Melanoma (October 2015): Molecular Oncology Tumor Boards

ASCO University
Oct 14, 2015 10:22 AM

User Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration between the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP).

A new case will be presented each month with discussions led by an expert pathologist and medical oncologist. This month’s topic is led by Drs. Alexander Lazar (The University of Texas MD Anderson Cancer Center) and Ryan Sullivan (Massachusetts General Hospital Cancer Center).

Users are encouraged to leave comments and post questions about the case in order to generate a wide discussion among the cancer care community. You can also receive email notifications when new comments are posted by clicking the “Follow this Conversation” option located at the bottom of this page. When posting, please abide by the terms and conditions of this website. 

Supplemental resources related to the case are attached for reference.



ASCO University
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 14, 2015 10:27 AM

Patient Case #1

Age/Sex: 40 year-old man

Medical History: No other past medical history, developed a changing mole in 2009 on his left upper back.

A punch biopsy was performed and pathology revealed a 3.5 mm thick, ulcerated nodular melanoma with 8 mitoses per square millimeter.  Soon after, a wide excision and sentinel lymph node evaluation was performed with no evidence of residual melanoma noted in the excision site and subcapsular microscopic involvement of the one identified left axillary sentinel lymph node.  A completion lymph node dissection was performed, eleven additional axillary nodes were identified, and 2 were microscopically involved with melanoma.  For his AJCC Stage IIIB melanoma (T3bN2aM0), he was offered a course of adjuvant interferon and completed a year of therapy.

Five years later, in the fall of 2014, a surveillance CT chest, abdomen, and pelvis identified a right lower lobe lung mass (2 cm).  The patient underwent a VATS wedge resection of this lung nodule and pathology was consistent with melanoma.  Molecular analysis using a focused cancer gene panel on a next generation sequencing platform was performed in the CLIA-certified laboratory showing the following:

Mutation detected in codon 600, exon 15 (GTG to AAG) of the BRAF gene that would change the encoded amino acid from Valine to Lysine (p.Val600Lys).  Click to View BRAF V600K NGS Sequence image

Standardized nomenclature for this mutation: NM_004333.4(BRAF):c.1798_1799delinsAA p.V600K

A brain MRI showed no metastatic involvement.  Since the wedge resection removed all evidence of disease (as defined by imaging), he was observed with quarterly PET/CT imaging and yearly brain MRIs.  Nine months later, routine imaging showed evidence of recurrence in the right lower lobe and multiple foci of bony involvement.  A fine needle aspirate of a T3 vertebral body lesion confirmed the diagnosis of recurrent and metastatic melanoma.  Soon after the patient commenced systemic therapy.

CT scans from February 2015 (left) and July 2015 (right) are shown.  A new right lower lobe mass (yellow arrow) is noted. Click here to View Image


ASCO University
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 14, 2015 10:29 AM

Discussion Questions
1. In general, would you be more inclined to offer a targeted therapy regimen or an immune therapy regimen?
2. If a BRAF-targeted therapy approach is selected, what therapeutic options are the most appropriate?
3. If an immune-targeted therapy approach is selected, what options are most appropriate?
4. What specific genes would one want to test for in a case such as this?


Anis Toumeh, MD
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 16, 2015 3:55 PM

1- This is an interesting question. We don't have enough data yet to support the optiaml first line therapy in BRAF positive tumors ( Targeted Vs Immuno). I think tumor extent, symptoms, LDH, disease tempo and contraindications to either approach are useful factors to consider before starting treatment. For symptomatic, extensive disease with high LDH I would favor starting with targeted treatment. Hopefully the EA-6134 will give us some answers. For this patient, I would probably go with immunotherapy first if he is asymptomatic. 

2- The data is overwhelmingly in favor of the combination of BRAF-MEK inhibitors over a solo BRAF-inhibitor approach, ( COMBI-D and COMBI-v trials) in terms of response rates, progression free and overall survival. And more recently, health related quality of life. 

3- As far as immunotheapy approach, the Anti-PD1 inhibitors seem to have more favorable adverse events profile and a better response rate. Long term survival data is available for ipilimumab though. Interestingly, the CheckMate 064 presented at the ESMO-ECC (Hodi S. et al. - 23LBA) this year reported improved efficacy outcomes  by induction with the nivolumab followed by ipilimumab versus ipilimumab followed by nivolumab and that the incidence of treatment-related AEs were numerically higher with Nivo first. I think I would go for an anti-PD1 first approach untill more data is clarifying. I am interested in knowing what other docs think about this issue.



