Response to Vemurafenib in Metastatic Triple-Negative Breast Cancer Harbouring a BRAF V600E Mutation: A Case Report and Electronically Captured Patient-Reported Outcome.
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ABSTRACT:
SUBMITTER: Pircher M
PROVIDER: S-EPMC8077504 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:To examine the association between level and patterns of baseline intra-tumoural BRAF(V600E) protein expression and clinical outcome of BRAF(V600E) melanoma patients treated with selective BRAF inhibitors.Fifty-eight BRAF(V600E) metastatic melanoma patients treated with dabrafenib or vemurafenib on clinical trials had pre-treatment tumour BRAF(V600E) protein expression immunohistochemically (IHC) assessed using the BRAF V600E mutant-specific antibody VE1. Sections were examined for staining intensity (score 1-3) and percentage of immunoreactive tumour cells, and from this an immunoreactive score (IRS) was derived (intensity × per cent positive/10). The presence of intra-tumoural heterogeneity for BRAF(V600E) protein expression was also assessed. BRAF(V600E) expression was correlated with RECIST response, time to best response (TTBR), progression-free survival (PFS) and overall survival (OS).Expression was generally high (median IRS 28 (range 5-30)) and homogeneous (78%). Expression of mutated protein BRAF(V600E) as measured by intensity, per cent immunoreactive cells, or IRS did not correlate with RECIST response, TTBR, PFS or OS, including on multivariate analysis. Heterogeneity of staining was seen in 22% of cases and did not correlate with outcome.In the current study population, IHC-measured pre-treatment BRAF(V600E) protein expression does not predict response or outcome to BRAF inhibitor therapy in BRAF(V600E) metastatic melanoma patients.
| S-EPMC3590666 | biostudies-other
Project description:BACKGROUND:Clinical benefit from cytotoxic chemotherapy for metastatic papillary thyroid carcinoma (PTC) is disappointing, and effective therapeutic approaches for these patients are urgently needed. Because kinase-activating mutations in the BRAF proto-oncogene commonly occur in advanced PTC, and inhibition of BRAF(V600E) has shown promising clinical activity in melanoma, BRAF inhibitor therapy may be an effective strategy to treat metastatic PTC. METHODS:The dose escalation portion of a first-in-human, phase I study of vemurafenib, a selective RAF inhibitor, included three patients with metastatic PTC harboring the BRAF(V600E) mutation. Vemurafenib was initially dosed at 240-360?mg twice a day, later escalated to 720 mg twice a day. Response evaluation was performed every 8 weeks per Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS:Among the three patients, one had a confirmed partial response with reduction of pulmonary target lesions by 31%, and the duration of response was 7.6 months before the disease progressed in the lungs and the bones. The time to progression was 11.7 months. The other two patients had stable disease, and the time to progression was 13.2 and 11.4 months, respectively. CONCLUSIONS:Vemurafenib appears to have a promising clinical activity in patients with metastatic PTC, and our data suggest that the BRAF(V600E) mutant kinase is a relevant target for therapy in this patient population. Further investigation of inhibitors of mutated BRAF kinase in patients with PTC in a phase II study is warranted.
| S-EPMC3967415 | biostudies-literature
Project description:BackgroundTreatment of metastatic malignant melanoma patients harboring BRAF(V600E) has improved drastically after the discovery of the BRAF inhibitor, vemurafenib. However, drug resistance is a recurring problem, and prognoses are still very bad for patients harboring BRAF wild-type. Better markers for targeted therapy are therefore urgently needed.MethodologyIn this study, we assessed the individual kinase activity profiles in 26 tumor samples obtained from patients with metastatic malignant melanoma using peptide arrays with 144 kinase substrates. In addition, we studied the overall ex-vivo inhibitory effects of vemurafenib and sunitinib on kinase activity status.ResultsOverall kinase activity was significantly higher in lysates from melanoma tumors compared to normal skin tissue. Furthermore, ex-vivo incubation with both vemurafenib and sunitinib caused significant decrease in phosphorylation of kinase substrates, i.e kinase activity. While basal phosphorylation profiles were similar in BRAF wild-type and BRAF(V600E) tumors, analysis with ex-vivo vemurafenib treatment identified a subset of 40 kinase substrates showing stronger inhibition in BRAF(V600E) tumor lysates, distinguishing the BRAF wild-type and BRAF(V600E) tumors. Interestingly, a few BRAF wild-type tumors showed inhibition profiles similar to BRAF(V600E) tumors. The kinase inhibitory effect of vemurafenib was subsequently analyzed in cell lines harboring different BRAF mutational status with various vemurafenib sensitivity in-vitro.ConclusionsOur findings suggest that multiplex kinase substrate array analysis give valuable information about overall tumor kinase activity. Furthermore, intra-assay exposure to kinase inhibiting drugs may provide a useful tool to study mechanisms of resistance, as well as to identify predictive markers.
