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William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO
Posted: Monday, October 3, 2022
APOBEC-positive and homologous recombination deficient (HRD)-positive genomic signatures may be associated with shorter survival after treatment in patients with estrogen receptor–positive/HER2-negative (ER+/HER2–) metastatic breast cancer, according to Antonio Marra, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. In fact, genomic instability related to APOBEC and HRD mutations may lead to early resistance to CDK4/6 inhibition and endocrine therapy. These findings were presented during the European Society for Medical Oncology (ESMO) Congress 2022 (Abstract 210O).
Clinical and genomic data were obtained from breast cancer samples (n = 4,595), and targeted sequencing along with the SigMA algorithm were used to classify samples as APOBEC+, HRD+, or APOBEC–/HRD–. Metastatic samples were nearly two times more likely to express APOBEC+ and HRD+ signatures than primary tumors (P < .001). ER+/HER2– and HER2+ subtypes were more likely to express APOBEC+ (19% and 47%, respectively), whereas the HRD+ subtype was more common within triple-negative samples (36%). The most common signature for lobular breast cancers was APOBEC+. ER+/HER2– metastatic breast cancers with APOBEC had fewer ESR1 hotspot mutations than other types of breast cancer.
Metastatic breast cancer tumors expressing APOBEC+ (n = 395) tended to be associated with shorter median progression-free survival in patients treated with one or two lines of endocrine therapy, regardless of the agent (P = .001). CDK4/6 inhibition plus endocrine therapy also resulted in shorter median progression-free survival in metastatic breast cancer samples that were APOBEC+ and HRD+, compared with APOBEC–/HRD– samples (P = .001).
Patients with metastatic breast cancer samples that tested positive for APOBEC and HRD who were treated with one line of CDK4/6 inhibition plus endocrine therapy had poorer progression-free survival than negative samples, regardless of the agent. Shorter progression-free survival for HRD+ breast cancers was observed following two or three lines of CDK4/6 inhibition plus endocrine therapy.
Disclosure: For full disclosures of the study authors, visit cslide.ctimeetingtech.com.
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