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29-08-2017 | Melanoma | Article

Interim analysis of survival in a prospective, multi-center registry cohort of cutaneous melanoma tested with a prognostic 31-gene expression profile test

Journal: Journal of Hematology & Oncology

Authors: Eddy C. Hsueh, James R. DeBloom, Jonathan Lee, Jeffrey J. Sussman, Kyle R. Covington, Brooke Middlebrook, Clare Johnson, Robert W. Cook, Craig L. Slingluff Jr, Kelly M. McMasters

Publisher: BioMed Central

Abstract

Background

A 31-gene expression profile (GEP) test that provides risk classification of cutaneous melanoma (CM) patients has been validated in several retrospective studies. The objective of the reported study was a prospective evaluation of the GEP performance in patients enrolled in two clinical registries.

Methods

Three-hundred twenty two CM patients enrolled in the EXPAND (NCT02355587) and INTEGRATE (NCT02355574) registries met the criteria of age ≥ 16 years, successful GEP result and ≥1 follow-up visit for inclusion in this interim analysis. Primary endpoints were recurrence-free (RFS), distant metastasis-free (DMFS), and overall survival (OS).

Results

Median follow-up was 1.5 years for event-free patients. Median age for subjects was 58 years (range 18–87) and median Breslow thickness was 1.2 mm (range 0.2–12.0). Eighty-eight percent (282/322) of cases had stage I/II disease and 74% (237/322) had a SLN biopsy. Seventy-seven percent (248/322) had class 1 molecular profiles. 1.5-year RFS, DMFS, and OS rates were 97 vs. 77%, 99 vs. 89%, and 99 vs. 92% for class 1 vs. class 2, respectively (p < 0.0001 for each). Multivariate Cox regression showed Breslow thickness, mitotic rate, and GEP class to significantly predict recurrence (p < 0.01), while tumor thickness was the only significant predictor of distant metastasis and overall survival in this interim analysis.

Conclusions

Interim analysis of patient outcomes from a combined prospective cohort supports the 31-gene GEP’s ability to stratify early-stage CM patients into two groups with significantly different metastatic risk. RFS outcomes in this real-world cohort are consistent with previously published analyses with retrospective specimens. GEP testing complements current clinicopathologic features and increases identification of high-risk patients.

Trial registration

ClinicalTrials.gov, NCT02355574 and NCT02355587

Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27:6199–206.CrossRefPubMedPubMedCentral

Edge SB, Compton CC. The American joint committee on cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–4.CrossRefPubMed

Shaikh WR, Dusza SW, Weinstock MA, Oliveria SA, Geller AC, Halpern AC. Melanoma thickness and survival trends in the United States, 1989 to 2009. J Natl Cancer Inst. 2015; https://doi.org/10.1093/jnci/djv294.

Whiteman DC, Baade PD, Olsen CM. More people die from thin melanomas (1 mm) than from thick melanomas (>4 mm) in Queensland. Aust J Invest Dermatol. 2015;135:1190–3.CrossRef

Glazer AM, Winkelmann RR, Farberg AS, Rigel DS. Analysis of trends in US melanoma incidence and mortality. JAMA Dermatol. 2017;153:225–6.CrossRef

Andtbacka RH, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene Laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33:2780–8.CrossRefPubMed

Bhutiani N, Egger ME, McMasters KM. Optimizing follow-up assessment of patients with Cutaneous melanoma. Ann Surg Oncol. 2017;24:861–3.CrossRefPubMed

Leon-Ferre RA, Kottschade LA, Block MS, McWilliams RR, Dronca RS, Creagan ET, et al. Association between the use of surveillance PET/CT and the detection of potentially salvageable occult recurrences among patients with resected high-risk melanoma. Melanoma Res. 2017; doi:10.1097/CMR.0000000000000344.

Nishino M, Giobbie-Hurder A, Ramaiya NH, Hodi FS. Response assessment in metastatic melanoma treated with ipilimumab and bevacizumab: CT tumor size and density as markers for response and outcome. J Immunother Cancer. 2014; doi:10.1186/s40425-014-0040-2.

10.

Park TS, Phan GQ, Yang JC, Kammula U, Hughes MS, Trebska-McGowan K, et al. Routine computer tomography imaging for the detection of recurrences in high-risk melanoma patients. Ann Surg Oncol. 2017;24:947–51.CrossRefPubMedPubMedCentral

11.

