In a paper published by Pruessmann et al in Nature Cancer, investigators presented a new, quantitative technique that leverages DNA sequencing to make more sophisticated and accurate predictions about which primary melanomas are likely to recur and spread.
"As recently as 10 years ago, the outlook for metastatic melanoma was dismal, but we now have treatments to offer patients with metastatic disease and may also be able to apply these treatments when primary disease hasn't metastasized,” said corresponding study author Thomas Kupper, MD, Chair of the Department of Dermatology at Brigham and Women’s Hospital. “Because of the advent of these new immunotherapy treatments, it's important to have a clear idea of which patients are likely to progress so that we can tailor treatment accordingly.”
Immune checkpoint inhibitors, which can reawaken T cells to mount an immune response against cancer cells, have radically changed outcomes and options available to patients whose skin cancer has spread. In some patients, they can elicit dramatic responses, but identifying patients at greatest risk for disease progression has remained an unmet need.
Background and Methodology
To address this, Dr. Kupper and colleagues sought to determine if certain measurable features of T cells could predict recurrence in patients whose primary melanoma had been removed and were free of disease. T1 melanomas (< 1 mm) rarely metastasize, so they studied T2 (1–2 mm), T3 (2–4 mm) and T4 (> 4 mm) primary melanomas. The research team faced a unique hurdle in acquiring tumor samples—unlike most malignancies, which are removed by a surgeon at a hospital, skin lesions can be removed in private practices and ambulatory clinics, which means that specimens are not concentrated in hospital settings. In addition, specimens must be kept for several years after removal, delaying their availability for research studies. To collect enough samples, investigators from Brigham and Women’s Hospital, the Melanoma Institute of Australia, and the Zealand University Hospital in Denmark pooled their resources. The current analysis includes more than 300 samples from patients across these sites.
The team compared samples from patients whose primary melanoma progressed to metastatic disease to patients whose primary melanoma did not. They used high-throughput DNA sequencing to analyze the T-cell repertoire of the tumors.
KEY POINTS
- Patients with a T-cell fraction of lower than 20% were more at risk of disease progression than patients with a T-cell fraction of higher than 20%.
- Even for patients whose lesion thickness was the same, T-cell fraction was able to predict which patients were more likely to have metastatic disease.
Results
The investigators found that of all variables identified, the T-cell fraction (the proportion of cells in the lesion that were T cells) was a powerful, independent predictor of which patients would progress. Even for patients whose lesion thickness was the same, T-cell fraction was able to predict which patients were more likely to have metastatic disease. Patients with a T-cell fraction of lower than 20% were more at risk of disease progression than patients with a T-cell fraction of higher than 20%. For patients with T3 melanoma, 5 years after having their primary lesion removed, 51% of those with lower T-cell fraction experienced recurrence, compared to 24% with higher T-cell fraction.
The test used in this work is commercially available for research use only and is not currently yet available in the clinic. The authors also note that the current study is retrospective, looking at samples from patients whose outcomes are already known. Prospective studies of patients whose outcomes are not yet known will be needed to further validate the test. If brought to the clinic, Dr. Kupper and colleagues envision that the test could strengthen current prediction models and improve patient care.
“This is a simple, elegant test. It's quantitative rather than subjective, and it may be able to add value to predictions about disease progression,” said Dr. Kupper. “In the future, such a test could help us tailor treatment; patients with high T-cell fraction may further benefit from checkpoint inhibitor therapy, while [patients with] low T-cell fraction may need additional intervention.”
Disclosure: This study was funded by the National Institutes of Health, the German Research Foundation, the Novo Nordisk Foundation, and the Lundbeck Foundation. For full disclosures of the study authors, visit nature.com.
