Endocrine therapy for breast cancer: a model of hormonal manipulation

Oestrogen receptor (ER) is the driving transcription factor in 70% of breast cancer. Endocrine therapies targeting the ER represent one of the most successful anticancer strategies to date. In the clinic, novel targeted agents are now being exploited in combination with established endocrine therapies to maximise efficacy. However, clinicians must balance this gain against the risk to patients of increased side effects with combination therapies. This article provides a succinct outline of the principles of hormonal manipulation in breast cancer, alongside the key evidence that underpins current clinical practice. As the role of endocrine therapy in breast cancer continues to expand, the challenge is to interpret the data and select the optimal strategy for a given clinical scenario

Baseline Mutations and ctDNA Dynamics as Prognostic and Predictive Factors in ER-Positive/HER2-Negative Metastatic Breast Cancer Patients.

PURPOSE: Prognostic and predictive biomarkers to cyclin-dependent kinases 4 and 6 inhibitors are lacking. Circulating tumor DNA (ctDNA) can be used to profile these patients and dynamic changes in ctDNA could be an early predictor of treatment efficacy. Here, we conducted plasma ctDNA profiling in patients from the PEARL trial comparing palbociclib+fulvestrant versus capecitabine to investigate associations between baseline genomic landscape and on-treatment ctDNA dynamics with treatment efficacy. EXPERIMENTAL DESIGN: Correlative blood samples were collected at baseline [cycle 1-day 1 (C1D1)] and prior to treatment [cycle 1-day 15 (C1D15)]. Plasma ctDNA was sequenced with a custom error-corrected capture panel, with both univariate and multivariate Cox models used for treatment efficacy associations. A prespecified methodology measuring ctDNA changes in clonal mutations between C1D1 and C1D15 was used for the on-treatment ctDNA dynamic model. RESULTS: 201 patients were profiled at baseline, with ctDNA detection associated with worse progression-free survival (PFS)/overall survival (OS). Detectable TP53 mutation showed worse PFS and OS in both treatment arms, even after restricting population to baseline ctDNA detection. ESR1 mutations were associated with worse OS overall, which was lost when restricting population to baseline ctDNA detection. PIK3CA mutations confer worse OS only to patients on the palbociclib+fulvestrant treatment arm. ctDNA dynamics analysis (n = 120) showed higher ctDNA suppression in the capecitabine arm. Patients without ctDNA suppression showed worse PFS in both treatment arms. CONCLUSIONS: We show impaired survival irrespective of endocrine or chemotherapy-based treatments for patients with hormone receptor-positive/HER2-negative metastatic breast cancer harboring plasma TP53 mutations. Early ctDNA suppression may provide treatment efficacy predictions. Further validation to fully demonstrate clinical utility of ctDNA dynamics is warranted

CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2- Metastatic Breast Cancer.

PURPOSE: In hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC), it is imperative to identify patients who respond poorly to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting, but further validation is needed. EXPERIMENTAL DESIGN: We performed mRNA gene expression profiling and correlation with progression-free survival (PFS) on 455 tumor samples included in the phase III PEARL study, which assigned patients with HR+/HER2- MBC to receive palbociclib+endocrine therapy (ET) versus capecitabine. Estrogen receptor-positive (ER+)/HER2- breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET. RESULTS: Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4 months with palbociclib+ET and 9.3 months with capecitabine; HR 4.16, adjusted P value < 0.0001. Tumors with high CCNE1 expression (above median) also had worse median PFS with palbociclib+ET (6.2 months) than with capecitabine (9.3 months); HR 1.55, adjusted P value = 0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile), we found higher levels of Polo-like kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2- cell line models, we show that PLK1 inhibition reverses resistance to palbociclib+ET. CONCLUSIONS: We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i

Overall survival with palbociclib plus endocrine therapy versus capecitabine in postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer in the PEARL study.

BACKGROUND: An earlier analysis of the PEARL phase III study showed that palbociclib plus endocrine therapy (ET) does not improve progression-free survival (PFS) over capecitabine in aromatase inhibitor-resistant, hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer (MBC) patients. Here, we report the final overall survival (OS) analysis. METHODS: Postmenopausal patients (N = 601) were randomized 1:1 to capecitabine or palbociclib plus ET (exemestane, Cohort 1; fulvestrant, Cohort 2). OS was analysed in Cohort 2, the wild-type ESR1 population and the overall population. Additionally, we analysed subsequent systemic therapies and explored PFS2 (time from randomization to the end of the first subsequent therapy/death). RESULTS: OS was 31.1 months for palbociclib plus fulvestrant and 32.8 months for capecitabine (adjusted hazard ratio [aHR] 1.10, 95% confidence interval [CI] 0.81-1.50, P = 0.550). In the wild-type ESR1 population, OS was 37.2 months for palbociclib plus ET and 34.8 months for capecitabine (aHR 1.06, 95% CI 0.81-1.37, P = 0.683). In OS analyses, no subgroup showed superiority for palbociclib plus ET over capecitabine. OS in the overall population was 32.6 months for palbociclib plus ET and 30.9 months for capecitabine (P = 0.995). Subsequent systemic therapy was given to 79.8% and 82.9% of patients with palbociclib plus ET and capecitabine, respectively. Median PFS2 was similar between study arms (Cohort 2, P = 0.941; wild-type ESR1 population, P = 0.827). No new safety findings were observed. CONCLUSIONS: Palbociclib plus ET did not show a statistically superior OS compared to capecitabine in MBC patients progressing on aromatase inhibitors. TRIAL REGISTRATION: NCT02028507 (ClinTrials.gov), 2013-003170-27 (EudraCT)

Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL.

BackgroundPalbociclib plus endocrine therapy (ET) is the standard treatment for hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial.Patients and methodsPEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitors (AIs)-resistant MBC were included in two consecutive cohorts. In cohort 1 (C1), patients were randomised 1:1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about oestrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2 (C2), in which patients were randomised 1:1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in C2 and in wild-type ESR1 patients (C1+C2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA.ResultsFrom March-2014 to July-2018, 296 and 305 patients were included in C1 and C2, respectively. Palbociclib plus ET was not superior to capecitabine in both C2 (median PFS: 7.5 vs. 10.0 months; adjusted hazard ratio [aHR]: 1.13; 95% confidence Interval [CI]: 0.85-1.50) and wild-type ESR1 patients (median PFS: 8.0 vs. 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant, and capecitabine were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85).ConclusionsThere was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life