ctDNA target mutations show prognostic value in advanced breast cancer
medwireNews: Circulating tumor (ct)DNA target mutations may represent a promising prognostic biomarker among women receiving first-line ribociclib plus letrozole for hormone receptor-positive, HER2-negative advanced breast cancer, research suggests.
Giampaolo Bianchini from Ospedale San Raffaele in Milan, Italy, told delegates at the 2021 San Antonio Breast Cancer Symposium that “[t]he presence of a detectable mutation in baseline liquid biopsies appears to be a negative prognostic factor.”
By contrast, clearance of such mutations during the first cycle of ribociclib and letrozole “was informative of treatment benefit and associated with a lower risk of progression,” he said.
The findings are a result of the BioItaLEE trial, which included 263 postmenopausal women who were treated with first-line ribociclib 600 mg (3 weeks on, 1 week off) and letrozole 2.5 mg/day.
Of these, 43% had a single nucleotide variant or insertion/deletion mutation in one of 39 breast cancer-related genes at baseline, with a mean variant allele frequency (VAF) of 11.3%.
Bianchini reported that individuals with no target mutations at baseline had a significant 59% lower risk for disease progression during a mean 26.9 months of follow-up than those with mutations. Indeed, median progression-free survival (PFS) was not reached in the women without mutations but was 16.6 months in those with mutations.
The researchers then looked at early ctDNA dynamics and found that there were significant reductions in VAF of 64.3% and 68.6% by day 15 of cycle 1 and day 1 of cycle 2, respectively.
Furthermore, 47.1% of patients with a target mutation at baseline experienced VAF clearance, defined as 100% decrease in a target mutation, at day 15 and that proportion increased to 52.4% by day 1 of cycle 2.
Importantly, individuals with VAF clearance at day 15 had a significant 49% lower risk for progression than those without clearance (median PFS, 21.9 vs 12.1 months), while those with VAF clearance on day 1 of cycle 2 had a significant 56% lower risk (median PFS, 22.1 vs 12.3 months), each after adjustment for cancer status (recurrent or de novo), tumor luminal type, visceral metastases, and organ involvement.
Bianchini and team also found that 22.7% of the 150 patients without a detectable target mutation at baseline had a new, detectable mutation during follow-up.
The median PFS in this group was 15.9 months, whereas it was not reached for individuals who maintained no detectable mutations throughout the study. The risk for progression was a significant 55% lower among the people who stayed mutation-free relative to those who did not.
And further analysis showed that mutation status at day 15 “was the most informative of patient outcome,” Bianchini said. Specifically, 66.8% of participants were mutation-free at day 15, and these individuals had a significant 68% lower risk for progression during follow-up than those with a target mutation at this time point. Median PFS was not reached in the group without mutations at day 15 compared with 16.5 and 11.1 months in those with a mutation at low (below median) and high VAF, respectively.
Bianchini concluded: “Overall, both pre-treatment and early dynamics of ctDNA may represent promising prognostic and predictive biomarkers in patients with hormone receptor-positive, HER2-negative advanced breast cancer treated with ribociclib plus letrozole.”
He added; “Further studies are warranted to validate the clinical utility of these biomarkers.”
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