Which melanoma patients benefit from genetic testing?

Which melanoma patients benefit from genetic testing? Michael A. Marchetti, MD Assistant Attending, Dermatology Service Memorial Sloan Kettering Cancer Center American Academy of Dermatology Annual Meeting San Diego, California, USA February 17, 2018 2:50 PM 3:10 PM

DISCLOSURE OF RELATIONSHIPS WITH INDUSTRY Michael A. Marchetti, MD S027 Managing Patients with Melanoma or Other Melanocytic Neoplasms DISCLOSURES I do not have any relevant relationships with industry.

Germline testing for familial melanoma CDKN2A BAP1 Somatic testing of primary melanoma Diagnostic Myriad mypath Melanoma Prognostic DecisionDx TM -Melanoma (Castle Biosciences)

Most primary cutaneous melanomas are sporadic, not familial CDKN2A Population-based estimate = ~0.2-2% 2,3 1 Hansen, Lancet Onc, 2004 2 Aitken et al, JNCI, 1999 3 Begg et al, JNCI, 2005

Alternative splicing of CDKN2A gene produces 2 proteins 20-40% of familial melanoma Melanoma Pancreatic Rare (<1%) Melanoma Neural Aoude et al., Pigment Cell Melanoma Res 2014

CDKN2A germline mutations affect cell-cycle control Schadendorf D et al. Nat Rev Dis Prim. 2016.

CDKN2A (p16) mutation: key concepts AD inheritance; founder mutations Variable MM penetrance Risk modified by mutation type, environment, and/or other melanoma predisposition genes? Early onset melanoma mean age at dx is 35 yrs (US) MC1R Melanoma Penetrance (by age 80) by Region 58% Europe 76% USA 91% Australia Bishop JNCI 2002

Rule of 2 Low Incidence Region Rule of 3 High Incidence Region Leachman et al, JAAD, 2009

Individual 3 invasive melanomas 1 invasive melanoma + Family 2 invasive melanomas or pancreatic cancers 1 st and 2 nd degree same side of family Leachman et al, JAAD, 2009

CDKN2A mutation testing: non-appropriate settings! 1. Early-onset melanoma? <1% of individuals with melanoma younger than 40 years will test positive 2. Atypical mole syndrome (high-risk nevus phenotype)? Very low prevalence outside of familial melanoma setting 3. In-situ melanoma? Do not count 4. Individual without melanoma history but family hx is suggestive? Testing of affected family member is appropriate but interpretation of negative results of non-affected family member can be problematic and should be avoided, if possible Leachman et al, JAAD, 2009

CDKN2A mutation carriers: practical considerations Evidence on how to screen? Interval: q6 months Aids: Dermoscopy, TBP, sequential digital dermoscopic imaging +Quarterly SSEs aided by TBP Bottom line: melanomas caught at early stages (median: in situ) Moloney et al, JAMA Derm, 2014

CDKN2A mutation carriers: practical considerations Pancreatic screening? 1. Mutation-specific range of penetrance estimates (no association in Australia?) 2. Effective? Harms? 5-year survival 24% (v. expected 5%) Limited by lead and length-time biases Unclear impact on mortality (survival can be misleading in screening studies) Vasen H et al. JCO 2016

CDKN2A mutation carriers: practical considerations Pancreatic screening? Value not yet proven (and potential for harms) Optimal interval, method, and age of initiation/cessation is not defined If considered: Research setting ideally Specialized programs with high-volume pancreatic surgery and welldefined screening protocols Combination of MRI (solid tumors) and EUS (cystic tumors) Vasen H. Familial Cancer. 2018

CDKN2A mutation testing: practical considerations Do patients at high familial melanoma risk benefit from testing? lack of evidence that these patients (and family members) should be managed differently according to their mutation test results Screening should be considered only after a thorough clinical risk assessment and appropriate genetic counseling Enrollment in a research study is ideal Patients at sufficiently high risk should be allowed to weigh the pros and cons of testing

