Elevated Levels of <i>BRAF<sup>V600</sup></i> Mutant Circulating Tumor DNA and Circulating Hepatocyte Growth Factor Are Associated With Poor Prognosis in Patients With Metastatic Melanoma.
retrospective_cohort · Level III
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- Also identified by DOI 10.1200/PO.17.00168.
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Abstract
We performed a retrospective exploratory analysis to evaluate the prognostic and predictive effect of two circulating biomarkers, <i>BRAF<sup>V600</sup></i> mutant circulating tumor DNA (ctDNA) and circulating hepatocyte growth factor (cHGF), in metastatic melanoma. This study evaluated patients from BRIM-3, a phase III trial comparing vemurafenib and dacarbazine in 675 patients with <i>BRAF<sup>V600</sup></i> mutated advanced melanoma. ctDNA was measured using droplet digital polymerase chain reaction, and cHGF was measured by enzyme-linked immunosorbent assay. Overall survival (OS) was estimated using the Kaplan-Meier method, and hazard ratios (HRs) were estimated using Cox proportional hazards modeling. Partitioning analysis was used to group patients into risk categories. Patients with elevated levels of baseline <i>BRAF<sup>V600</sup></i> ctDNA had significantly shorter median OS than those with undetectable levels of ctDNA (vemurafenib arm, 9.9 <i>v</i> 21.4 months, respectively, and dacarbazine arm: 6.1 <i>v</i> 21.0 months, respectively). Median OS was also shorter in patients with high levels of cHGF compared with those with low cHGF (vemurafenib arm, 11.9 <i>v</i> 17.3 months, respectively, and dacarbazine arm, 6.1 <i>v</i> 14.4 months, respectively). In a multivariable proportional hazards model with adjustment for lactate dehydrogenase, Eastern Cooperative Oncology Group status, disease stage, and treatment, ctDNA and cHGF were both independent prognostic factors for OS, (HR, 1.75; 95% CI, 1.35 to 2.28 for high <i>v</i> undetectable ctDNA; HR, 1.24; 95% CI, 1.00 to 1.53 for high <i>v</i> low cHGF). Using partitioning analysis, we found that patients with elevated ctDNA combined with elevated cHGF constituted the highest risk group with significantly shorter OS. Here, we report that BRIM-3 patients with high levels of ctDNA and cHGF have worse OS regardless of treatment and that these factors are independent prognostic markers for metastatic melanoma.