Genomic Landscape of Circulating Tumor DNA in Patients With Hormone Receptor-Positive/Human Epidermal Growth Factor
Masaya Hattori1, Victoria Serelli-Lee2, Yoichi Naito3
1Aichi Cancer Center Hospital, Nagoya, Japan.
Purpose:
To understand the mutational landscape of circulating tumor DNA (ctDNA) and tumor tissue of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer (MBC) treated with abemaciclib + endocrine therapy (ET).
Methods:
Blood samples for ctDNA and/or tissue samples were collected from abemaciclib-treated patients with HR+/HER2- MBC enrolled in the SCRUM-Japan MONSTAR-SCREEN project. Blood samples were collected before abemaciclib initiation (baseline) and at disease progression/abemaciclib discontinuation (post abemaciclib treatment). Clinical and genomic characteristics including neoplastic burden (measured by shedding rate and maximum variant allele frequency [VAF]) were assessed at baseline. Genomic alterations in ctDNA were compared in paired baseline and post abemaciclib treatment samples.
Results:
All patients (N = 97) were female (median age, 57 years [IQR, 50-67]). In baseline ctDNA (n = 77), PIK3CA (37%), TP53 (28%), ESR1 (16%), and GATA3 (11%) were the most frequently mutated genes. Baseline tissue samples (n = 79) showed similar alteration frequencies. Among patients with baseline ctDNA data, 30% had received previous ET. ESR1 alteration frequency (35% v 8%; P < .01), median shedding rate (3 v 2), and maximum somatic VAF (4 v 0.8; both P < .05) were significantly higher in ctDNA from patients with previous ET than those without previous ET. In paired ctDNA samples (n = 33), PIK3CA and ESR1 alteration frequencies were higher after abemaciclib treatment than at baseline, though not statistically significant. Among the post-treatment alterations, those newly acquired were detected most frequently in FGF3/4/19 (18%); PIK3CA, TP53, CCND1, and RB1 (all 15%); and ESR1 (12%).
Conclusion:
We summarized the ctDNA and cancer tissue mutational landscape, including overall neoplastic burden and PIK3CA and ESR1 hotspot mutations in abemaciclib-treated patients with HR+/HER2- MBC. The data provide insights that could help optimize treatment strategies in this population.
Insights
This study analyzed circulating tumor DNA (ctDNA) in patients with metastatic breast cancer (MBC) treated with abemaciclib. Key mutations like PIK3CA and ESR1 were identified, offering insights for optimizing treatment strategies.
Area of Science:
- Oncology
- Genomics
- Translational Medicine
Background:
- Hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer (MBC) is a significant clinical challenge.
- Abemaciclib combined with endocrine therapy (ET) is a treatment option for HR+/HER2- MBC.
- Understanding the mutational landscape of circulating tumor DNA (ctDNA) and tumor tissue is crucial for treatment optimization.
Purpose of the Study:
- To characterize the mutational landscape of ctDNA and tumor tissue in HR+/HER2- MBC patients treated with abemaciclib plus ET.
- To assess the neoplastic burden and identify frequently mutated genes, including PIK3CA and ESR1.
- To compare genomic alterations in ctDNA at baseline and after abemaciclib treatment.
Main Methods:
- Blood and/or tissue samples were collected from HR+/HER2- MBC patients enrolled in the SCRUM-Japan MONSTAR-SCREEN project.
- ctDNA was analyzed at baseline and post-abemaciclib treatment.
- Neoplastic burden was assessed using shedding rate and maximum variant allele frequency (VAF).
Main Results:
- PIK3CA (37%), TP53 (28%), ESR1 (16%), and GATA3 (11%) were the most frequent mutations in baseline ctDNA.
- Patients with prior ET showed significantly higher ESR1 alteration frequency and neoplastic burden markers.
- Post-treatment ctDNA revealed increased frequencies of PIK3CA and ESR1 alterations, with new mutations in FGF3/4/19, PIK3CA, TP53, CCND1, RB1, and ESR1.
Conclusions:
- The study provides a comprehensive overview of the ctDNA and tissue mutational landscape in abemaciclib-treated HR+/HER2- MBC patients.
- Identified mutations, particularly PIK3CA and ESR1, offer potential targets for treatment stratification.
- These findings can guide the optimization of treatment strategies for this patient population.
