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

Abstract

PURPOSE This analysis evaluated the genomic landscape of premenopausal patients with hormone receptor–positive and human epidermal growth factor receptor 2–negative advanced breast cancer and the association of genetic alterations with response to ribociclib in the phase III MONALEESA-7 trial. METHODS Premenopausal patients were randomly assigned 1:1 to receive endocrine therapy plus ribociclib or placebo. Plasma collected at baseline was sequenced using targeted next-generation sequencing for approximately 600 relevant cancer genes. The association of circulating tumor DNA alterations with progression-free survival (PFS) was evaluated to identify biomarkers of response and resistance to ribociclib. RESULTS Baseline circulating tumor DNA was sequenced in 565 patients; 489 had evidence of ≥ 1 alteration. The most frequent alterations included PIK3CA (28%), TP53 (19%), CCND1 (10%), MYC (8%), GATA3 (8%), receptor tyrosine kinases (17%), and the Chr8p11.23 locus (12%). A treatment benefit of ribociclib was seen with wild-type (hazard ratio [HR] 0.45 [95% CI, 0.33 to 0.62]) and altered (HR 0.57 [95% CI, 0.36 to 0.9]) PIK3CA. Overall, patients with altered CCND1 had shorter PFS regardless of treatment, suggesting CCND1 as a potential prognostic biomarker. Benefit with ribociclib was seen in patients with altered (HR 0.21 [95% CI, 0.08 to 0.54]) or wild-type (HR 0.52 [95% CI, 0.39 to 0.68]) CCND1, but greater benefit was observed with altered, suggesting predictive potential of CCND1. Alterations in TP53, MYC, Chr8p11.23 locus, and receptor tyrosine kinases were associated with worse PFS, but ribociclib benefit was independent of alteration status. CONCLUSION In this study—to our knowledge, the first large study of premenopausal patients with hormone receptor–positive and human epidermal growth factor receptor 2–negative advanced breast cancer—multiple genomic alterations were associated with poor outcome. A PFS benefit of ribociclib was observed regardless of gene alteration status, although in this exploratory analysis, a magnitude of benefits varied by alteration.

Exploratory analysis of biomarkers associated with clinical outcomes from the study of palbociclib plus endocrine therapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer

“…ESR1 mutation was found in low frequency (3.4%) which is related to the absence of aromatase inhibitor treatment of participants in this study. Some molecular alteration such as high TMB, TP53 mutation, PTEN loss of function and RB pathway alteration may be associated with resistance of palbociclib plus ET treated patients as consistently reported in other studies [17]. Even though the sample size was not enough AURKA alteration (mutation, amplification and expression), BRIP1/ MYC/RAD51C amplification and HRR loss of function mutation may predict the poor prognosis among palbocliclib plus ET treated patients.…”

Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer

“…With regard to CDK4/6 inhibitors, mechanisms of resistance are now also increasingly being described. 185,186 The acquired loss of RB and PTEN and alterations in CCND1 seem to be associated with resistance to ribociclib. 185,186 PTEN loss, numerically slightly more prevalent in ILC as in NST (Table 1), is also linked to resistance to PI3K inhibitors like alpelisib.…”

“…185,186 The acquired loss of RB and PTEN and alterations in CCND1 seem to be associated with resistance to ribociclib. 185,186 PTEN loss, numerically slightly more prevalent in ILC as in NST (Table 1), is also linked to resistance to PI3K inhibitors like alpelisib. 185 Metastases are often difficult to biopsy; therefore, treatment resistance in patients with ILC is difficult to study.…”

Liquid biopsies to predict CDK4/6 inhibitor efficacy and resistance in breast cancer

“…In addition, patients in the placebo arm with mutant PIK3CA had a worse median PFS, suggesting the role of PIK3CA mutations in endocrine therapy resistance instead of as a biomarker of CDK4/6 inhibitor treatment. In contrast, another study of baseline ctDNA of advanced breast cancer patients treated with palbociclib or ribociclib found that patients with PIK3CA mutations had a shorter median PFS than wildtype [82] . Due to a lack of a control treatment arm, this study could not assess the treatment effect with PIK3CA.…”