Resident Rounds Part III: Metastatic Melanoma Patient on Vemurafenib Develops Multiple Primary Cutaneous Melanomas

March 2015 | Volume 14 | Issue 3 | Features | 316 | Copyright © March 2015

Jeffrey Brackeen MD, Jordan Jamerson BS, and Amy Brackeen MD

Texas Tech University Health Sciences Center, Lubbock, TX



A 45-year-old Caucasian female with a history of melanoma, 1.0mm in depth, Sentinel lymph node biopsy negative, 11-years prior, presented for routine skin exam and was noted to have lymphadenopathy of the right side of her neck. A subsequent CT scan revealed 10cm lesions in both the liver and spleen. Biopsies demonstrated metastatic melanoma; no cutaneous manifestations were present. Interferon treatment was initially used with no response. Genetic analysis revealed a positive BRAFV600E mutation, and vemurafenib therapy was initiated. One month after starting vemurafenib, two superficial spreading melanomas on the left mid back and left upper abdomen were discovered, depth 0.25mm and 0.60mm, respectively. The visceral tumors responded well, each shrinking to less than 2cm. Over the next 11 months four additional superficial spreading melanomas emerged, on the left upper and left superior upper arm, depth 0.32mm and 0.80mm, and the mid back and mid upper back, 0.27mm and 0.50mm. All six primary melanomas were confirmed by two dermatopathologists at separate institutions. Two of the six melanomas occurring while on vemurafenib were tested and were BRAF mutation negative. The patient is currently closely monitored. She continues to be treated with vemurafenib and more recently taxol, as 3 years after starting vemurafenib therapy, the tumors have grown back to their original diameters of 10cm. In addition to the aforementioned melanomas, 2 atypical melanocytic proliferations, 9 dysplastic nevi some with moderate cytologic atypia, and 5 compound melanocytic nevi were removed. In summary, a total of 6 superficial spreading melanomas, each uniquely located, developed after vemurafenib initiation.
Unresectable or metastatic melanoma has a poor prognosis with a 1-year survival rate of 25.5%.1 For years, dacarbazine or interferon was the standard care for these patients. In phase III clinical trials (BRIM-3), vemurafenib compared to dacarbazine demonstrated significant reduction in risk of death, clinical superiority in median overall survival, 13.6 to 9.7 months, and a significant increase in progression free survival, median of 5.3 to 1.6 months.2 Vemurafenib is an inhibitor for mutated BRAFV600E, which is a common mutation found in up to 66% of metastatic melanomas3 and constitutively activates a specific RAF kinase involved in the MAPK cellular proliferation pathway. While vermurafenib specifically inhibits proliferation in BRAF-mutated cells, it can paradoxically activate wild-type cells with mutated or activated RAS, previously found in potentially precancerous actinic keratoses.4 Cutaneous squamous cell carcinomas (cSCCs) or keratoacanthomas (KAs) may occur in approximately 25% of patients.4 Often, they occur in the first 2-3 months after starting therapy on sunexposed areas.4 Oberholzer et al found that squamous cell tumors treated with a RAF inhibitor had higher rates of HRAS mutations, despite similar rates of total mutations. Increased RAS mutation rates in these cutaneous cancers plus its preferential development in sun-exposed locations on older patients rapidly following treatment initiation supports the theory of an underlying mutational predisposition that is unmasked due to a RAF inhibitor pro-proliferative state.4 RAS-mutated tumors in BRAF wild type cells allow inhibitor binding to cause RAF dimerization, permitting transactivation of the drug-free promoter and activating the MEK substrate.5 Aside from the risk of cutaneous carcinomas, RAS mutations in BRAF positive cells may be a mechanism for BRAF inhibitor resistance as well as potentially increase the risk of extracutaneous cancer, since RAS mutations are seen in many types including colon, pancreatic, and lung, although this not been seen.4