Study of Rare BRAF Mutations in Melanoma May Impact Treatment

BRAF^K601E(K601E) andBRAF^L597(L597).¹

These two subtypes have different distribution patterns on the body and L597 mutation melanomas having more favorable prognostic characteristics than those with the K601E mutation. Preliminary reports show these mutations may respond to targeted therapies, and the authors urge that prospective studies be conducted to clarify the responses of these mutations to BRAF and MEK inhibition.^1,2,3

Methods and Mutations

The researchers employed data from the Melbourne Melanoma Project database to arrive at their conclusions. The data included patients recruited between 2009 and May 2013 and contained molecular analysis data for primary melanomas in 1159 patients (99.7% of the total database). After excluding data onin situmelanomas, cutaneous metastases, benign nevi, and spitzoid tumors of unknown malignant potential, the final total of 1119 examples of invasive melanomas remained.BRAFmutations were found in melanomas in 435 patients. The majority of these were V600 mutations (n = 406) the most common being the V600E mutation (n=310). BRAF wild type (BRAF wt), were encountered in 684 patients, and among these, 37 hadNRASmutations and 4 hadKITmutations.

The team also found less common V600 mutations, such as V600D (n=4), V600M (n=1), V600K (n=86), and V600R (n=5). Sunburn history was reported by similar proportions of patients (V600E, 60.5%; K601E, 66.7%; L597, 66.7%;BRAFwt, 65.5%;P= .4).¹

BRAF^L597andBRAF^K601Ewere the most commonly found non-V600 mutations, comprising 3.3% and 3.1% of allBRAFmutations. The patients were predominantly male, (K601E:71.4%; L597: 73.3%) and this gender difference was statistically significant (P= .002).¹

BRAF^L597

Mutations

These patients were significantly older versus patients with the V600E mutation (median 66 years range 58-71; median 50 years, range 40-61;P= .001). Using the presence or absence of solar keratoses as a measure of prior sun exposure, it was found that a history of solar keratosis was more common in patients with the L597 mutation (58.3%) than in patients with V600E mutations (P= .04). L597 melanomas were most often located on the extremities in 40% of patients, and on the head and neck in a further 33% of patients.

When assessed by Breslow thickness, it was found that 35.5% of V600E, 42.9% of L597, and 27.9% of BRAF wt melanomas were <1.0 mm. Examination of histological subtypes revealed that 66.7% of L597 melanomas were of the superficial spreading subtype (SSM), and this association was statistically significant. However, they were more likely to be of the lentigo maligna subtype (LMM) than SMM when compared with V600E- mutant melanomas (P = .02). Ulceration, a poor prognostic feature, was seen in 33.3% of L597 cases, and 85.7% had &ge;1 mitoses/mm².¹

BRAF^K601EMutations

In contrast to patients with L597 mutations, these individuals were younger, had a median age of 58 years (31-86) and this was not significantly different from patients with the V600E mutation (P= .2). Thirty six percent of patients with the K601E mutation and 50.6% of patients with V600E were under 50 years of age. With respect to a history of solar keratoses, patients with the K601E mutation had an incidence of only 16.7% (similar to V600E patients). Given this finding, the authors reiterated that the K601E and V600E-mutant primary lesions were more often found on the trunk, areas with less sun exposure, versus BRAF wt lesions, which are more common on sun-exposed sites (K601E, 64.3%,P= .01; V600E, 39.8%,P= .001 versus BRAFwt, 25.8%).

Regarding Breslow thickness, a smaller percentage of K601E melanomas (21.4%) had a median thickness of <1mm with 35.7% having a thickness >4.0 mm. There was a difference in melanoma histology between K601E and L597 mutations. A greater proportion of K601E melanomas were nodal melanomas, with fewer SMM versus the other mutations, but this was not statistically significant. However, 43% of patients with the K601E mutation had nodal disease on diagnosis versus only 14% of patient with BRAF wt tumors (P= .003).¹

Contrasting the Mutations

The authors suggest theBRAF^K601E- andBRAF^L597- harboring melanomas differ in terms of mutation load. The finding that BRAF^K601Emelanomas lacked an association with chronic sun damage suggests the mutation is more likely to occur in low mutation load melanomas. This melanoma is more likely to occur in patients with &ldquo;nevus prone&rdquo; skin, who develop melanomas at an earlier age with less prior sun damage.

The scenario is different for melanomas with the L597 mutation. These are considered to be more likely to arise in high mutation load tumors, and high mutation load may be a predictor of response to therapy with immune checkpoint inhibitors.⁴The L597 mutation melanomas generally had more favorable prognostic features than those harboring the K601E mutation because they were thinner and nodal involvement was less common.

Implications for Treatment

The paper calculates that the incidence rate of the mutations L597 and K601E is 2.6%, and that in 2012 the absolute number of these patients would be 1976 in the United States alone. There is clearly a precedent for investigating the clinical impact of these mutations particularly since major clinical trials only recruit V600E or V600K mutations. In-vitro sensitivity of these mutations to MEK and BRAF inhibition has been demonstrated, and a small number of patients with these mutations have shown responses to therapy with a MEK inhibitor.^2,3

A phase II clinical trial that recruited patients with recurrent or stage III/IV melanoma with BRAF non-V600 mutations is currently evaluating the MEK inhibitor, trametinib (NCT02296112). The estimated primary completion date is January 2018. The authors conclude these mutations are a significant minority of melanomas and a prospective evaluation of possible therapeutic approaches is warranted.

References

1. Voskoboynik M, Mar V, Mailer S, et al. Clinico-pathological characteristics associated with BRAF(K) (601E) and BRAF(L) (597) mutations in melanoma.Pigment Cell Melanoma Res. 2015 Dec 8. doi: 10.1111/pcmr.12450.
2. Dahlman KB, Xia J, Hutchinson K, et al. BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors.Cancer Discov. 2012;2(9):791-797.
3. Bowyer SE, Rao AD, Lyle M, et al. Activity of trametinib in K601E and L597Q BRAF mutation-positive metastatic melanoma.Melanoma Res. 2014;24(5):504-508.
4. Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma.N Engl J Med. 2014;371(23):2189-2199.