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Melanoma

Melanoma Molecular Biomarkers

About 44–70% of melanoma cases harbour a BRAF mutation. In cutaneous melanoma, the BRAF gene is mutated in ~60% of cases and p.V600E (c.1799T>A) accounts for more than 90% of BRAF mutations. This leads to constitutive activation of the MAPK pathway and increased cell proliferation, metastasis, and survival mechanisms. BRAF is also an important prognostic and treatment decision genetic biomarker in other cancer types 1.

The current standard for determining eligibility of patients with metastatic melanoma for BRAF-targeted therapy is tissue-based testing of BRAF mutations. Targeted therapy with anti-BRAF inhibitors (BRAFi) remains the first-line treatment for melanoma tumours that harbour a BRAF mutation, particularly in Australia 2.

Other oncogenic driver mutations have been identified in melanomas for which targeted therapies have demonstrated clinical activity. Detection of cKIT mutations may guide the selection of KIT TKIs (imatinib and sunitinib) for the melanoma treatment 3. It has been shown that melanoma patients with cKIT mutations treated with imatinib may have a better outcome compared to BRAF melanoma patients treated with BRAF inhibitors 4.

Another important oncogene, neuroblastoma RAS (NRAS) oncogene mutations have been more frequently detected in melanoma (13–25%) and in thyroid cancers (~6%) where they have been suggested to increase sensitivity to the mitogen-activated protein kinase signalling inhibitor (MEKi) 5.

References:
1. Brose MS et al., (2002) Cancer Res 62(23):6997–7000.
2. Spagnolo F et al., (2015) Onco Targets Ther 8:157–168.
3. Minor DR et al., (2012) Clin Cancer Res 18:1457–1463.
4. Daniels M et al., (2011) Cancer Lett 312:43–54.
5. Fedorenko IV et al., (2017) Oncogene. 32:3009–3018.



Somatic Mutation | Solid Tissue Molecular Profiling in Melanoma

Melanoma Solid Tissue Gene Panel

The melanoma gene panel can detect actionable DNA alterations that guide treatment decisions as detailed below.

Gene panel includes:

BRAF cKIT
NRAS  
When to Order: At diagnosis or on therapy for treatment selection.
How to Order: Fill out our Somatic Mutation testing request form and tick the Somatic Mutation test panel required.
Turnaround Time: 5–7 business days from the sample receipt date.
Specimen Required: Formalin-fixed paraffin-embedded (FFPE) tissue of a solid melanoma tumour.
Test Cost: Medicare rebate available if criteria is met. If criteria is not met there is an out-of-pocket fee of $230.

A negative result does not rule out the presence of a mutation that may be present but below the limits of detection for this assay (<5%).

"Rapid" (48-hr) BRAF Mutation Analysis

Used to detect BRAF mutation in the solid tumour samples from a patient, within a 48-hour turnaround from sample receipt.

Gene panel includes:

  • BRAF mutation test
    - Exon 15 codon 600 (variants V600E, V600D, V600K, V600R, V600M)

When to Order: At diagnosis or on therapy for treatment selection.
How to Order: Fill out our Somatic Mutation testing request form and tick the Somatic Mutation test panel required.
Turnaround Time: 48 business hours from the sample receipt date.
Specimen Required: Formalin-fixed paraffin-embedded (FFPE) tissue of a solid melanoma tumour.
Test Cost: An out-of-pocket fee of $350 applies (with partial Medicare rebate available if criteria is met).

A negative result does not rule out the presence of a mutation that may be present but below the limits of detection for this assay (<5%).


Aspect ctDNA Liquid Biopsy in Melanoma

Unfortunately, most melanoma patients receiving BRAFi therapy inevitably develop resistance to targeted therapy within six to 12 months. BRAF V600E mutations are associated with resistance to the tyrosine kinase inhibitors Cetuximab or Panitumumab.

As patients are rarely re-biopsied, detection in blood might be advantageous by enabling a comprehensive assessment of tumour mutational status in real time and thereby representing a non-invasive biomarker for monitoring BRAF therapy.

Haselmann et al. supported the routine use of ctDNA analysis to establish tumour genotype at diagnosis when treatment with targeted therapies is considered 1. Beyond the determination of baseline mutational status, the minimally invasive nature of ctDNA sample acquisition enables routine monitoring of response and resistance to targeted therapy 2,3,4. This is of particular importance for melanoma patients because of the lack of clinically useful biomarkers.