Podlipnik S, Carrera C, Sanchez M, Arguis P, Olondo ML, Vilana R, et al. Performance of diagnostic tests in an intensive follow-up protocol for patients with American joint committee on cancer (AJCC) stage IIB, IIC, and III localized primary melanoma: a prospective cohort study. J Am Acad Dermatol. 2016;75:516–24.CrossRefPubMed

12.

Gerami P, Cook RW, Wilkinson J, Russell MC, Dhillon N, Amaria RN, et al. Development of a prognostic genetic signature to predict the metastatic risk associated with cutaneous melanoma. Clin Cancer Res. 2015;21:175–83.CrossRefPubMed

13.

Onken MD, Worley LA, Tuscan MD, Harbour JW. An accurate, clinically feasible multi-gene expression assay for predicting metastasis in uveal melanoma. J Mol Diagn. 2010;12:461–8.CrossRefPubMedPubMedCentral

14.

Onken MD, Worley LA, Ehlers JP, Harbour JW. Gene expression profiling in uveal melanoma reveals two molecular classes and predicts metastatic death. Cancer Res. 2004;64:7205–9.CrossRefPubMedPubMedCentral

15.

Jaeger J, Koczan D, Thiesen HJ, Ibrahim SM, Gross G, Spang R, et al. Gene expression signatures for tumor progression, tumor subtype, and tumor thickness in laser-microdissected melanoma tissues. Clin Cancer Res. 2007;13:806–15.CrossRefPubMed

16.

Bittner M, Meltzer P, Chen Y, Jiang Y, Seftor E, Hendrix M, et al. Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature. 2000;406:536–40.CrossRefPubMed

17.

Haqq C, Nosrati M, Sudilovsky D, Crothers J, Khodabakhsh D, Pulliam BL, et al. The gene expression signatures of melanoma progression. Proc Natl Acad Sci U S A. 2005;102:6092–7.CrossRefPubMedPubMedCentral

18.

Mauerer A, Roesch A, Hafner C, Stempfl T, Wild P, Meyer S, et al. Identification of new genes associated with melanoma. Exp Dermatol. 2011;20:502–7.CrossRefPubMed

19.

Scatolini M, Grand MM, Grosso E, Venesio T, Pisacane A, Balsamo A, et al. Altered molecular pathways in melanocytic lesions. Int J Cancer. 2010;126:1869–81.PubMed

20.

Smith AP, Hoek K, Becker D. Whole-genome expression profiling of the melanoma progression pathway reveals marked molecular differences between nevi/melanoma in situ and advanced-stage melanomas. Cancer Biol Ther. 2005;4:1018–29.CrossRefPubMed

21.

Gerami P, Cook RW, Russell MC, Wilkinson J, Amaria RN, Gonzalez R, et al. Gene expression profiling for molecular staging of cutaneous melanoma in patients undergoing sentinel lymph node biopsy. J Am Acad Dermatol. 2015;72:780–5. e3CrossRefPubMed

22.

Zager JS, Gastman BR, Messina J, Sondak VK, Ferris L, Cook RW, et al. Performance of a 31-gene expression profile in a previously unreported cohort of 334 cutaneous melanoma patients. J Clin Oncol. 2016;34(Suppl 15):9581.

23.

Burton AL, Egger ME, Gilbert JE, Stromberg AJ, Hagendoorn L, Martin RC, et al. Assessment of mitotic rate reporting in melanoma. Am J Surg. 2012;204:969–75.CrossRefPubMed

24.

Morton DL, Thompson JF, Cochran AJ, Mozzillo N, Nieweg OE, Roses DF, et al. Final trial report of sentinel-node biopsy versus nodal observation in melanoma. N Engl J Med. 2014;370:599–609.CrossRefPubMedPubMedCentral

25.

Coit DG, Thompson JA, Algazi A, Andtbacka R, Bichakjian CK, Carson WE 3rd, et al. Melanoma, version 2.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2016;14:450–73.CrossRef

26.

Onken MD, Worley LA, Char DH, Augsburger JJ, Correa ZM, Nudleman E, et al. Collaborative ocular oncology group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology. 2012;119:1596–603.CrossRefPubMedPubMedCentral

27.

van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med. 2002;347:1999–2009.CrossRefPubMed

28.

Kaufman H, Amatruda T, Nemunaitis JJ, Chesne JA, Delman KA, Spitler LE, et al. Tumor size and clinical outcomes in melanoma patients (MEL pts) treated with talimogene laherparepvec (T-VEC). J Clin Oncol. 2015;33(Suppl 15):9074.

29.

Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, et al. Association of pembrolizumab with tumor response and survival among patients with advanced melanoma. JAMA. 2016;315:1600–9.CrossRefPubMed