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In advanced melanoma, BRAF mutation testing is critical in predicting treatment response with targeted therapy (i.e., BRAF/MEK inhibitors). Certain features were identified in melanomas that harbor BRAF mutations (e.g., primary lesions located on the trunk, diagnosed in patients <50, visibly pigmented tumors and, at times, with ulceration or specific dermatoscopic features). For select advanced melanoma patients, delays in determining mutational status present a significant barrier to the prompt initiation of treatment. This can adversely impact patient outcomes, especially in the metastatic setting due to a rapidly progressive disease. Treatment in these cases needs to start promptly by a medical oncologist. Ordering BRAF testing by preceding members of the treating team will allow medical oncologists to initiate treatment at the first visit. According to poor survival outcomes, we propose that patients with thick tumors (>4.0 mm) or >2 mm tumors with ulceration (i.e., stage ≥IIB) should potentially be considered for systemic therapy, thus justifying reflex BRAF testing.
Features/Outcomes | Primary Melanoma | Metastatic Melanoma |
---|---|---|
BRAF mutation prevalence | Primary melanoma: 33–47% [6] | Metastatic melanoma: 41–55% [6] |
Recurrent melanoma found to have higher frequency of BRAF mutation [8] | - | |
Patient Features | ||
Age of diagnosis | <50 [6][9] | Younger individuals [6] |
UV exposure | High estimated lifetime exposure [10] and early-life exposure [10][11] | - |
Total body nevus count | Patients with high number of nevi on back (>14) [10] more likely to harbor a BRAF mutation | - |
Chronic sun-damaged skin | Fewer signs of chronic sun damage [9], such as lentigines [11] and solar elastosis [8][10] | Less chronic sun damage [6] |
Melanoma Features | ||
Number of primary lesions | - | Occult or 1 lesion [6] |
Location of primary melanoma | Truncal location [6][9][7] | Truncal location [6] |
Melanoma subtype | Superficial spreading [9] or nodular [8] | - |
Pigmentation | Presence of pigmentation on pathology and as detected by patient [11] | - |
Breslow thickness (of primary) | BRAF mutation associated with increased tumor thickness compared to wildtype [12][13] | - |
Ulceration (of primary) | BRAF mutation associated with the presence of ulceration [8][7][14][15] | No association [6] |
Dermoscopy features | Irregular peripheral streaks [16], blue-white veil [17], and “peppering” [18] | - |
Outcomes | ||
Stage at presentation | Presentation at a more advanced stage is associated with BRAF mutation [9][19] | |
Response to chemotherapy | - | No association [6] |
Response to BRAF/MEK inhibitor | - | Highly predictive of response to therapy [20] |
Disease-free interval (primary diagnosis to first distant metastasis) | - | No association [6] |
Outcome (survival) | No association [6] | Further investigation necessary |
Features | IHC | RT-PCR | HRM | Sanger | Pyrosequencing | NGS | |
---|---|---|---|---|---|---|---|
Cobas® | THxID® | ||||||
Detection of mutations [26][27] | VE1 antibody for V600E | V600E | V600E V600K |
Indirectly detects mutations | Whole exon, detects rare mutations | Optimized for V600 mutations | Whole exon, detects rare mutations |
Sensitivity | Up to 98.6% [28] | 95% [29] | >96% (V600E) >92% (V600K) [26] | 99% [27] | 92.5% (for V600E) [29] | 90 to 100% [27][30] | 99% [31] |
Specificity | 97.7% [28] | 98% [26] | 100% [26] | 100% [27] | 100% [27] | 95 to 100% [27][30] | 100% [31] |
Limit of detection (i.e., proportion of cells that are positive) | Few cells [32] | 7% [27] | 5% [26] | 6.6% [26] | 6.6% [33] | 5.0% [34] | 2% [27] |
Turnaround time [27] | <1 day | 1 day | 1 day | Up to 3 days | 2 days | Up to 5 days | |
Cost [27] | Low | Medium | Low | Medium | High | Very high |
The implementation of carefully developed disease-specific reflex testing criteria by a multidisciplinary team is important to avoid the futile use of valuable healthcare resources. For BRAF mutation in the context of melanoma, reflex testing criteria should include advanced disease characteristics, as these patients would benefit the most from rapid initiation of BRAF/MEK inhibitors. These features to a clinician/pathologist might include melanomas exhibiting clinical characteristics associated with BRAF mutation (Table 1), thick tumors of Breslow depth 2-4 or >4mm with or without ulceration (i.e., stages IIB and IIC, respectively) and all patients with nodal involvement (i.e., stage III) or lymphatic progression (satellitosis or in transit metastasis). While systemic therapies are not approved for patients with pathologic stage II melanoma, considering the risk of disease progression in these individuals and decreased 5 and 10-year survival rates (82% and 75%, respectively for stage IIC and 87% and 82%, respectively for stage IIB disease), knowledge of the BRAF mutational status may prove useful for selection of future therapies. Furthermore, most often if stage IIB/C melanoma recurs, this usually occurs within 2 years of surgery. Advanced knowledge of the mutation status will help initiate treatment faster for newly metastatic or recurrent disease. While many tertiary care centers and specialized melanoma programs have or are actively implementing reflex BRAF mutation testing, it is paramount to promote this change across community hospitals as well, so that patients with high risk (stage ≥IIB) melanoma can consistently arrive to their first medical oncology appointment with this information at hand to make an informed treatment decision. This maybe critically important for those patients, who present to the multidisciplinary clinic with far more advanced melanomas than implied by the microstaging features of the primary tumor. For example, patients with large infiltrating tumors of dubious resectability or tumors that involve vital structures might benefit from neoadjuvant targeted therapy to facilitate their removal. Furthermore, as noted earlier, ongoing clinical trials (MK-3475-716/KEYNOTE-716 and CheckMate76K that enroll stage IIB and IIC patients) should answer the question whether these patients might benefit from adjuvant targeted therapy. The collective agreement on worrisome signs identifiable by dermatologists, surgeons, pathologists and oncologists will enable for cost-effective reflex BRAF testing and timely management for patients.