A high circulating tumor cell (CTC) count (CTChigh) is a strong adverse prognostic factor in patients diagnosed with metastatic breast cancer (mBC). The use of CTC count to guide the choice between chemotherapy and endocrine therapy as first-line therapy for patients with metastatic, estrogen receptor (ER)-positive/HER2-negative breast cancer provided overall survival benefit, compared with physician’s choice of treatment.

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.

This conclusion is based on data from the STIC CTC trial, funded by the Institut National du Cancer, the Institut Curie SIRIC2 program, and Menarini Silicon Biosystems. The study results were presented at the San Antonio Breast Cancer Symposium (SABCS), held December 6-10, 2022 in San Antonio, Tx.

“The validity of CTC count has been studied extensively in metastatic breast cancer in the past two decades, and we and others have previously demonstrated its clinical validity as a biomarker of prognosis,” said study presenter François-Clément Bidard, MD, PhD, a professor of medical oncology at Institut Curie and Versailles Saint-Quentin University, Paris, France.

“We hypothesized that the CTC count could drive and help standardize the difficult treatment decision between endocrine therapy, which appears more suited for patients with good prognosis, and chemotherapy, which may benefit patients with worse prognosis,” Bidard explained.

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“In the absence of any recent trial comparing the two treatment strategies, the consensus among experts is to exhaust all endocrine therapy options before switching to chemotherapy to treat patients with metastatic breast cancer. Such recommendation is based on the limited side effects of endocrine therapy compared to chemotherapy. However, treatment decisions are highly heterogenous among physicians and centers,” Bidard added.

Study design
To test the ability of the CTC count to improve patient outcomes when used to drive the treatment decision between chemotherapy and endocrine therapy in women with metastatic, ER-positive/HER2-negative breast cancer, Bidard and colleagues designed the STIC CTC trial, in which 755 patients were randomly assigned (1:1) to having their treatment decided by the investigator or by their CTC count.

In the CTC arm, participating patients (N=377) had their treatment determined by baseline CTC count: CT if CTChigh (≥5 CTCs/7.5 mL, CellSearch®), ET if CTClow. In the standard arm, participating patients (N=378), the choice was left to the investigator: CT if clinical high risk (Clinhigh), ET if clinical low risk (Clinlow).

As a result, patients with discordant Clinlow/CTChigh or Clinhigh/CTClow profiles had their first line treatment escalated from ET (standard arm) to CT (CTC arm) or de-escalated from CT (standard arm) to ET (CTC arm), respectively. Patients with concordant Clinlow/CTClow and Clinhigh/CTChigh profiles received ET and CT in both arms, respectively.

“We anticipated that most patients would have their treatment unchanged, while some would have their treatment escalated from endocrine therapy recommended by investigators to chemotherapy based on high CTC count, or vice versa, de-escalated from chemotherapy to endocrine therapy if their CTC count was low,” said Bidard.

Updated reports
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 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.

The study showed that among 755 randomized patients 25.0% (N=189) had a Clinlow/CTChigh profile, 13.6% (N=103) Clinhigh/CTClow, 48.2% (N=363) Clinlow/CTClow and 13.2% (N=100) Clinhigh/CTChigh.

The OS was analyzed after a median follow-up of 57 months and 382 events (50.6%).

Summary of study results

  • Among the Clinlow/CTChigh subgroup of patients representing 25.0% of the study population, for whom endocrine therapy 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 overall survival (mOS) and experienced a 47% reduction in their risk of death compared to patients in the same group who received endocrine therapy.
  • In this In the subgroup, CT in the CTC arm led a longer OS (mOS: 51.8 months [43.3-NR]) than ET in the standard arm (35.4 months [30.4-45.4]; HR=0.53 [0.36-0.78], p=0.001).
  • Among Clinhigh/CTClow subgroup of patients who were assigned to chemotherapy by investigator’s choice but had low CTC count, corresponding to 14% of the study population, those who received endocrine therapy had a comparable overall survival (OS) to those who received chemotherapy.
  • In In this subgroup, no significant difference was observed whether they received CT (standard arm) or ET (CTC arm) (45.9 months [36.3-59.8] vs 49.4 months [35.4-65.4]; HR=0.88 [0.51-1.51], p=0.63).

