The following article features coverage from the 2021 San Antonio Breast Cancer Symposium. Click here to read more of Cancer Therapy Advisor’s conference coverage.

The presence of detectable mutation in a baseline liquid biopsy appeared to be a negative prognostic factor for women with hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced breast cancer treated with first-line ribociclib and letrozole, according to the results of the BioItaLEE trial ( Identifier: NCT03439046).

The absence of a target mutation at baseline was associated with a 59% reduced risk of progression (hazard ratio [HR], 0.41; 95% CI, 0.27-0.61; P <.0001). 

Giampaolo Bianchini, of Ospedale San Raffaele in Milan, Italy, presented these results at the 2021 San Antonio Breast Cancer Symposium (SABCS).

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“Overall, both pretreatment and early dynamics of ctDNA may represent promising prognostic and predictive biomarkers in patients with HR+/HER2- advanced breast cancer treated with ribociclib plus letrozole in the first line,” Bianchini said.

According to Bianchini, the addition of ribociclib significantly improved progression-free and overall survival in the MONALEESA studies regardless of endocrine therapy partner or menopausal status in women with HR+/HER2- advanced breast cancer. However, data on predictive biomarkers of response are limited.

Circulating tumor DNA (ctDNA) is an attractive noninvasive approach to characterize tumor biology, describe its evolution over time, and predict prognosis and treatment benefit.

This study of ctDNA included 287 postmenopausal women. Participants had liquid biopsies collected at baseline (D0; 263 patients), day 15 of cycle 1, day 1 of cycle 2, and at first imaging at approximately 12 weeks. ctDNA analysis was done using a panel that covers the coding exons of 39 breast cancer-related genes. Target mutations were defined as single-nucleotide variants or insertion/deletion detected at baseline. When multiple target mutations were detected, the one with the highest variant allele frequency (VAF) was considered.

With a median follow-up of 26.9 months, the median progression-free survival was 23.39 months. At baseline, 43.0% of patients had target mutations detected; 57% were wild type at baseline.

A strong and robust ctDNA dynamic was observed during the first cycle, Bianchini said. Among patients with a detectable mutation at baseline, treatment with ribociclib plus letrozole led to VAF clearance in 47.1% of patients at day 15 and 52.4% of patients at day 1 of cycle 2.

The researchers evaluated the association of early ctDNA dynamics with clinical outcome. Considering only patients with baseline target mutations, the group achieving VAF clearance at day 15 was associated with statistically significant lower risk of progression with HR of 0.51 (P =.022). A similar analysis on day 1 of cycle 2 also showed significantly improved progression-free survival in patients with a baseline target mutation with VAF clearance (HR, 0.44; P =.052).

Among patients without detectable mutations at baseline, 22.7% had appearance of detectable mutations at any of the later timepoints. The group that maintained no detectable mutations had significantly lower risk of progression (HR, 0.45; P =.01).

Patients without a target mutation at day 15 had an extremely favorable outcome (HR, 0.32; P <.0001). Notably, within the group with detectable target mutations, Bianchini and colleagues observed patients with VAF below the median had a trend toward better prognosis compared with patients with high VAF.

According to Bianchini, further studies are warranted to demonstrate the clinical utility of these biomarkers.

Disclosures: This research was supported by Novartis Farma SpA, Italy. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

Read more of Cancer Therapy Advisor’s coverage of SABCS 2021 by visiting the conference page.


Bianchini G, Malorni L, Arpino 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. Presented at SABCS 2021; December 7-10, 2021; San Antonio, TX. Abstract GS3-07.