Long-Term Outcomes in a Multicenter, Prospective Cohort Evaluating the Prognostic 31-Gene Expression Profile for Cutaneous Melanoma

Abstract

Purpose: Current guidelines for postoperative management of patients with stage I-IIA cutaneous melanoma (CM) do not recommend routine cross-sectional imaging, yet many of these patients develop metastases. Methods that complement American Joint Committee on Cancer (AJCC) staging are needed to improve identification and treatment of these patients. A 31-gene expression profile (31-GEP) test predicts metastatic risk as low (class 1) or high (class 2). Prospective analysis of CM outcomes was performed to test the hypotheses that the 31-GEP provides prognostic value for patients with stage I-III CM, and that patients with stage I-IIA melanoma and class 2 31-GEP results have metastatic risk similar to patients for whom surveillance is recommended.

Materials and methods: Two multicenter registry studies, INTEGRATE (ClinicalTrials.gov identifier:NCT02355574) and EXPAND (ClinicalTrials.gov identifier:NCT02355587), were initiated under institutional review board approval, and 323 patients with stage I-III CM and median follow-up time of 3.2 years met inclusion criteria. Primary end points were 3-year recurrence-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS).

Results: The 31-GEP was significant for RFS, DMFS, and OS in a univariate analysis and was a significant, independent predictor of RFS, DMFS, and OS in a multivariable analysis. GEP class 2 results were significantly associated with lower 3-year RFS, DMFS, and OS in all patients and those with stage I-IIA disease. Patients with stage I-IIA CM and a class 2 result had recurrence, distant metastasis, and death rates similar to patients with stage IIB-III CM. Combining 31-GEP results and AJCC staging enhanced sensitivity over each approach alone.

Conclusion: These data provide a rationale for using the 31-GEP along with AJCC staging, and suggest that patients with stage I-IIA CM and a class 2 31-GEP signature may be candidates for more intense follow-up.

Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Eddy C. Hsueh Speakers' Bureau: Amgen, Castle BiosciencesJeffrey J. Sussman Consulting or Advisory Role: Castle BiosciencesKyle R. Covington Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Gene expression profile tests Travel, Accommodations, Expenses: Castle BiosciencesHillary G. Caruso Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Chimeric antigen receptors (CARs) and CAR-expressing T cells are provided that can specifically target cells that express an elevated level of a target antigen. Likewise, methods for specifically targeting cells that express elevated levels of antigen (eg, cancer cells) with CAR T-cell therapies are provided Travel, Accommodations, Expenses: Castle BiosciencesAnn P. Quick Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Travel, Accommodations, Expenses: Castle BiosciencesRobert W. Cook Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Castle Biosciences related patents Travel, Accommodations, Expenses: Castle BiosciencesCraig L. Slingluff Consulting or Advisory Role: Immatics, Polynoma, CureVac Research Funding: GlaxoSmithKline, Merck Sharp & Dohme, 3M, Theraclion, Celldex Patents, Royalties, Other Intellectual Property: Licensing and Ventures Group of the University of Virginia Travel, Accommodations, Expenses: Polynoma Uncompensated Relationships: Agenus No other potential conflicts of interest were reported.Eddy C. Hsueh Speakers' Bureau: Amgen, Castle Biosciences Jeffrey J. Sussman Consulting or Advisory Role: Castle Biosciences Kyle R. Covington Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Gene expression profile tests Travel, Accommodations, Expenses: Castle Biosciences Hillary G. Caruso Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Chimeric antigen receptors (CARs) and CAR-expressing T cells are provided that can specifically target cells that express an elevated level of a target antigen. Likewise, methods for specifically targeting cells that express elevated levels of antigen (eg, cancer cells) with CAR T-cell therapies are provided Travel, Accommodations, Expenses: Castle Biosciences Ann P. Quick Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Travel, Accommodations, Expenses: Castle Biosciences Robert W. Cook Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Castle Biosciences related patents Travel, Accommodations, Expenses: Castle Biosciences Craig L. Slingluff Consulting or Advisory Role: Immatics, Polynoma, CureVac Research Funding: GlaxoSmithKline, Merck Sharp & Dohme, 3M, Theraclion, Celldex Patents, Royalties, Other Intellectual Property: Licensing and Ventures Group of the University of Virginia Travel, Accommodations, Expenses: Polynoma Uncompensated Relationships: Agenus No other potential conflicts of interest were reported.Eddy C. Hsueh Speakers' Bureau: Amgen, Castle Biosciences Jeffrey J. Sussman Consulting or Advisory Role: Castle Biosciences Kyle R. Covington Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Gene expression profile tests Travel, Accommodations, Expenses: Castle Biosciences Hillary G. Caruso Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Chimeric antigen receptors (CARs) and CAR-expressing T cells are provided that can specifically target cells that express an elevated level of a target antigen. Likewise, methods for specifically targeting cells that express elevated levels of antigen (eg, cancer cells) with CAR T-cell therapies are provided Travel, Accommodations, Expenses: Castle Biosciences Ann P. Quick Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Travel, Accommodations, Expenses: Castle Biosciences Robert W. Cook Employment: Castle Biosciences Stock and Other Ownership Interests: Castle Biosciences Patents, Royalties, Other Intellectual Property: Castle Biosciences related patents Travel, Accommodations, Expenses: Castle Biosciences Craig L. Slingluff Consulting or Advisory Role: Immatics, Polynoma, CureVac Research Funding: GlaxoSmithKline, Merck Sharp & Dohme, 3M, Theraclion, Celldex Patents, Royalties, Other Intellectual Property: Licensing and Ventures Group of the University of Virginia Travel, Accommodations, Expenses: Polynoma Uncompensated Relationships: Agenus No other potential conflicts of interest were reported.

