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A case report of a patient with metastatic ocular melanoma who experienced a response to treatment with the BRAF inhibitor vemurafenib
© The Author(s). 2016
Received: 27 October 2015
Accepted: 1 August 2016
Published: 12 August 2016
Conjunctival malignant melanoma (CMM) is a rare malignancy and in the advanced setting there is no effective treatment. In contrast, half of cutaneous melanomas have BRAF mutations and treatment with BRAF inhibitors is established for patients with disseminated disease. The most common form of ocular melanoma, uveal melanoma, lacks these mutations, however, their presence has been reported for CMM.
We used the BRAF inhibitor vemurafenib to treat a 53 year-old female suffering from a BRAFV600E mutated metastatic CMM. The patient benefited from the treatment, a response was evident within a week and she experienced a progression free survival of four months.
To our knowledge, this is the first described case of response to vemurafenib treatment in a patient with ocular melanoma.
Two subtypes of primary ocular melanoma have been described, uveal and conjunctival. Conjunctival malignant melanoma (CMM) is a rare condition with an incidence of 0.2 to 0.8 per million in Caucasian populations. It is a frequently lethal non-cutaneous neoplasm with an average 10-year mortality rate of 30 % . Studies over the past two decades have revealed different genetic subsets of melanoma [2–4]. Half of cutaneous melanomas harbor activating mutations in BRAF and the most abundant is BRAFV600E followed by BRAFV600K. However, the most common form of ocular melanoma, uveal melanoma, lacks these mutations except from its smallest subgroup, iris melanoma. CMMs have not been well characterized at the genetic level, however, BRAFV600E mutations have been reported in 14 % to 50 % [5–7].
At present no effective treatment is available for metastatic CMM, hence the need for new therapies is essential. In contrast, treatment with the BRAF inhibitors vemurafenib and dabrafenib is established for patients with BRAFV600E and BRAFV600K mutated disseminated cutaneous melanomas [8, 9]. BRAF status might also be a predictive marker in deciding whether to use BRAF inhibitors for the treatment of patients with advanced CMM . Here we present a case of a patient with metastatic CMM positive for the BRAFV600E mutation who was treated with vemurafenib. To our knowledge, there is no previously described treatment response to vemurafenib in ocular melanoma.
Tissue from the primary tumor was tested for BRAF status, revealing the presence of the V600E mutation.
We report on a patient with disseminated CMM who was treated with the BRAF kinase inhibitor vemurafenib due to the presence of the BRAFV600E mutation. She had received all established treatments and even experimental therapy; AdCD40L.
Ocular melanoma is a rare type of malignant melanoma. For most small and medium size tumors, irradiation is recommended. Surgery is often the treatment of choice for recurrent disease, after initial radiotherapy. Approximately half of the patients with ocular melanoma develop metastatic disease . In general, prognosis is very poor for patients with advanced disease, and without treatment the median survival is around eight months .
In the common clinical practice, all patients with advanced cutaneous malignant melanoma who meet the criteria for treatment with a BRAF inhibitor are tested for the presence of the BRAF mutation . However, BRAF therapy is not established for patients with CMM or other ocular melanomas. Vemurafenib is a highly selective inhibitor of mutated BRAF, it induces objective responses in 50 % of patients and prolongs survival when compared to traditional chemotherapeutic agents [14–16]. The drug is even effective in patients with brain metastases . Unfortunately, most, if not all, patients eventually develop resistance to vemurafenib [18–20]. For many years it was thought that patients with ocular melanoma could not benefit from treatment with BRAF-kinase inhibitors due to the fact that the RAS-BRAF kinase pathway is not involved in the most common ocular melanoma, the choroidal melanoma [10, 21]. However, it was eventually shown that BRAF mutations are present in conjunctival melanomas [5, 7].
Since the patient had received and experienced disease progression on all established treatments, vemurafenib treatment was considered an option. A clear correlation between the on-set of vemurafenib therapy and the regression of the metastases in the orbit and parotid gland was clinically observed. However, it cannot be ruled out that the major regression of the metastasis of the orbit partly was a result of the whole brain radiotherapy. It is also unclear whether the response in the parotid gland represents an effect of vemurafenib alone. A late synergistic effect with gene therapy (AdCD40L) is possible despite the obvious systemic resistance to that treatment as pointed out with the occurrence of brain metastases after the last injection of AdCD40L. Of note is that there was a clear response in the non-localized treated lung metastasis emphasizing that the vemurafenib treatment was beneficial. In the only conducted study with AdCD40L administered in metastatic melanoma patients no late immune responses were noted . In addition, other immunotherapy approaches in ocular melanoma patients have not proved effective in contrast to cutaneous melanoma. In fact, treatment with the anti-CTLA-4 antibody ipilimumab showed limited treatment benefit [23–25] and preliminary data from ongoing clinical trials with PD-1 antibodies are not encouraging . It is therefore unlikely that the patient’s response represents a late systemic synergistic effect with AdCD40L treatment.
The treatment was well tolerated after an early 25 % reduction of the initial dose. The patient’s general condition was considerably improved alongside with rapid regression of tumor lesions. The patient passed away five months after the initiation of the treatment with vemurafenib, shortly after the treatment’s discontinuation.
According to the registration trial and Drummer et al. [14–17] the median progression free survival after vemurafenib treatment is 3.9 months for patients with BRAFV600E-mutant metastatic cutaneous malignant melanoma with non-excisable previously treated brain metastases. The patient described in this case report clearly benefitted from the treatment and the gain was very similar to the average for the corresponding group of patients with cutaneous malignant melanoma.
It is reasonable to believe that all patients with BRAF-mutant cancer would benefit from treatment with BRAF inhibitors. However, colon cancer patients harboring the BRAFV600E oncogenic lesion have a poor prognosis and do not respond to vemurafenib therapy. It was shown that this unresponsiveness depends on BRAF inhibition through feedback activation of EGFR .
Two attempts of treating metastatic CMM with vemurafenib have previously been reported. One of these patients experienced a mixed response, which after a short period was followed by evident disease progression . In a Chinese CMM trial one of the patients’ tumor was tested positive for the BRAF mutation and treatment with vemurafenib was given. However, the outcome was unclear for this second reported case . In addition, a patient who received dabrafenib experienced an objective response but disease progression was evident after 6 months .
In conclusion, we show for the first time that treatment of BRAF mutated metastatic CMMs with vemurafenib could be of value. Further studies are needed to assess the efficacy of BRAF and PD1 inhibitors in the different subtypes of ocular melanoma.
The CMM subtype of ocular melanoma is however very rare making it extremely difficult to perform a randomized clinical study.
The authors would like to thank The research foundation Stiftelsen Onkologiska Kliniken i Uppsala Forskningsfond and Lion’s Cancer Fund at Uppsala University Hospital.
Availability of data and materials
Patient data cannot be shared since they are stored in the electronic patient annotation systems Cosmic and Take Care.
AM and GU have written the manuscript and together with PB been responsible for the patient’s treatment. GÅ has assessed the scans and he and PB have critically reviewed the manuscript. All authors have read and approved the manuscript.
The authors declare that they have no competing interests.
Consent for publication
Consent for publication in print and electronically has been obtained from the patient’s closest relative, her father and not the patient herself since she was deceased before the plan to write this article took form.
Ethics approval and consent to participate
Ethics approval is not applicable. The patient gave her informed consent to be treated.
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