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Characterization of Sentinel Lymph Node Immune Signatures and Implications for Risk Stratification for Adjuvant Therapy in Melanoma

  • Melanoma
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

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

  1. 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.

    Article  Google Scholar 

  2. 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.

    Article  Google Scholar 

  3. 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.

    Google Scholar 

  4. 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.

    Article  CAS  Google Scholar 

  5. 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.

    Article  CAS  Google Scholar 

  6. 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.

    Article  Google Scholar 

  7. 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.

    Article  CAS  Google Scholar 

  8. 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.

    Article  CAS  Google Scholar 

  9. 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.

    Article  CAS  Google Scholar 

  10. 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.

    Article  Google Scholar 

  11. 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.

    Article  Google Scholar 

  12. 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.

    Article  CAS  Google Scholar 

  13. 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.

    Article  CAS  Google Scholar 

  14. 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.

    Article  Google Scholar 

  15. 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.

    Article  CAS  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. 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.

    Article  CAS  Google Scholar 

  18. 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.

    Google Scholar 

  19. 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.

    Article  CAS  Google Scholar 

  20. 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.

    Article  Google Scholar 

  21. 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.

    Article  CAS  Google Scholar 

  22. 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.

    Article  Google Scholar 

  23. 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.

    Article  CAS  Google Scholar 

  24. 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.

    Google Scholar 

  25. 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.

    Article  Google Scholar 

  26. 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.

    Article  CAS  Google Scholar 

  27. 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.

    Article  CAS  Google Scholar 

  28. 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.

    Article  CAS  Google Scholar 

Download references

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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Authors and Affiliations

  1. Department of Surgery, Duke University Medical Center, Durham, NC, USA

    Norma E. Farrow MD MHS, Eda K. Holl PhD, Paul J. Mosca MD PhD, Smita K. Nair PhD & Georgia M. Beasley MD MHS

  2. Duke Cancer Institute, Durham, NC, USA

    Eda K. Holl PhD, Paul J. Mosca MD PhD, Smita K. Nair PhD & Georgia M. Beasley MD MHS

  3. Emory University, Atlanta, Georgia

    Jeanne Jung

  4. Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA

    Junheng Gao PhD & Sin-Ho Jung PhD

  5. Department of Pathology, Duke University, Durham, NC, USA

    Rami N. Al-Rohil MBBS, Maria A. Selim MD & Smita K. Nair PhD

  6. Department of Surgery, University of North Carolina Chapel Hill, Chapel Hill, NC, USA

    David W. Ollila MD

  7. Department of Medicine, Duke University, Durham, NC, USA

    Scott J. Antonia MD PhD

  8. Medical Branch Department of Surgery, University of Texas, Austin, USA

    Scott J. Antonia MD PhD

  9. Department of Neurosurgery, Duke University, Durham, TX, USA

    Douglas S. Tyler MD & Smita K. Nair PhD

Authors
  1. Norma E. Farrow MD MHS
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  2. Eda K. Holl PhD
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  3. Jeanne Jung
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  7. Maria A. Selim MD
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  9. David W. Ollila MD
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  10. Scott J. Antonia MD PhD
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  13. Georgia M. Beasley MD MHS
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Correspondence to Georgia M. Beasley MD MHS.

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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

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