© 2021 by American Society of Clinical Oncology.

Figures

FIG 1.

Study design for INTEGRATE and EXPAND registries. Enrollment and eligibility of 372 consecutively tested patients with 31-GEP in INTEGRATE and EXPAND registries. Inclusion criteria for enrollment were ≥ 16 years of age and no prior history of cancer. Exclusion criteria for analysis were

FIG 2.

Survival outcomes of patients with stage I-III CM by 31-GEP results. RFS, DMFS, and OS were estimated by Kaplan-Meier analysis and P values determined by logrank test. Tables beneath the graphs show survival rates and number of events in each GEP class. CM, cutaneous melanoma; DMFS, distant metastasis-free survival; GEP, gene expression profile; OS, overall survival; RFS, recurrence-free survival.

FIG 3.

Survival outcomes of patients with stage I-IIA CM by 31-GEP results compared with stage IIB-III overall. RFS, DMFS, and OS were estimated by Kaplan-Meier analysis and P values determined by logrank test. Tables beneath the graphs show survival rates and number of events in each GEP class. CM, cutaneous melanoma; DMFS, distant metastasis-free survival; GEP, gene expression profile; OS, overall survival; RFS, recurrence-free survival.

FIG A1.

Survival outcomes of patients with stage I-III CM by 31-GEP subclass. RFS, DMFS, and OS were estimated by Kaplan-Meier analysis and P values determined by logrank test. Tables beneath the graphs show survival rates and number of events in each GEP subclass. CM, cutaneous melanoma; DMFS, distant metastasis-free survival; GEP, gene expression profile; OS, overall survival; RFS, recurrence-free survival.

FIG A2.

Survival outcomes of patients with stage I-IIA CM by 31-GEP subclass. RFS, DMFS, and OS were estimated by Kaplan-Meier analysis and P values for statistical differences between GEP subclasses determined by logrank test. Table beneath the curve show the number of patients at risk each year, 3-year survival, and event rates for each population. CM, cutaneous melanoma; DMFS, distant metastasis-free survival; GEP, gene expression profile; OS, overall survival; RFS, recurrence-free survival.