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A model for cutaneous squamous cell carcinoma in vemurafenib therapy.

In 1975, a 20-year-old white female presented with a solitary lesion on her right lower extremity. Following the diagnosis of melanoma, the patient was treated with wide local excision and nodal dissection up to and including her right inguinal lymph nodes, which were all found negative for metastasis. Thirty-five years later, at age 55, the patient presented with a subcutaneous nodule in her right popliteal fossa, and an excisional biopsy showed the presence of melanoma within the popliteal nodes. The workup included a PET scan that showed metastases to her lung, liver, kidneys, and brain. The patient began an intensive five-month regimen of chemotherapy, which consisted of dacarbazine, temozolomide, and vinblastine every three weeks. She also began an immunotherapy regimen, which consisted of INF-alpha, IL-2, and IL-2-treated tumor stem cells. In addition, the patient underwent gamma-knife radiation and surgical resection for the brain metastasis.

Three months later, in May of 2011, she traveled to Nashville to become a part of a trial study on vemurafenib (Zelboraf, manufactured by Roche), an experimental drug for the treatment of metastatic melanoma. There, she began a regimen of vemurafenib 960 mg PO BID and was subsequently transferred to continue the trial in Dallas. Since she began vemurafenib therapy, there was a significant shrinkage of all tumors. Four months later, when the trial ended, the patient continued her vemurafenib therapy unchanged via her insurance.

Prior to vemurafenib therapy, our patient had a history of sun-damaged skin that included melanoma and actinic keratoses. While in Dallas as part of the vemurafenib study, the patient's dermatological evaluations yielded two more biopsy-proven actinic keratoses, both on the right upper extremity. Moreover, a 1.3 cm cutaneous squamous cell carcinoma (CuSCC) was diagnosed on her left lower extremity as a result of a dermatological evaluation six months after vemurafenib initiation. Wide local excision was performed, as per standard of care. Pathological testing of the CuSCC specimen for KRAS and BRAF mutations were both negative.

In August 2011, vemurafenib was FDA-approved as a chemotherapeutic drug for the treatment of metastatic melanoma patients harboring the BRAF V600E mutation. (1) BRAF V600E is a serine-threonine kinase of the RAS-RAF-MEK-ERK/MAPK signaling pathway with a transversion mutation at nucleic acid 1799 T>A, which results in a single amino acid substitution of valine 600 to glutamic acid in the activating region of the kinase domain. (2, 3) This mutation, although not evident in early-stage melanoma, is a mutation that has been tied with a more aggressive progression of metastatic melanoma lesions after distant or unresectable metastasis has developed. (4,5) One study found that 48% of metastatic melanoma cases had tumor cells carrying activating mutations in BRAF, with 74% of this cohort carrying the V600E mutation targeted by vemurafenib. (5)

Vemurafenib belongs to the class of designer drugs, which appear to be at the forefront of drug development today. After a long period of stasis in the realm of melanoma therapy, early reports of vemurafenib's efficacy are promising. In a phase 3 randomized clinical trial, which included 675 patients with previously untreated metastatic melanoma harboring the BRAF V600E mutation, vemurafenib was compared with dacarbazine (DTIC-Dome, originally marketed by Bayer), a well-established first-line chemotherapy in metastatic melanoma. (6) Within this study, vemurafenib produced significant improvement in rates of overall and progression-free survival in these patients. Furthermore, the results showed that at six months the overall survival was 84% (CI of 95%, 78-89) in the vemurafenib group compared to 64% (CI 95%, 56-73) in the dacarbazine group. In addition, at the interim analysis of overall survival, vemurafenib was associated with a relative reduction of 63% in risk of death; and at the final analysis of progression-free survival, vemurafenib was associated with a relative reduction of 74% in the risk of either death or disease progression, as compared with dacarbazine (P<0.0001 for both comparisons). During the trial, and after review of the interim analysis by an independent data and safety monitoring board, crossover from dacarbazine to vemurafenib was recommended. (6)

