Váraljai, et al. – Summary

Váraljai R., Wistuba-Hamprecht K., Seremet T., Diaz JMS, Nsengimana J., Sucker A., Griewank K., Placke J-M., Horn P.A., von Neuhoff N., Shannan B., Chauvistré H., Vogel F.C.E., Horn S., Becker J.C., Newton-Bishop J., Stang A., Neyns B., Weide B., Schadendorf D., Roesch A. Application of Circulating Cell-Free Tumor DNA Profiles for Therapeutic Monitoring and Outcome Prediction in Genetically Heterogeneous Metastatic Melanoma. JCO Precision Oncology 2019; :3, 1-10. Available at: https://ascopubs.org/doi/10.1200/PO.18.00229

The Journal of Clinical Oncology Precision Oncology (JCO® PO) has recently published the study entitled “Application of circulating cell-free tumor DNA profiles for therapeutic monitoring and outcome prediction in genetically heterogeneous metastatic melanoma” by MELGEN ESR Renata Varaljai.

This new study led by MELGEN supervisor Prof. Alexander Roesch has highlighted the clinical benefits of blood-based liquid biopsies in the management of metastatic melanoma. The study investigated the clinical utility of plasma circulating cell-free DNA (ctDNA); small fragments of DNA that are released to the bloodstream by dying tumor cells. Previous work has shown that plasma ctDNA can reflect the heterogeneous spectrum of mutations in cancer including metastatic melanoma.

In this study, the researchers analyzed the most common melanoma driver mutations, such as BRAFV600E, NRASQ61 and the TERTC250T and TERTC228T promoter mutations (termed TERTprom) on a highly sensitive droplet digital PCR technology (detection of mutant ctDNA down to 0.01% analytical sensitivity). It involved 3 research centers and over 700 plasma samples from 131 stage III and stage IV melanoma patients who received signaling targeted or immune checkpoint inhibitors.

The paper highlights that increasing ctDNA (irrespective of the genotype) is associated with increasing tumor stage; furthermore, that ctDNA dynamics match the clinically observed therapy kinetics. The research study involved establishment and validation of predictive thresholds based on receiver operating characteristics (ROC) statistical analyses.

Elevated ctDNA at baseline was a significant predictor of disease progression as compared to elevated LDH and S100 in multivariable cox proportional hazards model (Hazard ratio [HR] 7.43, P=0.05). Low ctDNA load (below ROC ctDNA threshold) under therapy showed significant association with prolonged progression free survival (PFS) compared to patients with high ctDNA load (P<0.0001).

Moreover, the study shows that in about 80% of the cases ctDNA precedes the radiologic diagnosis of response or progression. ctDNA provides in average a 3.5 month a lead-time window (see Figure 1). This finding is important, because ctDNA could be used to assess therapy response faster, treatment plans may be planned or changed during this time, which could improve the survival of melanoma patients.

Figure 1. ctDNA-based therapy monitoring for early prediction of therapy outcome. ctDNA dynamics of BRAFV600E (blue) and NRASQ61 (orange) levels under therapies. Changes in ctDNA levels predict radiologic outcome earlier as compared to radiologic scans (staging information depicted with black arrows on the x-axis; PR: partial response, SD: stable disease, PD: progressive disease). Capped line indicates the ctDNA lead-time window.

Finally, the authors provide evidence that the occurrence of NRASQ61 mutation in BRAFV600-inhibitor treated patients at therapy baseline contributes to treatment failure. Baseline NRASQ61 mutation was shown to be an independent predictor of shorter PFS (HR 2.69, P=0.02) as compared to BRAFV600E patients without the NRASQ61 mutation at therapy baseline.

Overall, ctDNA represents a favorable alternative to invasive tissue biopsies and could be applied as a sensitive biomarker for real-time therapy monitoring and early detection of disease progression.

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