How to Maximize the Potential of mTOR Inhibitors in Breast Cancer-More Questions Than Answers

The cornerstone of treatment for estrogen receptor (ER)-positive breast cancer is endocrine therapy, and there is a pressing need to combat de novo and acquired resistance to it. The basis of endocrine resistance is a complex crosstalk between ERs and the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway, as well as other cellular signaling pathways. Preclinical studies demonstrate that hyperactivation of the PI3K/mTOR pathway is associated with endocrine resistance, whereas inhibition correlates with sensitivity. This is significant since more than 30% of ER-positive breast cancers and 9% of ER-negative breast cancers harbor PI3K-activating mutations.[1] Pathway hyperactivation is also implicated in trastuzumab (Herceptin) resistance in human epidermal growth factor receptor 2 (HER2)-positive breast cancers.[2]

In this issue of ONCOLOGY, Shaveta Vinayak and Robert Carlson thoroughly summarize the preclinical and clinical studies of mTOR inhibitors, by breast cancer subtype, in both the metastatic and the adjuvant or neoadjuvant setting. Current clinical practice guidelines are then clearly described. The key point revealed in this review is the critical importance of patient selection for treatment. The presence of PI3K mutations, discordance in the mutational status between primary and metastatic tumor tissues, and alterations in crosstalk pathways must all be considered. In addition, prior exposure to therapy can prime tumor dependence on the PI3K/mTOR pathway, increasing sensitivity to pathway inhibitors and combination therapies. The studies described in the article highlight the complexity of the PI3K/mTOR pathway, with its incompletely understood feedback loops, escape pathways, and crosstalk with other pathways.

How can we improve upon patient selection and better harness the utility of PI3K/mTOR pathway inhibition? Much remains to be learned, beyond intrinsic subtyping and such prognostic and predictive biomarker assays as Oncotype DX. The importance of tumor heterogeneity, in the primary tumor and at the distant site, must be emphasized. Do therapy-resistant subpopulations pre-exist, or do they arise as a result of the selective pressure of treatment combinations? As we sort through the ever-increasing intricacy of molecular characterization of tumors, genome sequencing, expression profiling, epigenetic mapping, proteomics, metabolomics, lipidomics, etc, how can we organize and prioritize the enormous amount and complexity of data to predict patient response to treatment?

What role do host factors play in predicting efficacy of PI3K/mTOR pathway inhibition? Significant population differences exist in expression of cytochrome P450 enzymes, which play a major role in the metabolism of some mTOR inhibitors.[3] Furthermore, how do the systemic innate and acquired immune system, the immune microenvironment, and the stromal interactions, respond to the tumor and therapeutics? How does tumor burden affect patients’ response to treatment? All of these factors may contribute to disparities seen in treatment efficacy.

Can the metabolic effects of the toxicities related to mTOR inhibitors described by Vinayak and Carlson, such as hyperlipidemia and hyperglycemia, shed light on pathway mechanisms? Are there opportunities for dietary or drug interventions that could improve inhibition of the PI3K/mTOR pathway?

Such a systematic review of the current status of mTOR inhibitors in the treatment of breast cancer demonstrates holes in our knowledge of the role of the tumor, the host, and metabolic factors in breast cancer progression. Filling these gaps are opportunities to fine-tune patient selection for PI3K/mTOR inhibitors to further improve outcome, to explore new indications, and to develop additional strategies to overcome resistance to first-line therapies.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

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REFERENCES

1. Cancer Genome Atlas. 2012. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61-70.

2. Berns K, Horlings HM, Hennessy BT, et al. A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12:395-402.

3. Anglicheau D, Legendre C, Beaune P, Thervet E. Cytochrome P450 3A polymorphisms and immunosuppressive drugs: an update. Pharmacogenomics. 2007;8:835-49.