Clinicopathological features and genomics of ER-positive/HER2-negative breast cancer relapsing on adjuvant abemaciclib

Abstract

Background: Two years of adjuvant abemaciclib with endocrine therapy (ET) is standard for high-risk estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative, node-positive early-stage breast cancer. Relapse on adjuvant abemaciclib is poorly characterized.

Patients and methods: Patients with recurrence on adjuvant abemaciclib at Dana-Farber Cancer Institute were identified. ER, progesterone receptor (PgR), and HER2 expression pre- and post-abemaciclib was determined, and the duration of adjuvant abemaciclib, ET, and first-line metastatic treatment recorded. Genomic alterations associated with ET and cyclin-dependent kinase 4 and 6 inhibitor resistance were analyzed if next-generation sequencing (NGS) was carried out at recurrence.

Results: Among 163 patients who received adjuvant abemaciclib (2018-2024), 15 (9.2%) experienced recurrence. Median durations were 8.0 months [interquartile range (IQR) 3.8-21.2 months] for adjuvant abemaciclib, 18.5 months (IQR 7.0-23.0 months) for adjuvant ET, and 3.0 months (IQR 1.6-5.0 months) for first-line metastatic treatment. Among 12 patients with ER, PgR, and HER2 evaluable pre- and post-abemaciclib, 6 (50.0%) with strongly positive ER at diagnosis showed ER ≤10% and PgR <1% at recurrence. Of 10 patients with NGS at recurrence, 90% had P53 pathway alterations, with one ESR1 mutation and no RB1 mutations.

Conclusions: In this series of patients relapsing on adjuvant abemaciclib plus ET, 50% showed ER loss, 90% had P53 pathway alterations, and median first-line metastatic treatment lasted 3 months.

Keywords: adjuvant abemaciclib; breast cancer; endocrine therapy; precision medicine; recurrence; translational.

Figure 1

Swimmer plots illustrating the duration of treatment for adjuvant abemaciclib (left) and endocrine therapy (right). The black cross represents toxicity leading to abemaciclib discontinuation (patients #1, #9, #11, #13, #14, #21). Among the eight patients who experienced recurrence after discontinuing/completing adjuvant abemaciclib, six discontinued treatment due to toxicities (diarrhea, n = 4; decreased kidney function, n = 1; pneumonitis, n = 1), while two completed the full course of adjuvant abemaciclib as planned. Specifically, in this subset (n = 8), the median duration of treatment for adjuvant abemaciclib was 8.0 months (IQR 3.9-18.6 months) (not shown). None of these eight patients discontinued endocrine therapy before recurrence; rather, endocrine therapy was stopped due to disease recurrence. IQR, interquartile range.

Figure 2

Changes in hormone receptor status between diagnosis and recurrence (Panel A), and genomic alterations identified in recurrence tissue after relapse on adjuvant abemaciclib (Panel B). (A) Individual line plots showing ER (left) and PgR (right) statuses at primary diagnosis compared to recurrence for 12 of 15 patients with hormone receptor data available at both time points. ER and PgR statuses at diagnosis significantly differed from those at recurrence (two-tailed P = 0.0078 for ER and P = 0.0049 for PgR, Wilcoxon signed-rank test, significance set at P < 0.05). (B) Co-mutation plot showing the most frequent genomic alterations in breast cancer genes for 10 of 15 patients who relapsed on or after adjuvant abemaciclib and underwent next-generation sequencing specifically from recurrence tissue. Most patients had genomic alterations in the P53 pathway (n = 9, 90%): TP53 oncogenic mutations (n = 5), TP53 homozygous deletions (n = 1), and MDM2 high amplifications (copy number >20) (n = 3). One ESR1 oncogenic mutation and no RB1 oncogenic mutations were detected. Additional oncogenic alterations include those in the PI3K pathway [n = 3; PIK3CA oncogenic mutation (n = 2), PTEN oncogenic mutation (n = 1)], RTK oncogenic alterations [n = 5; FGFR1 high amplification (n = 2), ERBB2 oncogenic mutation (n = 1), FGFR2 high amplification (n = 2)], and CCND1 high amplification (n = 1). BRCA2, breast cancer susceptibility gene 2; CCND1, cyclin D1; CNV, copy number variation; Dx, diagnosis; ER, estrogen receptor; ERBB2, v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2; ESR1, estrogen receptor 1; FAT1, FAT atypical cadherin 1; FGFR, fibroblast growth factor receptor; GATA3, GATA binding protein 3; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; MDM2, murine double minute 2; mut, mutation; PI3K, phosphatidylinositol-3 kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin homolog; RB1, retinoblastoma protein; RTK, receptor tyrosine kinases; TP53, tumor protein p53.

Figure 2

Changes in hormone receptor status between diagnosis and recurrence (Panel A), and genomic alterations identified in recurrence tissue after relapse on adjuvant abemaciclib (Panel B). (A) Individual line plots showing ER (left) and PgR (right) statuses at primary diagnosis compared to recurrence for 12 of 15 patients with hormone receptor data available at both time points. ER and PgR statuses at diagnosis significantly differed from those at recurrence (two-tailed P = 0.0078 for ER and P = 0.0049 for PgR, Wilcoxon signed-rank test, significance set at P < 0.05). (B) Co-mutation plot showing the most frequent genomic alterations in breast cancer genes for 10 of 15 patients who relapsed on or after adjuvant abemaciclib and underwent next-generation sequencing specifically from recurrence tissue. Most patients had genomic alterations in the P53 pathway (n = 9, 90%): TP53 oncogenic mutations (n = 5), TP53 homozygous deletions (n = 1), and MDM2 high amplifications (copy number >20) (n = 3). One ESR1 oncogenic mutation and no RB1 oncogenic mutations were detected. Additional oncogenic alterations include those in the PI3K pathway [n = 3; PIK3CA oncogenic mutation (n = 2), PTEN oncogenic mutation (n = 1)], RTK oncogenic alterations [n = 5; FGFR1 high amplification (n = 2), ERBB2 oncogenic mutation (n = 1), FGFR2 high amplification (n = 2)], and CCND1 high amplification (n = 1). BRCA2, breast cancer susceptibility gene 2; CCND1, cyclin D1; CNV, copy number variation; Dx, diagnosis; ER, estrogen receptor; ERBB2, v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2; ESR1, estrogen receptor 1; FAT1, FAT atypical cadherin 1; FGFR, fibroblast growth factor receptor; GATA3, GATA binding protein 3; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; MDM2, murine double minute 2; mut, mutation; PI3K, phosphatidylinositol-3 kinase; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PTEN, phosphatase and tensin homolog; RB1, retinoblastoma protein; RTK, receptor tyrosine kinases; TP53, tumor protein p53.