myPath^® Melanoma:  Early and Accurate Diagnosis of Melanoma is Critical for Long-Term Survival

What is myPath^® Melanoma?

myPath^® Melanoma may be used as an adjunct to histopathology when the distinction between a benign nevus and a malignant melanoma cannot be made confidently by histopathology alone.  Reasons that definitive diagnosis may not be achievable by histopathology include indeterminate/ambiguous histopathologic features, diagnostic disagreement among physicians, or indications that additional workup or consultation are necessary.  The test measures the expression of 23 genes by qRT-PCR methodology and distinguishes melanoma from nevi with a sensitivity of 90-94% and a specificity of 91-96%.¹⁷

90% – 94%  –   Sensitivity

91% – 96%   –   Specificity

myPath^® Melanoma measures 23 genes for which expression patterns differ between malignant melanoma and benign nevi.  These genes are involved in cell differentiation, cell signaling, and immune response signaling.

myPath^® Melanoma provides confidence to personalize patient treatment recommendations as 10-15% of biopsied melanocytic lesions may be histopathologically ambiguous

The analysis of biopsied tissue using a microscope (histopathology) has long been the standard of care for melanoma diagnosis. While it is adequate for diagnosis in most cases, evidence suggests that approximately 10-15% of biopsied melanocytic lesions may be histopathologically ambiguous.^2-5 In these situations, microscopic examination may reveal a few features that are characteristic of melanoma but others that are more typical of a benign nevus (‘mole’). As a result, even experienced dermatopathologists occasionally disagree as to whether a given melanocytic lesion is benign or malignant.

The genes included in myPath^® Melanoma testing are:

• PRAME a single gene involved in cell differentiation
• S100A7, S100A8, S100A9, S100A12 and PI3, a group of genes involved in multiple cell signaling pathways
• CCL5, CD38, CXCL10, CXCL9, IRF1, LCP2, PTPRCand SELL involved in tumor immune response signaling
• Nine housekeeping genes that are measured to normalize RNA expression for analysis .Housekeeping genes included:CLTC, MRFAPI, PPP2CA, PSMA1, RPL13A, RPL8, RPS29, SLC25A3, and TXNLI

Understanding the myPath^® Melanoma Results

The myPath^® Melanoma test result is a single numerical score that classifies melanocytic lesions as likely benign, likely malignant, or indeterminate. The expression of each of the 23 genes that comprise the signature is measured by qRT-PCR. An algorithm is then applied that assigns a weight to each of the signature components and establishes a threshold value.

Distribution of myPath^® Melanoma Scores

Scores between -16.1 and -2.1 are reported as ‘likely benign’

Scores between -2.0 and -0.1 are reported as ‘indeterminate’

Scores between 0.0 and +11.1 are reported as ‘likely malignant’

Intended Use Population

myPath® Melanoma has been clinically validated to differentiate benign nevi from malignant melanoma. It is intended for use in patients whose melanocytic lesion is not clearly benign or malignant based on clinical and/or histopathological features alone.

Analytical Validity

Warf et al. performed an analytical validation study assessing performance of the myPath® Melanoma assay in a design consistent with Clinical Laboratory Improvement Amendments (CLIA) Guidelines.11 This study evaluated the test as run in the laboratory, including RNA yield, RNA stability, dynamic range, precision, linear range and stability of extracted RNA, and demonstrated that the myPath signature is robust and reproducible.

Clinical Validity

myPath® Melanoma is the most extensively researched and validated ancillary diagnostic test for melanoma. The assay was developed in a training cohort of 464 melanocytic lesions.7 myPath® Melanoma scores were subsequently validated in three cohorts, including over 1,300 melanocytic neoplasms, distinct from the training cohort.8-10 Clinical validation studies utilized either histopathology or actual patient outcomes as reference standards. In melanoma, a complete representation of a test’s validity can be achieved only through validation against both histopathology and patient outcomes.

