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ESMO Breast 2021 | E-cadherin inactivation by Trop-2 drives metastases in TNBC

Saverio Alberti, MD, PhD, Università di Messina, Messina, Italy, talks on the role of E-cadherin inactivation by TROP2 in epithelial-to-mesenchymal transition (EMT)-less metastatic relapse in triple-negative breast cancer (TNBC). Dr Alberti describes how TROP2 status could be used to stratify patients with TNBC, in particular with regard to the use of anti-TROP2 therapies. Loss-of-function of E-cadherin has been identified as the main driver of cell-to-cell detachment enabling metastases. Dr Alberti outlines the mechanism of action through which TROP2 causes the loss of function of E-cadherin. This interview took place at the virtual European Society for Medical Oncology (ESMO) Breast Cancer Congress 2021.

Transcript (edited for clarity)

We’ve been working for several years on triple -negative breast cancers. This breast cancer subtype is the worst one, the most aggressive one. And we know it’s a heterogeneous entity, but there are means for dissect, accurately 10 BC some types are very poor. We had the identified TROP2 as a main driver for tumor growth and metastasis. So, we asked ourselves, would we be able to dissect triple-negative breast cancer, according to the TROP2 impact on the metastatic diffusion...

We’ve been working for several years on triple -negative breast cancers. This breast cancer subtype is the worst one, the most aggressive one. And we know it’s a heterogeneous entity, but there are means for dissect, accurately 10 BC some types are very poor. We had the identified TROP2 as a main driver for tumor growth and metastasis. So, we asked ourselves, would we be able to dissect triple-negative breast cancer, according to the TROP2 impact on the metastatic diffusion.

We wish to notice that an anti-TROP2 therapy, an antibody-drug conjugate has been recently approved by the FDA. So, we are opening up a window whereby we could both project disease outcome and dissecting patients and design, personalize the therapy, in this case of very serious disease.

So we analyzed a large case series, so in other cases of breast cancer. We identified the subgroup we were most interested in. And we defined all the major determinants of disease growth and metastatic diffusion. This work led us to identify a loss of function of E-cadherin as the main thing that would drive cell-to-cell detachment. This is essential because this allows cancer cells to detach from the main body of the primary cancer and to start invading neighboring tissues.

But we wanted more, we wanted to know the mechanism. And we defined, actually, these are very recent findings. We are glad to add that to the text of the abstract because it’s been completed in the last few weeks.
We identified the means by which TROP2 induces cell-cell detachment. TROP2 induces the activation of D-protease ADAM10, which activates TROP2 by cleavage, and it’s a feed forward loop because ADAM10, which is bound to TROP2 – TROP2 is bound to E-cadherin – ADAM10 cleaves the tail, terminal tail of E-cadherin. This is essential because this acts as a hook on the cell’s cytoskeleton. So, by cleaving this piece of E-cadherin off, E-cadherin is detached from the cell-cell cytoskeleton, and nothing works. This is known since several years. This is a major mechanism for E-cadherin inactivation. So TROP2 drives a specific E-cadherin inactivation in triple-negative breast cancers. So we know.

Now the second perspective is, is this at all useful to us as a medical oncologist? And the answer is a big yes, because we can easily detect TROP2, we can easily detect E-cadherin, we can easily detect activated downstream mechanisms. The main one is beta-catenin, a very famous molecule. So, if we identify all of these partners together on the same cancer type, our prediction was we should be able to dissect triple-negative breast cancers according to the main players in tumor pathology. So, this is what we did.

So, we analyzed our case series. We followed it for 15 years, one five. So it’s an extremely long time. We’re very proud of that because it’s a big investment in time, in effort, and patient dedication to this. So, we are very proud of this.

Now in our e-poster there are the Kaplan-Meier curves. What is a Kaplan-Meier? Kaplan-Meier shows when an event is happening in any patient in the case series. And it looks like a step going down, which provides also the meaning.
Now, if we look at the upper bar, I mean the most important one, which is a disease-free survival of these patients, we identify a staggering- if our driver, TROP2, is low and if the end engine of this pathway, beta-catenin, is low, then we have an extremely surprising finding and a very good one. We predict low malignancy and none, I say none of these patients relapses over 15 years. So, they’re cured. They’re healthy. So, we can identify within this very aggressive subgroup of cancers the good ones, and we can tell the patients and this of course is a huge impact on our cancer care strategies.

Now the opposite side of the spectrum. We expect that the TROP2 high, beta-catenin high, E-cadherin rearranged as I was describing, to be bad, very bad factors in tumor progression. And this is unfortunately very true. This combination is lethal. This combination drives all patients to premature relapse. And in metastatic cancer, premature relapse is of course a very poor prognosis.

So, we think we have identified a fundamental mechanism for tumor progression in the case of the most aggressive breast cancer type. And so, we expect to be able to drive this group of patients to personalized therapy targeting TROP2 and the other players we’ve just described.

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