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omitting XRT in this low-risk CTC-negative disease, essentially focusing for the first time on this “indolent”
luminal cohort. On the other hand, much of the attention has been focused on patients with detectable
CTCs. Studies aimed at using CTC enumeration as selection criteria for additional “adjuvant” therapy have
been planned, particularly in hormone-receptor positive disease where CTCs appear associated with late-
[76]
recurrence and, possibly endocrine resistance . One of such potential, example has been the study testing
HER2+ therapies in patients with detectable cells, TREAT-CTC represented an intriguing approach with an
[77]
ambitious goal but it was stopped for futility due to slow accrual and no indication of benefit . In fact, the
study enrolled sixty-three patients with non-metastatic HER2-negative breast cancer and detectable CTCs (>
1/7.5 mL blood) after neoadjuvant chemotherapy and surgery randomized to trastuzumab (Herceptin) or
observation. There was no difference in CTCs at week 18, the trial’s primary endpoint, maybe due to CTCs-
HER2 definition or true lack of efficacy of the intervention.

In summary, this review showed that in spite of emerging data on the prognostic role of CTCs, the lack
of consensus about the “positive” detection cut-off (0, > 1, or > 5), the evaluation timing (at completion of
surgery or adjuvant treatment), and the lack of biomarker assessment along with missing clinical utility
prospective data may have limited the clinical application of CTC enumeration in early breast cancer.
Future studies will evaluate therapeutic strategies for both, de-escalation for CTC-negative disease and,
secondary adjuvant for potential late-recurrence in CTC-positive disease. It is likely that combining
molecular information such as CTCs, biomarkers, or integration with sensitive and complementary ctDNA
technologies may be the key for the practice-changing implementation of liquid biopsy in early disease.

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception and design of the work: D’Amico P
Performed acquisition and analysis of data and have drafted the manuscript: D’Amico P, Corvaja C,
Gerratana L, Reduzzi C
Revised the manuscript critically and added important intellectual content: Cristofanilli M, Curigliano G

Availability of data and materials
Not applicable.

Financial support and sponsorship
PD is supported by the American-Italian Cancer Foundation Post-Doctoral Research Fellowship, year
2019-2020.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2021.

REFERENCES
1. Society A cancer. Cancer Facts and Figures 2020. Available from: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-