Abstract
Background
Although sentinel lymph node (SLN) biopsy is a standard procedure used to identify patients at risk for melanoma recurrence, it fails to risk-stratify certain patients accurately. Because processes in SLNs regulate anti-tumor immune responses, the authors hypothesized that SLN gene expression may be used for risk stratification.
Methods
The Nanostring nCounter PanCancer Immune Profiling Panel was used to quantify expression of 730 immune-related genes in 60 SLN specimens (31 positive [pSLNs], 29 negative [nSLNs]) from a retrospective melanoma cohort. A multivariate prediction model for recurrence-free survival (RFS) was created by applying stepwise variable selection to Cox regression models. Risk scores calculated on the basis of the model were used to stratify patients into low- and high-risk groups. The predictive power of the model was assessed using the Kaplan–Meier and log-rank tests.
Results
During a median follow-up period of 6.3 years, 20 patients (33.3%) experienced recurrence (pSLN, 45.2% [14/31] vs nSLN, 20.7% [6/29]; p = 0.0445). A fitted Cox regression model incorporating 12 genes accurately predicted RFS (C-index, 0.9919). Improved RFS was associated with increased expression of TIGIT (p = 0.0326), an immune checkpoint, and decreased expression of CXCL16 (p = 0.0273), a cytokine important in promoting dendritic and T cell interactions. Independent of SLN status, the model in this study was able to stratify patients into cohorts at high and low risk for recurrence (p < 0.001, log-rank).
Conclusions
Expression profiles of the SLN gene are associated with melanoma recurrence and may be able to identify patients as high or low risk regardless of SLN status, potentially enhancing patient selection for adjuvant therapy.
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References
Thomas DC, Han G, Leong SP, et al. Recurrence of melanoma after a negative sentinel node biopsy: predictors and impact of recurrence site on survival. Ann Surg Oncol. 2019;26:2254–62.
Landow SM, Gjelsvik A, Weinstock MA. Mortality burden and prognosis of thin melanomas overall and by subcategory of thickness, SEER registry data, 1992–2013. J Am Acad Dermatol. 2017;76:258–63.
Eggermont AMM, Dummer R. The 2017 complete overhaul of adjuvant therapies for high-risk melanoma and its consequences for staging and management of melanoma patients. Eur J Cancer Oxford Engl 1990. 2017;86:101–5.
Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378:1789–801.
Weber J, Mandala M, Del Vecchio M, et al. Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma. N Engl J Med. 2017;377:1824–35.
Oh A, Tran DM, McDowell LC, et al. Cost-effectiveness of nivolumab-ipilimumab combination therapy compared with monotherapy for first-line treatment of metastatic melanoma in the United States. J Manag Care Specialty Pharm. 2017;23:653–64.
Eggermont AM, Chiarion-Sileni V, Grob JJ, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375:1845–55.
Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813–23.
Coit DG, Thompson JA, Albertini MR, et al. Cutaneous melanoma, version 2.2019 NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019;17:367–402.
Balch CM, Gershenwald JE, Soong SJ, et al. Multivariate analysis of prognostic factors among 2313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 2010;28:2452–9.
Gershenwald JE, Scolyer RA, Hess KR, et al. Melanoma staging: evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67:472–92.
Cochran AJ, Huang RR, Lee J, Itakura E, Leong SP, Essner R. Tumour-induced immune modulation of sentinel lymph nodes. Nat Rev Immunol. 2006;6:659–70.
Holtzhausen A, Zhao F, Evans KS, et al. Melanoma-derived Wnt5a promotes local dendritic-cell expression of IDO and immunotolerance: opportunities for pharmacologic enhancement of immunotherapy. Cancer Immunol Res. 2015;3:1082–95.
van den Hout M, Koster BD, Sluijter BJR, et al. Melanoma sequentially suppresses different DC subsets in the sentinel lymph node, affecting disease spread and recurrence. Cancer Immunol Res. 2017;5:969–77.
Tsang HF, Xue VW, Koh SP, Chiu YM, Ng LP, Wong SC. NanoString, a novel digital color-coded barcode technology: current and future applications in molecular diagnostics. Expert Rev Mol Diagnostics. 2017;17:95–103.
Geiss GK, Bumgarner RE, Birditt B, et al. Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat Biotechnol. 2008;26:317–25.
Eggermont AM, Suciu S, MacKie R, et al. Postsurgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005;366:1189–96.
Mocellin S, Lens MB, Pasquali S, Pilati P, Chiarion Sileni V. Interferon alpha for the adjuvant treatment of cutaneous melanoma. Cochrane Database Syst Rev. 2013(6):CD008955.
Hauschild A, Gogas H, Tarhini A, et al. Practical guidelines for the management of interferon-alpha-2b side effects in patients receiving adjuvant treatment for melanoma: expert opinion. Cancer. 2008;112:982–94.
Sinnamon AJ, Song Y, Sharon CE, et al. Prediction of residual nodal disease at completion dissection following positive sentinel lymph node biopsy for melanoma. Ann Surg Oncol. 2018;25:3469–75.
Luke JJ, Ascierto PA, Carlino MS, et al. KEYNOTE-716: phase III study of adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma. Future Oncol. 2020;16:4429–38.
Zager JS, Gastman BR, Leachman S, et al. Performance of a prognostic 31-gene expression profile in an independent cohort of 523 cutaneous melanoma patients. BMC Cancer. 2018;18:130.
Keller J, Schwartz TL, Lizalek JM, et al. Prospective validation of the prognostic 31-gene expression-profiling test in primary cutaneous melanoma. Cancer Med. 2019;8:2205–12.
Amaral TMS, Hoffmann MC, Sinnberg T, et al. Clinical validation of a prognostic 11-gene expression-profiling score in prospectively collected FFPE tissue of patients with AJCC v8 stage II cutaneous melanoma. Eur J Cancer Oxford, Engl 1990. 2020;125:38–45.
van ‘t Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression-profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530–6.
Paik S, Shak S, Tang G, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med. 2004;351:2817–26.
Veldman-Jones MH, Brant R, Rooney C, et al. Evaluating robustness and sensitivity of the NanoString Technologies nCounter Platform to enable multiplexed gene expression-analysis of clinical samples. Cancer Res. 2015;75:2587–93.
Tarhini AA, Floros T, Lin HM, et al. A unique gene-expression signature is significantly differentially expressed in tumor-positive or tumor-negative sentinel lymph nodes in patients with melanoma. Melanoma Res. 2017;27:429–38.
Acknowledgments
Dr. Beasley is supported by the Society of Surgical Oncology Young Investigator award (2019) and by NIH K08 CA237726-01A1. Dr. Farrow is supported by a National Institutes of Health T-32 grant (T32-CA093245) for translational research in surgical oncology.
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The authors report no conflicts on interested related to this work. Dr. Beasley was a one-time consultant for Regneron in 2019.
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Farrow, N.E., Holl, E.K., Jung, J. et al. Characterization of Sentinel Lymph Node Immune Signatures and Implications for Risk Stratification for Adjuvant Therapy in Melanoma. Ann Surg Oncol 28, 3501–3510 (2021). https://doi.org/10.1245/s10434-020-09277-w
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DOI: https://doi.org/10.1245/s10434-020-09277-w