Molecular Methods in the Diagnosis and Prognostication of Melanoma: Pros & Cons

Transcription

1 Molecular Methods in the Diagnosis and Prognostication of Melanoma: Pros & Cons Ben J. Friedman, MD Senior Staff Physician Department of Dermatology Department of Pathology and Laboratory Medicine Henry Ford Hospital, Detroit, MI, USA

2 Disclosures I have no conflicts of interest

3 Question Can adjunctive molecular assays help us make more accurate diagnoses and prognosticate better? 3

4 Outline Diagnosis 1. Array Comparative Genomic Hybridization (acgh) 2. Fluorescence In-Situ Hybridization (FISH) Multiprobe Assay 3. MyPath [Gene Expression Profiling (qrt-pcr)] Prognosis 4. Decision Dx-Melanoma TM [Gene Expression Profiling (qrt-pcr)] 4

5 Problem Histopathologically ambiguous lesions common Misdiagnosis has consequences Thickness/ sentinel node limited predictive ability N Engl J Med Sep 28;355(13):

6 How often do you request ancillary molecular testing for ambiguous melanocytic lesions? Never < 5 times per 5 -> 20 times > 20 times year per year per year EXPERT PANEL 23% 51% 22% 4% AUDIENCE 0% 14% 57% 29% **Poll from 2018 American Society of Dermatopathology Annual Meeting, Chicago, IL** 6

7 Gold Standard Limitation for Diagnostic Assays Need substantially more data on long term clinical outcome in cases with ambiguous morphology! J Am Acad Derm Oct;75(4):

8 Array Comparative Genomic Hybridization (aka Chromosomal Microarray Analysis, SNP array) 8

9 Array CGH Detects and maps DNA copy # alterations (CNA) Multiple CNA common in melanoma (>95%) Nevi have no CNA or rarely n= 1 or n=2 Cancer Res May 15;58(10): Am J Pathol Nov;163(5): Dermatol Ther Jan-Feb;19(1):

10 JAAD Jun;72(6):943-58

11 11

12 Array CGH: Pros Surveys the whole genome Sensitivity and specificity for CNA > than FISH Degree of agreement with expert morphologists acgh > FISH > GEP Hum Pathol Dec 18. pii: S (18)30488 Mod Pathol Nov;31(11): Mod Pathol Aug;29(8):832-43

13 Array CGH: Cons Not for point mutations/ balanced translocations High tissue requirement (>0.4mm BD) Limited CNA: likelihood of progression? Cost: ~1800$ Turnaround time: ~3-4 weeks J Mol Diagn Sep;15(5):

14 FISH Multiprobe Assay 14

15 FISH Multiprobe Assay Fluorescent probes-> bind specific DNA segments Detects deleterious gains and losses (acgh data) 6p25, 8q24, 9p21, and 11q13 94% sensitive, 98% specific (n=102) Am J Surg Pathol. 2009;33(8): Am J Surg Pathol. 2012;36(6):

16 8q24 (MYC) Pathology Dec;49(7):

17 FISH Pros Less technical requirements than acgh Detection of malignant subpopulations Insurance more likely to cover Turnaround time ~5 days Am J Surg Pathol May;37(5):

18 FISH Cons Heterogeneity of melanoma Tetraploidy pitfall Poor performance in ambiguous lesions? Cost: ~$ Am J Surg Pathol May;37(5): Am J Surg Pathol Dec;37(12): Ann Diagn Pathol Jun;28:

19 mypath [GEP (qrt-pcr)] 19

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21 GEP (mypath ) Validation study n=1400 specimens Triple DP consensus, lack of indeterminate score, and samples >10% tumor volume n=736 specimens Sensitivity: 91.5%, Specificity 92.5% Cancer Feb 15;123(4):

22 GEP [mypath ]: Pros Tumor-immune microenvironment Cell differentiation, cell signaling, immune response Lower tissue requirement than acgh Turnaround time ~7 days J Cutan Pathol Apr;42(4):

23 GEP [mypath ]: Cons Indeterminate scores: up to 16% Insufficient RNA: up to 8% Not for: recurrent lesions, re-excisions, immunosuppressed Reliability in ambiguous lesions unknown Cost: 1950$ Cancer Feb 15;123(4):

24 Molecular Prognostication of Melanoma 24

25 TNM staging AJCC 7th Edition Cancer Staging- Cutaneous Melanoma 25

26 Decision DxMelanomaTM [GEP (qrt-pcr)] 26

27 Prognostic 31-gene signature Clin Cancer Res Jan 1;21(1):

28 GEP (Decision Dx) Low risk (class 1) & high risk (class 2) enhanced surveillance of high risk adjuvant/ earlier therapy for high risk reduce anxiety for low risk Clin Cancer Res Jan 1;21(1):

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30 n=523; stage 1, 2, and 3 J Am Acad Derm Jan;80(1):

31 GEP (Decision DxTM): Pros Strong independent prognostic indicator NPV of Class 1A: >/= ~85% GEP+SNL status: better risk stratification J Am Acad Dermatol May;72(5):780-5.e3 BMC Cancer Feb 5;18(1):130 31

32 GEP (Decision DxTM): Cons PPV of Class 2 in AJCC Stage 1= ~10% or less Weak evidence for radiologic screening Cost effective? => $8,000 Dermatol Surg Dec;44(12): BMC Cancer Feb 5;18(1):130 J Am Acad Derm Jan;80(1):

33 Conclusion acgh, FISH, GEP (mypath ) are promising adjuncts to histopathology LTO data in ambiguous tumors limited GEP (mypath ): need independent nonmanufacturer conducted studies 33

34 Conclusion GEP (Decision Dx TM) = independent prognostic parameter Need prospective studies -> clinical utility Low PPV in stage 1, may limit use to thicker tumors in conjunction with SNL status 34

35 References 1. Cancer Res May 15;58(10): Am J Pathol Nov;163(5): Dermatol Ther Jan-Feb;19(1): Hum Pathol Dec 18. pii: S (18) Mod Pathol Nov;31(11): Mod Pathol Aug;29(8): J Mol Diagn Sep;15(5): Am J Surg Pathol. 2009;33(8): Am J Surg Pathol. 2012;36(6): Am J Surg Pathol Dec;37(12): Ann Diagn Pathol Jun;28: J Cutan Pathol Apr;42(4):

36 References 13. Cancer Feb 15;123(4): Cancer Epidemiol Biomarkers Prev Jul;26(7): Hum Pathol Dec 16. pii: S (18) doi 16. J Invest Dermatol Apr;135(4): N Engl J Med Sep 28;355(13): Dermatol Surg Dec;44(12): Clin Cancer Res Jan 1;21(1): J Am Acad Dermatol May;72(5):780-5.e3 21. J Am Acad Derm Jan;80(1): Am J Surg Pathol May;37(5): Pathology Dec;49(7):