As a molecular-based therapy, vemurafenib has the appeal of potential decreases in systemic toxicity and side effects. However, as these types of targeted therapies are seeing more and more use, physicians and researchers alike are seeing these drugs, as those before them, come at their own costs. This point is further emphasized by combination therapy, which may be necessary to get the most out of drugs in this class. A wide range of side effects with vemurafenib therapy has been observed, as outlined in the prescribing manual by Roche. (7) One notable association that correlates with the previously discussed case is the increased prevalence of CuSCC and keratoacanthomas (KA), an association shared with some other BRAF inhibitors. (2,7) Within a series of Phase 1, 2, and 3 trials of vemurafenib therapy, the range of CuSCC was from 12-31%. (7) Furthermore, Roche-cited-trials reported a 24% incidence of these lesions within their prescribing manual, and in another study with type 1 BRAF inhibitors, vemurafenib, and dabrafenib, 15-30% of patients treated had developed such lesions. (2,7) Pathological analysis of these tumors for BRAF mutations yields negative results, which point towards a separate etiology of these lesions from the primary melanoma. The increased incidence of tumors in these patients expresses the nature of the complex systems that are being manipulated in signal transduction interventional therapy. If you look at the outlined scheme of the MAPK pathway, then you can see the potential calculable risks and the consequences of such by alteration of a pathway that ultimately controls cell growth.

One explanation for the increased prevalence of these lesions is that vemurafenib is accelerating tumor progression in cells with pre-existing mutations. (8) One study, which supported this suggestion, tested 21 CuSCC and KA specimens from vemurafenib-treated patients, from which 13 specimens contained 14 upstream mutations in either N, H, or KRAS. (2) Of this cohort, 8/14 of the mutations were HRAS Q61L, a HRAS substitution at codon 61. Furthermore, a validation study looked at a similar group of 14 patients in which RAS testing showed 8/14 samples to have mutations, 4 HRAS, and 4 KRAS. (2)

HRAS Q61L was then transfected into NIH3T3 cells, an immortalized fibroblast cell line with wild type RAS. (2) These cells transfected with the use of a control vector did not form any colonies; however, when transfected with HRAS, colonies formed, and their sizes increased in a dose-dependent fashion with exposure to vemurafenib. This particular experiment suggests that vemurafenib is acting as a tumor promoter in cell lines with this pre-existing HRAS Q61L mutation via the paradoxical activation of the MAPK pathway in non-melanomatous cells with wild type BRAF, as evidenced by increased ERK phosphorylation and increased expression of ERK-related genes. (2) With this said, vemurafenib's proposed role as a tumor promoter is most likely not solely linked with HRAS Q61L, but with many other pre-existing mutations within the MAPK pathway as well.

The same research group that conducted the previously mentioned study went further to support vemurafenib's role as a tumor promoter in these lesions. (2) They conducted an experiment that used a two-stage skin carcinogenesis mouse model in which topical application of an HRAS Q61L mutation inducing carcinogen was applied to mouse keratinocytes with subsequent application of a stock-tumor-promoter to both control and experimental groups. (2)

Within the control group, well-differentiated invasive CuSCC and KAs did form. In the experimental group, PLX4720, an analog of vemurafenib with improved oral bioavailability in mice, was also administered. Here, although no increase in the number of lesions occurred, tumor latency was reduced by 45% and the time interval between the initial development of lesions and the maximal tumor burden reduced by 35%. Additionally, clinical evidence comes from reports that vemurafenib-induced tumors frequently arise in sun-damaged skin and that 20% of the non-melanoma, skin tumor developing cohort had a clinical history of previous CuSCC or KA. (2) These findings together serve a role in support that these lesions are not the result of activating mutations but tumor promotion by vemurafenib. In addition, it makes an important point regarding the rapidity at which these tumors are progressing. Due to the observed decreases in time span of tumor development, the usual indolent nature of CuSCC may not hold true with such rapid progressing tumors. We propose these lesions may have increased potential for early metastasis due to these observances, and thus, the nature of such lesions change with regard to the prudence of resection. However, patients with these lesions are doing well with resection, as per standard of care for CuSCC, and we have found no trials that show increased incidence of metastases from these tumors to date.

