Abstract
Introduction
Palbociclib is highly efficacious and well tolerated in hormone-receptor positive
(HR+) metastatic breast cancer (BC) but its activity for HER2+ BC with brain metastases
(BM) is unknown.
Methods
In a single-arm phase II study we evaluated palbociclib with trastuzumab for patients
with HER2+ MBC and BM. The primary endpoint was BM response rate. Circulating tumor
DNA (ctDNA) was evaluated at baseline, and in a subset of patients at cycle 3 and
progression. We also retrospectively identified additional patients with metastatic
BC, active BM, and a ctDNA assessment prior to therapy for BM.
Results
Twelve patients with HER2+ MBC were enrolled, 4 with HR+ and 8 with HR- disease. No
responses were seen. Best response was stable disease for 6 patients and progressive
disease for 6 patients. The median PFS was 2.2 months, interquartile range (IQR) was
1.56 to 3.63 months. The median OS was 13.1 months and IQR was 9.4 to 23.8 months
The CNS was the primary site of progression for all patients. The median variant allele
fraction (VAF) of the dominant variant in each patient was 0.18% (interquartile range
[IQR] 0.12%-0.47%) with a median number of somatic alterations of 1. We additionally
evaluated ctDNA results from 26 patients with BC and active BM, among whom the median
VAF was 11.8% (IQR 3.9%-27.3%) with a median number of alterations was 6 (IQR 4-9).
Notably, progressive systemic disease was significantly less frequent in the trial
cohort compared with additional retrospectively identified patients (8% vs. 81%).
Conclusion
Palbociclib did not demonstrate activity in HER2+ MBC with BM. Patients with progressive
BM but stable, responding, or absent systemic disease have low VAF and number of alterations
detected by ctDNA analysis from blood.
Keywords
Abbreviations:
BM (brain metastases), BC (breast cancer), BBB (blood brain barrier), CNS (central nervous systemic), ctDNA (circulating tumor dna), CI (confidence interval), CDK (cyclin dependent kinase), HR+ (hormone-receptor positive), MBC (metastatic breast cancer), NOA (number of alterations), OS (overall survival), ORR (overall response rate), PFS (progression free survival), TN (triple negative), VAF (variant allele fraction)To read this article in full you will need to make a payment
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References
- Brain metastases.Nature Reviews Disease Primers. 2019; 5: 5
- Impact of breast cancer molecular subtypes on the incidence, kinetics and prognosis of central nervous system metastases in a large multicentre real-life cohort.British Journal of Cancer. 2019; 121: 991-1000
- Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases.J Clin Oncol. 2012; 30: 419-425
- Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer.New England Journal of Medicine. 2015; 372: 724-734
- Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer.New England Journal of Medicine. 2018; 380: 617-628
- Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA.Annals of oncology : official journal of the European Society for Medical Oncology. 2015; 26: 113-119
- Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA.Annals of oncology : official journal of the European Society for Medical Oncology. 2014; 25: 1116-1121
- Intracranial Efficacy and Survival With Tucatinib Plus Trastuzumab and Capecitabine for Previously Treated HER2-Positive Breast Cancer With Brain Metastases in the HER2CLIMB Trial.J Clin Oncol. 2020; 38: 2610-2619
- The efficacy of lapatinib and capecitabine in HER-2 positive breast cancer with brain metastases: A systematic review and pooled analysis.Eur J Cancer. 2017; 84: 141-148
- Palbociclib in Hormone-Receptor–Positive Advanced Breast Cancer.New England Journal of Medicine. 2015; 373: 209-219
- Palbociclib and Letrozole in Advanced Breast Cancer.New England Journal of Medicine. 2016; 375: 1925-1936
- Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer.New England Journal of Medicine. 2018; 379: 1926-1936
- PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro.Breast Cancer Res. 2009; 11: R77
- Cyclin D1 is required for transformation by activated Neu and is induced through an E2F-dependent signaling pathway.Mol Cell Biol. 2000; 20: 672-683
- Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts.Cancer research. 2010; 70: 3228-3238
- PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma.PLoS One. 2013; 8: e77639
- Positive predictive value of ERBB2 copy number gain by tissue or circulating tumor DNA next-generation sequencing across advanced cancers.Oncotarget. 2022; 13: 273-280
- A Phase II Study of Abemaciclib in Patients with Brain Metastases Secondary to Hormone Receptor–Positive Breast Cancer.Clinical Cancer Research. 2020; 26: 5310-5319
- Tucatinib, palbociclib, and letrozole in HR+/HER2+ metastatic breast cancer: Report of phase IB safety cohort.Journal of Clinical Oncology. 2019; 37 (1029-1029)
- Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with hormone receptor-positive, HER2-positive advanced breast cancer (monarcHER): a randomised, open-label, phase 2 trial.Lancet Oncol. 2020; 21: 763-775
- Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With ≥ 2 HER2-Directed Regimens: Phase III NALA Trial.J Clin Oncol. 2020; 38: 3138-3149
- Abstract PD4-05: Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases (BCBM).Cancer Research. 2022; 82 (PD4-05-PD04-05)
- T-DM1 and brain metastases: Clinical outcome in HER2-positive metastatic breast cancer.Breast. 2018; 41: 137-143
- Cerebrospinal fluid cell-free tumour DNA as a liquid biopsy for primary brain tumours and central nervous system metastases.Ann Oncol. 2019; 30: 211-218
- Utilizing phenotypic characteristics of metastatic brain tumors to improve the probability of detecting circulating tumor DNA from cerebrospinal fluid in non-small-cell lung cancer patients: development and validation of a prediction model in a prospective cohort study.ESMO Open. 2022; 7100305
- Genomic Profiling of Circulating Tumor DNA From Cerebrospinal Fluid to Guide Clinical Decision Making for Patients With Primary and Metastatic Brain Tumors.Frontiers in Neurology. 2020; : 11
Article info
Publication history
Published online: December 14, 2022
Accepted:
December 12,
2022
Received in revised form:
November 3,
2022
Received:
September 6,
2022
Identification
Copyright
© 2022 Published by Elsevier Inc.