BAP1 germline mutation Autosomal Dominant Cancer Predisposition Syndrome Mesothelioma Uveal melanoma Cutaneous melanoma Clear cell renal cell carcinoma Characteristic nevi = BAPoma Wiesner nevus; melanocytic BAP1- mutated atypical intradermal tumors (MBAITs), Atypical spitz tumor, nevoid melanoma-like melanocytic proliferations (NEMMP) B-RAF V600E -mutated, BAP1-negative tumors

Multiple melanomas (n=7), atypical moles, BAPomas, but no family hx of ocular melanoma, mesothelioma, or kidney cancer Gerami P, JAMA Derm, 2015

BAP1 germline mutation testing: when to consider among cutaneous melanoma patients? Melanoma patient with a 1 st or 2 nd degree family hx of 1 case of mesothelioma, uveal melanoma, clear cell RCC, and/or BAPoma Melanoma-only families that meet criteria for CDKN2A testing? Consider BAP1 IHC in atypical spitz w/ epithelioid component Much remains unknown: - Penetrance across cancer types, screening recommendations, and incidence of sporadic BAPomas - clinical/dermoscopy case-control study of BAPomas under way

Germline testing for familial melanoma CDKN2A BAP1 Somatic testing of primary melanoma Diagnostic Myriad mypath Melanoma DermTech Pigmented Lesion Assay Prognostic DecisionDx TM -Melanoma (Castle Biosciences)

Available molecular tests to aid in melanoma diagnosis CGH (comparative genomic hybridization) FISH (fluorescence in situ hybridization) Gene expression profiling by quantitative reverse transcription polymerase chain reaction Not a stand-alone test for melanoma diagnosis!

Myriad MyPath Melanoma https://myriad.com

<-2-2 to 0 Results should always be considered within the context of all other available clinical, histopathologic, and molecular data when rendering a final diagnosis Not a stand-alone test >0

1400 cases prospectively submitted Excluded: indeterminate scores, lack of triple-consensus pathology review, low tumor-volume (<10%) 736 cases Sensitivity = 91.5% Specificity = 92.5% Clarke LE et al. Cancer. 2017

Elmore JG et al. BMJ. 2017.

DermTech Pigmented Lesion Assay (gene expression) 2-gene PLA from stratum corneum obtained from nonadhesive patch LINC PRAME Positive or Negative Result Gerami P. JAAD. 2017

DermTech Pigmented Lesion Assay (gene expression) ***Among 203 serially collected samples, sensitivity was 79% and specificity 80% Gerami P. JAAD. 2017

***not in situ formalin-fixed, paraffin embedded slides

27% of US Deaths from melanomas <1mm Although prognosis of melanoma <1mm is excellent, accounts for 27% of deaths in US Gershenwald, et al. CA Cancer J Clin. 2018 Geller AC, et al. JAAD. 2011

Retrospective independent cohorts validate differences in RFS, DMFS, and MSS between Class 1 and Class 2 patients Recurrence-free survival Distant metastasis free survival Melanoma specific survival Zager et al. BMC Cancer. 2018.

Prospective data confirm difference in recurrence-free survival between Class 1 and Class 2 patients Hsueh E et al. J of Heme and Onc. 2017

NCCN 2.2018 guidelines on GEP for prognosis While there is interest in [GEP for prognosis] it is not recommended outside of a clinical study Specific Comments: Validated as independently predictive of outcome compared to AJCC stage or SLN status Not directly evaluated in context of all known prognostic characteristics of localized melanoma Independent prognostic value not yet confirmed in a large population of patients with average to low-risk melanoma Inconsistency of results across studies and minimal overlap in signatures Coit D, et al. NCCN 2.2018

My concerns with use of commercially-available GEP test consider Stage I 597 Stage I patients 1,2 508 Class 1 -> 25 recurrences 89 Class 2 -> 13 recurrences True Positive True Negative Class 2 13 76 Class 1 25 483 Sensitivity Specificity PPV NPV Stage I 34% 86% 14% 95% Leachman S et al. SMR Congress 2017 Zager et al. BMC Cancer. 2018.