Circulating Tumor Cell Count–Driven Treatment Decisions May Improve Long-Term Outcomes for Patients With Metastatic Breast Cancer

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The use of circulating tumor cell counts to guide the choice between chemotherapy and endocrine therapy as first-line treatment for patients with metastatic, estrogen receptor–positive, HER2-negative breast cancer provided overall survival benefits compared with physician’s choice of treatment, according to new findings presented by Bidard et al at the 2022 San Antonio Breast Cancer Symposium (Abstract GS3-09).


“The validity of [circulating tumor cell] count[s] has been studied extensively in metastatic breast cancer in the past 2 decades, and we and others have previously demonstrated its clinical validity as a biomarker of prognosis,” said study author François-Clément Bidard, MD, PhD, Professor of Medicine in the Department of Medical Oncology at Université de Versailles Saint-Quentin-en-Yvelines, as well as a medical oncologist and coordinator of breast cancer research at Institut Curie Hospitals and. “We hypothesized that the [circulating tumor cell] count could drive and help standardize the difficult treatment decision between endocrine therapy, which appears more suited for patients with good prognoses, and chemotherapy, which may benefit patients with worse prognoses.”

In the absence of any recent trials comparing the two treatment strategies, the consensus among experts has been to exhaust all endocrine therapy options before switching to chemotherapy to treat patients with metastatic breast cancer. Such a recommendation is based on the limited side effects of endocrine therapy compared with those of chemotherapy. However, treatment decisions are highly heterogeneous among physicians and centers.

Research Methods and Findings

To test the ability of the circulating tumor cell count to improve patient outcomes when used to drive the treatment decision between chemotherapy and endocrine therapy among patients with metastatic, estrogen receptor–positive/HER2-negative breast cancer, Dr. Bidard and his colleagues designed the STIC circulating tumor cell trial—in which 755 patients were randomly assigned to having their treatment decided by the investigator or by their circulating tumor cell count.

“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 [a high circulating tumor cell] count, or vice versa, de-escalated from chemotherapy to endocrine therapy if their [circulating cell count] count was low,” said Dr. Bidard.

The primary results of this trial—initially reported at the 2018 Symposium—showed a progression-free survival benefit among patients whose treatment was escalated from endocrine therapy to chemotherapy based on their circulating tumor cell count.

After a follow-up of nearly 5 years, the researchers reported that the overall survival analysis of the trial showing that, among patients with discordant recommendations between the investigator’s choice of therapy and the circulating tumor cell count, the strategy based on the circulating tumor cell count resulted in better long-term outcomes.

Among a subgroup of patients representing 25% of the study population—for whom endocrine therapy was the recommended treatment by investigator’s choice but who displayed high circulating tumor cell counts—those who were treated with chemotherapy had an absolute gain of 16 months in median overall survival and experienced a 47% reduction in their risk of mortality compared with patients in the same group who received endocrine therapy.

Among the subgroup of patients who were assigned to chemotherapy by investigator’s choice but had low circulating tumor cell counts—14% of the study population—those who received endocrine therapy had a comparable overall survival to those who received chemotherapy.


“The STIC [circulating tumor cell] trial is the first to establish the clinical utility of the [circulating tumor cell] count as a biomarker in breast cancer care, indicating that a single assessment of the [circulating tumor cell] count before the start of treatment can guide the treatment decision between chemotherapy and single-agent endocrine therapy in [estrogen receptor]-positive/HER2-negative metastatic breast cancer,” emphasized Dr. Bidard, highlighting that “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 [circulating tumor cell] count—representing 48% of the study population—had a median overall survival of about 5 years, even though these patients did not receive cyclin-dependent kinase 4 and 6 inhibitors as part of their first-line treatment.”

The limitations of this study included that it was conducted before the introduction of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, which are now widely used for the first-line treatment of metastatic estrogen receptor–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. Endocrine therapy with CDK4/6 inhibitors is the preferred option for [patients who are] treatment-naive, 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,” explained Dr. Bidard. He continued, “In that scenario, based on the STIC [circulating tumor cell] trial results, the [circulating tumor cell] 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.”

The researchers also expressed hope at the potential clinical utility of circulating tumor cell counts to adjust systemic treatment for metastatic breast cancer in second- and later-line treatments, following progression on CDK4/6 inhibitors.

Disclosure: The research in this study was funded by the Institut National du Cancer, the Institut Curie SIRIC2 program, and Menarini Silicon Biosystems.

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