A group of researchers is in the spotlight for finding a clue to solve hormone resistance, a problem in an aggressive type of recurrent and metastatic breast cancer.
They used genomic analysis to identify characteristics of patients who develop resistance to palbociclib, a targeted antitumor drug used to treat recurrent or metastatic breast cancer.
Professor Park Yeon-hee of the Department of Hematology and Oncology at Samsung Medical Center, Park Kyung-hee, a researcher at Samsung Genome Institute, Professors Im Seock-ah and Lee Kyung-hun of the Department of Hematology and Oncology at Seoul National University Hospital, and Dr. Zhneyan Kan of Pfizer conducted the research.
Palbociclib is a drug that inhibits the enzymes of cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) involved in cancer growth.
It has been combined with endocrine therapy for HR+/HER2- breast cancer, the most common type of breast cancer, to improve the survival rate of patients with metastasis and recurrence. However, one in four patients does not respond to the drug; even if they do, their disease progresses due to resistance.
The researchers used NGS analysis of tumor tissue from 89 patients at Samsung Medical Center and Seoul National University Hospital who received palbociclib, fulvestrant, and an aromatase inhibitor for metastases and relapse between 2017 and 2020, identifying the leading causes of resistance.
Tumor tissue and blood from patients before, during, and after treatment were subjected to RNA sequencing and whole-exome sequencing (WES) to compare the extent to which they affected progression-free survival (PFS).
According to the researchers, the average age of the patients was 45 years, with a median progression-free survival (PFS) of 15 months. Disease progression was observed in 72 percent of patients.
In particular, the researchers found that patients with metastatic or recurrent HR+/HER2- breast cancer had molecular characteristics differing from those before treatment.
The study cited homologous recombination deficiency (HRD) and estrogen-induced genomic scarring as "biomarkers" of patient prognosis. HRD refers to the inability of cells to repair damaged DNA.
The team said the study is significant because it revealed that not only BRCA1 and 2 gene mutations, which cause hereditary breast cancer but also pre- and post-treatment tumor mutations contribute to resistance.
The team also found that TP53 gene variants, associated with tumor growth inhibition, promote chemoresistance when combined with high HRD, leading to poorer patient outcomes. The study also found that patients with the mutation had a 16.3 times higher risk of disease progression compared to those without the mutation.
APOBEC-mediated alterations in the RB1, ESR1, PTEN, and KMT2C genes, which are enzymes involved in gene mutation, stood out, suggesting these genes are also deeply involved in disease progression.
"As there are currently no markers to distinguish which patients with metastatic breast cancer who require CDK4/6 inhibitors can overcome resistance, we are fortunate to have identified the genes responsible for resistance by multi-omics analysis," the researchers said. "We look forward to further studies to identify new strategies to target these genes so patients with metastatic breast cancer can relieve their suffering."
The study was published in a recent issue of Genome Medicine.