A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival

Ugurel, Selma; Loquai, Carmen; Kähler, Katharina C.; Hassel, J.C.; Berking, Carola; Zimmer, Lisa; Haubitz, Imme; Satzger, Imke; Müller-Brenne, Tina; Mikhaimer, N.C.; Becker, Jürgen C.; Kilian, Katharina; Schadendorf, Dirk; Heinzerling, Lucie; Kaatz, Martin; Utikal, Jochen; Göppner, Daniela; Pföhler, Claudia; Pflugfelder, Annette; Mößner, Rotraut; Gutzmer, Ralf

doi:10.1093/annonc/mdu573

Cited by 20 publications

(14 citation statements)

References 20 publications

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“…Finally we could not demonstrate a relationship between pretreatment serum LDH levels and response to therapy or survival in this limited number of patients studied. This finding is not consistent with previous studies (Abusaif et al., ; Ugurel et al., ). A previous large multicentre study including 300 patients from 14 clinical centres who were treated with vemurafenib (serum LDH available in 96.3% of patients) showed a significant reduction in both PFS and OS in univariate studies in patients with high levels of pretreatment serum LDH (Ugurel et al., ).…”

Section: Discussioncontrasting

confidence: 99%

Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma

Ardakani

Leslie

Grieu-Iacopetta

et al. 2017

Pigment Cell Melanoma Res

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Heterogeneity of BRAF mutation in melanoma has been a controversial subject. Quantitative data on BRAF allele frequency (AF) are sparse, and the potential relationship with response to BRAF inhibitors (BRAFi) in patients with metastatic melanoma is unknown. We quantitatively measured BRAF AF in a cohort of treatment naïve metastatic melanoma samples by pyrosequencing and correlated with survival data in patients treated with BRAFi as part of their clinical care. Fifty-two samples from 50 patients were analysed. BRAF V600E mutations were detected in 71.1% of samples followed by V600K (25%) and V600R (3.9%). There was a wide range of AF from 3.9% to 80.3% (median 41.3%). In 33 patients treated with BRAFi, there was no difference in overall or progression-free survival when the patients were categorized into high or low AF groups. There was no correlation between AF and degree of response, and no difference in survival based on genotype.

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Section: Discussioncontrasting

confidence: 99%

Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma

Ardakani

Leslie

Grieu-Iacopetta

et al. 2017

Pigment Cell Melanoma Res

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“…29 In this study, females had superior PFS and OS when they were treated with MAPK inhibitors, but because the degree of response was not statistically different from that of males (although a trend was observed), this may simply represent the natural history. Interestingly, the study by Ugurel et al 21 and early data from Flaherty et al 22 show improved OS for males. A subgroup analysis of the metastatic MAPK inhibitor trials should clarify this issue.…”

Section: Discussionmentioning

confidence: 96%

“…21,22 One study of 300 patients treated with vemurafenib demonstrated that LDH, ECOG PS, and age were associated with PFS and OS, and male sex was associated with OS. 21 In contrast to this study, however, 34% of the patients were not enrolled in clinical trials and, therefore, did not have prospective response assessments; 43% had received prior systemic treatment for metastatic disease, including immunotherapy (13%) and MAPK inhibitors (7%); the maximum follow-up was only 25 months; and the influence of post-vemurafenib systemic therapies on OS was not assessed. Initial data presented from a second study of 54 patients treated with CombiDT with a maximum follow-up of approximately 3 years showed in a multivariate model that improved OS was associated with males, normal LDH levels, and fewer metastatic disease sites.…”

Section: Discussionmentioning

confidence: 99%

“…PFS and OS associations were shown for 342 patients treated with BRAF inhibitors in a univariate model when LDH was examined as a continuous variable as well as the aforementioned vemurafenib analyses. 16,21,23,24 The fact that the degree of the tumor response was also inferior in those with an elevated LDH level suggests that LDH is not simply prognostic. The biology of metastatic tumors that produce different levels of LDH may be distinct; for example, it has been shown that a high serum LDH level reflects an anaerobic oxidative metabolic state.…”

Section: Discussionmentioning

confidence: 99%

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Clinicopathologic features associated with efficacy and long‐term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors

Menzies

Wilmott

Drummond

et al. 2015

Cancer

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BACKGROUND:The degree of response and the duration of survival of patients treated with mitogen-activated protein kinase (MAPK) inhibitors are highly variable. Whether baseline clinicopathologic factors can predict the clinical course with treatment is largely unknown. METHODS: For 142 consecutive immunotherapy-and MAPK inhibitor-naive patients with BRAF-mutant metastatic melanoma who were treated during clinical trials with BRAF inhibitors (n 5 111) or a combination of dabrafenib and trametinib (n 5 31), clinicopathologic factors were correlated with the response to MAPK inhibitors and survival. RESULTS: The median follow-up was 15.7 months (range, 0.6-60.5 months). The 2-, 3-, and 4-year overall survival (OS) rates were 43%, 24%, and 24%, respectively. A multivariate analysis demonstrated that the only clinicopathologic factors associated with longer progression-free survival (PFS) and OS were female sex and a normal pretreatment serum lactate dehydrogenase (LDH) level. The BRAF V600E genotype and an absence of primary melanoma ulceration were also independently associated with longer PFS but not OS. The median OS was 23.5 months for patients with normal LDH levels and 7.3 months for those with elevated LDH levels (hazard ratio, 0.31; P < .001). Complete responders had the best survival, but disease progression still occurred in 2 of 7 patients. CONCLUSIONS: Long-term survival occurs for a minority of patients receiving MAPK inhibitor treatment alone. Sex, serum LDH, BRAF genotype, and primary melanoma ulceration status are independent factors associated with treatment outcomes. Patients with a complete response to treatment have the best survival, but relapses still occur. Cancer 2015;121:3826-35.

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“…For example, mutations of RAS or its upstream/downstream effectors occur almost in every lung cancer cell, and expression of activated KRAS in mice has been a robust model for lung cancer development, particularly non-small cell lung cancer (NSCLC). Furthermore, targeted therapy towards growth factor receptor gene mutations in NSCLC has significantly improved the quality of life in a subset of lung cancer patients (Robert et al, 2015; Thomas et al, 2015; Thress et al, 2015; Tricker et al, 2015; Ugurel et al, 2015; Weber et al, 2015; Yang et al, 2015a, 2015b). In addition, gene mutations in the p53 and RB/p16 pathways are common in lung cancer (Cooper et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development

Zhang

et al. 2015

Journal of Genetics and Genomics

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Lung cancer causes more deaths than breast, colorectal and prostate cancers combined. Despite major advances in targeted therapy in a subset of lung adenocarcinomas, the overall 5-year survival rate for lung cancer worldwide has not significantly changed for the last few decades. DNA repair deficiency is known to contribute to lung cancer development. In fact, human polymorphisms in DNA repair genes such as xeroderma pigmentosum group C (XPC) are highly associated with lung cancer incidence. However, the direct genetic evidence for the role of XPC for lung cancer development is still lacking. Mutations of the Kirsten rat sarcoma viral oncogene homolog (Kras) or its downstream effector genes occur in almost all lung cancer cells, and there are a number of mouse models for lung cancer using these mutations. Using activated Kras, KrasLA1, as a driver for lung cancer development in mice, we showed for the first time that mice with KrasLA1 and Xpc knockout had worst outcomes in lung cancer development, and this phenotype was associated with accumulated DNA damage. Using cultured cells, we demonstrated that induced expression of oncogenic KRASG12V led to increased levels of reactive oxygen species (ROS) as well as DNA damage, and both can be suppressed by anti-oxidants. Thus, it appears that XPC may help repair DNA damage caused by KRAS-mediated production of ROS.

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A multicenter DeCOG study on predictors of vemurafenib therapy outcome in melanoma: pretreatment impacts survival

Cited by 20 publications

References 20 publications

Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma

Clinical and therapeutic implications of BRAF mutation heterogeneity in metastatic melanoma

Clinicopathologic features associated with efficacy and long‐term survival in metastatic melanoma patients treated with BRAF or combined BRAF and MEK inhibitors

Genetic Evidence for XPC-KRAS Interactions During Lung Cancer Development

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