Alexander Lazar, MD, PhD
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 19, 2015 2:34 PM

Course Faculty Response

In a case such that above, a reasonable approach would be to test for BRAF, NRAS and KIT.  While mutations in KIT are rare in cutaneous melanoma, if present it presents an alternative range of therapeutic options.  Specific therapy for NRAS mutated melanoma is not well established, but clinical trials are available.  BRAF mutations seen in around 50% of melanoma are most commonly seen in exon 15 with the hotspot being at codon 600.  The most common variant is V600E followed by V660K.  These are predictive of response to BRAF inhibition therapy.  However, both the likelihood of objective tumor response and duration of response to BRAF/MEF inhibition are markedly better for BRAF V600E cases.  BRAF mutations in exon 15 outside of codon 600 and those in exon 11 generally show a poor response to BRAF inhibition.  Other commonly mutated genes of interest include NF1, TP53, and PTEN but mainly in the context of clinical trial eligibility.


Ryan J. Sullivan, MD
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 19, 2015 2:38 PM

Course Faculty Response

One of the major challenges in this new era of melanoma therapy is deciding initial treatment for patients with advanced (defined here as unresectable stage III or Stage IV), BRAF-mutated melanoma.  There are two options, to commence BRAF-targeted therapy or immune-targeted therapy, and no randomized data to lean upon to help make decisions.  Thus, it is necessary to pull in data from several prospective therapeutic trials, including subset analyses, and retrospective studies to help make an informed treatment recommendation for each individual patient.  

The case for frontline BRAF-targeted therapy is based upon several key pieces of data.  First, clinical benefit occurs in nearly every patient treated with combined BRAF and MEK inhibitor therapy, which, based on the results of three randomized trials comparing BRAF/MEK inhibitor combination to single agent BRAF inhibitor therapy, is unequivocally the standard of care BRAF-targeted therapy.  Second, improvements in survival are seen across all subgroups of patients including those with more aggressive and limited disease, an elevated LDH or non-elevated LDH, and active brain metastases.  Third, the median overall survival is over two years with combined BRAF/MEK inhibitor therapy and durable remissions lasting over three to four years have been seen with each of the three BRAF/MEK combination therapies.  Fourth, the response rates to anti-PD1 therapy (most robust data is with nivolumab) are similar in BRAF-mutant patients with advanced melanoma previously treated and not previously treated with BRAF inhibitor therapy.  

The case for frontline immune targeted therapy in BRAF-mutated patients can also be made.  The median survival of front-line anti-PD1 monotherapy, both nivolumab and pembrolizumab, nears two years and that of combination ipilimumab plus nivolumab may significantly exceed this.  Also, the combination of ipilimumab and nivolumab is associated with high response rates (in excess of 60%) that may occur relatively quickly (within weeks as opposed to months).  Additionally, the fact that BRAF-targeted therapy response rates are similar before and after immune-targeted therapy and that data from two retrospective analyses showed that patients who received immunotherapy (in this case ipilimumab) prior to BRAF-targeted therapy had better outcomes than those who received BRAF-targeted therapy prior to ipilimumab, supports the decision for frontline immune-targeted therapy.  Finally, a subset of patients, at least 20 percent with ipilimumab and as many as 30-40% with single agent anti-PD1 antibodies, will experience durable remissions that may last years. 

As described above, optimal BRAF-targeted therapy consists of combination BRAF and MEK inhibitor therapy.  The data to support this statement comes from three randomized trials of BRAF plus MEK inhibitor therapy compared to single-agent BRAF inhibitors that demonstrated the superiority of combination therapy with respect to response rate, progression free survival (PFS), and overall survival (OS) without a significant difference in toxicity.  

The optimal front-line immune targeted therapy is less clear-cut.  One definite is that frontline anti-PD1 antibody therapy is better than chemotherapy and ipilimumab, based on randomized data showing superior response, PFS, and OS with anti-PD1 antibodies.  The trickier issue is whether frontline single-agent anti-PD1 therapy or combined ipilimumab plus anti-PD1 combination should be the favored frontline option. Without mature overall survival data, all we can truly say is that combination therapy is associated with improved response rates and possibly PFS compared to anti-PD1 therapy at the expense of significantly increased toxicity.  For now, it is reasonable to consider either single-agent anti-PD1 antibody therapy or combined ipilimumab and nivolumab as frontline immune-targeted therapy for patients with advanced melanoma.


