Real-world data of pyrotinib-based therapy for patients with brain metastases of HER2-positive advanced breast cancer: a single-center retrospective analysis and molecular portraits

Abstract

Introduction: Pyrotinib is a novel irreversible pan-HER tyrosine kinase inhibitor (TKI). However, real-world data of pyrotinib-containing therapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and developing brain metastases (BMs) are limited, and the genomic profile of this subpopulation is almost undefined.

Methods and materials: Patients with BM of HER2-positive MBC (n = 35) treated with pyrotinib-containing therapy were enrolled in this analysis. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and toxicity profiles were evaluated. Hazard ratios (HRs) and 95% confidence intervals (CIs) for disease progression were estimated using the Cox proportional hazards models. Targeted next-generation sequencing of 618 cancer-relevant genes was performed on plasma and primary breast tumors from patients with BM and without BM.

Results: The median PFS time was 8.00 (95% CI, 5.98-10.017) months, and the median OS time was 23 (95% CI, 10.412-35.588) months. The ORR was 45.7%, and the DCR was 74.3%. In the Cox multivariate analysis, prior exposure to brain radiotherapy (HR = 3.268), received pyrotinib as third- or higher-line treatment (HR = 4.949), subtentorial brain metastasis (HR = 6.222), and both supratentorial and subtentorial brain metastases (HR = 5.863) were independently associated with increased risk of progression. The frequent grade 3-4 adverse event was increased direct bilirubin (14.3%), and two patients suffered from grade 3-4 diarrhea. In the exploratory genomic analysis, altered frequencies of FGFR3, CD276, CDC73, and EPHX1 were higher in the BM group. The consistency of mutated profiles of plasma and primary lesion in the BM group was significantly lower (30.4% vs. 65.5%; p = 0.0038).

Conclusions: Pyrotinib-containing therapy shows favorable effectiveness and tolerable safety in patients with BM of HER2-positive MBC, particularly in a population that is brain radiotherapy-naïve, received pyrotinib as first- or second-line treatment, and developed supratentorial brain metastasis. In the exploratory genomic analysis, patients with BM showed distinct genomic features from patients without BM.

Keywords: HER2-positive breast cancer; brain metastases; clinical benefits; genomic profile; pyrotinib.

Figure 1

Kaplan–Meier estimates of overall survival for total patients (A), progression-free survival for total patients (B), and progression-free survival for patients who received across lines therapy of pyrotinib (C). mPFS, median progression-free survival; mOS, median overall survival.

Figure 2

Mutational landscape and KEGG pathways. (A) Mutational landscape of primary breast tumors from four of seven patients with BM and five of 10 patients without BM. Displayed are mutations, indels, and amplification likely to be pathogenic, summarized by gene for each patient. Bottom bar refers to group (BM and non-BM). Right, variant classification of the alterations within each gene. (B) KEGG pathways of all samples from patients with BM (including 17 plasma samples and four tissue samples of primary breast tumors). The y-axis represents KEGG-enriched terms. The x-axis represents the rich factor. The size of the dot represents the number of genes under a specific term. The color of the dots represents the adjusted p-value. BM, brain metastasis; KEGG, Kyoto Encyclopedia of Genes and Genomes.

Figure 3

Discrepancies of TMB, number of clusters, and consistency of mutated profiles of peripheral blood and primary lesion in patients with brain metastasis and without brain metastasis. (A) Clonal cluster number from seven patients with BM and nine of 10 patients without BM; p- values by t-test. (B) TMB from seven patients with BM and 10 patients without BM; p -values by Mann–Whitney U-test. (C) Discrepancy of consistency of mutated profiles of peripheral blood and primary lesion between patients with BM and without BM; p -values by Mann–Whitney U-test. BM, brain metastasis; TMB, tumor mutational burden.