ESR1-Driven Resistance to CDK4/6 Inhibitors in Breast Cancer Thwarted by SERDs

Mutations in ESR1 do not appear to confer breast cancer resistance to cyclin-dependent kinase (CDK)4/6 inhibitors, an analysis of clinical practice data suggested.

Patients with metastatic hormone receptor-positive breast cancer had a similar time to next treatment with CDK4/6 inhibition regardless of ESR1 mutation status. Stratification by concurrent endocrine partner showed that patients with ESR1 mutations had worse outcomes when a CDK4/6 inhibitor was paired with an aromatase inhibitor but not with fulvestrant.

The findings support existing evidence that the type of endocrine therapy used with a CDK4/6 inhibitor affects efficacy in ESR1-mutant metastatic breast cancer, reported Seth A. Wander, MD, PhD, of Massachusetts General Hospital Cancer Center and Harvard Medical School in Boston, and co-authors in NEJM Evidence.

"When patients with CDK4/6 inhibitor exposure were stratified by ESR1 status, there was no clear difference in clinical outcome, supporting the notion that ESR1 mutation itself does not provoke pan-CDK4/6 inhibitor resistance," the authors wrote. "At the same time, when stratifying specifically by endocrine therapy in patients receiving palbociclib [Ibrance], the presence of ESR1 mutations correlated with inferior duration on an aromatase inhibitor, whereas no difference was appreciated in patients receiving fulvestrant."

"These real-world data suggest that, despite clear resistance to aromatase inhibitor-based therapy, CDK4/6 inhibitors may retain efficacy when combined with a SERD [selective estrogen receptor degrader] in ESR1-mutated metastatic breast cancer," they added.

Findings from this study, combined with evidence from prior studies, suggest that the best endocrine partner for a CDK4/6 inhibitor might be a SERD, such as fulvestrant, according to the authors of an accompanying editorial.

"Because fulvestrant with a CDK4/6 inhibitor is potentially used earlier in the treatment hierarchy, clinically relevant questions that will emerge include whether fulvestrant can be used after disease progression or whether one of the newer SERDs in development, such as camizestrant and amcenestrant, will be effective post-fulvestrant in those with ESR1 or other mutations," wrote Patricia Robinson, MD, and William J. Gradishar, MD, of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University in Chicago.

"Understanding the changing mutational landscape in each tumor over time may provide a 'signature' of molecular alterations that would offer insights into the best therapeutic option or one to avoid. The article by [Wander and colleagues] offers a road map for how to do this going forward," they continued.

In metastatic breast cancer, ESR1 mutations drive aromatase inhibitor resistance and reduce binding affinity for fulvestrant. Whether ESR1 mutations drive breast cancer resistance to endocrine therapy combined with a CDK4/6 inhibitor remains unclear, Wander and co-authors noted in their introduction.

To examine CDK4/6 inhibition in ESR1-mutated metastatic breast cancer, the investigators analyzed the GuardantINFORM database of real-world clinical outcomes in patients who were tested for genomic alterations from June 2014 through June 2021. They hypothesized that in a real-world setting, ESR1 mutations would not be associated with universal CDK4/6 inhibitor resistance, but that ESR1-mutated breast cancers might be less susceptible to treatment on the basis of the endocrine therapy chosen to pair with the CDK4/6 inhibitor.

"Compared with clinical trial populations, real-world evidence has the potential advantage of representing a more diverse group of patients," Wander and team wrote. "Real-world data are expected to comprise heterogeneous patients treated by providers with diverse practice patterns, although race and ethnicity information in our study were not available for investigation."

They acknowledged that real-world data typically are not as well curated as data from a clinical trial.

Data analysis comprised 145 patients with ESR1 mutations and 612 without the mutations as determined by the Guardant360 genomic test. All were treated with an approved CDK4/6 inhibitor and concurrent endocrine therapy. The primary objective was time to next treatment, defined as the start of a breast cancer treatment to initiation of the subsequent treatment.

Of the patients, 60% with and 71% without ESR1 mutations received palbociclib. Patients with ESR1-mutated breast cancer were more heavily pretreated (≥3 lines of therapy 44% vs 34%) and were more likely to receive a SERD as the concurrent endocrine therapy (78% vs 41%). The most common co-existing mutations were PIK3CA (43% in the mutated group vs 35% in the non-mutated group) and TP53 (40% vs 34%, respectively).

Overall, time to next treatment did not differ significantly between patients with and without ESR1 mutations (HR 1.02, 95% CI 0.82-1.23). Among patients receiving a CDK4/6 inhibitor as first-line therapy, median time to next treatment was 6.9 months in patients with ESR1-mutated cancers and 6.8 months in those with non-mutated cancers. For patients who received a CDK4/6 inhibitor in the second line or beyond, median time to next treatment was also similar between the two groups.

Wander and co-authors examined endocrine pairing more closely in a subgroup of 197 patients treated with palbociclib. Median time to next treatment was significantly shorter in patients with ESR1-mutated tumors treated with an aromatase inhibitor versus palbociclib (3.9 vs 7.0 months). In contrast, the time to next treatment was similar in mutated versus non-mutated tumors treated with fulvestrant (4.0 vs 4.5 months).

The investigators also analyzed results from patients with the ESR1-Y537S mutation, previously linked to disease progression on fulvestrant-based treatment. The data showed no significant difference (HR 1.01) between patients with the Y537S mutation (n=45) versus other variants (n=100).

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