ASCO University
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 19, 2015 2:44 PM

Patient Case #2

Age/Sex: 45 year-old man

Medical History: No past medical history developed a right upper arm skin lesion in mid-2012.

A punch biopsy was performed by his dermatologist and pathology revealed a 1.75 mm thick, non-ulcerated superficial spreading melanoma with no evidence of ulceration and 1 mitosis per square millimeter. He underwent a wide excision and sentinel lymph node evaluation, which showed no evidence of residual melanoma in the excision site and no evidence of involvement of either of the two identified right axillary sentinel lymph nodes.  He was diagnosed with AJCC Stage IB (T2aN0) melanoma and followed expectantly by his surgeon.

In January 2015, he presented to his local ED with left hand weakness.  A brain MRI was performed and revealed multiple enhancing masses including a 4.5 cm mass in the right posterior frontal lobe, which was associated with substantial mass effect and edema, and a 3.0 cm left temporal lobe mass with associated intratumoral hemorrhage. He was taken for palliative resection of these two large masses and noted improvement of his neurologic symptoms. A staging torso CT scan was performed and showed innumerable pulmonary nodules, measuring 2-25 mm, consistent with metastases.  He received post-operative whole brain radiation and readied for systemic therapy. Molecular analysis of the right frontal lobe mass using  a focused cancer gene panel on a next generation sequencing platform was performed in the CLIA-certified laboratory showing the following:
Mutation detected in codon 61, exon 3 (CAA to CGA) of the NRAS gene that would change the encoded amino acid from Glutamine to Arginine (p.Gln61Arg)

Standardized nomenclature for this mutation:    NM_002524.4(NRAS):c.182A>G p.Q61R

Click here to View Images


ASCO University
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 19, 2015 2:46 PM

Discussion Questions

1.    How do you approach the treatment of a melanoma patient with active CNS and non-CNS metastases?
2.    Does the presence of an NRAS mutation influence selection of front-line therapy?
3.    What types of targeted therapies are being developed for patients with NRAS mutations?


Douglas Buckner Johnson, MD
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 22, 2015 3:08 PM

1. The data for the new agents is much less robust for patients with CNS metastases. Several small studies have shown some activity for patients treated with ipilimumab as well as for single agent BRAF inhibitors. At least in the ipilimumab trial, patients with symptomatic brain metastases on corticosteroids had generally poor outcomes. Treatment of symptomatic brain metastases should usually then be prioritized over systemic treatment. Several clinical trials are ongoing to assess the activity of BRAF + MEK inhibition in the setting of brain metastases, as well as the combination of ipilimumab + nivolumab.

2. In my opinion, the presence of an NRAS mutation does not influence choice of first line therapy. There is some retrospective data that suggests that these patients may respond better to immune therapy although there were relatively small numbers examined, and immune therapy would be the first-line therapy anyway.

3. The major class of therapy being developed for NRAS mutations are MEK inhibitor directed strategies. Binimetinib is now being compared with chemotherapy in a phase III study for treatment refractory patients. MEK inhibitor combinations, including with CDK4/6 inhibitors may also hold promise.


Alexander Lazar, MD, PhD
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 26, 2015 11:23 AM

Course Faculty Response
Until recently, there were no therapeutic options for patients with NRAS mutated melanoma.  With new laboratory studies and innovative clinical trials, this is rapidly changing.


Ryan J. Sullivan, MD
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 26, 2015 11:27 AM

Course Faculty Response

The treatment options for patients with advanced melanoma have similarly improved for those with and without brain metastases.  In the past several years, clinical trial data has been generated showing activity in untreated brain metastases with ipilimumab, the BRAF inhibitor dabrafenib, and pembrolizumab.  The key to the successful management of patients with CNS metastases is multidisciplinary care with neurosurgery, radiation oncology, and medical oncology, and ideally a tumor board setting discussion to determine the most appropriate approach and sequence of interventions for individual patients.  In general, surgery is performed for symptomatic metastases and those associated with significant edema that will necessitate large doses of glucocorticoids, which may limit the effectiveness of immune checkpoint inhibitors.  Radiation therapy is ideally given as stereotactic radiosurgery, though there may be a role for whole-brain radiation therapy in patients with diffuse metastases.  Systemic therapy is always considered and should be started as soon as possible.

