Melanoma (December 2017): Molecular Oncology Tumor Boards

ASCO University
Dec 06, 2017 10:09 AM

Participant 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. Boris Bastian (Pathologist from UCSF) and Jason Luke (Medical Oncologist from the University of Chicago).

To view relevant recruiting Clinical Trials related to this case and topic, view PDF.

Do you have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.

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Comments

15261

ASCO University
Re: Melanoma (December 2017): Molecular Oncology Tumor Boards
Dec 06, 2017 10:16 AM

Patient Case

Age/Sex: 63 F
Medical History:
12/2016 developed rectal bleeding from a prominent rectal mass, which was proven to be melanoma by biopsy
2/2017 tumor was deemed initially unresectable and patient started with Ipilimumab + Nivolumab x2 cycles. Tumor shrunk by 30% but treatment was discontinued due to Grade 3 diarrhea (12 bowel movements per day).
3/2017 Patient referred to expert surgical center
4/2017 Abdominal-perineal resection of tumor. Pathology showed residual viable tumor cells, all 20 resected lymph nodes were tumor-free
4/2017 Paired sequencing of 500 cancer related genes in tumor and normal tissue was performed
10/2017 Patient developed multiple new nodules in the lung biopsy proven to be recurrent melanoma.

Type of Tumor: Mucosal melanoma
Relevant Markers:  KIT mutation
Prior Treatment History/Response: Ipilimumab + nivolumab
Co-morbidities: HTN
Images/Scans/Pathology: View Images
     APR resection: 6 cm melanoma. IHC + S100, HMB45

15266

ASCO University
Re: Melanoma (December 2017): Molecular Oncology Tumor Boards
Dec 06, 2017 10:17 AM

Discussion Questions

1. What are conceivable next steps in managing this patient?
2. How does the molecular biology of mucosal melanoma vary from cutaneous melanoma?
3. What factors would guide subsequent treatment options?

15281

Boris C. Bastian, MD, PhD
Re: Melanoma (December 2017): Molecular Oncology Tumor Boards
Dec 11, 2017 2:43 PM

Course Faculty Response

Melanomas originating from the mucosa share several features with acral melanomas, i.e. melanomas originating from glabrous (non-hair-bearing) skin of the palms and soles and the nail apparatus. Both have characteristic morphological, epidemiological, and genetic features that set them aside from other subtypes. Glabrous skin, by definition, lacks hair follicles, but has eccrine glands. Mucosa lacks either structures, but has, depending on the site, mucosal glands. These differences may be relevant for the cell of origin of these melanoma types. While the bulge region of the hair follicle harbors melanocyte stem cells in the non-glabrous skin, the existence of an equivalent melanocyte stem cell reservoir in the mucosa is unclear. Both acral melanoma and mucosal melanoma often show a lentiginous component, in which melanocytes are found predominantly as single units in the basal layer of the epithelium. They originate from melanoma in situ, which can be very subtle and difficult to detect and remove, resulting in frequent local recurrences.

Mucosal melanomas lack the high mutation burden  of cutaneous melanomas  and have different spectrum of driver oncogenes . Instead they have a high degree of genomic instability resulting in gene amplifications and deletion as well as structural rearrangements. The driver alterations have not been fully catalogued however BRAFV600E mutations are rare. Approximately 15% have activating mutation of KIT and 20% have RAS mutations, mainly NRAS. Kinase fusions in ALK or BRAF are seen in a small minority of cases.

15286

Jason J. Luke, MD, FACP
Re: Melanoma (December 2017): Molecular Oncology Tumor Boards
Dec 11, 2017 2:45 PM

Course Faculty Response

Mucosal melanomas are a rare subset of all melanomas (< 2% in the US). The most common anatomical sites of involvement for these melnaomas include the nasopharyngeal, rectal or genital mucosa. Because of this anatomical distribution these lesions often become of advanced stage at the time of diagnosis.  Even considering this however, multiple reports have suggested that melanomas of mucosal origion have inferior stage for stage survival compared with cutaneous melanomas. The etiology of mucosal melanomas is additionally variant relative to cutaneous disease.  Mucosal melanomas do not demonstrate sun-damage associated changes but rather appear to arise in the setting of a putative “field-defect” in which large areas of melanoma in situ develop and eventually lead to multi-focal areas of true melanoma outgrowth.  Because of this patient commonly developed multiple cancers in the effected field that can be resected over time but eventually lead to metastatic disease.  

The molecular biology of mucosal melanoma is substantially different from cutaneous disease.  Whereas signature genetic lesions arising from ionizing radiation predominately from sun exposure can be easily documented in cutaneous melanoma leading to BRAF, RAS and NF1 mutations, among others, mucosal melanomas are much more commonly associated with chromosomal amplifications or translocations as well as lesions in RAS or c-KIT.  Additionally, the overall mutational burden of mucosal melanoma is on median an order of magnitude lower than that of cutaneous melanoma. Given these factors, subsequent treatment considerations would be guided by factors including but not limited to both prior response and toxicity to immunotherapy, molecular characteristics of the tumor, and goals of care for patient in metastatic setting.

15291

ASCO University
Re: Melanoma (December 2017): Molecular Oncology Tumor Boards
Dec 11, 2017 2:47 PM

Patient Case Update

How tissue was acquired/preserved:

  • Surgical debulking, FFPE slides

Testing Platform/Molecular Profiling:

  • KIT, PDGFRA amplification, CDKN2A,CDKN2B deep deletion, KIT p.V560D, SPRED1 deep deletion, PTEN p.V166fs, PTPRD deep deletion, SF3B1 p.R625C, MAP2K2 amplification

15296

ASCO University
Re: Melanoma (December 2017): Molecular Oncology Tumor Boards
Dec 11, 2017 2:49 PM

Discussion Questions

  1. How do these molecular results inform therapy?
  2. Does the genomic complexity of this case otherwise inform therapy selection?
  3. What is the role of radiotherapy in mucosal melanoma?
  4. What is the role of immune checkpoint blockade in mucosal melanoma?

