ctDNA is prognostic and predictive for response to ribociclib plus letrozole

Pre-treatment circulating tumour DNA (ctDNA) and early dynamics of ctDNA represent promising prognostic and predictive biomarkers in patients with hormone receptor (HR)-positive/HER2-negative advanced breast cancer treated with ribociclib plus letrozole in the first line.

Patients with HR-positive/HER2-negative metastatic breast cancer benefit from treatment with ribociclib plus letrozole, the MONALEESA trials showed [1-3]. However, data on predictive biomarkers for response are limited and inconclusive. The aim of the phase 3 BioItaLEE trial (NCT03439046) was to assess the prognostic and predictive role of baseline and dynamic ctDNA in patients with HR-positive/HER2-negative advanced breast cancer treated in the first line with ribociclib plus letrozole. Dr Giampaolo Bianchini (San Raffaele Scientific Institute, Italy) presented the results. [4]

The study enrolled 287 postmenopausal patients. ctDNA was collected at baseline (D0; n=263), day 15 of cycle 1 (D15; n=238), day 1 of cycle 2 (C2D1; n=241), and at first imaging (FI, at approximately 12 weeks; n=206). ctDNA analysis covered the coding exons of 39 breast cancer-related genes. Median follow-up was 26.9 months and median progression-free survival (PFS) was 23.4 months.

At baseline, target mutations were detected in 43% of patients, whereas 57% of patients were wild-type, e.g. no mutation present. The absence of target mutations at D0 was associated with good prognosis. Median PFS was not reached for ‘wild-type patients’ and was 16.6 months for ‘mutated patients’ (HR: 0.41; P<0.0001). A significant reduction in mutated ctDNA was observed at D15 and C2D1 with a mean change of -64.3% and -68.6% compared with D0, respectively.

Clearance at D15 or C2D1 was associated with improved PFS compared with no clearance (HR 0.44; 95% CI 0.25–0.78; P=0.0052; see Figure). Median PFS in patients who had no clearance, clearance at D15, and clearance at C2D1 was 12.3 months, 21.9 months, and 22.1 months, respectively. Patients achieving clearance at D15 until C2D1 had the lowest risk of progression compared with those who had no clearance at any or both time points. Of the 150 patients without a detectable target mutation at baseline, 34 (22.7%) patients had detectable mutations at later timepoints (D15, C2D1 and/or FI). Median PFS in these patients was 15.9 months.

Figure: Variant allele frequency clearance at C2D1 is associated with improved progression-free survival [4].



 

 

 

 

 

 

C, Cycle; CI, confidence interval; ctDNA, circulating tumour DNA; D, day; HR, hazard ratio; mPFS, medium progression-free survival; VAF, variant allele frequency

Considering all time points individually, D15 was the most informative of patient outcome. The presence of a detectable mutation in baseline liquid biopsies appears to be a negative prognostic factor. Within this high-risk group, early mutation clearance during the first ribociclib plus letrozole cycle was informative of treatment benefit and associated with a lower risk of progression. In addition, monitoring of ctDNA in patients without baseline mutations demonstrated that the detection of new mutations was associated with worse outcome.

“So overall, pre-treatment and early dynamics of ctDNA represent promising prognostic and predictive biomarkers in patients with HR-positive/HER2-negative advanced breast cancer treated with ribociclib plus letrozole in the first-line,” concluded Dr Bianchini. “Further studies are warranted to validate the clinical utility of these biomarkers.”

1. Hortobagyi GN, et al. Ann Oncol 2021; 32 (suppl_5): S1283-S1346


2. Slamon DJ, et al. N Engl J Med 2020; 38: 514-524.


3. Im S-H, et al. N Engl J Med 2019; 381:307-316.


4. Bianchini G, et al. Circulating tumor DNA (ctDNA) dynamics in patients with hormone receptor positive (HR+)/HER2 negative (HER2-) advanced breast cancer (aBC) treated in first line with ribociclib (R) and letrozole (L) in the BioItaLEE trial. GS3-07, SABCS 2021 Virtual Meeting, 7–10 December.

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Posted on 31 January, 2022