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Figure 2. Bubble representation of the most important clinical trials (name of first author and year of publication) assessing the
association between CTCs, ctDNA detection and prognosis. The data are retrieved from original manuscripts and shown in respect
of the 5 main management timepoints of early breast cancer (neoadjuvant treatment, surgery, adjuvant treatment, 2 years follow-
up, 5 years follow-up). Bubble size represents the number of analyzed patients. Bubble color represents a statistical association
between detection and either worse disease-free survival or worse overall survival (green = significant association, red = not significant
association). X-axis represents the treatment time frame for which data from the study refers to. Y-axis represents the year of
publication: closer to the x axis are the most recent trials. CTCs: circulating tumor cells; ctDNA: circulating tumor DNA. *Bubbles
dimension resized by a factor of 3. Figure references: Silva ’02 [24] , Rothe ’19 [25] , Murillas ’15 [26] , Murillas ’19 [27] , Chen ’17 [28] , Radovich
’20 [29] , Coombes ’19 [31] , Xenidis ’06 [35] , Rack ’14 [36] , Pierga ’08 [37] , Lucci ’12 [38] , Pierga ’17 [40] , Trapp ’19 [42] , Bidard ’09 [44] , Hall ’15 [48] ,
Riethdorf ’17 [74] , Sparano ’18 [76] , Bidard ’13 [73] , Bauer ’16 [78]

[41]
The CTCs analysis from the Geparquattro trial , after a median follow-up of 67.1 months, showed a
correlation between CTCs detection and reduced DFS and OS (P = 0.031 and P = 0.0057) only before
neoadjuvant treatment. The lack of prognostic value of post-neoadjuvant detection of CTCs was confirmed
[48]
in several studies [39,40,47] . However, Hall et al. specifically addressed this question. In a cohort of 57 TNBC,
detection of at least 1 CTC after NAT predicted decreased DFS (log-rank P = 0.03, HR = 5.25, 95%CI: 1.34-
20.56) and OS (log-rank P = 0.03, HR = 7.04, 95%CI: 1.26-39.35), suggesting a potential different biological
behavior across subtypes. For a comprehensive graphic representation of trials assessing the role of CTCs
and ctDNA detection as a prognostic biomarker among different timepoints of eBC treatment, see Figure 2.

A combined comparison of the data from the main prospective trials that occurred in the past years has
partially answered the above-mentioned questions. In a pooled analysis of 3,173 eBC patients, the presence
of CTCs at the time of primary diagnosis was significantly associated with shorter DFS and DDFS, with
multivariate HRs of 1.822 (95%CI: 1.470-2.258; P < 0.001) for DFS and 1.888 (95%CI: 1.485-2.401; P < 0.001)
for DDFS. The prognostic value of CTCs was significant for all CTC cut-off values ranging from 1 to 20
both for DFS (all P < 0.01) and for DDFS (all P < 0.01) and was confirmed across all subtypes. However,
CTC detection did not significantly predict OS in the subgroup of patients with nodal stage N0 disease,
showing indeed, higher effect on OS in high risk patients, defined as those with primary tumors larger than
[49]
2 cm and lymph node involvement (HR = 2.460; 95%CI: 1.784-3.390; P = 0.001) .
Furthermore, in a comprehensive international meta-analysis of 21 trials (the IMENEO study), the
number of CTCs detected before NAT administration had no detrimental impact on pathological complete