Validation of a 40-gene expression profile test to predict metastatic risk in localized high-risk cutaneous squamous cell carcinoma - 03/09/20

Doi : 10.1016/j.jaad.2020.04.088

Ashley Wysong, MD, MS ^a, Jason G. Newman, MD ^b, Kyle R. Covington, PhD ^c, Sarah J. Kurley, PhD ^c, Sherrif F. Ibrahim, MD, PhD ^d, Aaron S. Farberg, MD ^e,^f, Anna Bar, MD ^g, Nathan J. Cleaver, DO ^h, Ally-Khan Somani, MD, PhD ⁱ, David Panther, MD ^j, David G. Brodland, MD ^j, John Zitelli, MD ^j, Jennifer Toyohara, MD ^k, Ian A. Maher, MD ^l, Yang Xia, MD ^m, Kristin Bibee, MD ⁿ, Robert Griego, MD ^o, Darrell S. Rigel, MD ^p, Kristen Meldi Plasseraud, PhD ^c, Sarah Estrada, MD ^q,^r, Lauren Meldi Sholl, MS ^q, Clare Johnson, RN ^q, Robert W. Cook, PhD ^c,^⁎ , Chrysalyne D. Schmults, MD, MSCE ^s, Sarah T. Arron, MD, PhD ^t,^⁎
^a University of Nebraska Medical Center, Omaha, Nebraska
^b University of Pennsylvania, Philadelphia, Pennsylvania
^c Castle Biosciences, Inc, Friendswood, Texas
^d University of Rochester, Rochester, New York
^e Icahn School of Medicine at Mount Sinai, New York, New York
^f Arkansas Dermatology Skin Cancer Center, Little Rock, Arkansas
^g Oregon Health & Science University, Portland, Oregon
^h Cleaver Dermatology, Kirksville, Missouri
ⁱ Indiana University School of Medicine, Indianapolis, Indiana
^j Zitelli and Brodland, P.C. Skin Cancer Center, Pittsburgh, Pennsylvania
^k Adult & Pediatric Dermatology, Concord, Massachusetts
^l University of Minnesota, Minneapolis, Minnesota
^m Brooke Army Medical Center, San Antonio, Texas
ⁿ University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
^o Skin Cancer Specialists, Ltd, Mesa, Arizona
^p New York University School of Medicine, New York, New York
^q Castle Biosciences, Inc, Phoenix, Arizona
^r Affiliated Dermatology, Scottsdale, Arizona
^s Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
^t University of California San Francisco, San Francisco, California

^∗Correspondence to: Sarah T. Arron, MD, PhD, University of California, San Francisco, 1701 Divisadero St, Box 0316, San Francisco, CA 94143-0316.University of California, San Francisco1701 Divisadero StBox 0316San FranciscoCA94143-0316^∗Reprint requests: Robert W. Cook, PhD, Castle Biosciences, Inc, 820 S. Friendswood Dr., #201, Friendswood, TX 77546.Castle Biosciences, Inc, 820 SFriendswood Dr., #201FriendswoodTX77546

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Abstract

Background

Current staging systems for cutaneous squamous cell carcinoma (cSCC) have limited positive predictive value for identifying patients who will experience metastasis.

Objective

To develop and validate a gene expression profile (GEP) test for predicting risk for metastasis in localized, high-risk cSCC with the goal of improving risk-directed patient management.

Methods

Archival formalin-fixed paraffin-embedded primary cSCC tissue and clinicopathologic data (n = 586) were collected from 23 independent centers in a prospectively designed study. A GEP signature was developed using a discovery cohort (n = 202) and validated in a separate, nonoverlapping, independent cohort (n = 324).

Results

A prognostic 40-GEP test was developed and validated, stratifying patients with high-risk cSCC into classes based on metastasis risk: class 1 (low risk), class 2A (high risk), and class 2B (highest risk). For the validation cohort, 3-year metastasis-free survival rates were 91.4%, 80.6%, and 44.0%, respectively. A positive predictive value of 60% was achieved for the highest-risk group (class 2B), an improvement over staging systems, and negative predictive value, sensitivity, and specificity were comparable to staging systems.

Limitations

Potential understaging of cases could affect metastasis rate accuracy.

Conclusion

The 40-GEP test is an independent predictor of metastatic risk that can complement current staging systems for patients with high-risk cSCC.

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Key words : cutaneous squamous cell carcinoma, gene expression profile, metastasis, prognostication, risk

Abbreviations used : AJCC, BWH, cSCC, GEP, HR, LR, MFS, NCCN, NPV, PPV

Plan

Methods

Study design

Patient enrollment and specimen acquisition

Assay methods and statistical analyses

Results

Development of the prognostic signature

Independent validation of the 40-GEP prognostic signature

Prognostic accuracy of the 40-GEP test compared to staging systems

Discussion

	Drs Schmults and Arron are cosenior authors.
	Funding sources: Supported by Castle Biosciences, Inc, which provided funding for tissue and clinical data retrieval to contributing centers.
	Disclosure: Drs Wysong (steering committee), Newman (steering committee), Schmults (steering committee), Arron (steering committee), Ibrahim, Farberg, Bar, Cleaver, Somani, Brodland, Toyohara, Maher, Xia, Bibee, Griego, and Rigel are principal investigators for the study. Dr Wysong is an unpaid board member of the American College of Mohs Surgeons and World Congress of Dermatology. Drs Covington, Kurley, Meldi Plasseraud, Estrada, and Cook, and authors Scholl and Johnson are employees and options holders at Castle Biosciences. Dr Schmults is an investigator for Novartis, Genentech and Merck, a consultant for Sanofi and Regeneron (steering committee), and chair for the National Comprehensive Cancer Network. Dr Arron is an investigator for Pfizer, Regeneron and PellePharm, and a consultant for Enspectra Health, Rakuten Medical, and Gerson Lehrman Group. Drs Panther and Zitelli have no disclosures.
	Presented at the 2019 American Society for Dermatologic Surgery Annual Meeting, Chicago, IL, October 24-27, 2019.
	IRB approval status: Approved by IRBs before initiation. IRB granted a waiver of consent because of the nature of the disease under study.