Everolimus overcomes trastuzumab resistance in HER2+ early breast cancer

Some patients with early breast cancer had a benefit in clinical response rate when everolimus was added to trastuzumab treatment, though the benefit was statistically nonsignificant. These puzzling results suggested that this benefit was independent of the molecular pathways that could be expected to be involved.

"As more targeted cancer drugs are developed, the challenge is to identify which patients will benefit from individual agents," said Mario Campone, MD of the Institut Cancerologie de l'Ouest in Nantes, France. [WU1] Research related to that challenge was presented at the 5th IMPAKT Breast Cancer Conference in Brussels, Belgium. "One of the objectives of this study was to determine molecular biomarkers that predict whether a patient's cancer is sensitive to the combination of everolimus and trastuzumab compared to trastuzumab alone."

Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. Many patients who initially respond to trastuzumab develop resistance. In preclinical studies, everolimus, an oral inhibitor of an important molecule called mammalian target of rapamycin (mTOR), has demonstrated an ability to reverse trastuzumab resistance. However, the mechanisms of action involved in the reversion of trastuzumab resistance are not completely understood.

"Resistance to trastuzumab may result from several molecular alterations occurring at different levels of the downstream effectors in the PI3K/AKT pathway, all of them resulting in maintenance of signal transduction," said Campone. "Therefore, using everolimus to inhibit mTOR, a major downstream effector of this pathway, can restore sensitivity to trastuzumab. In a preclinical model, everolimus also reverses trastuzumab resistance caused by upregulation of IGF-1R expression, an alternative signaling pathway, allowing IGF-1 to drive cell growth and proliferation."

At the IMPAKT meeting, Campone's group reported the first results of a clinical study and analysis of seven biomarkers in patients with early HER2-overexpressing cancers who were receiving treatment with trastuzumab alone, or everolimus plus trastuzumab.

Among the 80 patients (40 per arm), the clinical response rate was 35% in the trastuzumab arm and 45% in the patients who received both drugs. On the other hand, the pathological response rate was 43.5% among patients in the monotherapy arm, and 47.5% in the combination arm of the study.

"The conclusion of this paper in clinical practice is that the addition of everolimus to trastuzumab seems to improve the clinical response rate but not the pathologic response," Campone said.

The researchers also studied a group of seven molecular markers to explore whether they could be used to predict which patients would respond to the combination of everolimus and trastuzumab. The biomarkers were p4EBP1, pS6, eIF4E, Ki67, pAKT, LKB1, and caspase 3, all of which are involved in pathways that lead to the activation of mTOR.

"None of these biomarkers was able to predict which patients would see the benefit of the two drugs," said Campone. "It appears the combination of everolimus and trastuzumab is effective independently of the activation of the PI3K/AKT/mTOR pathway and without any antiproliferative and proapoptotic effect."
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