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2.
The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).
We performed a prospective phase II study to assess the activity of thalidomide in patients with Waldenstrom's macroglobulinemia (WM).
Twenty patients with WM were treated with thalidomide at a ...starting dose of 200 mg daily with dose escalation in 200-mg increments every 14 days as tolerated to a maximum of 600 mg. All patients were symptomatic, their median age was 74 years, and 10 patients were previously untreated.
On an intent-to-treat basis, five (25%) of 20 patients achieved a partial response after treatment. Responses occurred in three of 10 previously untreated and in two of 10 pretreated patients. None of the patients treated during refractory relapse or with disease duration exceeding 2 years responded to thalidomide. Time to response was short, ranging between 0.8 months to 2.8 months. Adverse effects were common but reversible and consisted primarily of constipation, somnolence, fatigue, and mood changes. The daily dose of thalidomide was escalated to 600 mg in only five patients (25%), and in seven patients (35%), this agent was discontinued within 2 months because of intolerance.
Our data indicate that thalidomide has activity in WM but only low doses were tolerated in this elderly patient population. Confirmatory studies as well as studies that will combine thalidomide with chemotherapy or with rituximab may be relevant.
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