15306

Boris C. Bastian, MD, PhD
Re: Melanoma (December 2017): Molecular Oncology Tumor Boards
Dec 15, 2017 2:40 PM

Course Faculty Response

KIT is a receptor tyrosine kinase, which is normally expressed on melanocytes and critical for their development as well as migration to target sites during embryogenesis. The receptor is activated through dimerization and autophosphorylation upon binding its ligand, stem cell factor. KIT activation results in increased intracellular signaling through several pathways including PI3K, MAPK and STAT1. Pathogenic KIT mutations in melanoma are gain of function mutations, which turn KIT into an oncogene. As in other cancers such as gastrointestinal stromal tumor (GIST) and mast cell neoplasms this can occur by disrupting the autoinhibitory juxtamembrane domain (exon 11) through missense mutations or indels or by missense mutations of the kinase domain.  These most commonly effect exons 13, 17, 18 and rarely the extracellular domains of exon 9. Not all mutations in KIT are likely driver mutations and the frequency of passenger mutations is increased in melanomas with a high mutation burden, such as melanomas on chronically sun-damaged skin (i.e. – on the head and neck), a small subset of which is also driven by KIT mutations. However, the mutation burden in mucosal melanoma is usually low, making this less of a problem.

15311

Jason J. Luke, MD, FACP
Re: Melanoma (December 2017): Molecular Oncology Tumor Boards
Dec 15, 2017 2:43 PM

Course Faculty Response

From a clinical perspective KIT mutation in advanced melanoma can potentially be targeted with imatinib based on three phase II studies.  Data for other KIT inhibitors in the phase II setting also exists for sunitinib, dasatinib and nilotinib (in imatinib progressers).  That being said, not all mutations in KIT represent oncogenic drivers as some are passenger mutations that develop in the setting of tumors with higher mutational loads. These various oncogenic KIT mutations may have different sensitivities to different KIT inhibitors. For example, though on the order of 70% of KIT mutations identified in melanoma impact exon 11, and most commonly L576P in the juxtamembrane domain,  or  exon 13, most commonly K642E in the proximal kinase domain,  (exon 13, most commonly K642E), other mutations tend to represent passenger mutations of no biologic significance. 

When aggregating RECIST responses to imatinib in phase II trials of KIT mutant melanoma it is striking that the response rate is approximately 40% if mutation is in exon 11 or 13 however responses are few or none in the context of other aberrations.  Considering this, response to KIT inhibition in appropriately selected KIT mutant melanomas rivals response to monotherapy BRAF inhibitors in cutaneous melanomas.  Importantly however, patients with mucosal melanoma often have limited treatment options, especially as noted in this case with prior diarrhea from checkpoint blockade.  Therefore, consideration of treatment with a KIT inhibitor even in the context of other KIT mutations may be warranted if considering what other treatment options are available to the patient.  Rare responses have been observed in exon 17 mutant KIT melanoma as well as KIT amplified melanoma.  

Clinical trials of the KIT inhibitors mentioned above, novel KIT inhibitors and combinations of KIT inhibitors with PD1 based immunotherapy continue to investigate next steps in this field (Clinical Trial Table Below).  For the patient discussed in this case series, re-challenge with immunotherapy could be considered though the response rates appear to be lower in mucosal.  It is not completely understood why response rates are lower though one hypothesis centeres on mutational burden and presumed lower neo-antigen incidence.  Also in this patient the prior development of a diarrhea syndrome may make the patient or provider less enthusiastic about risking toxicity despite retrospective case series suggesting on the order of approximately 33% risk of induction of diarrhea/colitis on re-exposure to monotherapy PD1 antibody. No data for rechallenge with ipilimumab + nivolumab is avaialble however phase II data for ipilimumab do support a meaningful response rate for re-challenge and some patients in the KEYNOTE-001 trial of pembrolizumab who completed two years of therapy but then progressed off-treatment had response on re-challenge. No data on toxicity of 2nd treatment with ipilimumab + nivolumab as a combination is available however.    

15316

Boris C. Bastian, MD, PhD
Re: Melanoma (December 2017): Molecular Oncology Tumor Boards
Dec 20, 2017 9:59 AM

Course Faculty Summary
Primary mucosal melanoma with KIT p.V560D mutation, which has undergone amplification, indicating positive selection of this mutation
Codon V560 is part of a structural part of KIT that is enriched for activating mutations in a variety of cancers.

15321

Jason J. Luke, MD, FACP
Re: Melanoma (December 2017): Molecular Oncology Tumor Boards
Dec 20, 2017 10:59 AM

Course Faculty Summary

In this case of KIT mutant melanoma, consideration of treatment with a KIT inhibitor such as imatinib would be clinically justified.  In patients with melanomas mutated in exon 11 or 13 response rates are approximately 40% from phase II data sets.  Consideration of immunotherapy in this patient is also reasonable though informed consent would have to explicitly highlight the likelihood of toxicity that could be significant.  This case highlights that despite improvements in targeted therapy and immunotherapies in melanoma.  A clear unmet need remains for patients with rare sub-types and refractory disease.

15326

ASCO University
Re: Melanoma (December 2017): Molecular Oncology Tumor Boards
Dec 20, 2017 11:09 AM

Thank you to Drs. Bastian and Luke for 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 credit on ASCO University by clicking here.

Please check back in mid-February for a new case in this series related to Colorectal pMMR mutation.    


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