As outlined in the prescribing manual released by Roche concerning vemurafenib therapy, it is recommended that patients should have a dermatologic evaluation prior to the initiation of therapy and every two months while continuing therapy. (7) Furthermore, within the aforementioned phase 1, 2, and 3 trials, the number of lesions, lesion location, and their timing of presentation were widely variable. The majority of patients within these three trials had only one occurrence, with a range of 1-8. The median time of onset was 7.55 weeks between phase 2 and phase 3 trials, with a range of 2 to 36 weeks between phase 1 and phase 2 trials. With this said, it is important to follow through with full body skin checks during dermatological evaluation. Moreover, patients with higher levels of sun-damaged skin should be held at the highest level of probability for development of such lesions. In order to facilitate early presentation, patients should be educated on how to search for arising lesions and the type of lesions they are looking for. Decisively, no treatment adjustments are recommended following the occurrence of CuSCC or KA. (7)


Author Contributions: Dr. Sarah Glorioso, Dr. Mary Lowery Nordberg, and Mr. Rhett Kent had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Dr. Sarah Glorioso, Dr. Mary Lowery Nordberg, and Mr. Rhett Kent.

Acquisition of data: Dr. Sarah Glorioso, Dr. Mary Lowery Nordberg, and Mr. Rhett Kent.

Analysis and interpretation of data: Dr. Sarah Glorioso, Dr. Mary Lowery Nordberg, and Mr. Rhett Kent.

Drafting of the manuscript: Dr. Sarah Glorioso, Dr. Mary Lowery Nordberg, and Mr. Rhett Kent.

Critical revision of the manuscript for important intellectual content: Dr. Sarah Glorioso, Dr. Mary Lowery Nordberg, and Mr. Rhett Kent.

Statistical analysis: Dr. Sarah Glorioso, Dr. Mary Lowery Nordberg, and Mr. Rhett Kent.

Administrative, technical, or material support: Dr. Sarah Glorioso, Dr. Mary Lowery Nordberg, and Mr. Rhett Kent.

Study supervision: Dr. Sarah Glorioso, Dr. Mary Lowery Nordberg, and Mr. Rhett Kent.

No funding was obtained by anyone, including: Dr. Sarah Glorioso, Dr. Mary Lowery Nordberg, and Mr. Rhett Kent.


(1). The New York Times. Fast FDA approval of melanoma drug. <> (accessed 5 February, 2012).

(2.) Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med 2012;366:207-215.

(3.) Heakal Y, Kester M, Savage S. Vemurafenib (PLX4032): An orally available inhibitor of mutated BRAF for the treatment of metastatic melanoma. Ann Pharmacother 2011;45:1399-1405.

(4.) Dong J, Phelps RG, Qiao R, et al. BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma. Cancer Res 2003;63:3883-3885.

(5.) Long GV, Menzies AM, Nagrial AM, et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 2011;29:1239-1246.

(6.) Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-2516

(7.) Genentech, Inc. Highlights of prescribing information. <> (accessed 19 January, 2012).

(8.) Weeraratna AT. RAF around the edges--the paradox of BRAF inhibitors. N Engl J Med 2012;366:271-273.

Rhett Kent; Sarah Glorioso, MD; Mary Lowery Nordberg, MD

Mr. Kent is with the Louisiana State University Health Sciences Center in Shreveport. Dr. Glorioso is with the Willis Knighton Health System. Dr. Nordberg is Director of Delta Pathology Molecular Diagnostics (Delta MDx) and Professor of Medicine at the Feist-Weiller Cancer Center.
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Author:Kent, Rhett; Glorioso, Sarah; Nordberg, Mary Lowery
Publication:The Journal of the Louisiana State Medical Society
Article Type:Clinical report
Geographic Code:1USA
Date:Nov 1, 2012
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