The current standard in diagnosing melanocytic lesions is histopathologic diagnosis. In line with this practice, myPath® Melanoma was initially developed and evaluated using consensus histopathologic diagnosis as a reference standard. The first validation of myPath® Melanoma demonstrated greater than 92% diagnostic accuracy by comparison to concordant histopathologic diagnoses (diagnoses arrived at independently by multiple expert dermatopathologists).⁸

Clinical Utility and Impact on Patient Care

The myPath® Melanoma result directly impacts clinical management, and two clinical utility publications demonstrate a consistent increase in definitive diagnoses and changes in clinical decision-making and patient treatment following testing. myPath®utilization results in a reduction in unnecessary and costly treatments. ^{12, 13}

REDUCTION OF TREATMENT IN myPATH® Melanoma BENIGN CASES

80% reduction in re-excisions in cases receiving an initial indeterminate result

Summary

myPath® Melanoma is an objective and reproducible assay that improves the accuracy of diagnoses based on histopathology alone. The peer-reviewed, published data demonstrate that myPath® Melanoma is well-validated and has an overall diagnostic accuracy of >90% in melanocytic lesions with ambiguous histopathology, based on consistent results across studies performed in three independent validation cohorts. myPath® Melanoma provides additional information that has been proven to reduce indeterminate diagnoses, driving a reduction in overtreatment. myPath® is gaining support, as multiple organizations, including The National Comprehensive Cancer Network (NCCN) and the American Academy of Dermatology (AAD) recommend the use of molecular testing or gene expression testing for histologically equivocal lesions, which reflects the intended use of the assay.^14,15 Moreover, Medicare Administrative Contractor Palmetto GBA MolDX issued a final local coverage determination for myPath®, effective April 2019.¹⁶

For more information please call us or visit www.mypathmelanoma.com

References:

1.National Cancer Institute. (2019.) Retrieved May 2019 from: https://seer.cancer.gov/statfacts/html/melan.html

2. Guy G, et al. Prevalence and costs of skin cancer treatment in the U.S., 2002 – 2006 and 2007 – 2011. Am J Prev Med. 2015; 48(2):183-187.
3. American Cancer Society. (2017) Retrieved from: https:// www.cancer.org/ cancer/melanoma-skin-cancer/detection-diagnosis-staging/ survival-rates-for-melanoma-skin-cancer-by-stage
4. Elmore JG, et al. Pathologists’ diagnosis of invasive melanoma and melanocytic proliferations: observer accuracy and reproducibility study. BMJ. 2017; 28;357:j2813.
5. Veenhuizen KC, et al. Quality assessment by expert opinion in melanoma pathology: experience of the pathology panel of the Dutch Melanoma Working Party. J Pathol. 1997; 182:266-72.
6. Shoo BA, et al. Discordance in the histopathologic diagnosis of melanoma at a melanoma referral center. J Am Acad Dermatol. 2010; 62(5):751-756.
7. Clarke LE, et al. Clinical validation of a gene expression signature that differentiates benign nevi from malignant melanoma. J Cutan Pathol 2015; 42:244-5.
8. Clarke LE, et al. An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi. Cancer 2017; 123(4):617-628.
9. Ko JS, et al. Diagnostic distinction of malignant melanoma and benign nevi by a gene expression signature and correlation to clinical outcomes. Cancer Epidemiol Biomarkers Prev. 2017; 26(7):1107-1113.
10. Ko JS, et al. Correlation of melanoma gene expression score with clinical outcomes on a series of melanocytic lesions. Human Pathol. 2019; 86:213-221.
11. Warf MB, et al. Analytical validation of a melanoma diagnostic gene signature using formalin-fixed paraffin-embedded melanocytic lesions. Biomark Med 2015; 9:407-16.
12. Cockerell CJ, et al. The influence of a gene expression signature on the diagnosis and recommended treatment of melanocytic tumors by dermatopathologists. Medicine 2016; 95(40):e4887.
13. Cockerell CJ, et al. The influence of a gene-expression signature on the treatment of diagnostically challenging melanocytic lesions. Per Med 2017; 14(2):123–3.
14. NCCN Guidelines: Cutaneous Melanoma. Version 2.2019.
15. Swetter S, et al. Guidelines of care for the management of primary cutaneous melanoma. J Am Acad Dermatol. Nov 2018. https://doi.org/10.1016/j.jaad.2018.08.055
16. Centers for Medicare & Medicaid Services. (2019, April) Retrieved June 2019 from: https://www.cms.gov/medicare-coverage-database/reports/draft-lcd-status-report.aspx?name =238*2&bc=AQAAAgAAAAAAAA%3D%3D
17. Clarke L et al. Clinical validation of a gene expression signature that differentiates benign nevi from malignant melanoma J Cutan Pathol 2015; 42:244-252.