Circulating tumour cells-driven choice of first line therapy for ER+ HER2- metastatic breast cancer
The use of circulating tumour cell (CTC) count to guide the choice between chemotherapy and endocrine therapy as first line therapy for patients with metastatic, oestrogen receptor (ER)-positive/HER2-negative breast cancer provided overall survival benefit, compared with physician’s choice of treatment. As such, integrating prognostic biomarkers into the treatment algorithm can improve the management and outcomes of patients.
Over the past two decades, the validity of the circulating tumour cell (CTC) count has been studied extensively in metastatic breast cancer. By now, its clinical validity as a biomarker of prognosis has been validated and it was hypothesised that the CTC count could drive and help standardise the difficult treatment decision between endocrine therapy (ET), which appears more suited for patients with good prognosis, and chemotherapy, which may benefit patients with worse prognosis. In the STIC CTC trial, 775 patients with metastatic ER+/HER2- breast cancer were randomly assigned (1:1) to having their treatment decided by the investigator or by their CTC count.
Study design
In the CTC arm, 377 patients had their treatment determined by baseline CTC count: chemotherapy if CTChigh (≥5 CTCs/7.5 mL, CellSearch®), ET if CTClow. In the standard arm (N= 378 patients), the choice was left to the investigator: chemotherapy if clinical high risk (Clinhigh), ET if clinical low risk (Clinlow). Therefore, patients with discordant Clinlow/CTChigh or Clinhigh/CTClow profiles had their first line treatment escalated from ET (standard arm) to chemotherapy (CTC arm) or de-escalated from chemotherapy (standard arm) to ET (CTC arm), respectively. Patients with concordant Clinlow/CTClow and Clinhigh/CTChigh profiles received ET and chemotherapy in both arms, respectively.
Results
The primary results of this trial, reported at SABCS in 2018, showed a progression-free survival benefit in patients whose treatment was escalated from endocrine therapy to chemotherapy based on their CTC count. After a follow-up of nearly five years, the authors now report the overall survival (OS) analysis of the trial, showing that, in patients with discordant recommendations between the investigator’s choice of therapy and the CTC count, the strategy based on CTC count resulted in better long-term outcomes. OS was analysed after a median follow-up of 57 months and 382 events (50.6%). Among a subgroup of patients representing 25.0% of the study population, for whom ET was the recommended treatment by investigator’s choice but who displayed high CTC count, those who were treated with chemotherapy had an absolute gain of 16 months in median OS and experienced a 47% reduction in their risk of death compared to patients in the same group who received ET (HR[95%CI]: 0.53[0.36-0.78], p= 0.001). Among the subgroup of patients who were assigned to chemotherapy by investigator’s choice but had low CTC count, corresponding to 13.6% of the study population, those who received chemotherapy had a comparable OS to those who received ET (45.9 vs. 49.4 months, HR[95%CI]: 0.88[0.51-1.51], p= 0.64). Pooling the two discordant groups (Clinlow/CTChigh or Clinhigh/CTClow), the CTC-driven strategy was superior to the clinician-driven treatment decision (HR[95%CI]: 0.63[0.46-0.86], p= 0.02). Pooling all concordant and discordant groups together, a median OS of 45.5 and 51.3 months was observed in the standard and CTC arms, respectively (HR[95%CI]: 0.85[0.69-1.03], p= 0.11).
The limitations of this study include that it was conducted before the introduction of CDK4/6 inhibitors, which are now widely used for the first-line treatment of metastatic ER+/HER2- breast cancer.
Conclusion
Prognostic information brought by CTC or standard factors is discordant in 40% of patients with ER+/HER2- mBC. In case of a discordant estimate, the STIC CTC trial shows the superiority on OS of the CTC-driven treatment decision strategy. These results also suggest a possible clinical utility of CTC to adjust systemic treatment for mBC in second and later lines, after progression on CDK4/6 inhibitors.
Reference
Bidard F, et al. Circulating Tumor Cells-driven choice of first line therapy for ER+ HER2- metastatic breast cancer: overall survival analysis of the randomized STIC CTC trial. Presented at SABCS 2022; Abstract GS3-09.
