Genomic markers of early progression on fulvestrant with or without palbociclib for ER+ advanced breast cancer in the PALOMA-3 trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1010-1010 ◽  
Author(s):  
Ben O'Leary ◽  
Ros Cutts ◽  
Xin Huang ◽  
Sarah Hrebien ◽  
Yuan Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Tp53 Mutation ◽  
Dna Analysis ◽  
Multivariable Analysis ◽  
Gene Panel ◽  
Advanced Breast ◽  
Phase Iii ◽  
Tumor Purity ◽  
Early Progression

1010 Background: Markers of early progression on endocrine therapy in combination with CDK4/6 inhibitors remain limited despite the key role of these combinations in treating of ER+ advanced breast cancer (ABC). We investigated genomic aberrations in patients treated with fulvestrant, with and without palbociclib, with a circulating tumor DNA analysis of baseline plasma in the PALOMA-3 trial. Methods: PALOMA-3 was a phase III trial that randomized 521 patients with ER+/HER2- ABC 2:1 to palbociclib plus fulvestrant (P+F) or placebo plus fulvestrant (F). Using baseline plasma samples, somatic mutations were assessed with a 17 gene panel. Copy number aberrations (CNA) were characterized with a 14 gene panel including ~800 SNPs in 8 commonly altered regions for estimation of tumor purity, the percentage of plasma DNA that was derived from tumor cells. Results for mutations and CNAs were available in 310 pts (203 P+F, 107 F) and were associated with clinical characteristics and progression free survival (PFS) using univariable and multivariable Cox proportional hazards models, including tumor purity and treatment as variables. Results: In the multivariable analysis of the whole cohort, higher baseline tumor purity in plasma was associated with worse PFS (HR 1.20, 95% CI 1.09 – 1.32, p = 0.0001, HR per 10% increase in purity). Baseline TP53 mutation was also associated with shorter PFS (HR 1.84, 95%CI 1.27 – 2.65, p = 0.0011), as was baseline FGFR1 amplification (HR 2.91, 95%CI 1.61 – 5.25, p = 0.0004). PIK3CA and ESR1 mutations had no significant association with PFS in the multivariable model. Palbociclib treatment effect was comparable with the overall trial result (HR 0.43, 95%CI 0.32 - 0.57, p < 0.0001). TP53 mutations were significantly associated with visceral (q = 0.046) and soft tissue/LN metastases (q = 0.042) and the number of disease sites (q = 0.0086) after correction for multiple testing. Conclusions: TP53 mutation, FGFR1 amplification , and tumor purity in plasma identified patients at risk of early progression In PALOMA-3. If validated these results could inform future clinical trials of CDK4/6 inhibitors combinations.

scholarly journals Systemic immunity markers associated with lymphocytes predict the survival benefit from paclitaxel plus bevacizumab in HER2 negative advanced breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shogo Nakamoto ◽  
Masahiko Ikeda ◽  
Shinichiro Kubo ◽  
Mari Yamamoto ◽  
Tetsumasa Yamashita ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Multivariable Analysis ◽  
Absolute Lymphocyte Count ◽  
Predictive Markers ◽  
Advanced Breast ◽  
Chemotherapeutic Regimen ◽  
Systemic Immunity ◽  
Lymphocyte Ratio ◽  
Lymphocyte To Monocyte Ratio

AbstractAlthough paclitaxel plus bevacizumab (PB) therapy is an effective chemotherapeutic regimen for HER2-negative advanced breast cancer (ABC), predictive markers for its effectiveness remain undefined. We investigated the usefulness of systemic immunity markers associated with lymphocytes as predictive markers for PB therapy in patients with HER2-negative ABC. We retrospectively reviewed data from 114 patients with HER2-negative ABC who underwent PB therapy from November 2011 to December 2019. We calculated the absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) as representative systemic immunity markers. The time to treatment failure (TTF) and overall survival (OS) of the patients with high ALC, low NLR, and high LMR were significantly longer compared with those of the patients with low ALC, high NLR, and low LMR. A multivariable analysis revealed that high ALC, low NLR, and low PLR were independent predictors for TTF and high ALC, low NLR, and high LMR were independent predictors for OS. Systemic immunity markers were significantly associated with longer TTF and OS in patients who underwent PB therapy and may represent predictive markers for PB therapy in patients with HER2-negative ABC.

