Circulating tumor cell count: A reliable biomarker for treatment selection in metastatic breast cancer

According to Global cancer statistics 2020, breast cancer has surpassed lung cancer as the most common cancer in almost all countries worldwide. ¹ It is a major health problem and cause of cancer‐related death in most global regions, especially in China. ² , ³ Metastatic breast cancers that are positive for hormone receptor and negative for human epidermal growth factor receptor 2 (HER2) are the most common subset of metastatic breast cancers, accounting for two‐thirds of metastatic breast cancer cases. ⁴ The status of hormone receptors in metastatic breast cancer is the best‐established predictive marker for response to endocrine therapy. ⁵ Currently, whether endocrine therapy or chemotherapy would be the best first‐line treatment option for hormone receptor‐positive and HER2‐ negative metastatic breast cancer is a key issue. Wilcken et al. ⁶ conducted a meta‐analysis of published data from six clinical trials in 2003 (n = 692). They found that patients in the first‐line endocrine therapy group had similar overall survival to those in the chemotherapy group, but patients who received chemotherapy had a higher rate of toxicity. Nowadays, endocrine therapy is considered to be the preferred first‐line treatment for hormone receptor‐positive, HER2‐negative metastatic breast cancer. ⁷ However, some patients who receive endocrine therapy as up‐front treatment experience rapid disease progression, clinical symptoms, together with general impairment, or life‐threatening diseases. Therefore, until recently, about 15%–50% of hormone receptor‐positive and HER2‐negative metastatic breast cancer patients still choose chemotherapy as their first‐line treatment. ⁸ , ⁹

Circulating tumor cell (CTC) is the most important representation of liquid biopsy in metastatic breast cancer. ¹⁰ Cristofanilli et al. ¹¹ demonstrated for the first time that CTC count can effectively predict the prognosis of patients with metastatic breast cancer. They found that high CTC count (≥5 CTCs/7.5 ml) was associated with poor overall survival and progression‐free survival among patients with metastatic breast cancer. Multivariate analysis confirmed that performance status, tumor subtype, and baseline CTC count are three important prognostic markers for metastatic breast cancer patients. ¹² These findings indicated that baseline CTC count is a more reliable prognostic marker than clinical characteristics, and this prompted the US Food and Drug Administration to approve CTC count for clinical use. However, whether the CTC count could be used as alternative to the clinical evaluation to guide the choice between endocrine therapy and chemotherapy as first‐line treatment for hormone receptor‐positive and HER2‐negative metastatic breast cancer is still unknown.

In a study recently published in JAMA Oncology, Bidard et al. ¹³ conducted a randomized clinical trial (STIC CTC trial) to compare the efficacy of a CTC‐driven treatment choice versus a clinician‐driven treatment choice for first‐line treatment in hormone receptor‐positive and HER2‐negative metastatic breast cancer. A total of 755 female metastatic breast cancer patients (median age = 63 years, range = 30–88 years) were enrolled and randomly assigned (1:1) to the CTC‐driven choice arm (n = 377; median age = 64 years, range = 30–88 years) and the clinician‐driven choice arm (n = 378; median age = 63 years, range = 31–87 years). In the CTC‐driven choice arm, 63.4% (239/377) patients with low CTC count received endocrine therapy and 36.6% (138/377) patients with high CTC count received chemotherapy. Moreover, in the clinician‐driven choice arm, 72.7% (275/378) patients who were considered clinically low received endocrine therapy and 27.2% (103/378) clinically high patients received chemotherapy. The median progression‐free survival in the CTC‐driven choice arm was 15.5 months (95% CI: 12.7–17.3) and that in the clinician‐driven choice arm was 13.9 months (95% CI: 12.2–16.3). The primary endpoint with a hazard ratio of 0.94 was met (90% CI: 0.81–1.09). These data suggest that the CTC‐driven choice arm noninferior for progression‐free survival in metastatic breast cancer.

This randomized clinical trial is the first attempt to use a single biomarker to guide the selection of first‐line treatment in metastatic breast cancer. It aimed to verify whether CTC‐driven choice can replace clinician‐driven choice. In addition, it planned to degrade treatment in at least one patient subgroup (CTC low, clinically high), thus, it prefers a noninferiority design. This study reached its primary objective and proved that there was no significant difference in overall survival between the CTC‐driven choice arm and the clinician‐driven choice arm. Although the proportion of patients treated by chemotherapy was not lower in the CTC‐driven choice group, the reproducibility of CTC can allow treatment standardization in this population. Moreover, this study also observed that the CTC‐based strategy based on CTC count has more obvious advantages in elderly patients as compared with the strategy based on clinicopathological characteristics. This may be due to the fact that elderly patients are more inclined to use endocrine therapy as the clinically favored treatment. Interestingly, in 38.7% of patients in the clinically high/CTC low subgroup and clinically low/CTC high subgroup, the use of chemotherapy yielded a nonstatistically significant trend toward longer progression‐free survival and a statistically significantly longer progression‐free survival in the former subgroup and latter subgroup, respectively. However, when combining these two subgroups, the multivariate analysis showed that chemotherapy was statistically significantly associated with a benefit in both overall survival and progression‐free survival as compared to endocrine therapy. It suggests that up‐front chemotherapy may improve the prognosis of patients with intermediate‐risk estimate.

This study has several limitations. First, some clinical trials have reported that the first‐line combination of endocrine therapy with cyclin‐dependent kinase 4/6 inhibitors can improve patient prognosis, ¹⁴ but as the STIC CTC trial was conducted before the results of these clinical trials were obtained, no patients in the STIC CTC trial were treated with endocrine therapy plus cyclin‐dependent kinase 4/6 inhibitors. Second, the molecular characteristics of CTCs can also predict the efficacy of endocrine therapy, CDK4/6 inhibitors and chemotherapy in metastatic breast cancer, ¹⁵ but the STIC CTC trial did not analyze the molecular characteristics of CTCs. Third, the CTC detection/analysis system (CellSearch system) used in the STIC CTC trial may have missed some clinically meaningful mesenchymal‐like CTCs.

Although this study still has the limitations mentioned above, it demonstrated that CTC count is a single and reproducible biomarker for treatment selection. CTC count‐driven treatment selection strategy can be used to replace the existing treatment selection strategy which is based on multiple clinical parameters.

CONFLICT OF INTEREST

The author declares no competing interests.