COMMENTARY

TDM-1 Heavy Hitter in Heavily Treated Breast Cancer

Joseph Gligorov, MD, PhD; Javier Cortés, MD, PhD

Disclosures

October 07, 2013

In This Article

Sorting Out the Data on Biomarkers

Dr. Gligorov: We are living in a period of a lot of expectations and hope for HER2-positive patients, but the other point is how to define the best treatment for all patients. We have many biomarker studies and many data from these studies. You mentioned that you have selected as most important the results of the BOLERO-3 biomarker study.[2] The first presentation of the BOLERO-3 results was at ASCO 2013, showing superiority with the addition of everolimus to trastuzumab in patients who had progressed after treatment with chemotherapy and anti-HER2 treatment with trastuzumab.[3] We also have a lot of data on everolimus in other subtypes of breast cancer, and we are hoping to be able to better define the population that will benefit from this drug.

Dr. Cortés: You are completely right. We have many new drugs for the HER2-positive population, and it will be fantastic if we could select the patients who will benefit more and those who are not likely to benefit from these new drugs. At this meeting, we have exciting data from the BOLERO-3 trial, showing that patients with low PTEN (defined as levels of PTEN in the first to the 20th percentiles -- very low levels of PTEN) and patients with high phosphorylated S6 kinase-1 (p-S6K1) (downstream of mTOR) seem to benefit more from the administration of everolimus, with tremendous benefit in terms of the hazard ratio.[2]

On the other side, patients who did not have low PTEN or high levels of p-S6K1 did not seem to benefit from the addition of everolimus, but this was an exploratory analysis. It will be fantastic if we can confirm these results in prospective clinical trials, because if not, the results will be controversial. For example, in the HER2-negative population, the activity or the role of these biomarkers and the prognosis with everolimus is not that clear. We have to wait for further work in this setting and see whether we can serve the patient population on the basis of these biomarkers.

Dr. Gligorov: It is clearly important. Just to remind you, a presentation at the ASCO meeting on the biomarker issue found that p-S6K1 did not correlate with the impact of everolimus, but it was a small trial compared with the BOLERO-3 trial presented by Jerusalem this year.[2] We also have data from the neoadjuvant trials, particularly with the NeoSphere trial with pertuzumab,[5] which show that the mutation of PI3 kinase might be a prognostic factor in the HER2-positive population and possibly in the general breast cancer population. José Baselga will present the BOLERO-2 subgroup analysis concerning the biological points, and one of the conclusions will be that the PI3 kinase pathway and PI3 mutation are important,[6] but it is not so simple to discern because there are a lot of mutations, and some mutations give different information, so we will have a lot of work in the next year.

Dr. Cortés: That is a fantastic point. There is beautiful research coming from Brussels showing that the best way to address the efficacy of these compounds may be not only to look at specific proteins, but also try to identify which patients have the activation of the pathway, maybe by a signature or something like that, to try to identify when this pathway is activated, so there is beautiful work to do that.

Concluding Remarks

Dr. Gligorov: Thank you very much, Javier. To conclude: Looking at these 2 trials that we tried to share with you from this session, first, we have made a lot of progress in the HER2-positive population regarding the type of treatment we might use. Second, we are on the way to try to understand who will benefit and not benefit from the new strategy, but it still seems to be more complicated to define the predictive factors than to define just in general what kind of drugs we might use in this situation.

Thank you, Javier. It was a pleasure speaking with you. Thank you for joining us for Medscape Oncology Insights in breast cancer. This is Joseph Gligorov reporting from ECC 2013 in Amsterdam.

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