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T Cell Assessment in Primary Melanomas Can Help Predict Metastatic Recurrence

NEW YORK – An international team of researchers has found that assessing T cells in primary melanomas can help clinicians predict metastatic recurrence in patients whose cancerous lesions have been surgically resected.

In a study published Monday in the new journal Nature Cancer, the researchers also noted that T-cell fraction (TCFr) was second only to tumor thickness in its predictive value, and that adding TCFr to tumor thickness was superior to adding any other histopathological variable in order to accurately predict progression-free survival.

Recent studies have shown that the clonality of the T-cell repertoire in metastatic lesions, as measured by high-throughput sequencing of the TCR β-cell (TCRB), has been a useful biomarker of response to anti-PD-1 therapy in melanoma patients, the authors wrote. In this study, they performed high-throughput TCRB sequencing in 337 FFPE primary melanoma samples to calculate the TCFr and T-cell clonality in patients with surgically resected primary melanomas and identify a clinically translatable TCFr value that predicted recurrent disease.

After quality control, TCRB repertoire metrics could be analyzed in 209 of the FFPE samples and 199 of these had available progression-free survival (PFS) metadata. The researchers found that TCFr was a significant predictor of PFS whereas clonality was not. TCFr was also predictive of overall survival, and tumor thickness was the strongest predictor of PFS.

Based on further analyses, the researchers found that the optimal cutoff for the lowest TCFr occurred at 20 percent. They confirmed that a tumor's thickness didn't impact TCFr in high-TCFr and low-TCFr tumors based on this cutoff. When applied to the test cohort, 33 patients with a TCFr of 20 percent or more had notably less risk of progression than the 66 patients with a TCFr of less than 20 percent. At five years post-resection, 31 percent of patients with a TCFr of 20 percent or more and 57 percent with a TCFr of less than 20 percent experienced recurrence.

The researchers also calculated PFS stratified by tumor thickness. They considered either thickness alone or thickness plus the 20 percent TCFr cutoff, and found that the bivariate PFS prediction model was significantly more accurate than using tumor thickness alone.

"The difference in PFS for patients with a high and those with a low TCFr was most prominent for T3 [between 2 mm and 4 mm thick] primary melanomas," the authors wrote. "Only 23.4 percent of T3 melanomas with high TCFr progressed in five years, whereas 54.2 percent of those with a low TCFr progressed. For T3 primaries with high TCFr, the median PFS was not reached; for those with low TCFr, it was 23 months."

The researchers did note that there were limitations to their study. As this was a selected study cohort, the impact and clinical utility of TCFr as a molecular marker would need to be validated in future prospective clinical trials. Further studies are also needed to address the utility of computing TCFr in tumors without tumor infiltrating lymphocytes. Finally, they couldn't draw any conclusions about the role of T-cell fraction in thin melanomas of less than 1 mm in thickness.

But in terms of practical clinical use, analyzing the TCFr in primary tumors has the potential to identify patients at high risk of metastatic disease for potential adjuvant therapy, they added. The assay needed for this kind of testing — the researchers used Adaptive Biotechnologies' ImmunoSEQ assay — works reliably on FFPE samples, is already commercially available for research use, and could be easily translated to the clinical testing.

"The relatively favorable prognosis of patients with [more than] 20 percent TCFr might be further improved by the use of immune checkpoint inhibitor therapy," the authors concluded. "Patients with low TCFr and higher risk for recurrence may have some benefit, but will probably require additional adjuvant therapeutic interventions (for example, vaccination) to prevent disease progression. In this fashion, measuring the TCFr of primary melanomas could help move the field towards individualized tumor treatment by matching patients with their optimal immunotherapeutic approach."