Case 2: BRAF-Mutated Metastatic Melanoma

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Ahmad Tarhini, MD, PhD:Dr Wong, would you like to proceed with case no. 2,BRAF-mutated, metastatic melanoma?

Deborah J. Wong, MD, PhD:Yes. Here we have a 52-year-old woman who presented to her dermatologist for removal of a pigmented lesion that had been present for some time. But recently she had noticed that it has been changing color, it was becoming darker, and maybe started to ulcerate. Pathology from the resection revealed a melanoma with a Breslow depth of 1.2 mm. It was ulcerated with a mitotic rate of 4 per mm squared.

Ahmad Tarhini, MD, PhD:Obviously we have some concerning features of this primary tumor. Dr Emerick, what from your perspective are the next steps in the management of this patient?

Kevin S. Emerick, MD:We want to think about 2 things. One is removing that primary tumor, and based on this depth, we’d aim for a 1 to 2 cm margin around that primary tumor. But also based on these features, intermediate thickness, ulceration, and mitoses, this is roughly a 20%, maybe on the size of 25%, risk of occult regional metastasis. I think the next step for this patient is wide local excision and a sentinel lymph node biopsy.

Ahmad Tarhini, MD, PhD:Interesting practice-changing data came out from the MSLT-II study, and I would appreciate your take on the role of lymph node dissection in this era.

Kevin S. Emerick, MD:Yes. MSLT-I was an important study showing us the importance of sentinel lymph node biopsy in terms of a predictor of prognosis. But as we moved into the immunotherapy and targeted therapy realm, it also helped us identify people who might benefit from systemic therapy. The follow-up to that, being MSLT-II, is where we said, “If you have a positive sentinel lymph node biopsy, do you need any more surgery?” This is because prior to that study the standard was if you had a positive sentinel lymph node biopsy, we recommended completion lymphadenectomy.

That study said it may not be that helpful. As they looked at 2 populations, those who went on to have completion lymphadenectomy versus those who were closely watched, we did not see a difference in the survival of those 2 groups. I think many groups around the country, I know our group, we now do not perform completion lymphadenectomy in the setting of a positive sentinel node.

Ahmad Tarhini, MD, PhD:Understood. In terms of the risk of recurrence for this patient, what are the key features that you would consider?

Kevin S. Emerick, MD:The guidance from that primary tumor, the presence of ulceration in particular, says this patient is at a high risk of recurrence. That can be a local or regional with in-transit metastasis. But that ulceration says that this patient is also at risk for distant metastasis. That sentinel lymph node biopsy also gives us important guidance on the risk of recurrence. We know from MSLT-II that for the patient with a positive sentinel node that is watched, there’s somewhere between an 11% and 18% risk of having a positive nonsentinel node that could show up sometime in the next 2 years to 5 years. But that positive sentinel node also predicts a much higher risk of recurrence in the distant setting.

Ahmad Tarhini, MD, PhD:It’s interesting. As we see the emerging data in terms of the risk of nonsentinel lymph node recurring in the presence of systemic therapy, these patients now are getting effective adjuvant therapy and some groups are starting to report data where the risk appears to be lowered now.

Kevin S. Emerick, MD:For sure.

Ahmad Tarhini, MD, PhD:But that moves us to the AJCC [American Joint Committee on Cancer] staging system. Obviously, all these are part of the staging of these patients. Dr. Wong have you started using the 8th edition in your practice?

Deborah J. Wong, MD, PhD:Definitely. One of the key things is that the update from AJCC7 to AJCC8 helps us to better define prognosis for these patients. For example, in the metastatic setting, the AJCC 8th edition now includes subdivisions A through D, where M stage but with a subdivision of D portends CNS [central nervous system] metastases, which overall has a far poorer prognosis than those with subcutaneous or skin-only metastatic disease.

Ahmad Tarhini, MD, PhD:I agree. I think the changes in the 8th edition better define the prognosis of our patients and divide them into smaller subgroups. One would expect in the future, as we’re doing the genomic testing and tumor profiling, that we will be even more accurate in predicting their prognosis.

Would you like to continue the case? What happened to this patient?

Deborah J. Wong, MD, PhD:Sure. This patient did undergo a sentinel lymph node evaluation, and her sentinel lymph node was positive. This prompted a systemic evaluation with imaging and a CT [computed tomography] of the chest, abdomen, and pelvis was performed, which showed multiple lesions in both lungs, with the largest being 10 mm in size.

She underwent a core-needle biopsy of the largest lung lesion, and pathology revealed metastatic melanoma. She underwent mutational testing by IHC [immunohistochemistry], which was confirmed by next-generation sequencing. The melanoma did have aBRAFV600E mutation.

Ahmad Tarhini, MD, PhD:Dr McKean, what factors would you consider in deciding on the systemic therapy for this patient? Again, this is a patient with metastatic melanoma that has been shown to beBRAF-mutated. The mutation isBRAFV600E.

Meredith McKean, MD:First of all, it’s exciting to be talking about metastatic melanoma and systemic therapy options that we didn’t have a number of years ago. The 2 different approaches to consider for a patient with newly diagnosed metastatic melanoma in the setting of aBRAFV600E mutation will either be combination targeted therapy or considering combination immune therapy for a patient who would be able to tolerate it.

For the factors that would go into consideration for a patient who has diagnosed metastatic melanoma, I’d make sure to do a brain MRI [magnetic resonance imaging] to see if there’s a presence of any CNS metastases. In the presence of brain metastases, although the data for both targeted therapy and immune checkpoint inhibitors showed similar intracranial disease response, I think we’re seeing more durability with immune checkpoint inhibitors. So I might be more interested in immune checkpoint inhibition for that type of patient.

Otherwise I think outside of a CNS metastases, the considerations are the patient’s other comorbidities. Do they have any autoimmune condition? What is the timing of response? This a patient who’s very symptomatic from their disease; even though we can see some quick responses with the immune checkpoint inhibitor, I think we tend to use targeted therapy because we know it tends to be a faster response.

Sometimes discussing the differences and adverse effects for patients should be considered in that with immune checkpoint inhibitors some of these adverse effects can be chronic, long-term adverse effects that we have to manage. Versus oftentimes with targeted therapy they can be shorter adverse effects with fever, rash that we can stop pills, restart, and manage that way. I think just having that discussion with patients about the differences between both therapies is important.

Transcript edited for clarity.