Purpose: PIK3CA and ESR1 mutations have been implicated in resistance to endocrine therapy (ET) in HR+, HER2− advanced breast cancer (ABC). Inhibition of CDK4 and 6 has been hypothesized as a therapeutic strategy to overcome endocrine resistance in patients with PIK3CA- or ESR1-mutant breast cancers. The objective of this exploratory analysis was to assess efficacy of abemaciclib plus fulvestrant in patients with or without PIK3CA or ESR1 mutations in MONARCH 2. Patients and Methods: MONARCH 2 was a global, randomized, double-blind phase III trial of abemaciclib plus fulvestrant in 669 women with HR+, HER2− ABC, which had progressed on ET. Patients were randomized 2:1 to receive abemaciclib plus fulvestrant or placebo plus fulvestrant. Exploratory analyses assessed progression-free survival (PFS) and overall survival (OS), and other endpoints, in patients with or without PIK3CA or ESR1 mutations detectable in baseline ctDNA. Results: From the MONARCH 2 population, 219 and 248 patient samples were successfully analyzed for either PIK3CA or ESR1 mutations, respectively. Abemaciclib plus fulvestrant improved PFS compared with placebo plus fulvestrant in both PIK3CA-wild-type (median 16.9 months vs. 12.3 months; HR, 0.51; 95% CI, 0.33–0.78) and PIK3CA-mutant subgroups (median 17.1 months vs. 5.7 months; HR, 0.53; 95% CI, 0.33–0.84), as well as both ESR1-wild-type (median 15.3 months vs. 11.2 months; HR, 0.44; 95% CI, 0.27–0.71) and ESR1-mutant subgroups (median 20.7 months vs. 13.1 months; HR, 0.54; 95% CI, 5.7–16.9). Additional endpoints, including OS, were also improved following treatment with abemaciclib plus fulvestrant regardless of PIK3CA or ESR1 mutation status. Conclusions: Abemaciclib plus fulvestrant was effective regardless of PIK3CA or ESR1 mutation status, with benefit in both PFS and OS, with a numerically greater improvement in median PFS relative to placebo plus fulvestrant for PIK3CA- or ESR1-mutant tumors compared with the respective wild-type subgroups, in women with HR+, HER2− ABC that had progressed on ET.

Endocrine therapy is the mainstay of treatment for patients with hormone receptor–positive, ERBB2 (formerly HER2)-negative advanced breast cancer (ABC).¹ Three phase 3 studies have demonstrated that addition of inhibitors of cyclin-dependent kinase 4 and 6 (CDK4/6) palbociclib, ribociclib, and abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) in these patients improves median progression-free survival (PFS) from 14.5 to 16.0 months to 25.3 to 28.2 months, with hazard ratios (HRs) ranging between 0.54 and 0.58.^2-4 Consequently, the combination of a CDK4/6 inhibitor and NSAI has become the standard front-line regimen for this patient population.

The incorporation of circulating tumor DNA (ctDNA) into the management of operable breast cancer (BC) has been hampered by the heterogeneous results from different studies. We aimed to assess the prognostic value of ctDNA in patients with operable (non metastatic) BC. A systematic search of databases (PubMed/Medline, Embase, and CENTRAL) and conference proceedings was conducted to identify studies reporting the association of ctDNA detection with disease-free survival (DFS) and overall survival (OS) in patients with stage I-III BC. Log-hazard ratios (HRs) were pooled at each timepoint of ctDNA assessment (baseline, after neoadjuvant therapy, and follow-up). ctDNA assays were classified as primary tumor-informed and non tumor-informed. Of the 3174 records identified, 57 studies including 5779 patients were eligible. In univariate analyses, ctDNA detection was associated with worse DFS at baseline [HR 2.98, 95% confidence interval (CI) 1.92-4.63], after neoadjuvant therapy (HR 7.69, 95% CI 4.83-12.24), and during follow-up (HR 14.04, 95% CI 7.55-26.11). Similarly, ctDNA detection at all timepoints was associated with worse OS (at baseline: HR 2.76, 95% CI 1.60-4.77; after neoadjuvant therapy: HR 2.72, 95% CI 1.44-5.14; and during follow-up: HR 9.19, 95% CI 3.26-25.90). Similar DFS and OS results were observed in multivariate analyses. Pooled HRs were numerically higher when ctDNA was detected at the end of neoadjuvant therapy or during follow-up and for primary tumor-informed assays. ctDNA detection sensitivity and specificity for BC recurrence ranged from 0.31 to 1.0 and 0.7 to 1.0, respectively. The mean lead time from ctDNA detection to overt recurrence was 10.81 months (range 0-58.9 months). ctDNA detection was associated with worse DFS and OS in patients with operable BC, particularly when detected after treatment and using primary tumor-informed assays. ctDNA detection has a high specificity for anticipating BC relapse.