Dr William Jacout Offers Advice for Providers Using Genomics to Inform Breast Cancer Treatment


William Jacout, MD, a medical oncologist and researcher at the Institut du Cancer de Montpellier Val d'Aurelle in France, shares what providers should keep in mind when using genomics as a diagnostic and treatment decision-making tool for patients with breast cancer.

William Jacout, MD, a medical oncologist and researcher at the Institut du Cancer de Montpellier Val d'Aurelle in France, detailed results from a recent paper on the role that SPARC proteins can play in patient outcomes, as well as considerations for providers contemplating using genomics to diagnose and direct treatment decisions for patients with breast cancer.


You recently published a paper on the clinical relevance of SPARC in triple-negative breast cancer (TNBC). What can SPARC expression tell us about cancer-associated fibroblasts and patient outcomes for TNBC?

Yeah, it's the other side of the coin. We've focused this last decade on cancer cells, but a bigger and bigger room has been attributed to microenvironments. And we looked, on this specific publication, at the fibroblasts and the CAFs, cancer-associated fibroblasts. And we saw that based on the level of expression of SPARC, this extracellular matrix protein remodeling the extracellular matrix, that high levels of SPARC secreted by CAFs was associated with a more plastic phenotype of tumor cell of triple-negative breast cancer cells and increases their aggressiveness and lowers the prognosis of the population.

So, it's a big part of one of the teams I'm working with on preclinical studies. We are currently developing a dedicated anti-SPARC monoclonal antibody to try to build combos of chemotherapy with this kind of targeted therapy.

What are some important factors providers should keep in mind when using genomics to inform treatment decisions for patients with metastatic breast cancer?

Our first communication had been made last year. First of all, we need to focus on what is AMALEE. AMALEE was a randomized phase 2 study that was requested by the FDA after the approval of ribociclib and the development at the same time of a naturally adjuvant trial to look at the side effect mitigation effect of a reduced dose of ribociclib. The [control arm] dose being 600 mg and in AMALEE, this was compared to a 400-mg dose that is a classical first step reduction of dose.

Something we must highlight is that the primary end point was overall response rate. And it's probably my point of view that's the pitfall of this study, because we must remember we are dealing with hormone receptor–positive, HER2 [human epidermal growth factor 2]–negative metastatic breast cancers.

We thought this was quite a neat proportion of patients without measurable disease and with bone lesions that are not easy to evaluate to say overall response was yes or no. So, it's a primary end point to us: noninferiority of the 400 mg dosage compared to the 600 mg. And last year, our first communication was made detailing that this noninferiority was not met.

Here, we have some more mature data allowing one to see overall response and see the first evaluation of the progression-free survival [PFS], which is probably a more logical end point than that. The overall response rate remained lower, 47% vs 55%.

However, I must stress that the progression-free survival data is exactly identical between the 2 arms at 25 months. So, quite reassuring and at the same time with the secondary end point of this QD [one dose per day] that was the mitigating effect of reducing the dose regarding the classical side effects of ribociclib. The first of them being a QTc [QT corrected for heart rate] increase and the QTc increase is significantly lower in the 400-mg dose level and secondly, the neutropenic rate.

So, that's something that cannot be said to be noninferior in terms of overall response rate. However, with the same PFS and a better toxicity profile, it's quite reassuring for the clinical practice to say in case of toxicity, it doesn't look like we are losing chances to reduce the dose and we will alleviate part of the toxic effects.

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