Dissecting Liquid Biopsy in MBC: CTCs, ctDNA and CAMLs to Evaluate Innate Immunity

 

Emily Le:

Hi everyone. I am Emily Le from the Next Generation Diagnostics Summit. I'm really pleased to have the opportunity to speak with Dr. Massimo Cristofanilli, Professor of Medicine, Associate Director of Translational Research and Precision Medicine, and Director of the OncoSET precision medicine program from Northwestern University. He will be giving the keynote presentation at the Circulating Tumor Cells track as part of the 10th annual Next Generation Diagnostics Summit August 21 in Washington, D.C.

Massimo, thank you for joining us.

Massimo Cristofanilli:
Thank you for having me.

Emily Le:
What is the topic of your keynote talk and its significance?

Massimo Cristofanilli:
My presentation will focus on a combination of biomarkers that will be able to measure in the blood in patients with breast cancer that will focus clearly to metastatic breast cancer. We know about CTCs and diagnostic evaluation in CTC and how to get into specific biomarkers. We're discovering more and more of the values of the ctDNA, and a way to identify actionable mutation, but that is also a source of other type of cells that can be recovered, characterized, and monitored. For example, we studied a few years ago, starting with in 2014 these circulating macrophages associated with tumor cells that appeared to have an additional diagnostic/prognostic value when it got to the patients with metastatic breast cancer, and not only that but also with advanced malignancies. So we have presented additional data last year in ASCO, and this year, and I want to put it together, all these components to see how they interact and how we can gather information on patient outcome, but also in better ways to not only to design targeted and immune therapy studies, but also include new therapies for advanced metastatic breast cancer.

Emily Le:
That's wonderful. Now, in your opinion, are both CTCs and cfDNA important, or are they just redundant technologies?

Massimo Cristofanilli:
I think this is a very important question because the field has been shifting from CTC to DNA without truly understanding what's the role of each modalities and technology. I think they are actually complementary in a way because the DNA of the naturally identifying mutations derives on the metastatic lesions can give us some information about the better therapy and the mechanism of resistance. So the CTC might only be informative of the metastatic process, but that's why it's more difficult to detect in all patients but in a faction of them. There are different phenotypes of CTC so technology have been tried to capture as much as possible. We went from immune magnetic to microfluidic systems that allow us to perform some basic morphology assessment and immune histochemistry analysis the cells will recover beside mutation and single cell analysis. Both of them allow us to study tumor heterogeneity. It appears to be clearly a problem when you're trying to define treatments and treatment resistance.

Emily Le:
As of now, what do we know about the relationship between CTSs and the immune system, and how to leverage that knowledge for liquid biopsy application?

Massimo Cristofanilli:
I think the CTCs allow us to better assess the interaction with immune system. I mentioned the CAMLs (Cancer-associated macrophage-like cells) as expression of innate immunity but we're able to assess PD-L1 expression or we look at the interaction of cancer cells with T cells, sometimes we integrate those cells and we see if the patient with the disease will usually have a deficiency in both adaptive of innate immunity in general. So clearly indicating that in some of the subset with specific intervention of immune therapy may be perfect. Of course, it is much more common when you have cells with a certain type of stem cells especially with EMT cells, where the situation (immune deficiency) is frequently the rule. We have to virtually identify both allow us to study twin surveys with vaccines or other modality immunotherapy. So I think CTC is not only fundamental to the metastatic process per se, but also the mechanism of immune recognition and this is related primarily to this patient's immune system.

Emily Le:
What do you want to see more in the liquid biopsy field?

Massimo Cristofanilli:
I think it's time for the industry to incorporate liquid biopsy in patients' stratification and patients directed therapies. We have seen a number of retrospective analysis presented for metastatic breast cancer showing that patients with specific somatic mutations, such as ESR-1 mutations are resistant to aromatase inhibitors indicating the impact of this information. We have seen that, for example for the studies using tissue analysis for selection, this can be difficult to collect in metastatic studies and without ctDNA testing, the study will not allow to get this information in real time. We have seen that evaluating CTCs can help stratifying patients with aggressive vs. indolent disease, and this information still has to be integrated in the design of prospective clinical trials to show how our new treatments may have an impact on overall survival. So I think the incorporation (of liquid biopsy) into trial design is almost a necessary step and, what I would like to see for the field (therapeutics and diagnostics) and all the technologies to work together.

Emily Le:
In your opinion, when should one expect clinical unity of liquid biopsies, and would it be in five years or more than that?

Massimo Cristofanilli:
So this question is somewhat related to the one that we just addressed meaning that a therapeutic study is associated with the incorporation of liquid biopsy testing it would be much easier to understand of to use it in clinical care every day. We let clinical utilities. We know already from some retrospective studies in advanced breast cancer that patients with some mutations such as PI3KCa or ESR1 mutations may benefit from specific treatments and we know which treatment will work better. These molecular markers were not incorporate as primary endpoint in those studies but, simply evaluated as correlative studies. This obviously would take a step forward much thicker not only allowed in the treatment a full fashion but those facilitate the liquid biopsies incorporation in clinical practice. I don't think this is something that the technology companies should take themselves alone but, this should be done in collaboration (with Industry) to facilitate validation and incorporate in clinical practice. In the past we made the mistake to consider the technology aspect the most relevant in order to prove clinical utility. But without the therapeutic component I think we are missing that.

Emily Le:
Massimo, what presentations and sessions are you looking forward to the most meeting at the Circulation Tumor Cells meeting?

Massimo Cristofanilli:
The program is really rich, very difficult to pick one. I think I always admire Dr. Richard Cote, for his efforts in improving CTCs technology and of course for bringing his background in pathology. So I think I admire him for this major efforts, and I'm looking forward to his presentation. I also think that the Dr. Vanapalli’s talk would generate interest based on the topic addressing the gap between testing and therapy. This certainly is one of the presentations that deserve attention. Dr. Nagrath hardly require introduction for her incredible work that she did with new microfluidic systems. And the dream is still on to culture and develop organized from CTC because with such new perspectives and a new dimension that for me and you is probably one of the presentations that could provide us some new insights in that field.

Emily Le:
Massimo, thank you so much for your time and insights today.

Massimo Cristofanilli:
Thank you.

Emily Le:
That was Massimo Cristofanilli, Professor of Medicine from Northwestern University. He will be speaking in the Circulating Tumor Cells track at the Next Generation Diagnostics Summit this August in Washington, D.C. I'm Emily Le, thank you for listening.

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