Circulating Tumor DNA Genotyping of Intrinsic and Acquired Gene Alterations in Patients With Advanced Breast Cancer Receiving Palbociclib: Biomarker Results From POLARIS Study

Abstract

Purpose: To identify gene alterations in circulating tumor DNA (ctDNA) from palbociclib-treated patients with advanced or metastatic breast cancer (ABC) in POLARIS to identify potential mutagenic drivers of resistance.

Methods: POLARIS was a prospective, real-world study of palbociclib in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) ABC in the United States and Canada. Patients who received ≥1 palbociclib dose and had ≥1 ctDNA measurement were included in the biomarker analysis. ctDNA samples were analyzed using the Guardant360 platform (73 genes) at baseline, cycle 2 day 1 (C2D1), and end of treatment (EOT). Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs.

Results: A total of 344 patients were included in the biomarker analysis. Gene alterations were detected in 85% (286 of 336) of baseline samples, 72% (201 of 278) of C2D1 samples, and 85% (88 of 104) of EOT samples. The most frequently mutated genes were ESR1, PIK3CA, and TP53. CCND1, FGFR1, and EGFR were most frequently amplified. Real-world progression-free survival (rwPFS) was better in patients without baseline mutations in ESR1 (HR, 0.42) or PIK3CA (HR, 0.60) and amplifications in CCND1 (HR, 0.52) or FGFR1 (HR, 0.62) versus altered genes. Patients with undetectable versus detectable mutations at C2D1 also had better rwPFS (HR, 0.57).

Conclusion: Patients without altered ESR1, PIK3CA, CCND1, or FGFR1 at baseline had better rwPFS than patients with altered genes. Genotyping analysis of ctDNA over time highlights the emergence of mutations in estrogen receptor and cell cycle pathways under selective therapeutic pressure and could guide monitoring and therapeutic sequencing for patients with HR+/HER2- ABC.

Trial registration: ClinicalTrials.gov NCT03280303.

FIG 1.

Percentage of patients with (A) gene alterations and (B) gene amplifications by treatment stage. C2D1, cycle 2 day 1; EOT, end of treatment.

FIG 2.

(A) Genes most frequently identified with acquired and lost mutations at EOT and (B) most frequently acquired gene mutations in ESR1 at EOT. EOT, end of treatment.

FIG 3.

(A) Genes most frequently identified with acquired and lost mutations at EOT and (B) most frequently acquired gene mutations in ESR1 at EOT by treatment type. AI, aromatase inhibitor; EOT, end of treatment; FUL, fulvestrant; PAL, palbociclib.

FIG 4.

Kaplan-Meier curves for rwPFS with baseline (A) mutations in ESR1 and PIK3CA and (B) amplifications of CCND1 and FGFR1. C2D1, cycle 2 day 1; HR, hazard ratio; rwPFS, real-world progression-free survival; WT, wild-type.

FIG 5.

Forest plot depicting effects of baseline mutations in (A) ESR1 and (B) PIK3CA and amplifications in (C) CCND1 and (D) FGFR1 on rwPFS by treatment type and by line of therapy. AI, aromatase inhibitor; FUL, fulvestrant; HR, hazard ratio; PAL, palbociclib; rwPFS, real-world progression-free survival; WT, wild-type.

FIG 6.

Kaplan-Meier curve for rwPFS in patients with (A) detectable ctDNA at C2D1 versus those without and (B) tumor response associated with changes in ctDNA at C2D1. C2D1, cycle 2 day 1; ctDNA, circulating tumor DNA; HR, hazard ratio; mVAF, maximum value of variant allele fraction; rwCR, real-world complete response; rwPD, real-world progressive disease; rwPFS, real-world progression-free survival; rwPR, real-world partial response; rwSD, real-world stable disease.