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Table. Patient and Melanoma Characteristics in Study Cases
Table. Patient and Melanoma Characteristics in Study Cases
1.
Dalle S, Poulalhon N, Thomas L. Vemurafenib in melanoma with BRAF V600E mutation.  N Engl J Med. 2011;365(15):1448-1450PubMedArticle
2.
Hatzivassiliou G, Song K, Yen I,  et al.  RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.  Nature. 2010;464(7287):431-435PubMedArticle
3.
Murali R, Field AS, McKenzie PR,  et al.  Melanotic schwannoma mimicking metastatic pigmented melanoma: a pitfall in cytological diagnosis.  Pathology. 2010;42(3):287-289PubMedArticle
4.
Zimmer L, Hillen U, Livingstone E,  et al.  Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition.  J Clin Oncol. 2012;30(19):2375-2383PubMedArticle
5.
Guitera P, Menzies SW. State of the art of diagnostic technology for early-stage melanoma.  Expert Rev Anticancer Ther. 2011;11(5):715-723PubMedArticle
Research Letter
April 2013

Tracking of Second Primary Melanomas in Vemurafenib-Treated Patients

Author Affiliations

Author Affiliations: Unit of Dermatology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Lyon, France (Drs Dalle, Poulalhon, Debarbieux, Zaharia, and Thomas); Université Claude Bernard, Lyon (Drs Dalle, Zaharia, and Thomas); Cancer research center of Lyon, Lyon (Dr Dalle); Department of Dermatology, Harvard Medical School, Brigham and Women's Hospital and Dana Farber Cancer Institute, Boston, Massachusetts (Dr Mihm); Department of Medicine, Dermatology Service (Drs Lacouture, Rosen, and Marghoob), and Department of Pathology (Dr Busam), Memorial Sloan-Kettering Cancer Center, New York, New York; Unit of Pathology, Centre Hospitalier Lyon-Sud, Hopital Edouard Herriot, Hospices Civils de Lyon, Lyon (Drs Depaepe, Bringuier, and Balme); Departments of Dermatology (Dr Richez) and Oncology (Dr Baurain), Centre du Cancer, Cliniques Universitaires St Luc Université Catholique de Louvain, Brussels, Belgium; and Service de Génétique, Département de Biopathologie, Institut de Cancérologie Gustave Roussy, Villejuif, France, and INSERM, U946, Genetic Variation and Human Diseases Unit, Paris, France (Dr Bressac–de Paillerets).

JAMA Dermatol. 2013;149(4):488-490. doi:10.1001/jamadermatol.2013.21

Our research group1 recently reported the occurrence of second primary melanomas (SPMs) detected in patients with vemurafenib-treated metastatic melanomas. We report herein the changes observed, via routinely used diagnostic tools such as digital dermoscopy and reflectance confocal microscopy (RCM), in pigmented lesions in patients treated with vemurafenib.

Methods

All patients treated with vemurafenib, 960 mg twice daily, for metastatic V600E BRAF -mutated melanoma, underwent routine monthly total-body skin examination with dermoscopy and digital dermoscopy. The 5 initial cases were very briefly reported previously.1 Suspect or rapidly changing lesions were excised and submitted for pathologic examination by 2 dermatopathologists and externally by a third independent dermatopathologist.

Patients signed an informed consent for molecular testing and basic science research to be performed on skin samples. In vivo RCM was performed using the Vivascope 1500 (Lucid Inc). Mutation status was determined using a real-time polymerase chain reaction assay (Cobas 4800 BRAF V600 Mutation Test; Roche Molecular Systems). Patient DNA was subsequently retested with a validated 2-fold bidirectional Sanger sequencing method.

Eight patients diagnosed as having a second primary melanoma signed a written informed consent prior to undergoing germline mutational analysis of CDKN2A (exons 1α, 2 and 3), ARF (exon 1β), CDK4, and MITF genes. Institutional review board approval was also obtained (CCPPRB No. 01-09-05, Paris Necker).

Results

Twenty-five SPMs were diagnosed in 120 patients. The delay of the SPM diagnosis after vemurafenib treatment initiation ranged from 4 to 42 weeks. The median delay was 14 weeks (Table).

All the patients tested were found to be negative for the melanoma-prone genes germline mutation.

Two changing lesions were first reported by the patients themselves (cases 1 and 2). These were found to be invasive melanomas (Breslow thicknesses, 0.7 and 0.65 mm, respectively). Among the 9 lesions removed on the basis of handheld dermoscopy examination, thicknesses ranged from in situ to 0.45 mm. Under digital dermoscopy, significant changes were noted in 21 cases during short-term follow-up. The observed changes usually did not affect the external diameter of the lesion but were subtle modifications affecting the pigmented or vascular pattern within a given lesion. Those changes were invisible by naked-eye examination. Among the 21 lesions removed on the basis of digital dermoscopy follow-up, 12 were melanomas (ranging from in situ to 0.3 mm Breslow thickness).

