Study Detects Biomarkers for Poor Prognosis in Premenopausal Patients With HR+/HER2– Advanced Breast Cancer

Alterations in certain genes, particularly CCND1, can act as biomarkers for poorer outcomes in premenopausal patients with hormone receptor–positive (HR+) and human epidermal growth factor receptor 2–negative (HER2) advanced breast cancer, according to a recent study.

The study, published in JCO Precision Oncology, is the first large-scale genomic profiling study examining potential biomarkers in exclusively premenopausal patients with HR+ and HER2– advanced breast cancer (ABC). It also contained the largest data set of premenopausal patients with ABC receiving first-line endocrine-based therapy in a metastatic setting.

“Altogether, these findings highlight the potential role of genomic alterations in modulating clinical outcomes in premenopausal patients with ABC although these results are hypothesis generating and require confirmation in larger data sets,” wrote the investigators.

Premenopausal women with HR+ tumors are known to have worse prognosis and are underrepresented in clinical trials compared with postmenopausal women. As a result, treatment approaches for premenopausal women are usually extrapolated from data collected from postmenopausal women. Additionally, there is a lack of biomarker profiling across ABC cases, especially genomic profiling for premenopausal patients with ABC.

Ribociclib (Kisqali) is a treatment for many patients with HR+ and HER2– ABC. However, some patients exhibit de novo and/or acquired resistance to the drug, which functions as a cyclin-dependent kinase (CDK) 4/6 inhibitor, or endocrine therapy. Resistance to endocrine therapy can be caused by the modulation of receptor tyrosine kinase (RTK), alterations of GATA3, or dysregulation of FGFR1 signaling.

“Because various mechanisms can cause resistance to ET or CDK4/6 inhibition, identifying biomarkers predictive of sensitivity to these therapies can inform treatment decisions and future research. Thus, a key objective has been to identify biomarkers of resistance or response to ribociclib,” the investigators noted.

The investigators used data collected from the randomized, placebo-controlled, international, double-blind, phase 3 MONALEESA-7 study between December 17, 2014, and August 1, 2016. The trial randomly assigned 672 premenopausal patients to receive ribociclib (n = 335) or placebo (n = 337). Baseline circulating tumor DNA was sequenced using next-generation sequencing in 565 patients, 489 of whom had at least 1 genetic alteration and were included in the present analysis.

In the 489 included patients, 32 genes were altered in 5% or more of patients, with PIK3CA and TP53 alterations emerging as the most frequent (28% and 19%, respectively). Alterations for CCND1 (10%), MYC (8%), and GATA3 (8%) were also common. RTK was altered in 17% of patients and alterations for Chr8p11.23 locus were observed in 12% of patients.

A treatment benefit of ribociclib was observed with wild-type (HR, 0.45; 95% CI, 0.33-0.62) and altered (HR, 0.57; 95% CI, 0.36-0.9) PIK3CA.

Additionally, patients with altered CDND1 had shorter progressive free survival, which the investigators said could suggest that CCND1 alterations may serve as a prognostic biomarker for premenopausal patients. Ribociclib benefits were seen in patients with altered (hazard ratio, 0.21; 95% CI, 0.08-0.54) and wild-type (hazard ratio, 0.52; 95% CI, 0.39-0.68) versions of the gene, but were greater with altered CCND1, highlighting the predictive potential of CCND1.

Progression-free survival was also associated with TP53, MYC, Chr8p11.23 locus, and RTK alterations. However, the benefits of ribociclib were independent of whether these genes were altered.

The investigators listed several study limitations, including the retrospective nature of the analysis, the small sample sized of some subgroups, that samples with more tumor DNA in circulation may be sensitive to detection of DNA alterations, and that the study did not address the acquired resistance and the role of other biomarkers. Additionally, the investigators said that their results need to be confirmed in future analyses.

Reference

Bardia A, Su F, Solovieff N, et al. Genomic profiling of premenopausal HR+ and HER2-metastatic breast cancer by circulating tumor DNA and association of genetic alterations with therapeutic response to endocrine therapy and ribociclib. JCO Precis Oncol. 2021;5:1408-1420. doi:10.1200/PO.20.00445