NRAS mutations are seen in 20-30% of patients, may be associated with a higher mutation load compared with BRAF mutant and non-NRAS and non-NF1 altered melanomas, and have been shown to be associated with a higher response rate to immune-targeted therapy.  For this reason, frontline therapy for NRAS mutant patients is immune-targeted therapy.

Additionally, NRAS mutations tend to increase signaling thought the MAPK pathway and are potentially susceptible to MAPK pathway inhibitors.  Not surprisingly, MEK inhibitors are associated with responses in a minority of patients (~20%) and are currently being tested in randomized trials compared with chemotherapy.  The most advanced data is with binimetinib, and a randomized phase III trial is ongoing.  If this trial meets its primary endpoint (improved progression free survival), then it is expected that MEK inhibitor therapy will become a standard targeted therapy approach for these patients.  Additionally, in the past year, data from early phase trials has been presented showing responses to pan-RAF and ERK inhibitors in patients with NRAS mutant melanoma.


Roberto Antonio Leon-Ferre, MD
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 27, 2015 11:20 AM

In addition to MEK inhibitors in NRAS-mutated melanoma, is there a role for PI3K inhibitors?


Ryan J. Sullivan, MD
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 28, 2015 8:16 AM

Dr. Leon-Ferre, thanks for your question.

This is a clear theoretical rationale for using inhibitors of PI3K or its downstream mediators in NRAS-mutated melanoma, though the MAPK pathway would obviously be uninhibited with this type of approach and NRAS mutant melanomas abundantly activate the MAPK pathway leading to ERK activation.  One idea would be to provide either parallel inhibition of the pathways (e.g. MEKi and PI3Ki/AKTi), but dose limiting toxicity makes it challenging to treat with therapeutic doses of either pathway inhibitor.  An emerging combination is that of MEKi plus CDK4/6 inhibitor, that is based on preclinical models of NRAS mutations.  The first trial of this type of combination was reported by Jeff Sosman, on behalf of his colleagues, at the 2014 ASCO annual meeting.  Response rates with the binimetinib (MEKi) and LEE011 (CDK4/6i) combination were marginally better that those seen in a phase II trial of binimetinib in patients with NRAS mutant melanoma, however toxicity was a concern


Alexander Lazar, MD, PhD
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 28, 2015 3:49 PM

Course Faculty Summary

Interpretation of broad cancer gene panels in melanoma can be complicated by the high background of UV signature mutations making the differentiation of driver type and passenger mutational events challenging.  While there are many detectable genetic derangements in melanoma, a subset is recurrent (BRAF, NRAS, KIT, TP53, PTEN) and thus usually important, yet very few have specific therapeutic indications and only BRAF V600 mutations have an FDA approved therapy.   However, the field is and dynamic additional biomarkers, including NRAS, are likely to become more central to management of targeted therapy.  Another area in evolution is the search for biomarkers predicting response to immune checkpoint therapies.  While PD-1, PD-L1 and other immunohistochemical markers show some promise, there is still great variation in results from lab to lab and from antibody clone to antibody clone.  Recent work suggests that total mutation load might also be a reasonable marker, but more study is needed here as well.  None of these immunotherapy biomarkers is ready for prime time clinical use, but further experience and new studies will keep this field interesting for years to come.


Ryan J. Sullivan, MD
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 28, 2015 3:51 PM

Course Faculty Summary

In 2015, the role of molecularly targeted therapy for the treatment of melanoma is evolving.  With the emergence of highly effective immune-targeted therapy, treatment providers and patients have a number of options that have the potential to effectively treat this traditionally difficult to treat disease.  While immune-targeted therapy is given to most patients with advanced melanoma in the front-line setting, advances in molecular targeted therapy for both BRAF mutant patients (BRAF/MEK combinations) and NRAS mutant patients (pan-RAF, MEK, and ERK inhibitors) are being made. For this reason, molecular analysis is more important than ever in the management of our patients with melanoma for both upfront and second-line therapy decision-making.


ASCO University
Re: Melanoma (October 2015): Molecular Oncology Tumor Boards
Oct 28, 2015 3:57 PM

Thank you to Drs. Lazar and Sullivan leading the discussion of this case and also to all of those who contributed to the conversation! The forum is now closed to further comments but users have the opportunity to claim CME credit on ASCO University by clicking here
Please check back in November for a new case in this series related to thyroid cancer.