Forty-two lesions were examined by RCM following the observation of significant changes on digital dermoscopy. Nineteen of these were subsequently not excised because of the presence of a typical benign features, and they did not show any additional significant change on subsequent observations.

Twenty-one melanoma samples were genotypically tested for NRAS and BRAF mutations. All the cases were wild-type mutations for BRAF; 1 case was NRAS Q61R mutated.

Comment

The impact of BRAF inhibition on BRAF wild-type nevi or early melanomas remains unclear. Paradoxical activation of the RAF/MEK/ERK pathway by RAF kinase inhibitors through a CRAF activation sequence has been the major foreseeable effect determined from the in vitro studies conducted by Hatzivasilliou et al.2 Alternatively, vemurafenib-induced blockade of the BRAF pathway may favor alternate signaling pathways. Ultimately, although rare, HRAS mutations have been reported in pigmented lesions, and vemurafenib may enhance their malignant behavior.

The exact incidence of SPM in patients with metastatic melanoma is still debated. Recently, Murali et al3 reported in an Australian population a history of 2 melanomas in up to 10.8% of a cohort of patients with metastatic melanoma before and during a long-term follow-up period. In our series, as well as in the series reported by Zimmer et al,4 most of the melanomas developed within a few weeks of treatment and were detected at an early clinical stage. The first observations were made during a clinical trial comparing vemurafenib with dacarbazine. In contrast to our findings reported herein with vemurafenib-treated patients, in our earlier study, our group did not detect any SPM in the dacarbazine group,1 and both groups of patients underwent the same follow-up.

An effective strategy for early detection of new primary melanomas is needed because BRAF blocking agents are being evaluated in the adjuvant setting. Beyond handheld dermoscopy, digital dermoscopy is a powerful tool for detecting significant changes within multiple pigmented lesions.5

The occurrence of SPM alongside the remarkable therapeutic response of melanoma metastases with vemurafenib therapy reflects the heterogeneous response of melanocytic lesions to BRAF inhibitors. V600E BRAF -mutated melanoma metastases responded to therapy, whereas wild-type melanomas were activated.

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Article Information

Correspondence: Dr Dalle, Service de dermatologie, Centre Hospitalier Lyon Sud, 69495 Pierre Bénite, Lyon, France (stephane.dalle@chu-lyon.fr).

Accepted for Publication: January 8, 2013.

Author Contributions: Dr Dalle had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Dalle, Lacouture, and Thomas. Acquisition of data: Dalle, Poulalhon, Debarbieux, Zaharia, Mihm, Rosen, Marghoob, Busam, Bringuier, Richez, Baurain, Bressac–de Paillerets, and Thomas. Analysis and interpretation of data: Dalle, Marghoob, Busam, Depaepe, Richez, Baurain, Balme, and Thomas. Drafting of the manuscript: Dalle, Lacouture, and Thomas. Critical revision of the manuscript for important intellectual content: Poulalhon, Debarbieux, Zaharia, Mihm, Rosen, Marghoob, Busam, Depaepe, Bringuier, Richez, Baurain, Bressac–de Paillerets, Balme, and Thomas. Obtained funding: Thomas. Administrative, technical, and material support: Dalle, Zaharia, Lacouture, Busam, Depaepe, Baurain, Balme, and Thomas. Study supervision: Dalle, Mihm, Busam, Baurain, and Thomas.

Conflict of Interest Disclosures: None reported.

Funding/Support: This work was supported in part by grants from Lyon 1 University, the Hospices Civils de Lyon, and the liguecontre le cancer du Rhone (Dr Thomas).

References
1.
Dalle S, Poulalhon N, Thomas L. Vemurafenib in melanoma with BRAF V600E mutation.  N Engl J Med. 2011;365(15):1448-1450PubMedArticle
2.
Hatzivassiliou G, Song K, Yen I,  et al.  RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.  Nature. 2010;464(7287):431-435PubMedArticle
3.
Murali R, Field AS, McKenzie PR,  et al.  Melanotic schwannoma mimicking metastatic pigmented melanoma: a pitfall in cytological diagnosis.  Pathology. 2010;42(3):287-289PubMedArticle
4.
Zimmer L, Hillen U, Livingstone E,  et al.  Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition.  J Clin Oncol. 2012;30(19):2375-2383PubMedArticle
5.
Guitera P, Menzies SW. State of the art of diagnostic technology for early-stage melanoma.  Expert Rev Anticancer Ther. 2011;11(5):715-723PubMedArticle
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