The phase 3 BioItaLEE trial demonstrates that pre-treatment circulating tumor DNA (ctDNA) and early dynamics of ctDNA represent promising prognostic and predictive biomarkers in patients with HR-positive/HER2-negative advanced breast cancer treated with ribociclib/letrozole.

Patients with ER-positive/HER2-negative metastatic breast cancer benefit from treatment with ribociclib/letrozole, the MONALEESA trials have shown [1–3]. However, data on predictive biomarkers for response are limited and inconclusive. The aim of phase 3 BioItaLEE trial (NCT03439046) was to assess the prognostic and predictive role of baseline and dynamic ctDNA analysis in ER-positive/HER2-negative advanced breast cancer patients treated in first-line with ribociclib/letrozole. Dr. Giampaolo Bianchini (Ospedale San Raffaele, Italy) presented the results [4]. The study enrolled 287 post-menopausal 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 113 patients (43%), whereas 150 patients (57%) were wildtype for the selected 39 genes. The absence of target mutation at D0 was associated with good prognosis. Median PFS was not reached for ‘wildtype patients’ versus 16.6 months for patients with a target mutation (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. 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 and maintaining this at 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 mutation at later timepoints (D15, C2D1, and/or FI). Median PFS in patients developing a mutation was 15.9 months. Considering all timepoints individually, D15 was the most informative regarding patient outcomes. Patients without a target mutation at D15 (42.9%) had an extremely favorable outcome, either because they achieved early treatment-related clearance or maintained baseline absence of a target mutation. 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/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 outcomes. “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/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 B, 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. SABCS 2021 Virtual Meeting, abstract GS3-07.

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