Efficacy of palbociclib plus fulvestrant (P+F) in patients (pts) with metastatic breast cancer (MBC) and ESR1 mutations (mus) in circulating tumor DNA (ctDNA).
2016; Lippincott Williams & Wilkins; Volume: 34; Issue: 15_suppl Linguagem: Inglês
10.1200/jco.2016.34.15_suppl.512
ISSN1527-7755
AutoresNicholas C. Turner, Yuqiu Jiang, Ben O’Leary, Sarah Hrebien, Massimo Cristofanilli, Fabrice André, Sibylle Loibl, Patricia A. English, Ke Zhang, Sophia Randolph, Cynthia Huang Bartlett, María Koehler, Sherene Loi,
Tópico(s)Lung Cancer Research Studies
Resumo512 Background: PALOMA-3 is a randomized, double-blind, phase III study comparing P+F with fulvestrant plus placebo (F+Pla) in pre- and postmenopausal women with HR+/HER2– MBC that progressed on prior endocrine therapy. Recent studies have implicated ESR1 mu as a mechanism for acquired endocrine resistance in MBC. ctDNA assessed in plasma is a potential surrogate for a tumor’s genetic profile. Here, we assess the relationship between ctDNA ESR1 mu status and palbociclib sensitivity, and the reproducibility of ESR1 ctDNA analysis. Methods: 396 baseline plasma samples from 521 pts enrolled in PALOMA-3 were collected and consented for use in this study. DNA was extracted from 2 mL aliquots using the QIAamp Circulating Nucleic Acid Kit and 12 ESR1 ligand-binding domain mus were analyzed in exons 5, 7, and 8 by Sysmex Inostics. To assess reproducibility of ESR1 mu analysis, separate samples were analysed by droplet digital PCR. Results: ESR1 mus were detected in 106 (26.8%) of the 395 plasma samples tested, most frequently D538G (14.1%), E380Q (8.1%), Y537S (7.3%), and Y537N (4.5%). Mus were poly-clonal in 10.1% of pts. All 106 pts with ESR1 mus were previously treated with an aromatase inhibitor; no ESR1 mus were identified in pts previously treated with tamoxifen only. Overall, median progression-free survival (PFS) was 5.7 months (mos) (95% confidence interval [CI]: 3.7–9.4) for pts with ESR1 mus versus 9.2 mos (95% CI: 7.5–10.9) for pts without ESR1 mus (hazard ratio [HR] = 1.33 [95% CI: 0.99–1.80]; 2-sided P= 0.0572). Median PFS was significantly longer in the P+F group compared with the F+Pla group both in pts without a detectable ESR1 mu (9.5 vs 3.8 mos; HR = 0.44 [95% CI: 0.31‒0.62], 1-sided P< 0.0001) and in pts with an ESR1 mu (9.4 vs 4.1 mos; HR = 0.52 [95% CI: 0.32‒0.87], 1-sided P= 0.0052). In samples independently tested by droplet digital PCR (353/395), the concordance between the two assays was 94.1% (Kappa = 0.84). Conclusions: ESR1 mus, detected in plasma ctDNA, were identified in a high percentage of pts with HR+ MBC confirming an important role in endocrine-resistance. P+F treatment provided significant benefit for MBC pts with and without ESR1 mus. Clinical trial information: NCT01942135.
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