| S-EPMC3758344 | biostudies-literature
Project description:BackgroundPhase 1 and 2 clinical trials of the BRAF kinase inhibitor vemurafenib (PLX4032) have shown response rates of more than 50% in patients with metastatic melanoma with the BRAF V600E mutation.MethodsWe conducted a phase 3 randomized clinical trial comparing vemurafenib with dacarbazine in 675 patients with previously untreated, metastatic melanoma with the BRAF V600E mutation. Patients were randomly assigned to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg per square meter of body-surface area intravenously every 3 weeks). Coprimary end points were rates of overall and progression-free survival. Secondary end points included the response rate, response duration, and safety. A final analysis was planned after 196 deaths and an interim analysis after 98 deaths.ResultsAt 6 months, overall survival was 84% (95% confidence interval [CI], 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) in the dacarbazine group. In the interim analysis for overall survival and final analysis for progression-free survival, vemurafenib was associated with a relative reduction of 63% in the risk of death and of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.001 for both comparisons). After review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. Response rates were 48% for vemurafenib and 5% for dacarbazine. Common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, keratoacanthoma or squamous-cell carcinoma, photosensitivity, nausea, and diarrhea; 38% of patients required dose modification because of toxic effects.ConclusionsVemurafenib produced improved rates of overall and progression-free survival in patients with previously untreated melanoma with the BRAF V600E mutation. (Funded by Hoffmann-La Roche; BRIM-3 ClinicalTrials.gov number, NCT01006980.).
| S-EPMC3549296 | biostudies-literature
Project description:BackgroundAnaplastic thyroid cancer (ATC) is one of the most aggressive malignancies, representing less than 5% of all thyroid carcinomas. Τhe median survival is limited to months due to the resistance of ATC to surgery, radioiodine therapy, radiotherapy and chemotherapy. This review will cover novel agents involving several cellular signaling pathways including the BRAF pathway. The BRAF inhibitor vemurafenib improves survival among patients with metastatic melanoma, hairy-cell leukemia and intracranial neoplasms with BRAF gene mutations. The frequency of a BRAF (V600E) mutation in ATC is about 25%.Case presentationWe report the first case of a marked partial response to adjuvant first line monotherapy with vemurafenib in BRAF V600E-mutated ATC. The 78-year-old man showed a sustained response for 7 months, thereafter scans revealed progressive disease and the patient died 10 months after first diagnosis. This case report is accompanied by a comprehensive review of current strategies and tools for ATC treatment.ConclusionsThis case and the review of current data confirm the benefit of BRAF inhibition in BRAF-mutated ATC, limited by acquired resistance to targeted therapy.
| S-EPMC9976495 | biostudies-literature
Project description:To optimally integrate targeted kinase inhibitors and immunotherapies in the treatment of melanoma, it will be critical to understand how BRAFV600E mutational status and BRAFV600E inhibition influence the expression of genes that govern antitumor immune responses. Because major histocompatibility complex (MHC) molecules are critical for interactions between tumor cells and lymphocytes, we investigated the impact of BRAFV600E-selective inhibitors on the expression of MHC molecules. We found that the treatment of A375 melanoma cells with vemurafenib enhances the induction of MHC Class I and Class II molecules by interferon γ and IFNα2b. Consistent with these findings, we observed that the forced overexpression of BRAFV600E has the opposite effect and can repress the baseline expression of MHC Class I molecules in A375 cells. Further studies utilizing eight other melanoma cell lines revealed that the vemurafenib-mediated enhancement of MHC induction by IFNγ only occurs in the context of homozygous, but not heterozygous, BRAFV600E mutation. These findings suggest that BRAFV600E activity directly influences the expression of MHC molecules and the response to Type I and Type II IFNs. Furthermore, our data suggest that the effect of vemurafenib on the expression of immune system-relevant genes may depend on the zygosity of the BRAFV600E mutation, which is not routinely assessed in melanoma patients.
| S-EPMC3583938 | biostudies-literature
Project description:The BRAF kinase, within the mitogen activated protein kinase (MAPK) signaling pathway, harbors activating mutations in about half of melanomas and to a significant extent in many other cancers. A single valine to glutamic acid substitution at residue 600 (BRAFV600E) accounts for about 90% of these activating mutations. While BRAFV600E-selective small molecule inhibitors, such as debrafenib and vemurafenib, have shown therapeutic benefit, almost all patients develop resistance. Resistance often arises through reactivation of the MAPK pathway, typically through mutation of upstream RAS, downstream MEK, or splicing variants. RAF kinases signal as homo- and heterodimers, and another complication associated with small molecule BRAFV600E inhibition is drug-induced allosteric activation of a wild-type RAF subunit (BRAF or CRAF) of the kinase dimer, a process called "transactivation" or "paradoxical activation." Here, we used BRAFV600E and vemurafenib as a model system to develop chemically linked kinase inhibitors to lock RAF dimers in an inactive conformation that cannot undergo transactivation. This structure-based design effort resulted in the development of Vem-BisAmide-2, a compound containing two vemurafenib molecules connected by a bis amide linker. We show that Vem-BisAmide-2 has comparable inhibitory potency as vemurafenib to BRAFV600E both in vitro and in cells but promotes an inactive dimeric BRAFV600E conformation unable to undergo transactivation. The crystal structure of a BRAFV600E/Vem-BisAmide-2 complex and associated biochemical studies reveal the molecular basis for how Vem-BisAmide-2 mediates selectivity for an inactive over an active dimeric BRAFV600E conformation. These studies have implications for targeting BRAFV600E/RAF heterodimers and other kinase dimers for therapy.