Furthermore, ctDNA can potentially be used as an immunotherapy predictive marker. Gray et al. and Lee et al. showed that baseline ctDNA levels predict response to immunotherapy, PD-1 inhibitor, in melanoma patients, and that low basal ctDNA levels were significantly associated with long-term clinical benefit 5,6.

Melanoma ctDNA Gene Panel

The Aspect Liquid Biopsy melanoma ctDNA gene panel can detect DNA alterations specific to melanoma as detailed below.

Gene panel includes:

  • NRAS: 40 mutations across exon 2, 3 and 4
  • BRAF: 5 mutations across exon 11 and 15
When to Order: At diagnosis or on therapy for treatment selection.
How to Order: Health practitioners can order Aspect Liquid Biopsy for cancer patients using the Aspect Liquid Biopsy form.
Turnaround Time: 5–7 business days from the sample receipt date.
Specimen Required: This test requires TWO 10ml blood samples (special tubes), which can be taken at any of our collection centres.
Test Cost: No Medicare rebate available. An out-of-pocket fee of $550 applies.

A negative result does not rule out the presence of a mutation that may be present but below the limits of detection for this assay (<2%).

"Rapid" (48-hr) ctDNA BRAF Mutation Analysis

Used to detect a single gene target, BRAF, of circulating tumour DNA (ctDNA) in a patient’s blood, within a 48-hour turnaround from sample receipt.

Gene panel includes:

  • BRAF mutation test
    -
    Exon 15 codon 600 (variants V600E, V600K, V600R)

When to Order: At diagnosis or on therapy for treatment selection.
How to Order: Health practitioners can order Aspect Liquid Biopsy for cancer patients using the Aspect Liquid Biopsy request form.
Turnaround Time: 48 business hours from the sample receipt date.
Specimen Required: This test requires TWO 10ml blood samples (special tubes), which can be taken at any of our collection centres.
Test Cost: No Medicare rebate available. An out-of-pocket fee of $550 applies.

A negative result does not rule out the presence of a mutation that may be present but below the limits of detection for this assay (<1%).

References:
1. Haselmann V et al., (2018) Clinical Chemistry 64 (5):830–842.
2. Spagnolo F et al., (2015) Onco Targets Ther 8:157–168.
3. Garcia-Murillas I et al., (2015) Sci Transl Med 7 (302):302ra133–302ra133.
4. Bettegowda C et al., (2014) Sci Transl Med 6:224ra24.
5. Gray E et al., (2015) Oncotarget 6 (39):42008–42018.
6. Lee J et al., (2017), Ann Oncol.

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The content on our Molecular Cancer Services page is written by National Clinical Director of Molecular Genetic Pathology at Australian Clinical Labs, Associate Professor Mirette Saad

 

Assoc. Prof. Mirette Saad

MBBS (Hons), MD, MAACB, FRCPA, PhD
Lab: Clayton
Speciality: Chemical Pathology and Molecular Genetics
Areas Of Interest: Cancer Genetics, Antenatal Screening, NIPT, Endocrine, Fertility Testing and Research, Medical Teaching
Phone: 1300 134 111
Email: mirette.saad@clinicallabs.com.au

Associate Professor Mirette Saad is a Consultant Chemical Pathologist and the National Clinical Director of Molecular Genetic Pathology at Australian Clinical Labs. Associate Professor Saad obtained her fellowship in Chemical and Molecular Pathology with a clinical Microbiology sub-specialty in Egypt.

After several posts, she worked as a Medical Laboratory Director in private labs and as an Associate Professor and Examiner of Clinical Chemistry for postgraduate and undergraduate medical and nursing students at various institutions. Upon receiving the National Health and Medical Research (NHMRC) Scholarship in 2006, Associate Professor Saad commenced her PhD studies at Melbourne University and Peter MacCallum Cancer Institute in Cancer Genetics. Associate Professor Saad undertook her specialty training at Healthscope Pathology (now Australian Clinical Labs) and Monash Health and obtained the Chemical Pathology Fellowship (FRCPA) and the Membership (MAACB) by examination from the Royal College of Pathologists of Australasia (RCPA) and the Australasian Association of Clinical Biochemists (AACB) respectively.

She is currently a member of the Chemical Pathology Advisory Committee at RCPA. At Clinical Labs, A/P Saad supervises the antenatal screening program including combined First Trimester Screening and Non-Invasive Prenatal Testing (NIPT) along with the Molecular Genetic testing for hereditary disorders, personalised drug therapy and cancer.

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