<i>BRAF</i>
          V600E Mutation in Cell-Free DNA, Rather than in Lesion Tissues, at Diagnosis Is An Independent Prognostic Factor in Children with Langerhans Cell Histiocytosis

Wang, Chanjuan; Cui, Lei; Ma, Honghao; Wang, Dong; Zhang, Li; Liu, Hongyun; Li, Weijing; Zhang, Qing; Wang, Tianyou; Li, Zhigang; Zhang, Rui

doi:10.1158/1535-7163.mct-20-1075

Cited by 7 publications

(11 citation statements)

References 33 publications

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“…To this end, (longitudinal) assessment of mutant alleles in cellular or cell-free DNA derived from peripheral blood and/or bone marrow represents an interesting opportunity for prognostic staging and monitoring response to therapy. 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 …”

Section: Discussionmentioning

confidence: 99%

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

et al. 2023

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Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for approximately 80% of genetic driver alterations in neoplastic LCH-cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)-risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of SS-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival (EFS) in the overall cohort, neither BRAF nor MAP2K1 mutations associated with EFS when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH, but also question the independent prognostic value of lesional BRAFV600E status.

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Section: Discussionmentioning

confidence: 99%

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

et al. 2023

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“…18 Heritier et al 33 reported that patients with BRAF V600E mutation had an increased risk of frontline treatment and permanent consequences, such as DI and LCH-ND. 35 reported that cfBRAF V600E , rather than ltBRAF V600E , was a prognostic factor and was more closely associated with critical clinical characteristics and treatment outcomes.…”

Section: Discussionmentioning

confidence: 98%

“…Furthermore, no difference was found in OS and EFS between positive lt BRAF V600E detected using IHC or PCR and negative lt BRAF V600E . Wang et al 35 reported that cf BRAF V600E , rather than lt BRAF V600E , was a prognostic factor and was more closely associated with critical clinical characteristics and treatment outcomes. Cell‐free DNA originates from cell turnover, which involves the natural death of cells through apoptosis or necrosis and is becoming a widely used prognostic and predictive biomarker in oncology.…”

Section: Discussionmentioning

confidence: 99%

Clinical and prognostic features of Langerhans cell histiocytosis in adults

et al. 2023

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Langerhans cell histiocytosis (LCH) is a rare disease characterized by clonal expansion of CD1a+CD207+ myeloid dendritic cells. The features of LCH are mainly described in children and remain poorly defined in adults; therefore, we conducted a nationwide survey to collect clinical data from 148 adult patients with LCH. The median age at diagnosis was 46.5 (range: 20–87) years with male predominance (60.8%). Among the 86 patients with detailed treatment information, 40 (46.5%) had single system LCH, whereas 46 (53.5%) had multisystem LCH. Moreover, 19 patients (22.1%) had an additional malignancy. BRAF V600E in plasma cell‐free DNA was associated with a low overall survival (OS) rate and the risk of the pituitary gland and central nervous system involvement. At a median follow‐up of 55 months from diagnosis, six patients (7.0%) had died, and the four patients with LCH‐related death did not respond to initial chemotherapy. The OS probability at 5 years post‐diagnosis was 90.6% (95% confidence interval: 79.8–95.8). Multivariate analysis showed that patients aged ≥60 years at diagnosis had a relatively poor prognosis. The probability of event‐free survival at 5 years was 52.1% (95% confidence interval: 36.6–65.5), with 57 patients requiring chemotherapy. In this study, we first revealed the high rate of relapse after chemotherapy and mortality of poor responders in adults as well as children. Therefore, prospective therapeutic studies of adults with LCH using targeted therapies are needed to improve outcomes in adults with LCH.

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“…The combination of cladribine/Ara-C, as a salvage treatment, significantly improved the ORR and the survival rate of severe LCH patients, but the toxicity was high and the response was slow (Donadieu et al 2015 ). As a single agent, the BRAF V600E inhibitor can provide a rapid and robust clinical response, but the relapse rate after discontinuation is about 80% (Mohapatra et al 2022 ; Wang et al 2021 ). The clinical presentation of Langerhans cell histiocytosis (LCH) is influenced by the location of misdirected myeloid differentiation (Berres et al 2014 ).…”

Section: Discussionmentioning

confidence: 99%

“…Somatic BRAF V600E mutations in hematopoietic precursors increase the risk of developing multiple organ involvement in LCH (Rodriguez-Galindo and Allen 2020 ; Poch et al 2021 ). Moreover, the burden of these mutant clones correlates with the probability of relapse (Wang et al 2021 ; Milne et al 2023 ), emphasizing the importance of eliminating precursor cells for a cure. However, the persistence of BRAF V600E -positive mononuclear cells in both the blood and bone marrow, along with a high recurrence rate following drug withdrawal, suggests that vemurafenib monotherapy may be ineffective in completely eradicating LCH precursor cells (Eder et al 2022 ; Donadieu et al 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Vemurafenib combined with chemotherapy achieved sustained remission in pediatric LCH: a multi-center observational study

Lei,

Wang,

Lin

et al. 2024

J Cancer Res Clin Oncol

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Background Langerhans cell histiocytosis (LCH) is a myeloid neoplasia with potentially fatal consequences, and about 2/3 of cases involve the BRAFV600E kinase-activated mutation. Vemurafenib, a BRAF inhibitor, has demonstrated significant clinical improvements in LCH. However, the high relapse rate of LCH following cessation of vemurafenib therapy remains a major challenge, and alternative treatment strategies require further investigation. Methods In this retrospective multi-center study, we evaluated the efficacy and safety of vemurafenib combined with conventional chemotherapy in patients with severe or refractory LCH. Results Seventeen patients were enrolled in the study, with eleven classified as risk organ involvement (RO +). Six received the combination therapy as the primary treatment, and eleven after being refractory to prior chemotherapy. The overall response rate was 94.1%. Progression-free survival among all 17 patients was 70.6% (12/17) at a median follow-up of 32 months, and relapse-free survival among the 15 patients with discontinuation after a response was 73.3%(11/15) at a median follow-up of 34 months. Five of six patients (83.3%) with myeloid BRAFV600E mutations demonstrated molecular remission. The overall survival rate was 100%. Adverse events were mostly classified as grades 1 or 2. Conclusion Our data suggest that the combination of vemurafenib and chemotherapy can achieve sustained clinical and molecular level relief in children with LCH, and side effects are tolerable.

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BRAF V600E Mutation in Cell-Free DNA, Rather than in Lesion Tissues, at Diagnosis Is An Independent Prognostic Factor in Children with Langerhans Cell Histiocytosis

Abstract: BRAF V600E mutation in cell-free DNA, rather than in lesion tissues, at diagnosis is an independent prognostic factor in children with Langerhans cell histiocytosis Running title cfBRAF V600E is an independent prognostic factor in LCH

Cited by 7 publications

References 33 publications

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study

Clinical and prognostic features of Langerhans cell histiocytosis in adults

Vemurafenib combined with chemotherapy achieved sustained remission in pediatric LCH: a multi-center observational study

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