A pooled analysis of the study results further showed:

  • Pooling the two discordant groups (Clinlow/CTChigh or Clinhigh/CTClow), the CTC-driven strategy was superior to the clinician-driven treatment decision (HR=0.63 [0.46-0.86], p=0.02).
  • Pooling all concordant and discordant groups together, a median OS of 45.5 (95%CI=[40.9-51.1]) and 51.3 months [46.8-55.1] was observed in the standard and CTC arms, respectively (HR=0.84 [0.69-1.03], p=0.10).

“The STIC CTC trial is the first to establish the clinical utility of the CTC count as a biomarker in breast cancer care, indicating that a single assessment of the CTC count before the start of treatment can guide the treatment decision between chemotherapy and single agent endocrine therapy in ER-positive/HER2-negative metastatic breast cancer,” said Bidard.

“Our study demonstrates that integrating prognostic biomarkers into the treatment algorithm can improve the management and outcomes of metastatic breast cancer patients.

“Interestingly, the subgroup of patients with concordant favorable estimates by clinician assessment and CTC count, representing 48% of the study population, had a median overall survival of about five years, even though these patients did not receive cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors as part of their first-line treatment,” added Bidard.

Study limitations
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-positive/HER2-negative breast cancer.

“When the trial was designed, the question related to the choice between single-agent endocrine therapy and chemotherapy pertained to first-line therapy,” said Bidard. “Endocrine therapy with CDK4/6 inhibitors is the preferred option for treatment-naïve patients, but the dilemma between endocrine therapy and chemotherapy remains after disease progression on adjuvant or first-line therapy with CDK4/6 inhibitors,
where current guidelines advocate in favor of endocrine therapy despite its short-lived efficacy.

“In that scenario, based on the STIC CTC trial results, the CTC count, in combination with predictive biomarkers, whenever available, may help customize the early use of chemotherapy or antibody-drug conjugates, which are becoming more and more attractive,” continued Bidard.

Clinical trials
Medico-economic Interest of Taking Into Account Circulating Tumor Cells (CTC) to Determine the Kind of First Line Treatment for Metastatic, Hormone-receptors Positive, Breast Cancers – NCT01710605

[1] Bidard FC, Circulating Tumor Cells-driven choice of first line therapy for ER+ HER2- metastatic breast cancer: overall survival analysis of the randomized STIC CTC trial. Abstract: GS3-09, presented during the San Antonio Breast Cancer Symposium, held December 6 – 10, 2022.
[2] Bidard FC, Jacot W, Kiavue N, Dureau S, Kadi A, Brain E, Bachelot T, Bourgeois H, Gonçalves A, Ladoire S, Naman H, Dalenc F, Gligorov J, Espié M, Emile G, Ferrero JM, Loirat D, Frank S, Cabel L, Diéras V, Cayrefourcq L, Simondi C, Berger F, Alix-Panabières C, Pierga JY. Efficacy of Circulating Tumor Cell Count-Driven vs Clinician-Driven First-line Therapy Choice in Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer: The STIC CTC Randomized Clinical Trial. JAMA Oncol. 2021 Jan 1;7(1):34-41. doi: 10.1001/jamaoncol.2020.5660. PMID: 33151266; PMCID: PMC7645742.

Feature image: San Antonio Breast Cancer Symposium (SABSC), held December 6 – 10, 2022 at the Henry B. Gonzalez Convention Center in San Antonio, Tx. Photo courtesy: © 2022: AACR/SABCS MedMeetingImages/Todd Buchanan. Used with permission.


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