| S-EPMC5108658 | biostudies-literature
Project description:Treatment with vemurafenib, a potent and selective inhibitor of mitogen-activated protein kinase signaling downstream of the BRAFV600E oncogene, elicits dramatic clinical responses in patients with metastatic melanoma. Unfortunately, the clinical utility of this drug is limited by a high incidence of drug resistance. Thus, there is an unmet need for alternative therapeutic strategies to treat vemurafenib-resistant metastatic melanomas. We have conducted high-throughput screening of two bioactive compound libraries (Siga and Spectrum libraries) against a metastatic melanoma cell line (A2058) and identified two structurally analogous compounds, deguelin and rotenone, from a cell viability assay. Vemurafenib-resistant melanoma cell lines, A2058R and A375R (containing the BRAFV600E mutation), also showed reduced proliferation when treated with these two compounds. Deguelin, a mitochondrial complex I inhibitor, was noted to significantly inhibit oxygen consumption in cellular metabolism assays. Mechanistically, deguelin treatment rapidly activates AMPK signaling, which results in inhibition of mTORC1 signaling and differential phosphorylation of mTORC1's downstream effectors, 4E-BP1 and p70S6 kinase. Deguelin also significantly inhibited ERK activation and Ki67 expression without altering Akt activation in the same timeframe in the vemurafenib-resistant melanoma cells. These data posit that treatment with metabolic regulators, such as deguelin, can lead to energy starvation, thereby modulating the intracellular metabolic environment and reducing survival of drug-resistant melanomas harboring BRAF V600E mutations.
| S-EPMC6692247 | biostudies-literature
Project description:Vemurafenib induces tumour regression in most patients with BRAF(V600E)-mutant melanoma; eventually, most experience progressive disease (PD). Long-term follow-up of patients with BRAF(V600E) melanoma treated in the phase 1 vemurafenib trial is reported.Patients received vemurafenib 240-1120 mg (dose escalation cohort) or 960 mg (extension cohort) orally twice daily. Clinical response was evaluated every 8 weeks by Response Evaluation Criteria In Solid Tumors (RECIST). Patients with PD amenable to local therapy (surgery or radiotherapy) were allowed to continue vemurafenib after progression. Overall survival (OS) from time of treatment initiation and from PD was estimated. Sites of PD were recorded.Forty-eight patients (escalation cohort, n = 16; extension cohort, n = 32) received therapeutic doses of vemurafenib (? 240 mg twice daily). Forty-four patients had PD by the time of this analysis and four remained progression free (follow-up time, 1.2-56.1 months). Median OS was 14 months (range, 1.2-56.1); 3- and 4-year melanoma-specific survival rate in the extension cohort was 26% and 19%, respectively. Median OS was 26.0 months (range, 7.7-56.1) among 20 patients who continued vemurafenib after local therapy. Median treatment duration beyond initial PD was 3.8 months (range, 1.1-26.6). In the extension cohort, six and five patients were alive after 3 and 4 years, respectively, on vemurafenib monotherapy.Some patients with melanoma achieved long-term survival with vemurafenib monotherapy. Continuation of vemurafenib after PD might be beneficial in some patients because remaining disease might continue to respond to BRAF inhibition.
| S-EPMC5087591 | biostudies-literature
Project description:Digital patient monitoring gains importance for quality of clinical cancer care. Our case report provides insight into usability and acceptance of a smartphone app for monitoring of electronically captured patient-reported outcomes in patients undergoing immunotherapy. During 3 months, 6 patients with advanced or metastatic PD-L1-positive cancer of the lung, prostate, and bladder who underwent checkpoint immunotherapy were using the Consilium app for standardized and structured electronic reporting of symptoms and therapy side effects. We evaluated the number and quality of symptom entries as well as usability and safety of shared reporting between the patient and the treating physician. Duration of anti-PD-L1-directed immunotherapy in the 6 patients ranged from 4 to 10 months and comprised a total of 21 anti-PD-L1-directed immunotherapy cycles. Patients reported between 4 and 16 different symptoms, of which the most frequent (57%) were dry cough, fatigue, shortness of breath, fever, and appetite loss. Overall, 1,279 symptom entries were counted, corresponding to 2.4 symptom entries per patient per day. Symptom severity grading ranged from 0.1 (very slight symptoms) to 7.8 (severe symptoms), which triggered prespecified alerts in 4 of the 6 patients. No unplanned visits were noted, and no safety issues occurred. Satisfaction with the app usability was high, as was the beneficial effect on consultation. Usability and reviewed data entries indicate high shared reporting efforts of patients and treating physicians and overall satisfaction with electronically reported patient outcomes.
| S-EPMC7265704 | biostudies-literature