Plasma ESR1 Mutations and the Treatment of Estrogen Receptor–Positive Advanced Breast Cancer

2016 ◽  
Vol 34 (25) ◽  
pp. 2961-2968 ◽  
Author(s):  
Charlotte Fribbens ◽  
Ben O’Leary ◽  
Lucy Kilburn ◽  
Sarah Hrebien ◽  
Isaac Garcia-Murillas ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Advanced Breast Cancer ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Phase Iii ◽  
Wild Type ◽  
Estrogen Receptor Positive ◽  
Esr1 Mutations ◽  
The Impact

Purpose ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor–positive advanced breast cancer. Materials and Methods In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI and in baseline plasma from the PALOMA3 (Palbociclib Combined With Fulvestrant in Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction. Results In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wild-type ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P < .001). Conclusion ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required.

AMEERA-5: A randomized, double-blind phase III study of amcenestrant (SAR439859) + palbociclib versus letrozole + palbociclib for previously untreated ER+/HER2- advanced breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS1104-TPS1104
Author(s):  
Aditya Bardia ◽  
Javier Cortes ◽  
Sara A. Hurvitz ◽  
Suzette Delaloge ◽  
Hiroji Iwata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Phase I ◽  
Advanced Breast Cancer ◽  
Progression Free Survival ◽  
Advanced Breast ◽  
Phase Iii ◽  
Double Blind ◽  
Free Survival ◽  
Phase Iii Study

TPS1104 Background: Selective estrogen receptor degraders (SERDs) block estrogen receptor (ER) associated signaling and have created interest for treating patients (pts) with advanced ER+ breast cancer (BC). Fulvestrant is currently the only SERD available for advanced BC but requires intramuscular administration, limiting the applied dose, exposure and receptor engagement. Amcenestrant (SAR439859) is an oral SERD that binds with high affinity to both wild-type and mutant ER, blocking estradiol binding and promoting up to 98% ER degradation in preclinical studies. In the phase I AMEERA-1 study of pretreated pts with ER+/HER2- advanced BC, amcenestrant 150–600 mg once daily (QD) showed a mean ER occupancy of 94% with plasma concentrations > 100 ng/mL and a favorable safety profile (Bardia, 2019; data on file). Combination therapy with amcenestrant + palbociclib (palbo) was also evaluated as part of this ongoing phase I study. CDK 4/6 inhibitors (CDK4/6i) combined with an aromatase inhibitor (AI), the gold standard for first line treatment for advanced breast cancer, prolong progression free survival (PFS) in pts with no prior treatment for ER+/HER2- advanced BC, but OS benefit has not been shown yet in postmenopausal pts. There remains a clinical need for more effective treatments in this setting. Methods: AMEERA-5 (NCT04478266) is an ongoing, prospective, randomized, double-blind phase III study comparing the efficacy and safety of amcenestrant + palbo with that of letrozole + palbo in pts with advanced, locoregional recurrent or metastatic ER+/HER2- BC who have not received prior systemic therapy for advanced disease. The study includes men, pre/peri-menopausal (with goserelin) and post-menopausal women. Pts with progression during or within 12 months of (neo)adjuvant endocrine therapy using any of the following agents are excluded: AI, selective estrogen receptor modulators, CDK4/6i. Pts are randomized 1:1 to either continuous amcenestrant 200 mg or letrozole 2.5 mg QD orally with matching placebos; both combined with palbo 125 mg QD orally (d1–21 every 28-d cycle). Randomization is stratified according to disease type (de novo metastatic vs recurrent disease), the presence of visceral metastasis, and menopausal status. The primary endpoint is investigator assessed progression free survival (PFS) (RECIST v1.1). Secondary endpoints are overall survival, PFS2, objective response rate, duration of response, clinical benefit rate, pharmacokinetics of amcenestrant and palbo, health-related quality of life, time to chemotherapy, and safety. Biomarkers will be measured in paired tumor biopsies and cell free deoxyribonucleic acid (cfDNA) over time. Target enrolment = 1066 pts; enrolment as of 1/2021 = 33 pts. Bardia A, et al., J Clin Oncol. 2019; 37 (15 suppl):1054 Clinical trial information: NCT04478266 .

scholarly journals Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): Results of the phase III SOLAR-1 trial

2018 ◽  
Vol 29 ◽  
pp. viii709 ◽  
Author(s):  
F. André ◽  
E.M. Ciruelos ◽  
G. Rubovszky ◽  
M. Campone ◽  
S. Loibl ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Advanced Breast ◽  
Phase Iii
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