Are Circulating Tumor Cells (CTCs) Ready for Clinical Use in Breast Cancer? An Overview of Completed and Ongoing Trials Using CTCs for Clinical Treatment Decisions
Round 1
Reviewer 1 Report
The authors did a good job of summarizing current clinical trials utilizing CTCs for making treatment decisions.
However, it must be emphasized on how the cutoff of 5 was initially meant to be used. Using a cutoff of 5 was the number of CTCs which separated breast cancer patient into better overall survival from worse survival. It very well could have been 1 or more for worse survival but that would have taken longer to see the lines separate. This number was not meant to be used for treatment choice.
What does the presence of any CTCs mean? It means that the disease has become metastatic and moved from the primary site based simply on "primary"- not found outside of this point. If CTCs are found in the circulation they have moved from the primary site and most likely have seeded in other parts of the body by a spread through the lymph fluid with the potential of taking up residency in fertile lymph nodes providing food and growth factors. The greater the number of CTCs is usually associated with greater tumor burden. However, this is not always the case. CTCs do represent those tumor cells that are more aggressive and are dividing faster. Therefore, if a patient is responding to therapy, one can see a drop in the numbers of CTCs e.g. following treatment with trastuzumab (anti-Her2), if numbers were high prior o treatment and dropped after treatment it shows Her2 positive cells have been reduced. This can happen in as little as 7 days post the first treatment. The same happens within a short time after docetaxel treatment. And we would like to think this reflects what is happening at the tumor site, representing a lower overall tumor burden.
It is possible to collect the CTCs and interrogate them by protein expression e.g. Her2, ER/PR expression, or molecularly analyze them for various mutations to identify the more aggressive clone(s). If a patient is a responder for any period of time and CTCs return this should be repeated to determine whether the same clones have progressed (meaning you could repeat that therapy)or whether a alternate clone has now become the aggressive clone and design the next treatment around that.
Some patients never show CTCs regardless of their tumor burden. Yes, CTCs can stratify patients but unless one delves into the clonal representation, one cannot make a treatment choice.
Author Response
Please see the attachment.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
The manuscript summarizes current clinical trials assessing CTCs in breast cancer patients. As CTCs are a promising monitoring tool it is important to summarize results of clinical trials to show their real clinical validity and utility. The manuscript is comprehensive and well written. I only have minor comments.
Please describe how Her2 status was assessed in CTCs studies within CirCe T-DM-1 study. In this study the prevalence of HER2+ CTCs in HER2- patients seems to be much lower than in the DETECT study program. What could be the reason of such discordance? Are these methodological differences connected to the analysis of HER2 status in CTCs or are there other confounding factors? Could you please comment on this matter?
The authors mention that translational research is being conducted within DETECT study program. Please briefly describe what is the focus of these translational research. It is not clear what is the main interest of these translational studies. Are these mutations/SNPs/transcriptomic/genomic profiling of CTCs as single cells?
Author Response
Please see the attachement
Author Response File: Author Response.pdf
